Vaccine Safety E Course Manual PDF

VACCINE
SAFET Y
BASICS
l e a r n i n g m a n u a l
The content of this course has been compiled by leading international vaccine experts who are committed to the promo-
tion of best practice in the implementation of immunization programmes across the world.
CONTRIBUTORS
Molly Mort (project coordinator and writer of a pilot course, which served as basis of this course).
Adele Baleta (South Africa),
Frank Destefano (US CDC),
Jane G. Nsubuga (US CDC),
Claudia Vellozzi (US CDC),
Ushma Mehta (Medicines Control Council, South Africa),
Robert Pless (Public Health Agency of Canada),
Siti Asfijah Abdoellah (NADFC Indonesia),
Prima Yosephine (EPI-MOH, Indonesia),
Sherli Karolina (EPI-MOH, Indonesia).
PHOTO CREDITS
Barbara Pahud (Children’s Mercy Hospitals and Clinics, UMKC),
WHO Photo Library,
CDC Photo Library.
OVERALL COORDINATION (WHO)

Patrick Zuber,
Philipp Lambach.
DESIGN AND TECHNICAL IMPLEMENTATION

Oksana Fillmann, Munich.
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Please let us know how you liked the course.
Send us an email with your suggestions to: [email protected].
© World Health Organization 2013

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Table of Contents
Introduction....................................................................................................................................... 7
Getting starting................................................................................................................................. 8
MODULE 1: Introduction to vaccine safety................................................................................. 9

Overview................................................................................................................................ 10
Importance of immunization programmes....................................................................... 10
History of vaccine development........................................................................................ 11
Expectations towards safety of vaccines....................................................................... 13
How the immune system works........................................................................................ 14
How vaccines work.............................................................................................................. 16
Vaccine-preventable diseases.......................................................................................... 17
Types of vaccine................................................................................................................... 18
Adverse events..................................................................................................................... 19
Classification...........................................................................................................................19
Causes......................................................................................................................................20
Frequency and severity.........................................................................................................21
Vaccine safety in immunization programmes.................................................................23
Vaccine regulations............................................................................................................. 25
Pre-licensure vaccine safety.............................................................................................25
Post licensure surveillance options....................................................................................27
Balancing efficacy and safety...........................................................................................29
Summary................................................................................................................................ 31
ASSESSMENT 1..............................................................................................................................32
Assessment solutions.........................................................................................................36
MODULE 2: Types of vaccine and adverse reactions.............................................................. 38

Overview................................................................................................................................39
Types of vaccine...................................................................................................................40
Live attenuated vaccines......................................................................................................41
Inactivated whole-cell vaccines..........................................................................................44
Subunit vaccines....................................................................................................................45
Toxoid vaccines......................................................................................................................49
Combination vaccines.........................................................................................................50
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Components of a vaccine................................................................................................... 51
Route of administration.......................................................................................................53
Contraindications................................................................................................................. 55
Anaphylaxis...........................................................................................................................56
Immunizing the immunocompromised.............................................................................. 57
Immunization and pregnancy.............................................................................................58
Influenza...................................................................................................................................58
Tetanus.....................................................................................................................................59
Vaccination associations and public concern................................................................60
Summary................................................................................................................................60
ASSESSMENT 2.............................................................................................................................. 61
Assessment solutions......................................................................................................... 65
MODULE 3: Adverse events following immunization.............................................................. 67

Overview................................................................................................................................68
Classification of AEFIs........................................................................................................ 69
Vaccine reactions...................................................................................................................71
Immunization error-related reaction...................................................................................74
Immunization anxiety-related reactions.............................................................................76
Coincidental events................................................................................................................76
Mass vaccination campaigns............................................................................................ 78
Rates of adverse vaccine reactions................................................................................. 79
Summary................................................................................................................................ 82
ASSESSMENT 3..............................................................................................................................83
Assessment solutions.........................................................................................................87
MODULE 4: Surveillance............................................................................................................... 89
Overview................................................................................................................................90
Pharmacovigilance.............................................................................................................. 91
NRA’s role in the regulation of drug safety..................................................................... 92
Adverse Drug Reaction (ADR) surveillance....................................................................93
Immunization safety requires a modified surveillance system...................................93
Vaccine pharmacovigilance............................................................................................... 95
Special considerations for AEFI surveillance.................................................................96
Interactions between AEFI and ADR surveillance systems........................................ 97
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AEFI surveillance components..........................................................................................98
Detection and reporting........................................................................................................99
Investigation..........................................................................................................................101
Causality assessment of AEFIs..........................................................................................104
Risk/benefit assessment.....................................................................................................105
Summary.............................................................................................................................. 107
ASSESSMENT 4............................................................................................................................ 108

Assessment solutions........................................................................................................111
MODULE 5: Vaccine safety institutions and mechanisms................................................... 113

Overview.............................................................................................................................. 114
Overview of functions....................................................................................................... 115
NATIONAL LEVEL
National AEFI surveillance systems............................................................................... 116
National regulatory authority.......................................................................................... 117
Core functions specific to vaccines.................................................................................. 117
Functions depending on the source of vaccines............................................................118
Vaccine procurement and lot release............................................................................... 119
Regulation of drug safety....................................................................................................120
National immunization programmes (NIP)..................................................................... 121
Core functions specific to vaccine safety........................................................................122
Safety of vaccine administration.......................................................................................122
AEFI Review Committee................................................................................................... 123
Other support groups........................................................................................................ 123
INTERNATIONAL LEVEL
Global vaccine safety stakeholders and services........................................................ 125
Global analysis and response.......................................................................................... 127
Global Advisory Committee on Vaccine Safety (GACVS)..............................................127
Good information practices – Vaccine Safety Net.........................................................129
Global Capacity building and harmonized tools............................................................ 130
Brighton Collaboration – setting standards in vaccine safety......................................130
CIOMS/WHO working group...............................................................................................131
Vaccine safety training opportunities...............................................................................132
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Global signal evaluation and detection..........................................................................133
WHO Programme for International Drug Monitoring.....................................................133
Global Vaccine Safety DataNet (GVSD)............................................................................134
Product monitoring............................................................................................................ 136
Global Vaccine Safety Initiative...................................................................................... 137
Summary.............................................................................................................................. 138
ASSESSMENT 5............................................................................................................................ 139

Assessment solutions.......................................................................................................143
MODULE 6: Communication....................................................................................................... 145

Overview..............................................................................................................................146
Risk communication........................................................................................................... 147
Need for improved communication...................................................................................147
Communicate only reliable information............................................................................148
Simplified and key messages.............................................................................................149
Risk perception.....................................................................................................................151
Sources of information........................................................................................................153
Communicating in public.....................................................................................................154
Responding to vaccine safety crises.............................................................................. 156
Rumours and crises.............................................................................................................156
Impact of rumours and crises.............................................................................................157
Responding to rumours and crises....................................................................................159
Communicating with the media....................................................................................... 162
Preparing a press release...................................................................................................163
Preparing for an interview..................................................................................................164
Summary.............................................................................................................................. 166
ASSESSMENT 6............................................................................................................................ 167

Assessment solutions....................................................................................................... 171
Glossary......................................................................................................................................... 174
References..................................................................................................................................... 197
Questions solutions.....................................................................................................................202
6
INTRODUCTION
Goal
This course aims to establish a shared understanding among professionals whose work is linked to vac-
cine safety issues. This may include nurses/midwives/community health workers, as well as pharmacists
medical doctors and programme or technical officers.
The course
covers
Vaccines Communication
characteristics
of:
Adverse events Vaccine safety

following stakeholders
immunization
Pharmacovigilance
Rationale
Professionals involved in vaccine safety come from different backgrounds. As their jobs are all interrelated
and co-dependent, they need a ‘common language’ in order to ensure smooth collaboration.
This Learning manual on Vaccine Safety Basics is based on the E-learning Course on Vaccine
Safety Basics, which is available at www.vaccine-safety-training.org.
It has been designed to reach out to users that do not have internet access. In case you have
internet access, we encourage the online use of the E-learning Course on Vaccine Safety Basics,
which enables the learner to benefit from interactive case studies and online assessments.
The Learning manual on Vaccine Safety Basics meets different starting points, learning needs and coun-
try contexts. It offers the learner options to work at the speed and depth he prefers, recognizing his prior
knowledge. Accommodating the different mechanisms between regions and nations is a challenge to any
global course. For this reason we ask you from time to time to shift your focus to your own local context
and look how vaccine safety is ensured in your country.
7
GETTING STARTING
Modules
The modules introduce you to vaccine safety issues and provide you with the technical information
required to look at the case studies and take the assessments.
Each module will take you about 1 ½ hours to complete, but you may find that it takes you a little more or
a little less time than this. You can study this course at your own pace, pausing your learning at any point.
You will optimally benefit from the course by following the training path illustrated below.
MODULE 1: Introduction to vaccine safety ASSESSMENT
MODULE 2: Types of vaccine and adverse reactions ASSESSMENT
MODULE 3: Adverse events following immunization ASSESSMENT
MODULE 4: Surveillance ASSESSMENT
MODULE 5: Institutions and mechanisms ASSESSMENT
MODULE 6: Communication ASSESSMENT
GENERAL ASSESSMENT
Assessments
To ensure an interactive learning experience, you have the opportunity to take:
■■ Training questions within the module,
■■ Assessments testing your knowledge at the end of each module,
■■ A general assessment testing your understanding at the end of the whole course. This assess-
ment is only accessible online. Please visit: www.vaccine-safety-training.org, click “Start course”
and “General assessment” to register. Should you pass the general assessment, you will be pro-
vided with a downloadable document confirming your successful participation in the exam.
8
MODULE 1: Introduction to vaccine safety
MODULE 1
Introduction
to vaccine safety
Overview
Vaccination is one of the great public health achievements of human history. Vaccines used in national
immunization programmes (NIPs) are considered safe and effective when used correctly. Vaccines are,
however, not risk-free and adverse events will occasionally occur following vaccination. Public trust in
vaccine safety is key to the success of vaccination programmes.
This module serves as an introduction to the whole course. You will learn about the importance of immu-
nization programmes and how vaccines work. You will understand the relationship between vaccine
coverage, adverse events and disease spread. You will also learn about the importance of vaccine regula-
tions in ensuring the effectiveness of vaccine initiatives.
Module outcomes
By the end of this module you should be able to:
1 Explain the importance of Vaccination in the control of infectious diseases,

2 Describe the basic principles of vaccination,
3 Explain how the public are less tolerant of the risks associated with vaccines
(although very low) than they are of those associated with drugs used to treat disease,
4 List the main types of vaccine and illustrate them with examples,
5 Describe the importance of post marketing vaccine safety surveillance,
6 Identify some vaccines that have been associated with adverse vaccine reactions.
Importance of immunization programmes

Each year, vaccines prevent more than 2.5 million child deaths globally. An
additional 2 million child deaths could be prevented each year through
immunization with currently available vaccines.2
Why are vaccines so special?
■■ Vaccines promote health: unlike many other health interventions,
they help healthy people stay healthy, removing a major obstacle to
human development.
■■ Vaccines have an expansive reach: they protect individuals, com-
munities, and entire populations (the eradication of smallpox is a
case in point).
■■ Vaccines have rapid impact: the impact of most vaccines on This image shows a child
communities and populations is almost immediate. For example, with smallpox, a serious,
between 2000 and 2008, vaccination reduced global deaths from contagious, and sometimes
fatal infectious disease. The
measles by 78% (from 750,000 deaths to 164,000 deaths per year).3 only prevention of smallpox is
■■ Vaccines save lives and costs: recently, a panel of distinguished vaccination.
economists put expanded immunization coverage for children in
fourth place on a list of 30 cost-effective ways of advancing global welfare.4
10
Key point
The impact of vaccination on the health of the world’s peoples is hard to exaggerate. With
the exception of safe water, nothing else, not even antibiotics, has had such a major effect on
the reduction of mortality (deaths) and morbidity (illness and disability) and on population
growth.6
History of vaccine development

Although inoculation against smallpox was practiced over 2000 years
You can read more about the state
ago in China and India, a British physician, Edward Jenner, is gener- of the world’s vaccines and immu-
ally credited with ushering in the modern concept of vaccination. In nization in this Executive Summary
1796 he used matter from cowpox pustules to inoculate patients suc- from WHO:
cessfully against smallpox, which is caused by a related virus.
vaccine-safety-training.org/
tl_files/vs/pdf/who_
By 1900, there were two human virus vaccines, against smallpox
ivb_09_10_eng.pdf
and rabies, and three bacterial vaccines against typhoid, cholera,
and plague.
A worldwide case detection and vaccination programme against smallpox gathered pace and, in 1979,
the World Health Assembly officially declared smallpox eradicated — a feat that remains one of history’s
greatest public health triumphs.*
Question 1*
Smallpox has been declared eradicated in 1979. Can you tell the difference between eradi-
cation and elimination of a disease? Select the two correct definitions for eradication and
elimination of a disease:
❒❒ A. Eradication refers to the complete and permanent worldwide reduction to zero new
cases of the disease through deliberate efforts.
❒❒ B. Eradication refers to the reduction to zero (or a very low defined target rate) of new
cases in a defined geographical area.
❒❒ C. Elimination refers to the complete and permanent worldwide reduction to zero new
cases of the disease through deliberate efforts.
❒❒ D. Elimination refers to the reduction to zero (or a very low defined target rate) of new
cases in a defined geographical area.
During the 20th century, other vaccines that protect against once commonly fatal infections such as pertus-
sis, diphtheria, tetanus, polio, measles, rubella, and several other communicable diseases were developed.
As these vaccines became available, high-income industrial nations began recommending routine vaccina-
tion of their children. There are now over 20 vaccine-preventable diseases.
Based on the emerging success of the smallpox programme, in 1974, the World Health Organization
(WHO) launched the Expanded Programme on Immunization (EPI) 81. The initial EPI goals were to ensure
* The answer to all questions can be found at the end of this manual (page 202).
11
that every child received protection against six childhood diseases (i.e. tuberculosis, polio, diphtheria, per-
tussis, tetanus and measles) by the time they were one year of age and to give tetanus toxoid vaccinations
to women to protect them and their newborns against tetanus.
Since then, new vaccines have become available. Some of them, such as hepatitis B, rotavirus, Haemophi-
lus influenzae type b (Hib) and pneumococcal vaccines, are recommended by the WHO for global use.
Others, such as yellow fever vaccine, are recommended in countries where disease burden data indicate
they should be used.
Regulatory and safety issues of vaccines before and after licenses are granted are discussed
later in this module
1955 Polio (IPV)

1962 Polio (OPV)
1963 Measles
1967 Mumps
1969 Meningitis A
1923 Diphtheria 1970 Rubella
1981 Hepatitis B
1798 Smallpox 1923 Tuberculosis 1972 Haemophilus
1986 Meningitis B
influenzae
1885 Cholera 1924 Tetanus
1989 Hepatitis A
1976 Viral influenza
1885 Rabies 1926 Pertussis 2000 Pneumococcal
1995 Varicella zoster
1976 Pneumococcal conjugate
1891 Anthrax 1927 Tetanus
polysaccharide 1998 Rotavirus
2006 Human
1896 Typhoid 1935 Yellow fever
1977 Meningitis C 1999 Meningitis C papilloma
1897 Plague 1943 Typhus (polysaccharide) (conjugate) virus
1800 – 1899 1900 – 1949 1950 – 1979 1980 – 1999 2000
By 1990, vaccination was protecting over 80% of the world’s children from the six main EPI diseases, and
other new vaccines are continually being added to the EPI programmes in many countries.
In 1999, the Global Alliance for Vaccines and Immunization (GAVI) was created to extend the reach of
the EPI and to help the poorest countries introduce new and under-used life-saving vaccines into their
national programmes.
Strengthening immunization: WHO’s Expanded Programme on Immunization
1974 1990 1999

WHO launches EPI Vaccination Global Alliance
protects >80% of for Vaccines and
Goals:
world’s children Immunization
every child (< 1 year)
from six main EPI (GAVI)
receives protection against
six childhood diseases
diseases extends reach of
new vaccines EPI
• tuberculosis • pertussis
are continually
• polio • tetanus
being added to helps poorest
• diphtheria • measles the EPI countries
programmes in introduce new
tetanus toxoid many countries vaccines in
vaccinations protect national
women and their programmes
newborns
Although around 24 million infants are still not receiving the full complement of EPI vaccines in the first
year of life, the success of the EPI can be judged by the reduction in worldwide cases of measles and polio-
myelitis (see graphics). These two diseases are among several (including neonatal tetanus) targeted by the
WHO for elimination through vaccination.
12
Global annual reported incidence of measles and immunization coverage between 1980–2008 5
Global annual reported cases of Poliomyelitis and immunization coverage (3rd dose) between
1980–2010
Expectations towards safety of vaccines

Key point
Although vaccines used in national immunization programmes (NIPs) are considered safe
and effective, vaccines are not risk-free and adverse events will occasionally occur following
vaccination. Public trust in vaccine safety is key to the success of vaccination programmes.
Vaccines used in NIPs are safe and effective. However, like other pharmaceutical products, vaccines are not
completely risk-free and adverse events will occasionally result from vaccination. Although most adverse
events are minor (e.g. redness at injection site, fever), more serious reactions (e.g. seizures, anaphylaxis)
can occur albeit at a very low frequency.
13
The general public has low tolerance to any adverse events following vaccination, because vaccines are
given to healthy persons to prevent disease. For this reason, a higher standard of safety is expected of
immunizations compared with medications that are used to treat people who are sick (e.g. antibiotics,
insulin). This lower tolerance for risks from vaccines translates into a greater need to detect and investigate
any adverse event following immunization (AEFI) than is generally expected for other pharmaceutical
products.
Low public tolerance requires safe vaccination
General public has low tolerance to adverse events

as vaccines are usually given to healthy persons.
Expectation to safety standard is higher with

vaccines compared to medicines for sick people.
National regulatory authorities (NRAs) ensure with rigor the quality,

safety, & effectiveness of vaccines and pharmaceutical products.
Once introduced, NRAs monitor Before being

vaccines are and investigate introduced,
thoroughly and AEFIs to ensure vaccines
continuously safety for are assessed in
reviewed. population. clinical trials.
National regulatory authorities (NRAs) are responsible to ensure the quality, safety, and effectiveness of
vaccines and other pharmaceutical products. Before their introduction into an immunization programme,
vaccines undergo several steps of evaluation to assess their safety and efficacy in clinical trials. Once
introduced, vaccines undergo very thorough and continuous reviews of their manufacturing process and
NRAs continue to monitor and investigate adverse events following immunization to ensure that they are
safe for the entire population.
How the immune system works

To understand how and why vaccine reactions occur, Bacterium (example). Source: wikipedia.org
it is first necessary to understand how the immune
system helps to protect the body against infection. It
is designed to identify and destroy harmful foreign
organisms (pathogens) from the body, and neutralize
the toxins (poisons) that some bacteria produce.
The pathogens causing the vaccine-preventable
diseases described in this module are mainly microor-
ganisms such as bacteria or viruses.
■■ Bacteria are single-celled life-forms that can
reproduce quickly on their own.
■■ Viruses, on the other hand, cannot reproduce on their own. They are ultramicroscopic infec-
tious agents that replicate themselves only within cells of living hosts.
14
Virus infecting cell. Source: wikipedia.org The immune system responds to bacteria and
viruses in a very complex way: it recognizes unique
molecules (antigens) from bacteria and viruses and
produces antibodies (a type of protein) and special
white blood cells called lymphocytes that mark the
antigens for destruction.
During the primary immune response to the first
encounter with a specific pathogen, some lympho-
cytes called memory cells develop with the ability
to confer long-lasting immunity to that pathogen,
often for life. These memory cells recognize antigens on the pathogens they have encountered before, trig-
gering the immune system to respond faster and more effectively than on the first exposure.
Primary and secondary immune response. Source: wikipedia.org
The graph below compares the primary and secondary immune responses to the same pathogen. The
secondary response may eliminate the pathogens before any damage occurs.59
Primary and secondary immune responses to the same pathogen
Key point
Immunization triggers an immune system response by which the vaccinee develops long-term
protection (immunity) that would normally follow recovery from many naturally occurring
infections.
15
How vaccines work

Key point
Vaccines stimulate the immune system to develop long-lasting immunity against antigens
from specific pathogens.
The goal of all vaccines is to elicit an immune response against an antigen so that when the individual is
again exposed to the antigen, a much stronger secondary immune response will result. Vaccines contain
the same antigens that are found on pathogens that cause the associated disease, but exposure to the anti-
gens in vaccines is controlled. By priming the immune system through vaccination, when the vaccinated
individual is later exposed to the live pathogens in the environment, the immune system can destroy them
before they can cause disease.
Thus, there are two ways of acquiring immunity to a pathogen – by natural infection and by vaccina-
tion. Natural infections and vaccines produce a very similar end result – immunity – but the person who
receives a vaccine does not endure the illness and its potential life-threatening complications. The very low
risk of an adverse event caused by a vaccine greatly outweighs the risk of illness and complications caused
by natural infection. The following pages will discuss in further detail the attributes of vaccines and the
characteristic causes for adverse events.
Vaccines reproduce a natural infection with less complications
Natural infection IMMUNITY Vaccination
Immunization triggers an immune ☑ Vaccinee does not endure

system response by which the vaccinee the illness
develops long-term protection
(immunity) that would normally follow
☑ Low risk of adverse reaction
greatly outweighs the risk of
recovery from (sometimes several) complications by natural
naturally occurring infections. infection.
16
Vaccine-preventable diseases*
Question 2*
Can you recall the main vaccine-preventable diseases originally targeted by the EPI
(Expanded Programme on Immunization)? Select them from the following boxes:
The initial EPI goals were to vaccinate every child – by the time they were one year
of age – against:
❒❒ tuberculosis ❒ pertussis ❒ polio
❒❒ tetanus ❒ diphtheria ❒ measles
Vaccines to prevent other diseases have become available since the introduction of EPI and are recom-
mended by the WHO for global use. They cover diseases such as hepatitis B disease, diarrhoeal disease
caused by rotaviruses, and pneumonia and other respiratory tract infections caused by Haemophilus
influenzae type B and pneumococcal bacteria. Others, such as the vaccine against yellow fever, are recom-
mended in countries where the disease burden is significant.
The main vaccine-preventable diseases targeted by the EPI and the associated vaccines*****
Tubercle bacillus Bacillus Calmette-Guérin (BCG) vaccine
Oral polio vaccine (OPV) vaccine, I

Poliovirus
nactivated polio vaccine (IPV) vaccine
Corynebacterium diphtheriae
Diphtheria toxoid*** vaccine
(Diphtheria)**
Clostridium tetani (Tetanus)** Tetanus toxoid (TT) vaccine
Whole-cell pertussis (wP) vaccine,

Pertussis**
Acellular (cell-free) pertussis (aP) vaccine
Measles virus Measles vaccine
Hepatitis B virus Hepatitis B vaccine
Rotavirus Rotavirus vaccine
Haemophilus influenzae type B (Hib) Hib conjugate vaccine
Streptococcus Pneumoniae
Pneumococcal vaccines
(Pneumococcal infection)
Yellow fever virus Yellow fever vaccine
** Diphtheria, tetanus and pertussis vaccines are usually administered in combination vaccines (e.g. DTwP, DTaP) when given
to infants and young children. These vaccines are also available in combinations with hepatitis B (e.g. DTwP-HepB, DTaP-
HepB) and/or Hib vaccines (e.g. DTPwP-HepB+Hib, DTPaP-HepB+Hib).
*** Diphtheria toxoid is only available as a combined vaccine with tetanus toxoid and other childhood vaccines such as pertus-
sis, hepatitis B, Hib, and IPV.
17
Types of vaccine
There are many types of vaccines, categorized by the antigen used in their preparation. Their formulations
affect how they are used, how they are stored, and how they are administered. The globally recommended
vaccines discussed in this module fall into the four main antigen types shown in the diagram.
Types of Vaccine
Live attenuated (LAV)
– Tuberculosis (BCG)
– Oral polio vaccine (OPV)
– Measles
– Rotavirus
– Yellow fever
Inactivated (killed antigen)
– Whole-cell pertussis (wP)

– Inactivated polio virus (IPV)
Subunit (purified antigen)
– Acellular pertussis (aP),

– Haemophilus influenzae type b (Hib),
– Pneumococcal (PCV-7, PCV-10, PCV-13)
– Hepatitis B (HepB)
Toxoid (inactivated toxins)
– Tetanus toxoid (TT),

– Diphteria toxoid
Vaccine manufacturers strive to develop vaccines that:

■■ Are effective in preventing or reducing severity of infectious disease,
■■ Provide durable, long-term protection against the disease,
■■ Achieve immunity with a minimal number of doses,
■■ Provide the maximum number of antigens that confer the broadest protection against infection,
■■ Cause no or mild adverse events,
■■ Are stable at extremes of storage conditions over a prolonged period of time,
■■ Are available for general use through mass production,
■■ Are affordable to populations at risk for infectious disease.
18
Adverse events
Classification
An adverse event following immunization (AEFI) is any untoward medical occurrence which follows
immunization and which does not necessarily have a causal relationship with the usage of the vaccine.
AEFIs are divided in 5 categories.
Vaccine product-related reaction

An AEFI that is caused or precipitated by a vaccine due to one or more of the inherent properties of the
vaccine product.
Example: Extensive limb swelling following DTP vaccination.
Vaccine quality defect-related reaction

An AEFI that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine
product including its administration device as provided by the manufacturer.
Example: Failure by the manufacturer to completely inactivate a lot of inactivated polio vaccine leads to cases
of paralytic polio.
Immunization error-related reaction

An AEFI that is caused by inappropriate vaccine handling, prescribing or administration and thus by its nature
is preventable.
Example: Transmission of infection by contaminated multidose vial.
Immunization anxiety-related reaction

An AEFI arising from anxiety about the immunization.
Example: Vasovagal syncope in an adolescent during/following vaccination.
Coincidental event
An AEFI that is caused by something other than the vaccine product, immunization error or immunization anxiety.
Example: A fever occurs at the time of the vaccination (temporal association) but is in fact caused by malaria.
Coincidental events reflect the natural occurrence of health problems in the community with common
problems being frequently reported.
Key point
The difference between a reaction related to the vaccine and an adverse event which can have
other causes should be explained to patients and parents. This ensures that they have all
information they need to make an informed decision about receiving an immunization for
themselves or their children.
Trusted and well-informed health care providers are best suited to provide such information.
Information about the immunization(s) should be provided well ahead of the immunization
visit. This gives parents the time to understand the information well and ask questions that
will increase their trust.
19
Question 3*
It is important to understand the different meanings of an adverse event following immu-
nization (or AEFI) and an adverse vaccine reaction. Can you tell the difference? Select the
right answers:
❒❒ A. An adverse vaccine reaction is a vaccine-related event caused or precipitated by a

vaccine when given correctly.
❒❒ B. An adverse vaccine reaction can be caused by errors in the administration of the
vaccine.
❒❒ C. An adverse vaccine reaction can be the result of unrelated coincidence.
❒❒ D. An adverse event following immunization can be due to all of the causes stated in
A, B, and C.
Causes
Vaccines contain different components to make them effective. However, each component in a vaccine
adds a potential risk of an adverse reaction. Regulatory authorities must ensure that all vaccine compo-
nents, singly and in combination, do not compromise vaccine safety.
Vaccines are prepared with different types of antigens, using different scientific methods such as attenua-
tion, inactivation, and recombination DNA technology.
Some vaccines include components to enhance immune response, such as adjuvants and conjugated
proteins.
Vaccines can also include antibiotics, stabilizers, and preservatives to reduce contamination during the
manufacturing process and to maintain their effectiveness during transport and storage.
Routes of administration of several vaccines*
Manufacturers usually recommend the route of administration that limits best adverse reactions of the
respective vaccine.
20
Question 4*
Select among the following the components that contribute to the risk of an adverse reaction
(selection of several items is possible).
❒❒ Antigens ❒ Antibiotics ❒ Preservatives
❒❒ Adjuvants ❒ Stabilizers
Please note that Routes of administration (intradermal, subcutaneous or intramuscular injection, drops
given orally, or intranasal administration) also contribute to the risk of an adverse reaction: They are rec-
ommended by the manufacturer for each vaccine and are determined to maximize vaccine effectiveness
and limit adverse reactions.*
Frequency and severity

Under recommended conditions, vaccines should cause no adverse events and completely prevent the
infection that they target. Unfortunately, current technology does not allow for such perfection. The key
therefore is to minimize as much as possible adverse events and ensure a safe use of vaccines.
Adverse events following immunization (AEFIs) are classified by the cause of the event. As you have
learned previously, when an AEFI is caused by the properties of the vaccine, it is classified as a vaccine
(product or quality related) reaction. Other categories include immunization error-related, and immuniza-
tion anxiety-related reactions and coincidental events.
Key point
Vaccine adverse events are expected to occur with a certain frequency.
AEFI surveillance monitors adverse events and follows up severe events that may have been
due to the vaccine.
Question 5*
Which of the following statements is wrong:
❒❒ A. An event that occurs in 12 out of a hundred persons is regarded as very common.

❒❒ B. An event that occurs in 2 out of a hundred persons is regarded as common.
❒❒ C. An event that occurs in 1 out of 20,000 is regarded as very rare.
❒❒ D. An event that occurs in 2 out of a thousand persons is regarded as common.
❒❒ E. An event that occurs in 1 out of 9,000 is regarded as rare.
21
Frequency and severity of adverse vaccine reactions

Occurrence among persons
Frequency Severity of reactions
vaccinated in percent
Very common ≥ 10% Common and usually minor reactions:

• Are part of the immune response to vaccine,
• Reactions settle on their own,
Common • Examples include:
≥ 1% and < 10%
(frequent) –– Fever,
–– Malaise.
Uncommon Rare, usually more severe reactions:

≥ 0.1% and < 1%
(infrequent) 1. Usually require clinical management,
2. Examples include:
Rare ≥ 0.01% and < 0.1%
–– Severe allergic reaction (e.g., anaphylaxis) including
an exaggerated response to the vaccine antigen or
Very rare < 0.01% component,
–– Vaccine specific reactions, such as BCG osteitis.
Background rates
Background rates of vaccine adverse reactions worldwide are published by WHO. Background rates dif-
fer from country to country because of differences in national surveillance systems. Understanding the
background rates in a specific population is useful for monitoring the sensitivity of the AEFI surveillance
system in detecting changes in the frequency of vaccine reactions.
For example, using the background rate in comparison to the observed rate can be helpful to determine
the reaction rate of a vaccine (see graphic).
Example: Fever following vaccination
Any increase in the frequency of AEFIs should alert you to consider the quality of the vaccine and whether
there are special risks in local populations. In addition, knowing when vaccine reactions may appear (time
to onset) is useful for investigating and verifying cases, as Module 4 will describe.
Key point
Knowing the background rates in your population is essential in detecting changes in the fre-
quency of vaccine reactions and identifying trends of concern, such as rates reported by AEFI
surveillance that are higher than expected.
22
Vaccine safety
in immunization programmes
In the pre-vaccine era, morbidity and mortality caused by infectious diseases that are now preventable
were high. Obviously, as vaccines did not exist, there were no adverse events to them yet. The pre-vaccine
stage in the graph (STAGE 1) is the phase before the vaccine gets introduced.
Potential stages in the evolution of an immunization programme
Diagram adapted from Chen RT et al. The Vaccine Adverse Event Reporting SystemVaccine Adverse Event Reporting
System (VAERS). Vaccine, 1994: 12(6):542–550.
In STAGE 2, after an effective vaccine is introduced to prevent a particular disease, an increase in immu-
nization uptake will result in a decrease in disease incidence, but also adverse events (AEFI), real or
perceived, may become a major focus. Paradoxically, it is just when vaccine benefits are most apparent and
vaccine coverage is highest that vaccine safety concerns are most likely to increase in the general public.
This increased focus on AEFIs, often intensified by media coverage of one or a few case reports, may lead to:
■■ A loss of confidence in the vaccine by the public,
■■ A reduction in vaccine coverage,
■■ A resurgence of the disease to higher or even epidemic levels (STAGE 3).
The resurgence of disease or the availability of an alternative vaccine results in renewed public acceptance
of vaccination against the disease. Vaccination levels increase and the disease is reduced to earlier low
levels (STAGE 4).
For vaccine-preventable diseases such as smallpox that can be eradicated, vaccine use can be stopped,
thereby removing the risk of any adverse event resulting from its use (STAGE 5). To ensure that the cycle
displayed in the graph does not repeat, any vaccine safety issue requires timely detection, evaluation, and
response efforts to gain and maintain high public confidence.
23
Pertussis vaccine example

In the mid-1970s in England and Wales, anti-immunization groups caused parents to question the value of pertus-
sis vaccine. As a result, immunization rates fell from 81 to 31% in a span of just a few years. Two epidemics of
pertussis (whooping cough) followed, and many children died needlessly. As the population was confronted with
the scourge of pertussis returning to their community, immunization coverage rose steadily and even surpassed
previous highs.
Pertussis incidence in England and Wales (1965–1995)
Key point
The more successful a vaccination campaign is, the less visible the prevented disease may
become to the public. As the threat of the original disease vanishes in the perception of the
public, the attention of the population may focus to the adverse events of the vaccine. A dis-
torted perception of the risk of vaccines and negligence of the much greater health threat by
the original disease may lead to decreased acceptance of the vaccine.
To ensure continued public acceptance of vaccines, it is essential to:
• Monitor the incidence of AEFIs,
• Scientifically evaluate the likely associations,
• Respond to newly identified risks from vaccines,
• Communicate the benefits and risks to patients and parents through a trusted health
care source in advance of the vaccination visit.
24
Vaccine regulations
Formal regulation began with vaccine testing, and in response
to tragedies associated with vaccine use, more comprehensive
regulatory procedures began to be defined.11
In the United States of America, the country with the longest
history in vaccine regulation, 20 children became ill and 14 died
in 1901 following receipt of an equine-derived diphtheria anti-
toxin contaminated with tetanus toxin.
This event stimulated the first legislation to regulate the sale of
biologicals, the Biologics Control Act, signed into law in 1902.12
Today vaccine regulation includes a range of functions that cover the entire continuum of vaccine develop-
ment, licensure, and use.
Progress in vaccine regulation globally includes shifts towards strictly defined procedures for vaccine
consistency, reliance on Good Manufacturing Practices (GMPs) rather than final product testing and con-
tinued vaccine pharmacovigilance and impact surveillance rather than individual, sporadic field studies.
Pre-licensure vaccine safety

Vaccines, like other pharmaceutical products, undergo extensive testing and review for safety, immuno-
genicity, and efficacy in the laboratory, in animals, and in three phases of clinical trials in human subjects
before licensure.
Monitoring adverse vaccine reactions is a major safety component of pre-licensure clinical trials.
In the table below you can see the different steps including clinical trials and further assessment that
a vaccine must go through before entering the market. Look at the various sample sizes of the Clinical
trial phases and compare them to the classification of frequency of common and rare adverse events on
this module’s chapter “Adverse events: Frequency and severity” on page 21. Note that even trials in
Phase III are not generally designed to detect very rare reactions or reactions with vague or delayed onset.
Larger studies, often at prohibitive cost and risk to delay vaccine availability, are necessary to detect very
rare conditions that might result from vaccination.
Key point
Pre-licensure studies often identify common and acute negative reactions that occur with a
frequency greater than 1 in 10,000 vaccinations, depending on total sample size of the study.
The sensitivity of detection of uncommon or rare adverse events, or those with delayed onset
is, however, low in these trials.
As a result, continuous post-licensure monitoring of vaccine safety is needed to identify and
evaluate such adverse events.
25
Clinical trials and assessment of vaccine safety

Detection of Adverse
Sample size events
Activity
(estimates)
Common Rare
Clinical Trial
Test the safety and immunogenicity of a vaccine
Phase I
candidate in a few low-risk individuals (usually 10 – 100 +/– –
healthy adults) to determine tolerability.
Clinical Trial Monitor safety, potential side effects, immune

Phase II response, and determine optimum dosage and 100 – 1,000 + –
schedule.
Clinical Trial Address clinical efficacy in disease prevention

Phase III and provide further safety information from
1,000 – 10,000 + –
more heterogeneous populations and longer
times of observation.
Submission
The vaccine application is submitted to regulatory authorities for approval to market.
Introduction Involves making the vaccine available for use.
Rotavirus vaccine example

In August 1998 the first rotavirus vaccine, RotaShield®, was licensed in the USA. Pre-licensure literature noted
a suspicion of an increased risk of intussusception. After RotaShield® was licensed for routine use by the public
(approximately one million children vaccinated within the first nine months licensure) the American vaccine safety
surveillance, Vaccine Adverse Event Reporting System (VAERS), began to receive reports of intussusception
following administration of the vaccine. About 100 (0.01%) of the one million children vaccinated developed intus-
susception,16 a potentially life-threatening bowel obstruction that occurs for unknown reasons in about one child
per 10,000, regardless of whether or not they have received a vaccine.17 Because of the uncertainty about the
relationship between RotaShield® and intussusception cases following vaccination, the manufacturer voluntarily
took the product off the market in 1999.
This example demonstrates that even if no adverse event is observed in a trial of 10,000 vaccinees (as was the
case of RotaShield®’s phase III clinical trial), one can only be reasonably certain that the real incidence of the
adverse event is no higher than one in 3,333 vaccinees. Thus to be able to detect a risk of one adverse event per
10,000 vaccinees, a pre-licensure trial of at least 30,000 vaccinees and 30,000 controls is needed.14
Subsequent rotavirus vaccines were subjected to phase III trials that included at least 60,000 infants.18,19 While these
trials were adequately powered to detect the problem with intussusception found following RotaShield®, in general,
the cost of such large trials might limit the number of vaccine candidates that go through this process in the future.
26
Post-licensure vaccine safety

Key point
Spontaneous reporting is the cornerstone of most post-licensure safety monitoring systems
because of its relative ease of implementation and ability to capture unexpected events.
Post-licensure surveillance of vaccine safety is critical. The conditions and reasons for safety monitoring
change, following licensure and introduction of a new vaccine.
■■ Vaccines are now in use in the general population and recipients are no longer monitored in
clinical trials with narrow inclusion/exclusion criteria,
■■ Subpopulations commonly excluded in clinical trials (e.g. those with underlying medical condi-
tions, preterm infants) get vaccinated,
■■ Large numbers of people are being vaccinated, for example, entire birth cohorts receive infant
vaccines,
■■ Other factors that can lead to AEFIs, such as incorrect administration practices, need to be
monitored for safety,
■■ Uncommon and rare vaccine reactions, and reactions with delayed onset may not be detected
before vaccines are licensed,
■■ Health providers should understand that some commonly used vaccines have demonstrated rare
and potentially serious adverse events. In these instances, policy-making bodies have judged that
the individual and community benefits of vaccination outweigh the risks.
Rotateq® vaccine example

Since the US introduction of RotaTeq® in 2006, the USA’s Centers for Disease Control and Prevention’s Advisory
Committee on Immunization Practices (ACIP) has routinely reviewed post-licensure safety surveillance data re-
corded through the Vaccine Adverse Event Reporting System (VAERS).
One year following introduction, ACIP reviewed available data to evaluate the rate of reports of intussusception
following RotaTeq® vaccination and found that it did not exceed expected background rates in the absence of vacci-
nation. Additionally, active surveillance among a population of insured children did not identify any reports of intus-
susception within 30 days of more than 28,000 administered doses.22 As a result, the committee has expressed
no safety concerns regarding use of this vaccine and reaffirmed its 2006 recommendation for routine administra-
tion to all infants in the USA at ages two, four, and six months.23 Since introduction, the use of second generation
rotavirus vaccines in routine immunization has reduced hospitalizations for severe diarrhoea by 70 to 80% and may
have prevented illness in unvaccinated children by limiting the infections that spread the virus to others.
Post licensure surveillance options

AEFI surveillance systems are specific to monitoring adverse events associated with vaccine use. In con-
trast, adverse drug reaction (ADR) surveillance systems are used to monitor suspected adverse reactions
associated with medicines.
A range of surveillance options can be used to monitor the safety of vaccines and immunizations
post-licensure.
27
Passive surveillance systems
■■ Passive surveillance systems (or spontaneous reporting systems) are the corner-
stone of most post-licensure safety monitoring systems because of their relative
ease of implementation, their cost and ability to capture unexpected events.
Passive surveillance
systems
These reporting systems monitor events reported by health care providers and
consumers and do not actively seek out and collect data or measure outcomes
using study protocols.
Active surveillance systems
■■ Vaccines may undergo clinical trials after licensure to assess the effects of
changes in vaccine formulation, vaccine strain, age at vaccination, number
and timing of vaccine doses, simultaneous administration and interchange-
ability of vaccines from different manufacturers on vaccine safety and
Post-licensure clinical immunogenicity.14
trials and phase IV
surveillance studies ■■ To improve the ability to detect adverse events that are not detected during
pre-licensure trials, some recently licensed vaccines in developed countries
have undergone formal phase IV surveillance studies, involving cohorts as
large as 100,000 often recruited from health maintenance organizations
(HMOs), lasting four to six years.
■■ LLDBs are large administrative databases from defined populations (such as
a single health care provider or HMO) that were created separately from each
other and linked to enable the sharing of data across platforms. Such linked
databases have become useful to vaccine safety surveillance.
■■ Because LLDBs cover enrolee populations numbering from thousands to

millions, they can detect very rare adverse events. With denominator data on
doses administered and the ready availability of appropriate comparison (i.e.
Large linked unvaccinated) groups, these large databases provide an economical and rapid
databases (LLDBs) means of conducting post-licensure studies of the safety of drugs and vaccines.
They also represent powerful tools to allow for testing hypotheses when signals
or allegations create suspicions of a possible vaccine safety issue.
■■ The Vaccine Safety Datalink (VSD) project is an example of a LLDB between

the USA’s Centers for Disease Control and Prevention (CDC) and eight HMOs.
The VSD project was established in 1990 to monitor immunization safety and
to address the gaps in scientific knowledge about rare and serious events fol-
lowing immunization.20
■■ More recently, tertiary clinical centers have been used to conduct research on
immunization-associated health risks.
Clinical centers,
including the Clinical ■■ The USA’s Clinical Immunization Safety Assessment (CISA) Network is a
Immunization Safety national network of six medical research centers with expertise in immunization
Assessment (CISA) safety conducting clinical research on immunization-associated health risks.
centers Established in 2001 as a collaborative project between the CDC, six medical
research centers, and American Health Insurance Plans, CISA conducts clinical
research on vaccine adverse events and the role of individual variation.21
28
Balancing efficacy and safety

Vaccine efficacy refers to the ability of a vaccine to bring about the intended beneficial effects on vac-
cinated individuals in a defined population under ideal conditions of use. The potential benefits of an
effective vaccine – e.g. promotion of health and well-being, and protection from illness and its physical,
psychological and socioeconomic consequences – must be weighed against the potential risk of an adverse
event following immunization (AEFI) with that vaccine. Vaccine-associated risk is the probability of an
adverse or unwanted outcome occurring, and the severity of the resulting harm to the health of vaccinated
individuals in a defined population, following immunization with a vaccine under ideal conditions of use.
Potential benefits of an effective vaccine must be weighed against potential risk of an AEFI.
Key point
Public confidence in vaccine safety is increased by clear communication of risk/benefit assess-
ments, comparing the very low vaccine-associated risk with the very significant benefits of
vaccination.
An important criterion of vaccine safety that regulatory authorities must establish is the risk/benefit
assessment of immunization with a particular vaccine in a defined population. You will learn how to
conduct a risk/benefit assessment in Module 4 ‘Surveillance’ and about the actions that follow the identi-
fication of an increased or new vaccine risk. Here we introduce you to some basic principles and the issues
that regulatory authorities consider when balancing vaccine efficacy and vaccine safety.
Risk evaluation for a specific vaccine requires the collection and analysis of reliable data on:
■■ The incidence, severity, morbidity and mortality resulting from adverse vaccine reactions,
■■ Case investigation to determine whether the vaccine presents a new suspected risk,
■■ The probable mechanism and underlying cause of any vaccine reactions,
■■ The preventability, predictability and reversibility of the risk of a vaccine reaction occurring,
■■ The risks associated with alternative vaccines that protect against the same disease,
■■ The risks associated with not vaccinating, i.e. the risks arising from the infectious disease in
unvaccinated individuals. The table below illustrates this point very clearly for measles.
Summarizing the risk/benefit relationship of a vaccine in tables and diagrams is useful to:
29
■■ Relate the benefits to the seriousness of the target disease,

■■ Focus key messages on vaccine efficacy and safety in vaccination campaigns and routine immu-
nization programmes,
■■ Alert healthcare staff to the dominant risks associated with a vaccine and the probability of an
adverse vaccine reaction occurring,
■■ Encourage consideration of alternative vaccines which may offer greater efficacy and/or safety.
Risk of acquiring illnesses following infection versus risk following vaccination
Measles infectiona Measles vaccineb
Otitis 7 – 9% 0
Pneumonia 1 – 6% 0
Diarrhoea 6% 0
Post-infectious
0.5/1,000 1/100,000 – million
encephalomyelitis
SSPE 1/100,000 0
Anaphylaxis 0 1/100,000 – million
Thrombocytopenia Not properly quantifiedc 1/30,000d
Death 0.1 – 1/1,000 (up to 5 – 15%) 0
a. Risks after natural measles are calculated in terms of events per number of cases.
b. Risks after vaccination are calculated in terms of events per number of doses.
c. Although there have been several reports of thrombocytopenia occuring after measles including bleeding, the risk has not
been properly quantified.
d. This risk has been reported after MMR vaccination and cannot be only attributed to the measles component.
MMR = measles, mumps and rubella; SSPE = subacute sclerosing panencephalitis.
P. Duclos, BJ Ward. Measles Vaccines, A Review of Adverse Events, Drug Safety 1998; Dec 19 (6): 435—454
Key point
Risk/benefit assessments should be applied to most situations relating to the efficacy or safety
of vaccines to ensure public safety and public health.
30
Summary
You have now completed the learning for this module. These are the main points that you have learned.
RRWith the exception of water safety, vaccines have the greatest potential to promote public health.
They reduce morbidity and mortality from infectious disease, saving costs as well as lives.
RRPublic trust in vaccines is easily undermined: there is a lower tolerance for adverse events than for
other prescribed drugs.
RRThe five categories of AEFIs are:

1. Vaccine product-related reaction,
2. Vaccine quality defect-related reaction,
3. Immunization error-related reaction,
4. Immunization anxiety-related reaction,
5. Coincidental event.
RRVaccines generate an immune response in the body, and the characteristics of a vaccine that
increase the risk of an adverse reaction.
RRThe four main types of vaccine are live attenuated, inactivated, subunit and toxoid and there are
specific vaccines of each antigen type.
RRVaccines are regulated from development, to licensure, to use, and national regulatory authorities
play an important role in this process.
RRPost-licensure surveillance of a vaccine after its introduction to the market is critical as clinical tri-
als may not detect rare or very rare reactions, or reactions with delayed onset.
RRThe risks associated with vaccines are very low compared with the risks of the diseases they are
designed to prevent.
You have completed Module 1.

We suggest that you test your knowledge!
31
ASSESSMENT 1
ASSESSMENT 1
ASSESSMENT 1
Question 1
Which of the following statements is/are correct? Select one or more:
❒❒ A. Post-licensure AEFI surveillance is important because vaccine adverse reactions with

delayed onset may not be known at the time of vaccine licensure.
❒❒ B. Pre-licensure trials do not detect common minor vaccine reactions. These are discovered
in Post-licensure AEFI surveillance.
❒❒ C. Post-licensure AEFI surveillance is important because subpopulations commonly excluded

in clinical trials (e.g. persons with underlying medical conditions, premature infants) are
included in immunization programmes and may be at increased risk of AEFIs.
❒❒ D. Post-licensure AEFI surveillance of large cohorts may detect uncommon or rare severe
vaccine reactions that were not known at the time of vaccine licensure.
❒❒ E. Post-licensure clinical trials are not required to assess the effects of changes in vaccine
formulation or vaccine strain.
❒❒ F. Post-licensure AEFI surveillance does not identify errors in vaccine administration

practices.
Question 2
Complete each statement by choosing the correct option from the list below:
1. Transmission of infection by contaminated multidose vial is a ____ .
2. An AEFI that is caused or precipitated by a vaccine due to one or more of the inherent prop-
erties of the vaccine is a .
3. An adolescent fainting due to a vasovagal syncope during or following vaccination speaks for
a .
4. A fever occurs at the time of the vaccination (temporal association) but is in fact caused by
malaria is a .
5. Failure by the manufacturer to completely inactivate a lot of inactivated polio leading to

cases of paralytic polio is a .
a Immunization anxiety-related reaction d Vaccine product-related reaction

b Coincidental event e Vaccine quality defect-related reaction
c Immunization error-related reaction
33
ASSESSMENT 1
Question 3
1. Exposure to the first dose of naturally-occurring or vaccine

triggers a immune response.
2. Vaccination causes the immune system to produce types of protein called

and long-lived that confer lasting immunity.
3. The immune response is more rapid and effective than

the response and may eliminate the targeted pathogens
before symptoms occur.
4. The immune response to immunization with measles

mimics the immune response to the of the measles virus.
a primary e adjuvants
b secondary f immunity
c antibodies g antigens
d vaccine h memory cells
Question 4
Identify how the antigen in each of the following vaccines is prepared by choosing the cor-
rect option from the list below:
1. Oral polio vaccine (OPV)
2. Whole-cell pertussis vaccine (wP)
3. Hepatitis B vaccine (Hep B)
4. Tetanus toxoid (TT)
5. Rotavirus vaccine
6. Acellular pertussis vaccine (aP)
7. Measles vaccine
8. Haemophilus influenzae type b (Hib)
a live attenuated c inactivated toxin

b subunit (purified) antigen d inactivated (killed) antigen
34
ASSESSMENT 1
Question 5
An immunization programme can undergo several stages (Pre-vaccine, Increasing vaccina-

tion coverage, Loss of confidence, resumption of confidence, and eradication. Which of the
following statements are correct? Select one or more:
❒❒ A. Pre-vaccine (STAGE 1): No adverse events occur during the pre-vaccine stage.
❒❒ B. Increasing vaccination coverage (STAGE 2): The coverage of vaccination increase, the pre-
vented disease’s incidence decreases, adverse events to the vaccine decrease.
❒❒ C. Loss of confidence (STAGE 3): The reduced appearance of the prevented illness and the
increased focus on AEFIs, often intensified by media coverage lead to a loss of confidence
in the vaccine by the public. This leads to a reduction in vaccine coverage, which leads to a
resurgence of the disease to higher or even epidemic levels.
❒❒ D. Resumption of confidence (STAGE 4): Resurgence of disease and effective communication

work by immunization programme officers lead to a regain in public acceptance of the vac-
cine. Vaccination levels have increased and the disease incidence decreases.
❒❒ E. Eradication (STAGE 5): Once a disease is eradicated, vaccine use can be stopped.
You have completed Assessment 1.
35
ASSESSMENT 1
Assessment solutions
Question 1
Answers A, C and D are correct.
The key point is that in pre-licensure clinical trials, the sensitivity of detection is low for:
■■ uncommon or rare adverse reactions, or
■■ reactions with delayed onset, or
■■ reactions affecting subgroups excluded from clinical trials.
Continuous post-licensure monitoring of vaccine safety is therefore critical to identify and evaluate such
adverse events, particularly when there are changes in vaccine formulation or vaccine strain.
Question 2
The correct choices are:
1. Immunization error-related reaction,
2. Vaccine product-related reaction,
3. Immunization anxiety-related reaction,
4. Coincidental event,
5. Vaccine quality defect-related reaction.
Question 3
The correct answers are:
1. Exposure to the first dose of naturally-occurring or vaccine antigens triggers a primary immune
response.
2. Vaccination causes the immune system to produce types of protein called antibodies and long-lived
memory cells that confer lasting immunity.
3. The secondary immune response is more rapid and effective than the primary response and may
eliminate the targeted pathogens before symptoms occur.
4. The immune response to immunization with measles vaccine mimics the immune response to the
antigens of the measles virus.
36
ASSESSMENT 1
Question 4
The correct choices are:
1. Oral polio vaccine (OPV) – live attenuated,
2. Whole-cell pertussis vaccine (wP) – inactivated (killed) antigen,
3. Hepatitis B vaccine (Hep B) – subunit (purified) antigen,
4. Tetanus toxoid (TT) – inactivated toxin,
5. Rotavirus vaccine – live attenuated,
6. Acellular pertussis vaccine (aP) – subunit (purified) antigen,
7. Measles vaccine – live attenuated,
8. Haemophilus influenzae type b (Hib) – subunit (purified) antigen.
Question 5
Answers A, C, D and E are correct.
In the pre-vaccine era, morbidity and mortality caused by infectious diseases that are now preventable
were high. Obviously, as vaccines did not exist, there were no adverse events to them yet. The pre-vaccine
stage in the graph (STAGE 1) is the phase before the vaccine gets introduced.
STAGE 2, after an effective vaccine is introduced to prevent a particular disease, an increase in immuniza-
tion uptake will result in a decrease in disease incidence, but also adverse events (AEFI), real or perceived,
may become a major focus. Paradoxically, it is just when vaccine benefits are most apparent and vaccine
coverage is highest that vaccine safety concerns are most likely to increase in the general public.
This increased focus on AEFIs, often intensified by media coverage of one or a few case reports, may lead to:
■■ A loss of confidence in the vaccine by the public,
■■ A reduction in vaccine coverage,
■■ A resurgence of the disease to higher or even epidemic levels (STAGE 3).
The resurgence of disease or the availability of an alternative vaccine results in renewed public acceptance
of vaccination against the disease. Vaccination levels increase and the disease is reduced to earlier low
levels (STAGE 4).
For vaccine-preventable diseases, such as smallpox, that have be eradicated, vaccine use can be stopped,
thereby removing the risk of any adverse event resulting from its use (STAGE 5).
37
MODULE 2: Types of vaccine and adverse reactions
MODULE 2
Types of vaccine
and adverse reactions
Overview
There are many types of vaccines. Different types or formulations affect how they are used, how they are
stored, and how they are administered. If they are to be safe and effective, it is vital to be familiar with the
different types and to know how to handle them.
Different vaccines can cause different adverse reactions, and it is important to recognize what these may
be. Can you identify the contraindications for vaccination and know which present an additional risk?
What special considerations should you make when immunizing pregnant women or immunocompro-
mised clients?
This module will explain the different types of vaccine and the main routes of administration. You will
learn about the main vaccine reactions and the importance of understanding contraindications – as ignor-
ing these could lead to vaccine reactions. Finally, you will look at public concern over vaccines and consider
some rumours about vaccine safety that have been disproved by research.
Module outcomes
1 Explain the modes of action of live attenuated vaccines, conjugate vaccines, subunit vaccines, and
toxoid vaccines,
2 List types of vaccine components, including adjuvants and preservatives, and explain their
functions,
3 Explain the difference between live attenuated and inactivated vaccines,
4 Identify the contraindications for vaccination that may present an additional risk.
39
Types of vaccine
In module 1 we have learned that vaccines are used to prevent serious illnesses and that regulatory authori-
ties have strict requirements for safety before they are approved for use.
Vaccines require rigorous follow-up once approved for use to assess types and rates of adverse events. The
development of more effective and even safer vaccines as well as developing vaccines for more diseases
that are serious is always ongoing.
There are many types of vaccines, categorized by the antigen used in their preparation. Their formulations
affect how they are used, how they are stored, and how they are administered. The globally recommended
vaccines discussed in this module fall into four main types.
Types of Vaccine
Live attenuated (LAV)
– Tuberculosis (BCG)
– Oral polio vaccine (OPV)
– Measles
– Rotavirus
– Yellow fever
Inactivated (killed antigen)
– Whole-cell pertussis (wP)

– Inactivated polio virus (IPV)
Subunit (purified antigen)
– Acellular pertussis (aP),

– Haemophilus influenzae type b (Hib),
– Pneumococcal (PCV-7, PCV-10, PCV-13)
– Hepatitis B (HepB)
Toxoid (inactivated toxins)
– Tetanus toxoid (TT),

– Diphteria toxoid
Mono and polyvalent vaccines

Vaccines may be monovalent or polyvalent. A monovalent vaccine contains a single strain of a single
antigen (e.g. Measles vaccine), whereas a polyvalent vaccine contains two or more strains/serotypes of
the same antigen (e.g. OPV).
Combination vaccines
Some of the antigens above can be combined in a single injection that can prevent different diseases or that
protect against multiple strains of infectious agents causing the same disease (e.g. combination vaccine
DPT combining diphtheria, pertussis and tetanus antigens). Combination vaccines can be useful to over-
come logistic constraints of multiple injections, and accommodate for a children’s fear of needles and pain.
40
Live attenuated vaccines

Available since the 1950s, live attenuated vaccines (LAV) are derived from dis- BACTERIA
ease- causing pathogens (virus or bacteria) that have been weakened under Tuberculosis (BCG)
laboratory conditions. They will grow in a vaccinated individual, but because
they are weak, they will cause no or very mild disease. VIRUS
Oral polio vaccine (OPV)
Measles
Immune response Rotavirus
Yellow fever
LAVs stimulate an excellent immune response that is nearly as good as com-
pared to an infection with the wild-type pathogen.
Live microorganisms provide continual antigenic stimulation giving sufficient time for memory cell
production.
In the case of viruses or intracellular microorganisms where cell-mediated immunity is usually desired,
attenuated pathogens are capable of replicating within host cells.
Safety and stability

Since LAVs contain living organisms, there is a degree of unpredictability raising some safety and stability
concerns.
■■ Attenuated pathogens have the very rare potential to revert to a pathogenic form and cause dis-
ease in vaccinees or their contacts. Examples for this are the very rare, serious adverse events of:
–– vaccine-associated paralytic poliomyelitis (VAPP) and
–– disease-causing vaccine-derived poliovirus (VDPV) associated with oral polio vaccine (OPV).
■■ Functional immune systems eliminate attenuated pathogens in their immune response. Indi-
viduals with compromised immune systems, such as HIV-infected patients may not be able to
respond adequately to the attenuated antigens.
■■ Sustained infection, for example tuberculosis (BCG) vaccination can result in local lymphadeni-
tis or a disseminated infection.
■■ If the vaccine is grown in a contaminated tissue culture it can be contaminated by other viruses
(e.g. retro viruses with measles vaccine).
■■ As a precaution, LAVs tend not to be administered during pregnancy. However, the actual
potential for fetal damage remains theoretical. For example, numerous studies have demon-
strated that accidental rubella vaccination during pregnancy did not result in an increased risk
of birth defects.
■■ LAVs can have increased potential for immunization errors:
–– Some LAVs come in lyophilized (powder) form. They must be reconstituted with a specific
diluent before administration, which carries the potential for programmatic errors if the
wrong diluent or a drug is used.
–– Many LAVs require strict attention to the cold chain for the vaccine to be active and are
subject to programme failure when this is not adhered to.
41
IMMUNE RESPONSE SAFETY AND STABILITY

w Live microorganisms provide w Attenuated pathogens can revert
continual antigenic stimulation, to original form and cause disease.
giving sufficient time for
memory cell production. w Potential harm to individuals
with compromised immune
w Attenuated pathogens are capable systems (eg. HIV).
of replicating within host cells.
w Sustained infection
(BCG - local lymphadenitis).
Excellent immune response
w Contamination of tissue culture.
w Immunization errors
(Reconstitution, cold chain).
w Usually not given in pregnancy
Less safe compared
to inactivated vaccines
Adverse reactions associated with LAVs

Five vaccines that are recommended by WHO are produced using LAV technology which are displayed in
the table below:
■■ Tuberculosis (BCG),
■■ Oral Polio Vaccine,
■■ Measles,
■■ Rotavirus,
■■ Yellow Fever.
The table lists the rare, more severe adverse reactions of these vaccines. Note the frequency of the adverse
reactions to get an idea of how low or high the possibility of an adverse event is. Also read the Comments
to understand additional context details on the adverse events.*
Question 1*
Which of the following statements is correct (Several answers possible see also table on next
page):
❒❒ A. Febrile seizures are an uncommon reaction to vaccination with measles.

❒❒ B. Compared to giving the first dose of measles vaccine, allergic reactions are less likely
to occur during the second dose of measles vaccine.
❒❒ C. Live vaccines include BCG, Measles, Rotavirus, Pertussis vaccine and Yellow fever
vaccine.
❒❒ D. Vaccine associated paralytic poliomyelitis occurs very rarely among vaccines
(2 – 4 cases per 1,000,000 vaccinated persons).
42
Five WHO recommended vaccines using LAV technology

Rare, more severe
Vaccine Frequency Comment
adverse reactions
Almost exclusively occurs in inad-

very rare
Fatal dissemination of vertently immunized persons with
at 0.000019 –
BCG infection severely compromised cellular
B AC T E R I A
0.000159%
immunity.
Tuberculosis (BCG)28
In the past BCG osteitis has been
reported in connection with
BCG osteitis very rare
certain vaccine batches but now
occurs very rarely.
Vaccine- associated
very rare An essential component of the
Oral polio vaccine paralytic poliomyelitis
at 0.0002 – global polio eradication campaign
(OPV)29 (VAPP) in vaccinees
0.0004% despite adverse reactions.
and their contacts
uncommon Adverse reactions, with the

Febrile seizures
at 0.3% exception of allergic anaphylactic
reactions, are less likely to occur
Thrombocytopenic very rare after receipt of the second dose of
purpura at 0.03% measles vaccine.
Measles 31
Allergic reactions to vaccine com-

very rare ponents including neomycin and
Anaphylaxis
at 0.001% the stabilizers gelatine or sorbitol,
may follow vaccination.
To date, post-licensure surveil-

lance does not indicate any
VIRAL
increased risk of intussusception

Rotavirus61 None reported to WHO –
or other serious adverse reaction
associated with the use of current
rotavirus vaccines.
Sensitivity to egg, which is

Hypersensitivity commonly used to stabilize the
very rare
reactions vaccine, may explain at least
some of these cases.
Infants seem more susceptible to

Vaccine- associated
vaccine-associated neurotropic
Yellow fever (YF)62 neurotropic disease very rare
disease than the YF-vaccinated
(encephalitis)
population at large.
The elderly seem more suscep-

very rare in
Vaccine- associated tible to reaction (very rare at
children at
viscerotropic disease 0.04 – 0.05%) than the YF-vacci-
0.00001%
nated population at large.
43
Inactivated whole-cell vaccines

Inactivated vaccines are made from microorganisms (viruses, bacteria, other) BACTERIA
that have been killed through physical or chemical processes. These killed Whole-cell pertussis (wP)
organisms cannot cause disease.
VIRUS
Inactivated polio virus (IPV)
Immune response
■■ Inactivated whole-cell vaccines may not always induce an immune response and the response
may not be long lived.
■■ Several doses of inactivated whole-cell vaccines may be required to evoke a sufficient immune
response.

■■ Inactivated whole-cell vaccines have no risk of inducing the disease they are given against as
they do not contain live components.
■■ They are considered more stable than LAV vaccines.
to understand additional context details on the adverse events.

w May not always induce an immune w
response at first dose. no risk of inducing the disease.
w Response may not be long-lived, w
requiring several doses of vaccine.
Excellent stability profile
Less strong immune response
compared to live vaccines
Adverse reactions associated with inactivated whole-cell vaccines

Rare, more severe
Vaccine Frequency Comment
adverse reactions
Prolonged crying Minor adverse reactions such as local red-

and seizures are less than 1% ness and swelling, fever and agitation are
uncommon very common with wP vaccines (10 – 50%).
B AC T E R I A
Pertussis Although mild with no lasting effect, these

(wP)30 reactions have affected the acceptance of
Hypotonic, hypore-
less than wP vaccine in some populations. All wP (or
sponsive episodes
0.1 – 0.2% DTwP) vaccines contain aluminium salt as
(HHE) are rare
adjuvant and in some cases thiomersal as
preservative.
Many high-income countries have switched

Vaccine-associated
Inactivated from OPV to IPV, as IPV is considered safer.
VIRAL
paralytic poliomyelitis
polio vaccine None known IPV is more expensive than OPV and an
(VAPP) in vaccinees
(IPV)29 injectable vaccine. Many lower- and middle-
and their contacts
income countries use OPV.
44
Question 2*
Which of the following statements is incorrect?
❒❒ A. Inactivated whole-cell vaccines contain “killed” pathogens.

❒❒ B. Inactivated whole-cell vaccines can be considered safer than live vaccines, particularly
when used in vulnerable groups (immunocompromised persons).
❒❒ C. Inactivated whole-cell vaccines can be considered more effective compared to live
vaccines.
❒❒ D. Inactivated whole-cell vaccines should not be seen as ineffective – the immunization
schedule foresees repeated doses to ensure adequate immune responses in patients.
Subunit vaccines
Immune response
■■ Subunit vaccines, like inactivated whole-cell vaccines do not contain live
Protein-based
components of the pathogen. They differ from inactivated whole-cell vac-
cines, by containing only the antigenic parts of the pathogen. These parts
Polysaccharide
are necessary to elicit a protective immune response.
■■ This precision comes at a cost, as antigenic properties of the various poten- Conjugate
tial subunits of a pathogen must be examined in detail to determine which
particular combinations will produce an effective immune response within the correct pathway.
■■ Often a response can be elicited, but there is no guarantee that immunological memory will be
formed in the correct manner.

Like inactivated vaccines, subunit vaccines do not contain live components and are considered as very safe.

w Must determine which combination w
of antigenic properties will produce no risk of inducing the disease.
the correct pathway. w

w Excellent stability profile
with no guarantee that memory will
form for future responses.
Less strong immune response

compared to LAVs
45
Key point
Rather than introducing a whole-cell vaccine (either inactivated or attenuated) to an immune
system, a subunit vaccine contains a fragment of the pathogen and elicits an appropriate
immune response.
Subunit vaccines can be further categorized into:

■■ Protein-based subunit vaccines,
■■ Polysaccharide vaccines,
■■ Conjugate subunit vaccines.
Protein-based subunit vaccines

Protein based subunit vaccines present an antigen to the BACTERIA
immune system without viral particles, using a specific, iso- Acellular pertussis (aP)
Protein-based
lated protein of the pathogen. A weakness of this technique
VIRUS
is that isolated proteins, if denatured, may bind to different Hepatitis B (HepB)
Polysaccharide
antibodies than the protein of the pathogen.
Commonly used protein-based subunit vaccines are the Conjugate
following:
■■ Acellular pertussis (aP) vaccines contain inactivated pertussis toxin (protein) and may contain
one or more other bacterial components. The pertussis toxin is detoxified either by treatment
with a chemical or by using molecular genetic techniques.
■■ Hepatitis B vaccines are composed of the hepatitis B virus surface antigen (HBsAg), a protein
produced by hepatitis B virus. Earlier vaccine products were produced using purified plasma
of infected individuals. This production method has been replaced by recombinant technology
that can produce HBsAg without requiring human plasma increasing the safety of the vaccine
by excluding the risk from potential contamination of human plasma.
to understand additional context details on the adverse events.
Adverse reactions associated with subunit protein-based vaccines

Rare, more severe
Vaccine Comment
adverse reactions
B AC T E R I A
Acellular Same as tetanus and Acellular pertussis-containing vaccines are less reactogenic
pertussis diphtheria toxoid in terms of mild-to-moderate reactions than wP-containing
(aP)30 vaccines. vaccines. See “More about Pertussis vaccine”.
VIRAL
Hepatitis B
Very rare Reports of severe anaphylactic reactions are very rare.
(HepB)63
46
More about Pertussis vaccine

Both acellular (aP) and whole-cell pertussis (wP) vaccines are safe and effective. In terms of rare, more severe
adverse reactions, aP and wP vaccines appear to have the same high level of safety. However, mild-to-moderate
adverse reactions are more commonly associated with wP vaccines, and tend to increase with client age and the
number of injections. This is why wP vaccines are not recommended for use in adolescents and adults where aP
vaccines rather come to use.
Because the price of wP is considerably less than aP, where resources are limited and the vaccine is well accept-
ed by the local population, wP vaccine remains the vaccine of choice. In countries where a higher rate of adverse
reactions after immunization with wP prevents high vaccination coverage, aP is recommended instead, at least
for booster injections.30
More about Hepatitis B vaccines

The first available hepatitis B vaccines were plasma-derived, produced by harvesting hepatitis B surface antigen
(HBsAg) from the plasma of persons with chronic HBV infection. The particles are highly purified, and any residual
infectious particles are inactivated by various combinations of urea, pepsin, formaldehyde and heat. Although
concerns about transmission of bloodborne pathogens, including HIV, from plasma-derived vaccines have proven
to be unfounded, public concerns over the safety of the plasma-derived vaccine hampered its acceptance in many
populations. Therefore increased research efforts were made to develop a recombinant vaccine.
In 1986, a hepatitis B vaccine produced by recombinant technology was licensed, and a second followed in 1989.
The recombinant technology expressed HBsAg in other microorganisms and offered the potential to produce un-
limited supplies of vaccine.
Although both the plasma-derived and recombinant hepatitis B vaccines are safe and highly effective in protect-
ing against acute hepatitis disease as well as chronic disease, including cirrhosis and liver cancer, competition
among the various hepatitis B vaccine producers drove down the price (see figure). When the price of both the
plasma-derived and recombinant hepatitis B vaccines was relatively similar, the recombinant gradually replaced
the plasma-derived hepatitis B vaccine.
47
Polysaccharide vaccines
Some bacteria when infecting humans are often protected by a polysaccharide (sugar)
Protein-based
capsule that helps the organism evade the human defense systems especially in
infants and young children.
Polysaccharide
Polysaccharide vaccines create a response against the molecules in the pathogen’s
capsule. These molecules are small, and often not very immunogenic. As a conse- Conjugate
quence they tend to:
1. Not be effective in infants and young children (under 18–24 months),
2. Induce only short-term immunity (slow immune response, slow rise of antibody levels, no
immune memory).
Examples of polysaccharide vaccines include Meningococcal disease caused by Neisseria meningitidis
groups A, C, W135 and Y, as well as Pneumococcal disease.
Conjugate subunit vaccines

Conjugate subunit vaccines also create a response against the
Protein-based
molecules in the pathogen’s capsule. In comparison to plain BACTERIA
polysaccharide vaccines, they benefit from a technology that Haemophilius
Polysaccharide influenzae type b (Hib),
binds the polysaccharide to a carrier protein that can induce Pneumococcal
a long-term protective response even in infants. Conjugate (PCV-7, PCV-10, PCV-13)
Various protein carriers are used for conjugation, including

diphtheria and tetanus toxoid. Conjugate subunit vaccines, can therefore prevent common bacterial infec-
tions for which plain polysaccharide vaccines are either ineffective in those most at risk (infants) or provide
only short-term protection (everyone else).
The advent of conjugate subunit vaccines heralded a new age for immunization against diseases caused by
encapsulated organisms such as meningococcus, Haemophilus influenzae type b (Hib) and pneumococcus.
WHO recommends that children receive Haemophilus influenzae type b (Hib) and pneumococcal conjugate
vaccines. In addition, the meningococcal A vaccine introduced in Africa is also a conjugated subunit vaccine.
Adverse reactions associated with conjugate vaccines

Rare, more severe
Vaccine Comment
adverse reactions
Haemophilus influenzae Hib vaccine has not been associated with any rare,
None known
type b conjugate (Hib)65 more severe adverse reactions.
B AC T E R I A
Pneumococcal conjugate, PCV conjugate vaccines have not been associated

7-valent (PCV-7), with any rare, more severe adverse reactions. As with
None known
10-valent (PCV-10), the introduction of any new vaccine, continued sur-
13-valent (PCV-13)66 veillance for possible unexpected effects is important.
Key point
Conjugate vaccines can prevent common bacterial infections for which plain polysaccharide
vaccines are either ineffective in those most at risk (infants) or provide only short-term pro-
tection (everyone else).
48
Question 3*
Which of the following statements is incorrect:
❒❒ A. Polysacharide vaccines provoke an immune response against the polysaccharide

capsule.
❒❒ B. Conjugate vaccine binds the polysaccharide to a carrier protein.
❒❒ C. Polysacharide vaccines are targeted, but not very immunogenic. They induce only short-
term immunity. Polysacharide vaccines do not provoke a sufficient immune response in
infants and young children but can in adults.
❒❒ D. Measles vaccine is a typical example for a Conjugate vaccine that provides better pro-
tection for infants compared to a Polysaccharide vaccine.
❒❒ E. Conjugate vaccine is effective in those most at risk (infants) and provides longer term
protection (everyone else).
Toxoid vaccines
Toxoid vaccines are based on the toxin produced by certain bacteria (e.g. tetanus BACTERIA
or diphtheria). Tetanus toxoid (TT)
Diphtheria toxoid
The toxin invades the bloodstream and is largely responsible for the symptoms
of the disease. The protein-based toxin is rendered harmless (toxoid) and used
as the antigen in the vaccine to elicit immunity.
To increase the immune response, the toxoid is adsorbed to aluminium or calcium salts, which serve as
adjuvants.

Toxoid vaccines are safe because they cannot cause the disease they prevent and there is no possibility of
reversion to virulence. The vaccine antigens are not actively multiplying and do not spread to unimmunized
individuals. They are stable, as they are less susceptible to changes in temperature, humidity and light.76

w May require several doses and w Vaccine cannot cause disease it
usually need an adjuvant. prevents.
Not highly immunogenic

w Very rare local and systemic
reactions.
w Usually stable and long lasting.
Excellent stability profile
49
Adverse reactions associated with toxoid vaccines

Rare, more severe adverse
Vaccine Comment
reactions
Anaphylaxis (1 – 6 per million) and

Tetanus toxoid Local and systemic reactions increase with
brachial neuritis (5 – 10 per mil-
B AC T E R I A
(TT)66 increasing number of doses.

lion) are extremely rare
Diphtheria toxoid No anaphylactic reactions attributable to the

None known
(DT and Td)69 diphtheria component have been described.
Combination vaccines
Licensed combination vaccines undergo extensive testing before approval by national regulatory authori-
ties to assure that the products are safe, effective, and of acceptable quality.
Combination vaccines consist of two or more antigens in the same preparation. This approach has been
used for over 50 years in many vaccines such as DTwP and MMR. Combination products simplify vaccine
administration and allow for the introduction of new vaccines without requiring additional health clinic
visit and injections.
Potential advantages of combination vaccines include:
■■ Reducing the cost of stocking and administering separate vaccines,
■■ Reducing the cost of extra health care visits,
■■ Improving timeliness of vaccination (some parents and health-care providers object to adminis-
tering more than two or three injectable vaccines during a single visit because of a child’s fear of
needles and pain, and because of concerns regarding safety),
■■ Facilitating the addition of new vaccines into immunization programmes.
It is very important, however, that combination vaccines are carefully tested before introduction. For
instance, adjuvants in a combination vaccine could reduce the activity of one antigen and excessively
increase the reactivity of another antigen. There could also be interactions with other vaccine components
such as buffers, stabilizers and preservatives.
With all combinations, manufacturers must therefore evaluate the potency of each antigenic component,
the effectiveness of the vaccine components when combined to induce immunity, risk of possible reversion
to toxicity, and reaction with other vaccine components.
Key point
No evidence exists that the administration of several antigens in combined vaccines over-
whelms the immune system, which has the capability of responding to many millions of
antigens at a time. Combining antigens usually does not increase the risk of adverse reactions.
In fact, it can lead to an overall reduction in adverse reactions.
With all combinations, manufacturers must, however, evaluate the potency of each antigenic
component, the effectiveness of the vaccine components when combined to induce immunity,
risk of possible reversion to toxicity, and reaction with other vaccine components.
50
Question 4*
Can you identify which five antigens are included in the pentavalent vaccine
DTwPHepBHib?
Components of a vaccine*
Vaccines include a variety of ingredients including antigens, stabilizers, adjuvants, antibiotics, and
preservatives.
They may also contain residual by-products from the production process. Knowing precisely what is in
each vaccine can be helpful when investigating adverse events following immunization (AEFIs) and for
choosing alternative products for those who have allergies or have had an adverse event known or sus-
pected to be related to a vaccine component.
Antigens
Antigens are the components derived from the structure of disease-causing organisms, which are recog-
nized as ‘foreign’ by the immune system and trigger a protective immune response to the vaccine.
You have already learned about antigens on the chapter “Types of vaccine“.
Stabilizers
Stabilizers are used to help the vaccine maintain its effectiveness during storage. Vaccine stability is
essential, particularly where the cold chain is unreliable. Instability can cause loss of antigenicity and
decreased infectivity of LAV. Factors affecting stability are temperature and acidity or alkalinity of the
vaccine (pH). Bacterial vaccines can become unstable due to hydrolysis and aggregation of protein and
carbohydrate molecules. Stabilizing agents include MgCl2 (for OPV), MgSO4 (for measles), lactose-sorbitol
and sorbitol-gelatine.
Adjuvants
Adjuvants are added to vaccines to stimulate the production of antibodies against the vaccine to make it
more effective.
Adjuvants have been used for decades to improve the immune response to vaccine antigens, most often
in inactivated (killed) vaccines. In conventional vaccines, adding adjuvants into vaccine formulations is
aimed at enhancing, accelerating and prolonging the specific immune response to vaccine antigens. Newly
developed purified subunit or synthetic vaccines using biosynthetic, recombinant, and other modern tech-
nology are poor vaccine antigens and require adjuvants to provoke the desired immune response.
Chemically, adjuvants are a highly heterogeneous group of compounds with only one thing in common:
their ability to enhance the immune response. They are highly variable in terms of how they affect the
immune system and how serious their adverse reactions are, due to the resulting hyperactivation of the
immune system.
51
Today there are several hundred different types of adjuvants that are being used or studied in vaccine
technology.
Aluminium salts example

Aluminium salts are among the oldest adjuvants that are commonly used. They slow the escape of the antigen
from the site of injection thereby lengthening the duration of contact between the antigen and the immune sys-
tem (i.e. macrophages and other antigen-receptive cells).
Aluminium salts are generally recognized as safe, however, they can cause sterile abscesses and nodules at the
site of injection. The formation of a small granuloma is inevitable with alum-precipitated vaccines.
To ensure safe vaccination it is important that aluminium salts are administered intramuscularly and not subcutane-
ously. Subcutaneous administration can result in necrotic breakdown and cyst and abscess formation. To ensure
the proper handling of intramuscular injections, it is critical to ensure that vaccination staff has been well trained.
Antibiotics
Antibiotics (in trace amounts) are used during the manufacturing phase to prevent bacterial contami-
nation of the tissue culture cells in which the viruses are grown. Usually only trace amounts appear in
vaccines, for example, MMR vaccine and IPV each contain less than 25 micrograms of neomycin per dose
(less than 0.000025 g). Persons who are known to be allergic to neomycin should be closely observed after
vaccination so that any allergic reaction can treated at once.
■■ Used during the manufacturing phase to prevent bacterial contamination of tissue culture cells
in which viruses are grown,
■■ Usually only trace amounts appear in vaccines, for example, MMR and IPV vaccines each con-
tain less that 25 micrograms of neomycin per dose,
■■ Persons known to be allergic to neomycin should be closely observed after vaccination so any
allergic reaction can be immediately treated.
Preservatives
Preservatives are added to multidose vaccines to prevent bacterial and fungal growth. They include a
variety of substances, for example Thiomersal, Formaldehyde, or Phenol derivatives.
Thiomersal
■■ Very commomly used preservative. Thiomersal is an ethyl mercury-containing compound,
■■ It has been in use since the 1930ies and no harmful effects have been reported for doses used in
vaccination except for minor reactions (e.g. redness, swelling at injection site),
■■ It is used in multidose vials and for single dose vials in many countries as it helps reduce storage
requirements/costs,
■■ Thiomersal has been subjected to intense scrutiny, as it contains ethyl mercury. The Global
Advisory Committee on Vaccine Safety continuously review the safety aspects of Thiomersal. So
far, there is no evidence of toxicity when exposed to Thiomersal in vaccines. Even trace amounts
of thiomersal seem to have no impact on the neurological development of infants.
52
Formaldehyde
■■ Used to inactivate viruses (e.g. IPV) and to detoxify bacterial toxins, such as the toxins used to
make diphtheria and tetanus vaccines,
■■ During production, a purification process removes almost all formaldehyde in vaccines,
■■ The amount of formaldehyde in vaccines is several hundred times lower than the amount known
to do harm to humans, even infants. E. g., DTP-HepB + Hib “5-in-1” vaccine contains less than
0.02% formaldehyde per dose, or less than 200 parts per million.*
Question 5*
Which of the following answers is incorrect?
❒❒ A. Thiomersal prevents bacterial growth and therefore make vaccines more durable,
which is particularly helpful for storing and use of multi-dose vials.
❒❒ B. Aluminium salts primarily serve to prevent bacterial contamination of tissue culture cells.
❒❒ C. Adjuvants serve to enhance the immune response.
❒❒ D. Stabilizers make a vaccine more stable towards temporary changes in temperature
and pH.
Route of administration
The route of administration is the path by which a vaccine (or drug) is brought into contact with the body.
This is a critical factor for success of the immunization. A substance must be transported from the site of
entry to the part of the body where its action is desired to take place. Using the body’s transport mecha-
nisms for this purpose, however, is not trivial.
Intramuscular (IM) injection administers the vaccine into the
muscle mass. Vaccines containing adjuvants should be injected
IM to reduce adverse local effects.
Subcutaneous (SC) injection administers the vaccine into the
subcutaneous layer above the muscle and below the skin.
Intradermal (ID) injection administers the vaccine in the top-
most layer of the skin. BCG is the only vaccine with this route of
administration. Intradermal injection of BCG vaccine reduces the
risk of neurovascular injury. Health workers say that BCG is the
most difficult vaccine to administer due to the small size of new-
borns’ arms. A short narrow needle (15 mm, 26 gauge) is needed for BCG vaccine. All other vaccines are
given with a longer, wider needle (commonly 25 mm, 23 gauge), either SC or IM.
Oral administration of vaccine makes immunization easier by eliminating the need for a needle and syringe.
Intranasal spray application of a vaccine offers a needle free approach through the nasal mucosa of the
vaccinee.
53
Intranasal flu vaccine

In October 2000, an inactivated intranasal flu vaccine was licensed in Switzerland.
Results from a case control study and a case-series analysis indicated a significantly
increased risk of Bell’s palsy, a one-sided paralysis of facial muscles, developing after
intranasal immunization with the vaccine. Following spontaneous reports of Bell’s
palsy in vaccine recipients, the producer decided not to further market the vaccine.
As a result of the occurrence of Bell’s palsy, the Global Advisory Committee on

Vaccine Safety (GACVS) recommended additional caution for new intranasal vac-
cines under development and recommended that the follow-up period in the
context of clinical trials should be routinely extended to three months following
administration.
In 2003, a cold attenuated reassortant live intranasal vaccine was licensed in the
Bell’s palsy (a one-sided
US. This vaccine differs in formulation and manufacturing from adjuvanted inacti-
paralysis of facial muscles)
vated intranasal vaccine. Bell’s palsy was not observed in clinical trials of the cold
after intranasal immuniza-
attenuated reassortant live intranasal vaccine. As of 6 July 2006, with over four mil-
tion with the vaccine.
lion vaccine doses distributed, a total of five Bell’s palsy cases have been reported
to the adverse event reporting system of the US. A causal association between
these reported cases and the vaccine has not been established.
The GACVS continues to review the safety of vaccines administered by the intranasal route.
Routes of administration vary to maximize effectiveness of vaccine
Key point
Manufacturers usually recommend the route of administration that limits best adverse reac-
tions of the respective vaccine.
54
Contraindications
A contraindication to vaccination is a rare condition in a recipient that increases the risk for a serious
adverse reaction. Ignoring contraindications can lead to avoidable vaccine reactions. Most contraindica-
tions are temporary, and the vaccination can be administered later.
The only contraindication applicable to all vaccines is a history of a severe allergic reaction after a prior
dose of vaccine or to a vaccine constituent. Precautions are not contraindications, but are events or condi-
tions to be considered in determining if the benefits of the vaccine outweigh the risks. Precautions stated
in product labelling can sometimes be inappropriately used as absolute contraindications, resulting in
missed opportunities to vaccinate.
Signs of allergic reactions

Vaccinating health workers should know the signs of allergic reactions and be prepared to take immediate action.
Contraindications to vaccines*
Anaphylaxis after
Severely
Childhood previous dose or
Pregnancy immuno- Comment
vaccine severe allergy to
compromised*
vaccine component
Further information available at http://
BCG28 who.int/vaccine_safety/committee/topics/
bcg/immunocompromised/Dec_2006/en/
DTwP30
DTaP30
OPV29
IPV29 CAVEAT: allergy to neomycin.
Severe allergy to gelatine is a contraindi-

Measles31
cation to vaccination with MMR vaccine.
HepB63
Rotavirus61
Hib65
PCV-766
CAVEAT: severe allergy to egg.

Yellow
Contraindicated in infants less than
fever62
6 months.
* Includes symptomatic HIV/AIDS (but for most LAV vaccines, asymptomatic or properly treated HIV infection is not a
contraindication).
55
Key point
True contraindications are rare. Misconceptions about their frequency can lead to missed
opportunities to vaccinate and decrease immunization coverage, or conversely increase the
risk of adverse reactions, both of which reduce public confidence in the safety of the vaccine.
Anaphylaxis
Anaphylaxis is a very rare allergic reaction (one in a million vac-
The Brighton Collaboration case
cinees), unexpected, and can be fatal if not dealt with adequately. definition and guidelines for anaphy-
Vaccine antigens and components can cause this allergic reaction. laxis are available on their website:
These reactions can be local or systemic and can include mild-to-
brightoncollaboration.org
severe anaphylaxis or anaphylactic-like responses (e.g. generalized
urticaria or hives, wheezing, swelling of the mouth and throat,
breathing difficulties, hypotension and shock). Reports of anaphy-
laxis are less common in low- and middle-income countries compared to high-income countries, probably
because of reduced surveillance sensitivity and as the event may not be recognized (i.e. death attributed
to another factor).
Misdiagnosis of faints and other common causes of collapse, such as anaphylaxis, can lead to inappropriate
treatment (e.g. use of adrenaline and failure to recognize and treat other serious medical conditions).
WHO’s guidelines on recognition

Anaphylaxis of unknown cause and unrelated to vac- and treatment of anaphylaxis is in-
cluded in Annex C of Mass Measles
cines increases during adolescence, being more common
Immunization Campaigns: Report-
among girls. Vaccinators should be able to distinguish ing and investigating adverse events
anaphylaxis from fainting and vasovagal syncope (which following immunization.71
is also common in adolescents), as well as anxiety and vaccine-safety-training.org/
breath-holding spells, which are all common benign tl_files/vs/pdf/AEFI_mea-
adverse events. sles_campaigns.pdf
Distinguishing anaphylaxis from a fainting (vasovagal reaction)

Fainting Anaphylaxis
Usually at the time or soon after Usually some delay between 5 – 30 minutes
Onset
injection after injection
Symptoms
Red, raised, and itchy rash; swollen eyes, face;

Skin Pale, sweaty, cold and clammy
generalized rash
Noisy breathing from airways obstruction (wheeze

Respiratory Normal to deep breaths
or stridor
Bradycardia Tachycardia
Cardiovascular
Transient hypotension Hypotension
Gastrointestinal Nausea/Vomiting Abdominal cramps
Transient loss of consciousness,

Neurological Loss of consciousness, little response once prone
good response once prone
56
Using adrenaline to treat anaphylaxis

Adrenaline stimulates the heart and reverses the spasm in the blood vessels and the lung passages, reduces
oedema and urticaria, thus countering the anaphylaxis. But this very potent agent can cause irregular
heartbeat, heart failure, severe hypertension and tissue necrosis if used inappropriately, although not when
treating true anaphylaxis.
The expiry date of adrenaline should be written on the outside of the emergency kit. Adrenaline that has
a brown tinge must be discarded.
Key point
Each vaccinator who is trained in the treatment of anaphylaxis should have rapid access to an
emergency kit with adrenaline, and be familiar with its dosage and administration.
Immunizing the immunocompromised

People may be immunocompromised due to HIV/AIDS, congenital immune deficiencies or drug treat-
ments such as chemotherapy for cancer and other conditions and high dose steroids.
Measles vaccination and HIV infection

Measles in children with HIV infection is more often severe and results in higher mortality. Infants born to HIV-
infected mothers are at higher risk for measles from 9 months of age.
Measles vaccines, a live attenuated vaccine, are among the most safe and effective vaccines. They should be
given routinely to potentially susceptible, asymptomatic, HIV-infected children, adolescents and young adults.
Only those with severe clinical symptoms of HIV infection are contraindicated for vaccination. These people often
do not develop a protective immune response and are at increased risk of severe complications.
Given the high risk of measles at 9 months of age, WHO recommends that infants infected with HIV receive an early
dose of measles vaccine at 6 months of age, followed by a routine dose at 9 months (or according to the routine
immunization schedule). Earlier age of vaccination is recommended because HIV-infected infants exhibit a better
seroconversion rate at 6 months than at 9 months of age, possibly because of increasing HIV-associated immunode-
ficiency with age.
HIV-infected infants vaccinated at 6 and 9 months should receive a third measles vaccination (or second opportu-
nity) to prevent the proportion of unprotected children in the population from reaching dangerous levels. Recent
studies suggest waning immunity among HIV-infected children, making this recommendation especially impor-
tant in regions with high HIV prevalence.31
The potential risks of live vaccines need to be weighed against the benefits in immunocompromised clients
who may be particularly vulnerable to the vaccine-preventable disease. Concerns are that they may not
respond adequately to subunit and inactivated vaccination and that LAV vaccines are potentially pathogenic.
Routine childhood vaccinations – except BCG vaccination72 – are not contraindicated in children with
asymptomatic HIV-infection; however, timing of vaccination may be earlier or more frequent in this
subgroup.
In symptomatic HIV/AIDS, LAV vaccines are contraindicated, e.g. measles and yellow fever vaccines
should not be given.
57
BCG vaccination for infants at risk for HIV infection

As in infants symptoms of HIV-infection rarely appear before several months of age, BCG vaccination should be
administered to those infants regardless of HIV exposure, especially considering the high endemicity of tubercu-
losis in populations with high HIV prevalence.
Close follow-up of infants known to be born to HIV-infected mothers and who received BCG at birth is recom-
mended in order to provide early identification and treatment of any BCG-related complication.
In settings with adequate HIV services that could allow for early identification and administration of antiretroviral
therapy to HIV-infected children, consideration should be given to delaying BCG vaccination in infants born to
mothers known to be infected with HIV until these infants are confirmed to be HIV negative.
Infants who demonstrate signs or reported symptoms of HIV-infection and who are born to women
known to have HIV infection should not be vaccinated.
Immunization and pregnancy

Key point
No evidence exists of risk from vaccinating pregnant women with inactivated virus
or bacterial vaccines or toxoids.
Influenza
Inactivated influenza vaccine is now recommended for pregnant
women in many industrialized countries because of evidence of ben-
efit to the mother and the infant. LAV vaccines pose a theoretical risk
to the fetus and are generally contraindicated in pregnant women.
An additional vaccination recommended for pregnant women is
seasonal inactivated influenza vaccine. It is considered safe and is
recommended for all pregnant women during the influenza season.
This recommendation is motivated not only by the potential severe
course of influenza during pregnancy, but also to protect infants against influenza during their vulnerable
first months of life73. WHO’s Strategic Advisory Committee of WHO
SAGE Meetings: Information related
(SAGE) has recently discussed seasonal influenza vaccination and
to influenza immunization:
recommended pregnant women as the most important risk group
for seasonal influenza vaccination. SAGE also supported the recom- http://who.int/influenza/vac-
mendation, in no particular order of priority, of vaccination of the cines/SAGE_information
following targeted populations: 77
■■ Healthcare workers,
■■ Children 6 to 59 months of age,
■■ The elderly,
■■ Those with high-risk conditions.
58
Tetanus
Worldwide, all countries are committed to “elimination” of maternal and neonatal tetanus (MNT), i.e. a
reduction of neonatal tetanus incidence to below one case per 1000 live births per year in every district.
As of 2012, 35 countries have yet to eliminate MNT.
All women of childbearing age, either during pregnancy or outside of pregnancy, should be vaccinated
against tetanus to protect themselves and their newborn babies. Neonatal tetanus is almost always fatal
and is completely preventable by ensuring that pregnant women are protected through vaccination.
Benefits of vaccinating pregnant women usually outweigh potential risks when the likelihood of disease
exposure is high, when infection would pose a risk to the mother or fetus, and when the vaccine is unlikely
to cause harm. This should be assessed on a case-by-case basis.
Tetanus toxoid vaccine example

Tetanus is caused by bacteria that enter the body through open wounds. The bacteria cause an increased tighten-
ing of muscles, resulting in spasms, stiffness, and arching of the spine. Ultimately, breathing becomes more dif-
ficult, and spasms occur more frequently.
People of all ages can get tetanus. But the disease is particularly common and serious in newborn babies. This
is called neonatal tetanus. Most infants who get the disease die. Neonatal tetanus is particularly common in rural
areas where most deliveries are at home without adequate sterile procedures. WHO estimated that neonatal
tetanus killed about 128,000 babies in 2004.74
Tetanus can be prevented by immunizing women of childbearing age with tetanus toxoid, either during pregnancy or
before pregnancy. This protects the mother and – through a transfer of tetanus antibodies to the fetus – also her baby.
People who recover from tetanus do not have natural immunity and can be infected again and therefore need to
be immunized. To be protected throughout life, an individual should receive three doses of DTP in infancy, fol-
lowed by a booster containing tetanus toxoid (TT) – at school-entry age (4–7 years), in adolescence (12–15 years),
and in early adulthood.
The table below demonstrates the duration of protection against tetanus in women who missed the TT vaccina-
tion as infants and then received catch-up immunization during their childbearing years (usually taken to be from
15 to 49 years).
Duration of protection in women after 1–5 doses of TT vaccine

Dose (0.5ml) When given Duration of protections
At first contact with women of childbearing age,

TT1 No protection
or as early as possible in the pregnancy
TT2 At least 4 weeks after TT1 3 years
TT3 At least 6 months after TT2 5 years
TT4 At least 1 year after TT3 10 years
TT5 At least 1 year after TT4 All childbearing years
59
Vaccination associations and public concern

Beyond the true vaccine reactions that are well documented and
have been illustrated throughout this module, the notion that
vaccines could be responsible for serious health problems has led
to many allegations and many scientific reviews. Some allega-
tions often based on unfounded rumours or poor science have,
at times, profoundly affected the performance of immunization
programmes and limited the ability to prevent serious diseases.
More on rumours and how to manage can be found in Module 6.
For other health conditions, the scientific evidence available is insufficient to conclude that the association
is real, but also insufficient to exclude a link. Systematic study of such conditions can be made difficult as
the frequency of a true reaction can be extremely low, or effects would be very mild or they occur many
years after vaccination. In recent years, the availability of large computerized databases has allowed test-
ing of many of those potential delayed associations, demonstrating nearly ubiquitously that there is no
evidence for a link.
You can learn more about balancing vaccine efficacy and safety of vaccines, and the risks of measles infection
versus the risks of the measles vaccine, in Module 1, chapter “Balancing efficacy and safety” on page 29.
Summary
RRThe differences between and the modes of action of live attenuated vaccines, inactivated vaccines,
conjugate vaccines, subunit and toxoid vaccines and combined vaccines.
RRThe correct route of administration for different vaccines.

RRThe types of vaccine components that exist and their functions.
RRThe contraindications for vaccination that may present an additional risk.
RRThe vaccinations that are recommended during pregnancy and the contraindications for pregnant
women.
RRHow to recognize unfounded rumours that affect immunization programmes.

60
ASSESSMENT 2
ASSESSMENT 2
ASSESSMENT 2
Question 1
1. Live attenuated , contains living organisms that have been

weakened under laboratory conditions. It stimulates an immune response almost as strong as
an infection with .
2. Killed antigen vaccines, such as , are considered to be very safe

and stable and have no risk of .
3. Conjugated vaccines such as , and pneumococcal conjugate

vaccines can provide protection from in infants.
4. Recombinant technology is used to produce protein-based subunit vaccines such

as , by using other organisms (e.g. yeast cells) to express the
desired .
a inactivated polio vaccine (IPV) e wild-type viruses

b inducing the disease f acellular pertussis (aP) vaccines
c Haemophilus influenzae type b vaccine (Hib) g vaccine antigens
d common bacterial infections h measles vaccine
Question 2
Which of the following statements is correct? Select one or more:
❒❒ A. The oral polio vaccine (OPV) never causes paralysis in vaccinated children because the
polioviruses in the vaccine have been inactivated.
❒❒ B. Live attenuated vaccines may pose a risk to people whose immune system is deficient or
suppressed.
❒❒ C. Many live attenuated vaccines require strict adherence to the cold chain in order to main-
tain their efficacy.
❒❒ D. Tissue cultures in which live attenuated vaccines are grown may become contaminated
with other pathogens.
❒❒ E. Live attenuated vaccines induce a weak immune response and therefore always contain
adjuvants to enhance the immune response to the vaccine.
❒❒ F. Inactivated vaccines are more immunogenic than live attenuated vaccines and a single
dose usually produces long-lasting immunity.
62
ASSESSMENT 2
Question 3
Which of the following statements is correct? Select one or more:
❒❒ A. Live attenuated vaccines include: BCG, OPV, Measles, Rotavirus, whole-cell Pertussis and
Yellow fever vaccines.
❒❒ B. Osteitis has in the past been reported in connection with certain vaccine batches of BCG
vaccines, but now occurs very rarely.
❒❒ C. A vaccination with a second dose of a vaccine is contraindicated if a patient previously suf-

fered from anaphylaxis or a severe allergy due to this vaccine or one of its components.
❒❒ D. In individuals with symptoms of HIV/AIDS, LAV vaccines are contraindicated.

❒❒ E. Conjugate subunit vaccines overcome the problem posed by bacterial pathogens with poly-
saccharide capsules that protect them from host defences.
Question 4
1. Aluminium salts used in vaccines as can occasionally cause a

sterile abscess at the injection site.
2. The effectiveness of some live attenuated vaccines can be maintained during storage by the
addition of .
3. The addition of trace amounts of prevents bacterial contami-

nation of tissue culture cells in which vaccine viruses are grown.
4. Thiomersal is the most common of the used to prevent bacte-

rial and fungal growth in multidose vaccines.
5. The polioviruses used in manufacturing IPV are inactivated by treatment

with .
6. The immune response to some vaccines is enhanced by the addition

of .
a antibiotics d preservatives
b formaldehyde e stabilizers
c adjuvants
63
ASSESSMENT 2
Question 5
1. Vaccines that contain aluminium salts must be administered by

injection to reduce the risk of nodule/abscess formation.
2. BCG is the only routine EPI vaccine given to infants by

injection.
3. Current rotavirus vaccine should only be given by the route.
4. Combined diphtheria-tetanus-pertussis vaccines should only be given by

the route.
5. A needle-free method of giving flu vaccine is administration by ____ .
6. Measles vaccine should be injected into the layer.
a oral d intradermal
b intranasal spray e intramuscular
c subcutaneous
64
ASSESSMENT 2
Question 1
Correct answers:
1. Live attenuated measles vaccine, contains living organisms that have been weakened under labora-
tory conditions. It stimulates an immune response almost as strong as an infection with wild-type
viruses.
2. Killed antigen vaccines, such as inactivated polio vaccine (IPV), are considered to be very safe and
stable and have no risk of inducing the disease.
3. Conjugated vaccines such as Haemophilus influenzae type b vaccine (Hib) and pneumococcal con-
jugate vaccines can provide protection from common bacterial infections in infants.
4. Recombinant technology is used to produce protein-based subunit vaccines such as acellular pertus-
sis (aP) vaccine, by using other organisms (e.g. yeast cells) to express the desired vaccine antigens.
Question 2
Answers B, C, and D are correct.
Answer A: Polio is among the five vaccines that are recommended by WHO are produced using Live
attenuated vaccine technology: Tuberculosis (BCG), Oral Polio Vaccine, Measles, Rotavirus, Yellow Fever.
Answer E: Live attenuated vaccines stimulate an excellent immune response. Adjuvants are therefore not
critical elements of them.
(To revise information on Live attenuated vaccines go to the “Live attenuated vaccines” on page 41).
Question 3
Answers B, C, D, and E are correct:
Answer A: whole-cell Pertussis is an inactivated vaccine. More information on the “Inactivated whole-
cell vaccines” on page 44.
65
ASSESSMENT 2
Question 4
Correct answers:
1. Aluminium salts used in vaccines as adjuvants can occasionally cause a sterile abscess at the injec-
tion site.
2. The effectiveness of some live attenuated vaccines can be maintained during storage by the addition
of stabilizers.
3. The addition of trace amounts of antibiotics prevents bacterial contamination of tissue culture cells
in which vaccine viruses are grown.
4. Thiomersal is the most common of the preservatives used to prevent bacterial and fungal growth in
multidose vaccines.
5. The polioviruses used in manufacturing IPV are inactivated by treatment with formaldehyde.
6. The immune response to some vaccines is enhanced by the addition of adjuvants.
Question 5
Please note that the vaccine must be given by the same route as in the clinical trials that led to its approval.
Correct answers:
1. Vaccines that contain aluminium salts must be administered by intramuscular injection to reduce
the risk of nodule/abscess formation.
2. BCG is the only routine EPI vaccine given to infants by intradermal injection.
3. Current rotavirus vaccine should only be given by the oral route.
4. Combined diphtheria-tetanus-pertussis vaccines should only be given by the intramuscular route.
5. A needle-free method of giving flu vaccine is administration by intranasal spray.
6. Measles vaccine should be injected into the subcutaneous layer.
66
MODULE 3: Adverse events following immunization
MODULE 3
Adverse events following
immunization
Overview
Under recommended conditions, all vaccines used in national immunization programmes are safe and
effective if used correctly. In practice, however, no vaccine is completely risk-free and adverse events can
occasionally result after an immunization.
Adverse events can range from minor side-effects to more severe reactions. They can be a cause of public
concerns about vaccine safety. To understand a specific event and to be able to respond appropriately, there
are several questions that you need to answer:
■■ What caused the reaction?
■■ Was it related to the vaccine, or the way it was administered, or was it unrelated?
■■ Are the reactions minor or severe?
This module will help you to answer these questions. You will look at the main types of adverse events and
the situations in which they may occur. You will also be introduced to the challenges and opportunities
of mass vaccination campaigns. Because of the nature of these campaigns, adverse events may be more
noticeable.
Module outcomes
1 Define the main types of adverse events following immunization (AEFIs),

2 Differentiate between a reaction related to the vaccine itself, to the vaccination procedure (immu-
nization error), or to coincidental events that are not linked to the vaccine,
3 Differentiate between minor and severe vaccine reactions,
4 Describe potential underlying causes for each type of AEFI, and understand the link between the
AEFI and its cause,
5 Summarize the expected incidence of the different types of AEFI.
68
Classification of AEFIs
Although all vaccines used in NIPs are safe and effective if used correctly, no vaccine is completely risk-free
and adverse events will occasionally result after an immunization.
An Adverse event following immunization (AEFI) is any untoward medical occurrence which follows
immunization and which does not necessarily have a causal relationship with the usage of the vaccine.
The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom
or disease.
AEFIs are grouped into five categories.

An AEFI that is caused or precipitated by a vaccine due to one or more of the inherent properties of the
vaccine product.
Example: Extensive limb swelling following DTP vaccination.
Vaccine quality defect-related reaction

An AEFI that is caused or precipitated by a vaccine that is due to one or more quality defects of the vaccine
product including its administration device as provided by the manufacturer.
Example: Failure by the manufacturer to completely inactivate a lot of inactivated polio vaccine leads to cases
of paralytic polio.

An AEFI that is caused by inappropriate vaccine handling, prescribing or administration and thus by its nature
is preventable.
Example: Transmission of infection by contaminated multidose vial.

Example: Vasovagal syncope in an adolescent during/following vaccination.
Coincidental event
An AEFI that is caused by something other than the vaccine product, immunization error or immunization anxiety.
Example: A fever occurs at the time of the vaccination (temporal association) but is in fact caused by malaria.
Coincidental events reflect the natural occurrence of health problems in the community with common
problems being frequently reported.
Serious event
An AEFI will be considered serious, if it:
■■ results in death,
■■ is life-threatening,
■■ requires in-patient hospitalization or prolongation of existing hospitalization,
■■ results in persistent or significant disability/incapacity,
69
■■ is a congenital anomaly/birth defect, or

■■ requires intervention to prevent permanent impairment or damage.
Severe event
Severe is used to describe the intensity of a specific event (as in mild, moderate or severe); the event itself,
however, may be of relatively minor medical significance (e.g Fever is a common relatively minor medical
event, but according to its severity it can be graded as mild fever or moderate fever).
Adverse events following immunization (AEFI)

The pandemic influenza A (H1N1) vaccine was an example of where the AEFI classification was used to describe
events.
The European Medicines Agency (EMEA) publication “Recommendations for the Pharmacovigilance Plan as part
of the Risk Management Plan to be submitted with the Marketing Authorisation Application for a Pandemic Influ-
enza Vaccine” states that there should be “protocols in place [...] to ensure that immunogenicity, effectiveness
and safety of the final pandemic vaccine are adequately documented during use in the field (i.e., during the pan-
demic), since there will be only limited immunogenicity and safety data and no efficacy data at the time of licens-
ing”. This publication directed health workers to prioritize reports of the following adverse events:25
■■ Fatal or life-threatening adverse reactions,
■■ Serious unexpected adverse reactions. This refers to the classification of AEFIs that is discussed in
more detail later in this module,
■■ AEFI: neuritis, convulsion, anaphylaxis, syncope, encephalitis, thrombocytopenia, vasculitis, Guillain-

Barré syndrome and Bell’s palsy.
The Brighton Collaboration website:
For each of the above AEFI, standard case definitions from the Brigh-
ton Collaboration were used if available. This helped compare data brightoncollaboration.org
from different countries.
Key point
It is important to note that ‘serious’ and ‘severe’ are often used as interchangeable terms but
they are not.
Question 1*
True or false?
An anaphylactic reaction following immunization that results in the death of the patient is
considered a serious event.
70
Vaccine reactions
A vaccine reaction is an individual’s response to the
inherent properties of the vaccine, even when the
Vaccine quality defect-related reaction vaccine has been prepared, handled and adminis-
tered correctly. From the 5 causes for AEFI from
the previous page, vaccine reactions comprise vac-
Immunization anxiety-related reaction cine product-related reactions and vaccine quality
defect-related reactions.
Coincidental event
Vaccine reactions can be classified into two groups:
Minor reactions Severe reactions

■■ Usually occur within a few hours of injection. ■■ Usually do not result in long-term problems.
■■ Resolve after short period of time and pose ■■ Can be disabling.

little danger. ■■ Are rarely life threatening.
■■ Local (includes pain, swelling or redness at ■■ Include seizures and allergic reactions
the site of injection). caused by the body’s reaction to a particu-
lar component in a vaccine.
■■ Systemic (includes fever, malaise, muscle
pain, headache or loss of appetite).
Severe reactions is a term including serious reactions but also

including other severe reactions.
Key point
There is low public tolerance of vaccine adverse reactions. Vaccines are therefore only licensed
when the frequency of severe reactions is very rare and when only minor, self-limiting reac-
tions are reported.
Minor vaccine reactions

Ideally vaccines will cause no, or only minor (i.e. non-severe) adverse reactions.
Vaccination induces immunity by causing the recipient’s immune system
to react to antigens contained in the vaccine. Local and systemic reactions
such as pain or fever can occur as part of the immune response. In addition,
other vaccine components (e.g. adjuvants, stabilizers, and preservatives)
can trigger reactions. A successful vaccine keeps even minor reactions to a
minimum while producing the best possible immune response.
The frequency of vaccine reactions likely to be observed with some of the
most commonly used vaccines, and their treatments, are listed below. These
reactions typically occur within a day or two of immunization (except for Local reaction: Swelling/redness
at the site of injection
rash reactions after measles vaccine, which can arise up to 6 to 12 days after
immunization) and persist from one to a few days.26
71
Common, minor vaccine reactions and treatment

Local reactions Systemic reactions
Vaccine Irritability, malaise and
(pain, swelling, redness) Fever > 38°C
systemic symptoms
BCGa 90 – 95% – –
Adults up to 15%
Hepatitis B 1 – 6% –
Children up to 5%
Hib 5 – 15% 2 – 10%
Measles/MR/
~ 10% 5 – 15% 5% (Rash)
MMR
OPV None Less than 1% Less than 1%b
Pertussis
up to 50% up to 50% up to 55%
(DTwP)c
Pneumococcal
~ 20% ~ 20% ~ 20%
conjugatee
Tetanus/
~ 10%d ~ 10% ~ 25%
DT/aTd
• Cold cloth at injection site • Give extra oral fluids • Give extra oral fluids
• Paracetamolf • Wear cool clothing
Treatment
• Tepid sponge or bath
• Paracetamolf
a. Local reactogenicity varies from one vaccine brand to another, depending on the strain and the number of viable antigen in
the vaccine.
b. Diarrhoea, Headache and/or muscle pains.
c. When compared with whole cell pertussis (DTwP) vaccine, acellular pertussis (DTaP) vaccine rates are lower.
d. Rate of local reactions are likely to increase with booster doses, up to 50 – 85%.
e. Source: http://www.cdc.gov/vaccines/hcp/acip-recs/
f. Paracetamol dose: up to 15mg/kg every 6 – 8 hours, maximum of 4 doses in 24 hours.
Severe vaccine reactions

Severe vaccine reactions include among others seizures, thrombocytopenia, hypotonic hyporesponsive
episodes (HHE) and prolonged crying, which all need to be reported. Most severe vaccine reactions do
not lead to long-term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long-
term effects.
Key point
Severe allergic reactions (e.g. anaphylaxis) can be life threatening. Health workers who give vac-
cinations should know the signs of allergic reactions and be prepared to take immediate action.
72
Polio vaccine example

A well-documented example of a vaccine-associated adverse reac-
tion is vaccine associated paralytic poliomyelitis (VAPP). This is a very
rare event that occurs in about two to four in every million doses of
oral polio vaccine (OPV) given.29 A live viral vaccine, OPV contains an
attenuated (weakened) version of the disease-causing poliomyelitis
virus. The vaccine is given orally and causes a mild infection that
creates immunity against the wild poliovirus. However, in very rare
instances, OPV can cause paralysis (VAPP), either in the vaccinated
child, or in a close contact. VAPP can be proven by a laboratory test
that detects vaccine virus in a clinical case of polio.
When there are cases of poliomyelitis in the population, the very rare
risk of VAPP is very much less than the risk of acquiring polio by natural infection. However, in countries where
there are no longer cases of wild polio, VAPP can become a greater risk than wild polio. In many countries where
wild polio has been eliminated, programmes have switched to using inactivated (killed) polio vaccine (IPV), a more
expensive vaccine that does not carry the risk of VAPP, but must be injected by a trained health worker.
Severe vaccine reactions, onset interval, and rates associated with selected childhood vaccines
Frequency per
Vaccine Reactiona Onset interval26
doses given
BCG 28 Fatal dissemination of BCG infection 1 – 12 months 0.19 – 1.56/1,000,000
OPV 29
Vaccine associated paralytic poliomyelitis (VAPP) b
4 – 30 days 2 – 4/1,000,000
Prolonged crying and seizuresc 0 – 24 hours < 1/100

DTwP 30
HHE 0 – 24 hours < 1/1,000 – 2/1,000
Febrile seizures 6 – 12 days 1/3,000
Measles 31
Thrombocytopenia 15 – 35 days 1/30,000
Anaphylaxis 1 hour 1/100,000
a. Reactions (except anaphylaxis) do not occur if already immune (90% of those receiving a second dose); children >6 years
unlikely to have febrile seizures.
b. VAPP risk higher for first dose (1 in 750,000 compared with 1 in 5.1 million for subsequent doses), and for adults and immu-
nocompromised patients.
c. Seizures are mostly febrile. The risk of having a seizure depends on the persons age. The risk is much lower in infants < 4
months of age.
73
The difference between serious and severe adverse events

It is important to note that there is a difference between the terms “serious” and “severe” adverse events
or reactions. A serious adverse event or reaction is a regulatory term, which, as defined by the Uppsala
Monitoring Centre (UMC), is any untoward medical occurrence that at any dose results in death, requires
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant
disability/incapacity, or is life-threatening.
A severe reaction is a broader term, which includes severe reactions, but also other reactions that are severe
but do not necessarily lead to long term problems.
Severe reactions
(Not regulatory term)
Serious reactions
w Can be disabling and, rarely, (Regulatory term)
life threatening.
Any untoward medical occurrence
w Must be reported. that at any dose:
w Most do not lead to long- w Results in death,
term problems. w Requires inpatient hospitalization,
w Severe reactions include w
serious reactions but also disability,
include other severe
reactions.
w Is life-threatening.
Key point
Immunization errors often constitute the greatest proportion of AEFIs. They can include deaths
associated with the reconstitution of vaccines with an incorrect diluent or a drug (e.g. insulin).
Vaccine product-related reaction Immunization errors result from errors in vaccine

preparation, handling, storage or administration.
Vaccine quality defect-related reaction They are preventable and detract from the over-
Immunization error-related reaction all benefit of the immunization programme. The
identification and correction of these incorrect
Immunization anxiety-related reaction immunization practices are of great importance.
Coincidental event
Immunization errors can result in a cluster of events,
defined as two or more cases of the same adverse
event related in time, place or vaccine administered. These clusters are usually associated with a particular
provider or health facility, or a vial of vaccine that has been inappropriately prepared or contaminated.
Immunization errors can also affect many vials, for example, freezing vaccine during transport may result
in an increase in local reactions.
74
Examples of immunization errors and possible AEFIs

Immunization error Possible AEFI
Non-sterile injection • Local injection site reactions (e.g., abscess, swell-

• Reuse of disposable syringe or needle leading to ing, cellulitis, induration),
contamination of the vial, especially in multi-dose • Sepsis,
vials, • Toxic shock syndrome,
• Improperly sterilized syringe or needle, • Blood-borne transmission of disease,
• Contaminated vaccine or diluent. e.g., hepatitis B, HIV,
• Death
Reconstitution error • Local abcess,

• Inadequate shaking of vaccine, • Vaccine ineffective*,
• Reconstitution with incorrect diluent, • Effect of drug, e.g., insulin, oxytocin,
• Drug substituted for vaccine or diluent, muscle relaxants,
• Reuse of reconstituted vaccine at subsequent • Toxic shock syndrome,
session. • Death.
Injection at incorrect site • Local reaction or abscess or other local reaction,

• BCG given subcutaneously, • Local reaction or abscess or other local reaction,
• DTP/DT/TT too superficial, • Sciatic nerve damage.
• Injection into buttocks.
Vaccine transported/stored incorrectly • Increased local reaction from frozen vaccine,

• Freezing vaccine during transport, • Ineffective vaccine*
• Failure to keep vaccine in cold chain, exposing to
excessive heat or cold.
Contraindication ignored Avoidable severe reaction

• Vaccination staff ignoring or not becoming famil-
iar with contraindications for a vaccine.
***
Question 2**
What immunization error can most likely occur if vaccines are kept in the same refrigerator
as other drugs?
❒❒ A. The vaccine could be stored incorrectly.

❒❒ B. Contraindication could be ignored.
❒❒ C. A reconstitution error might occur.
❒❒ D. The injection may be non-sterile.
❒❒ E. The injection may occur at the wrong site.
It is vital that health workers or local vaccinators are In WHO’s Immunization in Practice, Module 658 en-
trained to store and handle vaccines properly, recon- titled “Holding an immu-nization session” includes
stitute and administer vaccinations correctly, and have the correct technique for giving each vaccine.
the right equipment and materials to do their job. http://vaccine-safety-training.org/tl_files/vs/
pdf/Module6_IIP.pdf
* Ineffective vaccine is not strictly an adverse event; it is a vaccine failure.
** The answer to all questions can be found at the end of this manual (page 202).
75
Immunization anxiety-related reactions

Vaccine product-related reaction Individuals can react in anticipation to and as a
result of an injection of any kind. These reactions
Vaccine quality defect-related reaction are not related to the vaccine, but to fear of the injec-
Immunization error-related reaction tion. There are four reactions you may encounter.26
Coincidental event
Fainting Hyperventilation
Fainting is relatively common, but Hyperventilation as a result of
usually only affects older children anxiety about immunization can
and adults. Fainting does not cause light-headedness, dizziness,
require any management beyond tingling around the mouth and in
giving the injection while patients the hands.
are seated (to avoid injury caused
by falling) and placing the patient
in a recumbent position after the
injection.
Vomiting Convulsions
Younger children tend to react An anxiety reaction to injection
differently, with vomiting a com- can, in rare cases, include convul-
mon anxiety symptom. Breath- sions. These children do not need
holding may occur, which can to be investigated but should be
end in a brief period of uncon- reassured.
sciousness, during which brea-
thing resumes. They may also
scream to prevent the injection
or run away.
Coincidental events
Coincidental events occur after a vaccination has
been given but are not caused by the vaccine or its
Vaccine quality defect-related reaction administration.
Immunization error-related reaction Vaccinations are normally scheduled in infancy and
Immunization anxiety-related reaction early childhood, when illnesses are common and
congenital or early neurological conditions become
Coincidental event apparent. Coincidental events are inevitable when
vaccinating children in these age groups, especially
during a mass campaign. Applying the normal incidence of disease and death in these age groups along
with the coverage and timing of immunizations allows estimation of the expected numbers of coincidental
events after immunization.
Estimates from the WHO Regional Office for the Western Pacific are presented in the table. For example,
in Australia, each year there are likely to be 11 coincidental infant deaths the day after immunization.
76
Influenza A (H1N1) vaccine example

In response to the pandemic influenza A H1N1 strain, many countries had engaged in mass immunization against
flu in 2009. Awareness of the expected background rates of possible adverse events was estimated crucial to
the assessment of possible vaccine adverse reactions.34
Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion and death, can occur in
close proximity to vaccination in substantial numbers when large populations are vaccinated.
For example, for every 10 million individuals vaccinated in the United Kingdom, 21.5 cases of Guillain-Barré
syndrome and 5.75 sudden deaths were expected to occur as unrelated coincidental events within 6 weeks of
vaccination.34
Careful interpretation of vaccine safety signals was crucial to detect real reactions to vaccine and to ensure that
coincidental events were not caused by vaccination and did not affect public confidence in the vaccine. Experts
compared background incidence rates of the condition with the rate following a vaccination programme to be able to
monitor potential increases of events.
Immediate investigation of a severe adverse event attributed to a vaccine, but not causally related to it, is
critical in order to:
■■ respond to a community’s concern about vaccine safety,
■■ maintain public confidence in immunization.
Calculating the expected rate of an adverse event may be helpful during its investigation. Knowing the
background rate of this adverse event enables the investigator to compare expected and post-vaccination
rates of the event. An increase or non-increase of the post-vaccination rate may give a clue on whether the
event is actually caused by the vaccine. With the background mortality of the AEFI that coincidentally
follow vaccination is key when responding to AEFI reports.26 Further information on this subject can be
found in this course on the page Rates of adverse reactions.47
Expected coincidental deaths following DTP vaccination in selected countries 26

Number of infant death during year in
Infant
Number of
Mortality Rate Month after Week after Day after
Country births per
per 1000 live immunization immunization immunization
year (N)
births (IMR)
= (IMRxN/12)×nv×ppv = (IMR×N/52)×nv×ppv = (IMR×N/365)×nv×ppv
Australia 5 267,000 300 69 10
Cambodia 69 361,000 5,605 1,293 185
China 18 18,134,000 73,443 16,948 2,421
Japan 3 1,034,000 698 161 23
Laos 48 170,000 1,836 424 61
New Zealand 5 58,000 65 15 2
Philippines 26 2,236,000 13,081 3,019 431
Note: Assumes uniform distribution of deaths and children who are near to death will still be immunized.
nv = number of immunization doses: assumed here to be three dose schedule; 3.
ppv= proportion of population vaccinated: assumed here to be 90% for each dose; 0.9.
77
Additional information WHO Informations sheets on observed

rates of vaccine reactions:
To support the analysis of events, WHO is developing vaccine
reaction rates information sheets. These include observed rates http://vaccine-safety-training.org/
tl_files/vs/pdf/VaccRate-Infos-
of vaccine reaction found in scientific literature. heet-Poster.pdf
Question 3*
Based on the data in the table, how many infant deaths would you expect to occur coinci-
dentally (i.e. not linked to the vaccine) in China the day after immunization with DTP?
❒❒ A. 2,421 ❒ C. 16,948
❒❒ B. 23 ❒ D. 185
*
Key point
Data banks that can provide locally relevant background rates of disease incidence are essen-
tial to aid assessment of vaccine safety and to determine whether AEFIs are causally related or
coincidental.
Mass vaccination campaigns

A mass vaccination campaign is a particular challenge to AEFI surveillance. It involves administration
of vaccine doses to a large population over a short period of time. As a result, adverse events may be more
noticeable to staff and to the public.
Common safety issues or concerns in vaccination campaigns include the following points.26
Staff unfamiliar with If vaccinated group Interest groups may Rumours rapidly
the vaccine or under has different age fuel concerns about damage the
pressure to vaccinate compared to routine AEFIs. campaign.
too many persons too immunizations,
quickly. different adverse
events may occur.
Staff may have less If not dealt with

Increase experience with Rumours jeopardize immediately,
in immunization adverse events justification of rumours may not be
errors. (e.g. fainting with campaign. countered
older children). sufficiently.
A campaign is an opportunity to strengthen or establish AEFI surveillance. National Immunization

Programmes (NIP) are a vital part of surveillance of AEFI, particularly with regards to detection and
investigation of AEFI in the field during a mass vaccination campaign.
78
Example Japanese encephalitis campaign
In 2006, inaccurate media reports about the Japanese encephalitis (JE) vaccine used in India’s mass vaccination
campaigns nearly derailed an immunization programme that aimed to protect millions of children and adolescents.
The Government of India responded promptly to these unfounded reports. It convened an independent expert
committee to investigate AEFIs and address any risks associated with vaccine administration. The expert com-
mittee conducted an extensive investigation of 504 adverse events reported through the AEFI system (including
22 deaths) and 29 additional cases identified through active case-finding. It found no link between the vaccine
and serious illnesses or deaths. The primary recommendation of the committee’s final report states: “No direct
causality has been established between the reported illnesses and the JE vaccine. Therefore, no stricture on the
further use of the vaccine is warranted.”37
The expert committee’s findings were presented at key global health events, including the Global Vaccine Re-
search Forum and a meeting of WHO’s Global Advisory Committee on Vaccine Safety.38
Understanding background mortality in the context of deaths temporally associated with vaccination is key when
responding to AEFI reports: The 22 deaths among children of the required age vaccinated during the campaign
was equivalent to a fatality rate of 0.24 deaths per 100,000. The background mortality in the same age group is
actually much greater at 8.6 per 100,000. The 22 deaths reported therefore do not reflect an excess mortality
caused by the vaccine.
Key point
A campaign is an opportunity for community outreach and education about local diseases
and the vaccinations used to prevent them.
Adverse events and their effects during a campaign can be To assist immunization managers pre-
minimized by proper planning aimed to reduce immunization pare and plan for safety issues associat-
errors. Components of such planning include thorough trained with immunization campaigns, WHO
ing of staff, monitoring and responding to AEFIs, and engaging provides a comprehensive checklist in
the community. It can also be helpful to train staff on how to an aide-memoire:
respectfully treat persons being immunized and their family. http://vaccine-safety-training.org/

This may limit the potential for negative publicity from an AEFI. tl_files/vs/pdf/campaigns.pdf
Rates of adverse vaccine reactions

Part of the work of health professionals and regulatory officials in
WHO vaccine reaction rates informa-
immunization programmes is to: tion sheets:
■■ Anticipate and/or evaluate AEFIs associated with spe- http://who.int/vaccine_safety/
cific vaccines, initiative/tools/vaccinfosheets/
■■ Compare reported AEFIs in their own jurisdictions with

‘expected’ adverse events in vaccinated and unvacci-
nated individuals,
■■ Facilitate the investigation and response to serious AEFIs.
However, one of the main challenges in surveillance of AEFIs is to differentiate coincidental events from
events that are caused by a raction to a vaccine or its components.
79
To help strengthen the capacity to introduce vaccines in Member States, WHO has published WHO Infor-
mation Sheets on Observed Rates of Vaccine Reactions online to provide details on selected vaccines
that are relevant to the analysis of reported events. These cover, for example, vaccines such as Anthrax,
BCG, Hep A, Hep B, Hib, HPV, Influenza, Pneumococcal, Rabies, Varicella Zoster.
Key point
Observing the rate of an adverse event in the vaccinated population and comparing it with the
rate of this event among the unvaccinated population can help to distinguish genuine vaccine
reactions.
The following graphic shows, how comparing the background rate with the observed rate of an event can
help to determine the vaccine reaction rate (i.e. the rate of events that are actually caused by the vaccine).
Example: Fever following vaccination
Terminology How is this measured Example
If we measured the temperatures

Background rates can be
of a population of 1,000 unvaccinated children dur-
determined in a population
ing one week, some children would present a fever
Background rate prior to the introduction of a
(defined as >38°C) during the time of observation
new vaccine or simultaneously
(e.g., infections). For example, a rate of 2 cases of
in non-vaccinated people.
fever per 1,000 children per week.
If we observe the same population of 1,000 children

but we now vaccinate all children and measure their
The observed rate can be mea-
Observed temperatures daily there will be greater rate of fever.
sured in pre-licensure clinical
(reported) rate Thus, the rate of fever may increase to 5/1,000 chil-
trials or post-licensure studies.
dren per week, with the increase concentrated in the
72 hours that follow vaccination.
Randomized clinical trials

Vaccine reaction Thus, the vaccine attributable rate of fever will be
which are placebo controlled.
rate (attributable 3/1,000 vaccinated children (that is the observed rate
Post-licensure studies – pas-
rate) minus the background rate).
sive surveillance.
80
Comparing observed with “expected” rates of adverse events

If the background rate of a particular adverse event is not known in a community (as is often the case),
you will need to compare the observed rate in your population with the ‘expected rate’ published by the
vaccine regulatory authorities. For example, this information, from WHO, shows the expected rates of
AEFIs following some childhood vaccines:
Expected rates of AEFIs following some childhood vaccines

Vaccine Estimated rate of severe reactions
BCG 1 in 1,000 to 1 in 50,000 doses
OPV (oral polio vaccine) 1 in 2 – 3 million doses (or 1 in 750,000 doses for the first dose)
Measles 1 in 1 million doses
DTP 1 in 750,000 doses
Question 4*
Imagine that rumours begin to circulate about a vaccine when cases of convulsions follow-
ing immunization occur amongst vaccinated infants. The background rate of convulsions in
this population is 1:1,000 infants. The observed rate in vaccinated infants is 1.2:1,000. What
is the vaccine attributable rate derived from these figures?
❒❒ A. 2 additional cases of convulsions in every 1,000 vaccinations, compared with the back-
ground rate.
❒❒ B. 2 additional cases in every 10,000 vaccinations, compared with the background rate.
❒❒ C. 1.2 additional cases in every 1,000 vaccinations, compared with the background rate.
❒❒ D. 1.2 additional cases in every 10,000 vaccinations, compared with the background rate.
Other factors to consider when comparing rates of AEFIs*

Keep in mind the other confounding factors that may influence the comparison of rates of adverse events.
A confounding factor is anything that is coincidentally associated with an event (in this case, an AEFI),
which may mislead the investigator into wrongly concluding that the factor is influencing the rate of an
adverse vaccine reaction. Here are some factors to consider when comparing one observed AEFI rate with
another.
Although a vaccine may have the same antigens, different manufacturers may
produce vaccines (or ‘lots’ of the same vaccine) that differ substantially in their com-
Vaccines position, including the presence of an adjuvant or other components. These variations
result in vaccines with different reactogenicity (the ability to cause vaccine reactions),
which in turn affects the comparison of their vaccine attributable rates.
The same vaccine given to different age groups may result in different vaccine-
attributable rates. For example, MMR vaccine given to infants may cause febrile
Age
convulsions. This symptom does, however, not occur in adolescents who are given
the same vaccine.
81
The same vaccine given as a ‘primary dose’ may have a different reactogenicity pro-
file than when it is given as a ‘booster dose’. For example, the DTaP vaccine given
Vaccine doses
as a primary dose is less likely to result in extensive limb swelling when compared
with this same vaccine given as a booster dose.
Adverse event may be defined differently in research studies that do not stick to the
Case definitions same case definition. Not using standardized case definitions may consequently
affect the estimation of the AEFI rate.
The way that surveillance data is collected may alter the rate. For example, sur-
Surveillance
veillance data may be collected actively or passively, using pre- or post-licensure
methods
clinical trials, with or without randomization and placebo controls.
The background rate of certain events may differ between communities. This can
Background influence the observed rate even though the vaccine attributable rate is the same in
rate both communities. For example, reports of death post-vaccination may be higher in
a country that has a higher background rate of deaths due to coincidental infection.
Summary
RRThe characteristics of the five types of AEFI are Vaccine product-related reaction, Vaccine quality
defect-related reaction, Immunization error-related reaction, Immunization anxiety-related reac-
tion, Coincidental event.
RRThe causes of the five types of AEFI and the practices that can minimize their occurrence.
RRMass vaccination campaigns can lead to an increase in immunization errors, for example, because
of staff inexperience in vaccinating a wider age group, and to the spread of unfounded rumours
that may damage the campaign.
RRThe importance of comparing background rates of adverse events with rates of vaccine-attributable
reactions and taking account of factors that may confound the results of an AEFI investigation.

82
ASSESSMENT 3
ASSESSMENT 3
ASSESSMENT 3
Question 1
Which of the following AEFIs would be classified as a ‘severe reaction’?

Select one or more:
❒❒ A. Vomiting, 5 minutes after receiving a BCG vaccination.

❒❒ B. Fainting, 5 minutes after receiving a DTP vaccination.
❒❒ C. Anaphylaxis, 5 minutes after receiving an Influenza-A vaccination.
❒❒ D. Febrile seizures, 4 days after a measles vaccination.
❒❒ E. Loss of appetite, 4 days after BCG vaccination.
Question 2
Which of the following onset intervals of severe adverse events following immunization is
probably not due to the given vaccine? Select one or more:
❒❒ A. Vaccine-associated paralytic poliomyelitis (VAPP) occurring 4 – 30 days after OPV.

❒❒ B. Febrile seizures occurring 6 – 12 days following measles vaccination.
❒❒ C. Thrombocytopenia occurring 15 – 35 days after measles vaccine.
❒❒ D. Anaphylaxis occuring 2 – 3 days after MMR vaccination.
❒❒ E. Prolonged crying for 0 – 24 hours after DTP vaccination.
84
ASSESSMENT 3
Question 3
For each of the following descriptions of an AEFI, decide what is the most likely cause by
choosing the correct option from the list below:
A. The rate of thrombocytopenia following immunization with measles was found to be slightly
higher than the background rate in the equivalent unvaccinated population.
B. Several 13-year-old girls reported feeling sick and two fainted soon after being vaccinated
against human papilloma virus (HPV) in a mass vaccination campaign at their school. All
the affected girls recovered without further ill effects.
C. Failure by the manufacturer to completely inactivate a lot of inactivated polio vaccine leads
to cases of paralytic polio.
D. Adverse reactions occurred after a nurse in charge of an outreach vaccination clinic used a
vial of measles vaccine which she had reconstituted the previous day.
E. A 10-week-old infant developed a high fever within 24 hours of receiving oral polio vaccine
(OPV). Malaria was diagnosed in the infant shortly thereafter.
a Immunization error-related reaction

b Vaccine product-related reaction
c Immunization anxiety-related reaction
d Coincidental event
e Vaccine quality related reaction
85
ASSESSMENT 3
Question 4
Which of the following are common safety issues or concerns in vaccination campaigns? Select
one or more:
❒❒ A. Staff who are unfamiliar with the given vaccine and are under pressure to vaccinate many
children in a short period of time.
❒❒ B. Different age groups receiving vaccines.

❒❒ C. Rumours spread by anti-vaccine lobbies. Nutritional status of the people/children receiv-
ing the vaccine.
❒❒ D. The nutritional status of a vaccinee.
Question 5
The country of Rubovia has a population of 60 million and the annual incidence of Guillain Barre
syndrome is 2/100,000 individuals.
In an immunization campaign, 5 million adults were immunised with an influenza-A vaccine. In
the 8 weeks following immunization 26 of them developed Guillain Barre syndrome.
Calculate the vaccine-attributable rate of Guillain Barre syndrome per 100,000 immunised
individuals.
Select one:
❒❒ A. 0.2
❒❒ B. 26
❒❒ C. 10
❒❒ D. 16
❒❒ E. 1
86
ASSESSMENT 3
Question 1
Answers C and D are correct.
Minor reactions usually occur within a few hours of injection, resolve after a short period of time and pose
little danger. These reactions are often local (including pain, swelling or redness at the site of injection) or
systemic (including fever, malaise, muscle pain, headache or loss of appetite).
Severe reactions usually do not result in long-term problems, but can be disabling and, rarely, life threat-
ening. These include, for example, seizures and allergic reactions caused by the body’s reaction to a
particular component in a vaccine.
Further information go to the chapter “Classification of AEFIs” on page 69.
Question 2
Answer D is incorrect.
Anaphylaxis has an onset interval of up to 1 hour following vaccination.
See the table “Severe vaccine reactions, onset interval, and rates associated with selected childhood vac-
cines” on page 73.
Question 3
Correct answers:
A. Vaccine product related reaction.
B. Immunization anxiety related reaction.
C. Vaccine quality related reaction.
D. Immunization error related reaction.
E. Coincidental event.
Further information go to the chapter “Classification of AEFIs” on page 69.
Question 4
Answers A, B and C are correct.
Common safety issues or concerns in vaccination campaigns include the following points:
A. Staff who are unfamiliar with the given vaccine or mass campaign situations, or who are under pres-
sure to vaccinate many children quickly may cause an increase in adverse events caused by immunization
errors.
87
ASSESSMENT 3
B. A wider age group may be targeted than for routine immunizations. Staff may have less experience with
adverse events that occur in this age group (e.g. fainting among older children and teenagers).
C. Some sectors may antagonize against the campaign, for a variety of reasons. This may add fuel to
concerns about AEFI during the efforts to justify the vaccination campaign. Rumours may spread rapidly
and damage the campaign before there is a chance to counter them.
D. The nutritional status of a vaccinee is usually not a common issue with mass vaccination campaigns.
For more information go to the chapter “Mass vaccination campaigns” on page 78.
Question 5
Answer A is correct.
The expected incidence of Gullain Barre syndrome in a population of 5million people in an 8 week period is:
5,000,000 × 2/100,000 × 8/50 =16
The number observed is 26, therefore the excess is 26 – 16 = 10
The excess incidence is 10/5,000,000 = 0.2/100,000 vaccinated individuals.
The correct answer is: 0.2.
88
MODULE 4: Surveillance
MODULE 4
Surveillance
Overview
Pharmacovigilance is the practice of detecting, assessing, understanding, responding and preventing
adverse drug reactions, including reactions to vaccines. It is now an integral part of the regulation of
drug and vaccine safety. Surveillance systems exist at national and international levels to ensure effective
monitoring and prompt actions in response to AEFIs.
Pharmacovigilance requires that incidents of adverse events are followed up in the correct way. Some
adverse events need to be reported and/or investigated, and you will need to know which to report, how
and to whom. Causality assessment procedures also need to be carried out effectively.
This module introduces you to the concept of pharmacovigilance and describes national and international
surveillance systems. It helps you to assess how to report an AEFI in the correct way and explains the pro-
cedure of causality assessment. Finally, you will look at the subject of risk/benefit assessment, including
the factors that influence the balance between risks and benefits of vaccines, risk evaluation and options
analysis.
Module outcomes
1 Describe the basic principles of pharmacovigilance and the special considerations that apply to
vaccination programmes,
2 Use AEFI case definitions to evaluate which AEFIs should be detected and reported to the
National regulatory authority (NRA) or its equivalent,
3 Describe the principles of risk-benefit analysis relative to the protective effect of immunization
and the importance of causality assessments to evaluate possible links between AEFIs and a vac-
cine or vaccine lot,
4 Explain how investigation of AEFI reports and vaccine testing can contribute to surveillance that
ensures vaccine safety.
90
Pharmacovigilance
Definition
Pharmacovigilance is the science and activities relating to the detection, assessment, under-
standing, response and prevention of adverse drug reactions (ADRs) and other potential
medicine-related problems – including adverse events following immunization.
The specific aims of pharmacovigilance are to:46

■■ Improve patient care and safety in relation to the use of medicines in medical and paramedical
interventions,
■■ including vaccination,
■■ Improve public health and safety in relation to the use of all medicines,
■■ Contribute to the assessment of benefit, harm, effectiveness and risk of medicines,
■■ Encourage the safe, rational and effective (including cost-effective) use of medicines,
■■ Promote understanding, education and clinical training in pharmacovigilance and effective
communication of its surveillance role to the public.
Origins of pharmacovigilance
The WHO Programme for International Drug Monitoring (PIDM)82 was established in 1968 in response
to the thalidomide disaster in which thousands of infants were born with congenital deformations follow-
ing fetal exposure to thalidomide, a medicine that had been used to treat morning sickness in pregnancy.
The PIDM, now coordinated through the Uppsala Monitoring Center (UMC)83 in Sweden, developed an
international system for detecting previously unknown or poorly understood adverse drug reactions
(ADRs). National regulatory authorities (NRAs) are responsible for reporting ADRs, particularly rare ones
or new signals, to the UMC so that they can be monitored within the global population.46
106 Official Member countries 34 Associate Member countries Countries that are not member of the WHO Pragramme
91
In many countries, National pharmacovigilance centres are established or existing entities are designated
to serve this function on behalf of the NRA. Such centres collect information about AEFI using standard-
ized methodologies. They analyse this information and communicate regularly with NRAs to update the
safety profiles of the products used in a country. You will learn more about vaccine safety institutions and
reporting mechanisms in Module 5.
NRA’s role in the regulation of drug safety

National regulatory authorities (NRAs) are responsible for ensuring that every pharmaceutical product –
including vaccines – used within the country is:
■■ Of good quality,
■■ Of known potency,
■■ Safe for the purpose or purposes for which it is proposed.
Whereas the first two criteria must be met before any consideration can be given to approval for medical
use, the issue of safety is more challenging.
There is a possibility that rare yet severe adverse events (such as those occurring with a frequency of one
in several thousand) may not be detected in the pre-licensure development of a drug. It is therefore gen-
erally accepted that part of the process of evaluating drug or vaccine safety must happen post-licensure
(post-marketing).
Pharmacovigilance is often conducted by national pharmacovigilance centres on behalf of/in collabora-
tion with NRAs. Pharmacovigilance centres have a significant role in post-licensure surveillance of ADRs.
They may conduct:
■■ Post-licensure surveillance of ADRs,
■■ Data collection on AEFIs using standardized methodologies,
■■ Data analysis,
■■ Regular communications with NRA to update safety profiles.
Example for collaboration among institutions: Canada

Canada’s national regulatory authority (NRA) is Health Canada. The Public Health Agency of Canada (PHAC) con-
ducts pharmacovigilance for vaccines in collaboration with public health authorities in the provinces and territo-
ries, and maintains the national database of reports of adverse events following immunization (AEFI).
During the 2009 influenza pandemic, PHAC used the vaccine safety monitoring system to identify a higher than
normal rate of anaphylaxis linked to one particular lot (Lot 7A) of a newly released adjuvanted H1N1 flu vaccine.
In close collaboration between PHAC and Health Canada, and following further investigation of serious adverse
event reports linked to Lot 7A, unused vaccines from this lot were withdrawn from use during the investigation.
92
Adverse Drug Reaction (ADR) surveillance

ADR surveillance is responsible for detecting and responding to adverse events associated with drugs.
Although vaccines represent less than 1% of all drug products, their use and purpose is very specific and
requires a modified ADR system able to detect and respond adequately and rapidly to occurring adverse
events. The following pages of this module will look into why vaccines are different and what the specific
needs and expectations are towards vaccine surveillance.
Post-licensure ADR surveillance is mainly conducted by national pharmacovigilance centres. In collabora-
tion with WHO’s Uppsala Monitoring Center (UMC), they have achieved a great deal in:
■■ Collecting and analyzing case reports of ADRs,
■■ Distinguishing signals from background ‘noise’ (or coincidental occurrences),
■■ Supporting regulatory decisions based on strengthened signals,
■■ Alerting prescribers, manufacturers and the public to new risks of ADRs.
The number of National pharmacovigilance centres participating in WHO’s PIDM has increased from
10 in 1968 (when the programme started) to 108 as of June 2012.42 The centres vary considerably in size,
resources, support structure and scope of activities. Collecting spontaneous reports of suspected ADRs
remains their core activity.
The stronger the national system of pharmacovigilance and ADR surveillance, the more likely it is that
evidence-based regulatory decisions will be made for the early release of new drugs with the promise of
therapeutic advances. Legislation governing the regulatory process in most countries allows for conditions
to be placed on approvals, such as the requirement that there should be detailed pharmacovigilance in the
early years after a drug’s release.
In many countries, pharmacovigilance and NRA approvals are linked by an ADR advisory committee
appointed by, and directly reporting to, the NRA. An ADR committee may include independent experts
in clinical medicine, epidemiology, paediatrics, toxicology, clinical pharmacology and other disciplines.
Such an arrangement inspires confidence amongst health personnel and can make a substantial contribu-
tion to public health.
Immunization safety requires

a modified surveillance system
Vaccines are considered drugs but require different “immunization safety” surveillance systems to moni-
tor adverse events.
Immunization safety is the process of ensuring and monitoring the safety of all aspects of immunization,
including:
■■ vaccine quality,
■■ adverse events,
■■ vaccine storage and handling,
■■ vaccine administration,
■■ disposal of sharps,
■■ management of waste.
93
The skills and infrastructure to deal with genuine vaccine adverse reactions are essential to public safety,
as well as to prevent or manage fear caused by false or unproven signals from patients and health workers.
Some of the key differences between vaccines and drugs, which lead to the need for specific AEFI surveil-
lance, are listed in the table below.*
VACCINES OTHER DRUGS
Who gets them?
Usually, healthy people including infants.
Often most of the population, birth cohort, or group at Usually, sick people.
high risk for disease or complications.
Why?
To prevent disease. Usually to treat disease.
How do they get them?
Vaccines are often administered through public health

programmes. Often administered by a medical doctor
In some countries, vaccination may be a prerequisite or pharmacist.
for enrolment in school.
When do they get them?
Most childhood vaccines are administered at specific

ages, or in relation to special circumstances such as
outbreaks or travel.
Normally at time of illness.
The age at the time of vaccination may coincide with
the emergence of certain age-related diseases (e.g.
neurodevelopmental disorders).
What about adverse events?
Low acceptance of risk.
Intensive investigation of severe AEFIs, even if rare, is

Acceptance of adverse events often
necessary.
depends on the severity of illness being
Minor AEFIs also should be carefully monitored treated and the availability of alternative
because they may suggest a potentially larger problem treatment options.
with the vaccine or immunization, or have an impact on
the acceptability of immunization in general.
How many?
8 – 15 Childhood vaccines globally recommended. Thousands of drugs are available.
Question 1*
When parents bring their children for immunization, why may they have a low tolerance for
any adverse events that follow?
94
Vaccine pharmacovigilance
Definition
According to the CIOMS/WHO Working Group on Vaccine Pharmacovigilance, Vaccine phar-
macovigilance is defined as
“the science and activities relating to the
■■ Detection,
■■ Assessment,
■■ Understanding and
■■ Communication
of adverse events following immunization and other vaccine- or immunization-related
issues, and to the prevention of untoward effects of the vaccine or immunization”.78
Like drug pharmacovigilance, vaccine pharmacovigilance aims to detect adverse events early to trigger
accurate risk assessment and appropriate response (risk-management) to the problem. This ensures the
minimization of negative effects to individuals. Another goal of vaccine pharmacovigilance is to lessen the
potential negative impact on immunization programmes.49
Vaccine pharmacovigilance relies on three steps:39
Develop hypo-
Detect signals Test hypotheses
theses about
suggesting AEFI through appropri-
causal association
is related ate epidemiologi-
between an AEFI
to a vaccine. cal methods.
and vaccination.
Rotavirus vaccine example

In August 1998 the first rotavirus vaccine, RotaShield®, was licensed in the USA. Pre-licensure literature noted
a possible increased risk of intussusception, a potentially life-threatening bowel obstruction that occurs for un-
known reasons in about one young child in every 10,000 regardless of vaccination history. The manufacturer
noted intussusception as a possible adverse reaction in the package insert and post-licensure surveillance for
intussusception was recommended by the United States’ vaccine safety surveillance Advisory Committee on Im-
munization Practices (ACIP).51
After RotaShield® was in routine use by the public (approximately one million children vaccinated within the first 9
months following licensure) VAERS began to receive reports of intussusception following administration of the vac-
cine. Intussusception was confirmed in 98 cases after vaccination with rotavirus vaccine and reported to VAERS,
approximately 0.01% of the one million children vaccinated. The passive surveillance system, relying primarily on
spontaneous reports from health workers, indicated at least a fourfold increase over the expected number of intus-
susception cases occurring within a week of receipt of rotavirus vaccine. As a result, additional studies were con-
ducted to better understand the relationship between rotavirus vaccine and intussusception. In light of these studies,
the rotavirus vaccine manufacturer voluntarily removed its product from the market less than a year after it had been
introduced, and the recommendation for routine use of rotavirus vaccine among infants in the USA was withdrawn.51
A different Rotavirus vaccine is now being used in the USA, after better understanding and appropriate recommen-
dation for its use.
95
Question 2*
In Module 1 you were introduced to the rotavirus vaccine case. Take a look at the additional
information in the Rotavirus vaccine example given in this question.
What hypothesis was developed as a result of the post-licensure surveillance of RotaShield®
vaccine to explain why the original clinical trial (on 10,000 vaccinees) did not detect the
incidence of intussusception?
Special considerations
for AEFI surveillance*
Three major factors need to be given special consideration because they could affect the type of AEFI
surveillance and its outcomes.
Training for health workers

Health workers administering vaccinations are on the frontlines and are usually the first responders to an
AEFI. They need to be trained how to detect, report, and respond to adverse events, including stabilizing
the patient (for example, in a case of anaphylaxis) and communicating with parents, the community and
the media.
Determining causality
Difficulties in determining causation between events that are linked in time are common to all drug and
vaccine safety monitoring systems. This is particularly challenging in the case of vaccines, because:
■■ Information on “dechallenge and rechallenge” is usually missing,
■■ Vaccines are given to most of the country’s birth cohort at an age when coincidental disease are
likely,
■■ Several vaccines are likely to be administered at the same immunization visit,
■■ Vaccine storage, handling, transport and administration must adhere to specific conditions.
Any of these, if not done correctly, can result in an adverse event. The possibility of immuniza-
tion errors therefore must be investigated.
Independent review is needed

There is a need for independent review of adverse events, separate from the immunization programme.
Causality assessment requires a team of investigators, including an immunologist or other experts,
depending on the nature of the adverse event. The team usually does not directly include officials from the
NIP. They may be perceived to have a conflict of interest as they are responsible for investigating adverse
events related to administration of a vaccine.
96
Interactions between AEFI and ADR

surveillance systems
The National Regulatory Authority is usually the only agency with the mandate to ensure the safety, effi-
cacy and quality of vaccines. While AEFI surveillance is a key function of National Regulatory Authorities,
monitoring the safety of vaccines requires the involvement of both the National Immunization Programme
and the National Regulatory Authority. Their good collaboration should be supported by clearly distin-
guishing their roles and responsibilities.
The most critical function necessary for meeting the National regulatory authority responsibility to ensure
vaccine safety is a strong AEFI surveillance system closely integrated with the system of vaccination
delivery.
Because the NRA may have limited knowledge of the structure and management of the National immu-
nization programme, it is essential that the immunization programme manager be involved in AEFI
surveillance and the roles of the two parties in this process must be clearly established.
NRA NIP
Monitoring safety of vaccines
Integrating AEFI surveillance with system of vaccine delivery
Clear distribution of roles in reporting and detection
There have been several instances where NIPs and NRAs have failed to work with each other when devel-
oping national AEFI or ADR surveillance systems. This has often resulted in duplication of effort and a
failure to capture all relevant data in one central repository. In addition, potential crises may go undetected
through such confusion and the health-care providers may see this as an additional barrier to reporting
AEFIs and ADRs.
Key point
A good collaboration between National Regulatory Authority and National Immunization
Programme are usually critical components of a strong AEFI surveillance system.
In some countries where the NRA is not in a position to execute the aforementioned tasks, the
National immunization programme may have taken over part of the activities of the NRA.
97
AEFI surveillance components

This section describes the objectives of AEFI surveillance, which adverse events should be reported and
by whom. Next we discuss how AEFI reports are generated, and how AEFI reports from health workers
lead to investigation and action at the highest levels of responsibility in the National regulatory authority
(NRA), the ministry of health and international organizations such as WHO and UNICEF.
The objectives for an effective AEFI surveillance system are to:
■■ Identify problems with vaccine lots or brands leading to vaccine reactions caused by the inher-
ent properties of a vaccine,
■■ Detect, correct and prevent immunization errors caused by errors in vaccine preparation, han-
dling, storage or administration,
■■ Prevent false blame arising from coincidental adverse events following immunization, which
may have a known or unknown cause unrelated to the immunization,
■■ Reduce the incidence of injection reactions caused by anxiety or pain associated with immuni-
zation, by educating and reassuring vaccinees, parents/guardians and the general public about
vaccine safety,
■■ Maintain confidence by properly responding to parent/community concerns, while increasing
awareness (public and professional) about vaccine risks,
■■ Generate new hypotheses about vaccine reactions that are specific to the population of your
country/region,
■■ Estimate rates of occurrence of AEFIs in the local population compared with trial and interna-
tional data, particularly for new vaccines that are being introduced.
The following pages describe the following components of AEFI surveillance:

■■ Detection and reporting,
■■ Investigation,
■■ Causality assessment of AEFIs,
■■ Risk/benefit assessment.
You will be introduced to the stakeholders involved in these processes, and their respective responsibilities.
98
Detection and reporting
Stakeholders
Parents of immunized infants/children, health workers at immu-
nization facilities and staff of accident and emergency rooms in
hospitals are most likely to recognize or detect AEFIs when they
first occur.
Health workers have the responsibility to detect AEFIs and report
AEFIs when appropriate. They also have the responsibility to treat
or refer patients for treatment. All immunization staff must be able
to identify and report adverse events. Detection requires effective staff training and education to ensure
accurate diagnosis of AEFIs based on clear case definitions, which can be included on the AEFI reporting
form and in the national AEFI guidelines.
Health workers
should be trained to
detect:
Any clusters of AEFIs

All cases corresponding (i.e., two or more cases of All other events
to locally suitable AEFI the same adverse event believed to be due to
case definitions. related in time or place or to immunization.
the vaccine administered).
Immunization programme managers should establish appropriate criteria for detecting AEFIs by identify-
ing adverse events of importance to the programme in their country.
Which AEFIs should be reported?
Key point
Any AEFI that is of concern to the parents or to the healthcare worker should be reported.
Serious AEFIs.
Signals and events associated with a newly introduced vaccine.
AEFIs that may have been caused by an immunization error.

In particular,
health workers Significant events of unexplained cause occurring within
should report: 30 days after a vaccination.
Events causing significant parental or community concern.
Swelling, redness, soreness at the injection site IF it lasts for more

than 3 days or swelling extends beyond nearest joint.
99
In addition to deciding which adverse events should be reported, it is essential that immunization pro-
gramme managers define the roles and responsibilities of stakeholders, clarify on the process of reporting,
and how to ensure/encourage reporting. The following questions should guide the immunization pro-
gramme manager when setting up and maintaining a detection and reporting mechanism.
Who should make the AEFI Make sure that health workers are aware of their responsibility to
report and to whom? report AEFI.
Reporting should be as standardized as possible, best done through
How should reporting occur?
an unambiguous and standardized reporting form.
This may depend on the local context. Keep in mind that with
What should the route of unclear responsibilities among stakeholders, there is the danger of
reporting be? double-reporting or under-reporting. Make sure that reporting lines
are simple and direct and clear to all stakeholders involved.
Any AEFI that is of concern to the parents or to the healthcare
When should AEFIs be
worker should be reported. See above for a list of events that must
reported?
be reported.
Health workers may be afraid of getting penalized for reporting.
It is important that reporting health workers understand that
How to improve/encourage
adverse events following immunization – related to the vaccine or
reporting?
not – must be expected and can happen independent of the health
worker’s action.
Question 3*
Case definitions support reporting of standardized diagnoses, which provides investiga-
tors with data that is comparable. Which of the following statements has or have not been
reported in line with the examples of standard case definitions of the Brighton collaboration
provided and may therefore lead to misinterpretation of data? Select one or more:
❒❒ A. “Child developed high fever” (temperature measured was 41 degree Celsius).

❒❒ B. “The child suffered from afebrile seizures” (body temperature was normal).
❒❒ C. “A severe local reaction occurred at the injection site” (the occurred swelling extended
beyond the nearest joint and lasted for 3 days).
❒❒ D. “Patient developed symptoms of encephalopathy due to vaccination with DTP given
4 weeks before occurrence of symptoms”.
100
Investigation
Conducting an AEFI investigation

Some AEFI reports will need further investigation. The purpose of an AEFI
investigation is to:
■■ Confirm the diagnosis (or propose other diagnoses) and deter-
mine the outcome of the adverse event,
■■ Identify specifications of implicated vaccine(s) used to immu-
nize patient(s),
■■ Examine operational aspects of the immunization programme,
which may have led to immunization errors,
■■ Justify the search for other AEFI cases/clustering,
■■ Compare background risk of adverse event (occurring in
unimmunized people) to the reported rate in the vaccinated
population.
A key instrument to organize an AEFI investigation is WHO’s “Aide-Memoire on AEFI Investigation”.
Look at the Aide-Memoire to find out more about key definitions, guidance to prepare for an investigation,
as well as a checklist providing useful information for each step of an investigation. See the graphic below
to view a list of practical steps that should be considered when developing AEFI investigation procedures.
Have a system in
Design the
place for
Decide what should investigation • collecting and
be investigated Decide who procedure and testing any samples Decide which
based on case conducts investi- forms to collect all of suspect vaccines events require
gations and in relevant data to and diluents. an investigation
what timeframe. determine cause • conducting post beyond local level.
of AEFI cluster. and assessing mortems and testing
samples from patients
causality.
(blood samples, etc.)
Practical issues for developing your AEFI investigation procedures

■■ Decide what should be investigated (develop the reporting system around these events), based on
case definitions and identification of AEFI clusters (see below for cluster investigation).
■■ Decide who should conduct investigations and in what timeframe.
■■ Design the investigation procedure and forms to collect all relevant information for determining cause
and assessing causality.
■■ Have a system in place for collecting and testing any samples of suspect vaccines and diluents.
■■ Have a system in place to conduct post mortems and test samples from patients (blood samples, etc.)
■■ Decide which events require high-level versus lower-level investigation.
101
AEFI reports to be investigated

Not all AEFI reports will need investigation. Reported events requiring the initiation of an investigation are:
■■ Serious AEFIs, i.e. adverse events or reactions that result in death, hospitalization (or prolonga-
tion of existing hospital stay), persistent or significant disability or incapacity (e.g. paralysis), or
are potentially life-threatening,
■■ Clusters of minor AEFIs,
■■ Signals and events associated with newly introduced vaccines,
■■ Other AEFIs as recommended by WHO:
–– AEFIs that may have been caused by immunization error (e.g. bacterial abscess, severe local
reaction, high fever or sepsis, BCG lymphadenitis, toxic shock syndrome, clusters of AEFIs),
–– Significant events of unexplained cause occurring within 30 days after a vaccination,
–– Events causing significant parental or community concern.
AEFI cluster investigations

A cluster of AEFI is defined as two or more cases of the same adverse event related in time, place or the
vaccine administrated. Apart from checking on these three factors (e.g. checking vaccine batch), the inves-
tigator should check for AEFIs occurring in similar age groups and populations with genetic predisposition
or disease.
Examples of AEFI clusters

Example 1
An outbreak of lymphadenitis 3 months after BCG immunization was
traced to a switch to a different strain of vaccine. The investigation
also highlighted a number of immunization errors (vaccines not prop-
erly reconstituted, and injections not given intradermally).
Cause: vaccine reaction compounded by immunization errors.
Illustration 2
Four children died and a fifth was hospitalized after receiving measles
vaccine from the same vial. The vaccine was not refrigerated, and was transported from house to house for im-
munization. Reactions began 4-5 hours after vaccination, with vomiting, unconsciousness, and meningeal irritation.
Staphylococcus aureus bacteria were cultivated from the incriminated vial.
Cause: sepsis caused by inappropriate vaccine handling.
Cluster investigation begins by establishing the case definition and identifying all cases that meet the case
definition. The immunization programme manager should then take two actions.
1. Identify the immunization history of the cluster cases including details of when, where and
which vaccines were given, by collecting and recording:
–– Detailed data on each patient,
–– Programme-related data (storage and handling, etc.),
–– Immunization practices and the associated health workers’ practices.
102
2. Identify any common exposures among the cases, for example:

–– All data on vaccine(s) used (name, lot number, etc.),
–– Data on other people in the area (also non-exposed).
Including vaccine testing in an AEFI investigation

If it is appropriate to the working hypothesis on the possible cause of the vaccine reaction, collecting and
testing a vaccine specimen may confirm or rule out a suspected vaccine-associated cause of the AEFI.
For vaccine testing, collect a vial of the residual vaccine (if possible) from the health facility. Retain ade-
quate samples from the same site of unopened vaccine and diluent vials if the vaccine was reconstituted.
The samples should be maintained under correct storage conditions until a decision on testing is made.
If a vaccine is implicated in an AEFI case or cluster, it is rarely necessary to test the vaccine quality, which
should already be part of the national regulatory protocols. Potency testing is of little value and is only
useful to determine reasons for lack of vaccine efficacy.
If a decision is made to test the vaccine (and where appropriate, the diluent), the test(s) chosen depend on
the nature of the adverse event and the working hypotheses on the possible causes. One or more of the
following tests may be carried out:
■■ Visual test for clarity, presence of foreign matter, turbulence or discoloration,
■■ Sterility testing (vaccine and/or injection equipment) if an infectious cause is suspected,
■■ Chemical composition analysis: preservatives, adjuvant level, etc. (e.g. aluminium content);
abnormal components (e.g. suspect drug used instead of vaccine or diluent),
■■ Biological tests for foreign substances or toxins if abnormal toxicity is suspected (note: OPV-neuro-
virulence testing is expensive and adequate samples are not usually available),
■■ Additional field performance information should be obtained from the vaccine manufacturer.
103
Causality assessment of AEFIs

Most countries have AEFI systems and attach great importance
GACVS report “Causality assess-
to reports of suspected adverse events. These systems have been ment of adverse events follow-
successful in identifying severe AEFIs after vaccines are licensed. ing immunization” that includes
Follow-up studies are usually needed to further investigate causal- other conditions and provisions that
ity of AEFIs. should be applied in evaluating cau-
sality in the field of vaccine safety.
Although the most reliable way to determine whether an adverse vaccine-safety-training.org/
event is causally related to vaccination is through a randomized tl_files/vs/pdf/GACVS_cau-
clinical trial, such trials are limited to the clinical development sality.pdf
phase of vaccines. Once a vaccine is licensed, controlled trials are no
longer an option owing to ethical reasons (withholding vaccination).
Causality assessment is the systematic review of data about an AEFI The WHO Aide-Memoire on causal-
case. It determines the likelihood of a causal association between ity assessment serves as a guide to
the event and the vaccine(s) received. Causality assessment helps a systematic, standardized causality
determine: assessment process for serious
adverse events following immuniza-
■■ If an AEFI is attributable to the vaccine or the vaccination tion (including clusters).36
programme, who.int/vaccine_safety/ini-
■■ What steps – if any – need to be taken to address the event. tiative/investigation/New_
aide_mem_causal_assmt.
Causality assessment outcomes help raise awareness of vaccine pdf
associated risks among healthcare workers. This, combined with

knowledge of benefits of immunization, forms the basis of vaccine
information for parents and/or vaccinees.
The quality of a causality assessment depends on:
■■ Quality of AEFI case report,
■■ Effectiveness of AEFI reporting system,
■■ Quality of the causality review process.
There are five principles that underpin the causality assessment of vaccine adverse events.35
Specificity
Strength of Temporal
association relation
CAUSALITY Biological
Consistency
plausibility
Consistency: The association of a purported AEFI with the administration of a vaccine should be con-
sistent. The findings should be replicable in different localities, by different investigators not unduly
influencing one another, and by different methods of investigation, all leading to the same conclusion(s).
Strength of association: The association between the AEFI and the vaccine should be strong in terms of
magnitude and also in the dose-response relationship of the vaccine with the adverse event.
104
Specificity: The association should be distinctive. The adverse event should be linked uniquely or spe-
cifically with the vaccine concerned rather than occurring frequently, spontaneously or commonly in
association with other external stimuli or conditions.
Temporal relation: There should be a temporal relationship between the vaccine and the adverse event.
For example, that receipt of the vaccine should precede the earliest manifestation of the event.
Biological plausibility: The association should be coherent, that is, plausible and explicable according to
known facts in the natural history and biology of the disease.
Risk/benefit assessment
Continuous evaluation of risks and benefits of vaccines is required to strengthen the confidence in immu-
nization programmes. In Module 1 you looked at the need to balance vaccine efficacy and vaccine safety
(page 29) by conducting risk/benefit assessments.
On this page, let us look at how risk/benefit assessments are conducted and acted upon. A risk/benefit
assessment should:
■■ Address the population at risk (not the individual at risk),
■■ Take into account contextual issues (economics, availability of alternative vaccines, sociopoliti-
cal and cultural factors),
■■ Be prompted by a newly identified risk, but must remain holistic (e.g. take into account the entire
safety profile of a vaccine, not only the specific information relating to the event that was detected),
■■ Run in parallel to active enquiry, cooperation and exchange of information.
The need for urgent action should be weighed against the need for further investigation; the question below
illustrates this principle.*
Question 4*
Think about this example:
During a mass measles campaign for 7.5 million children aged from 9 months to 14 years, a
7-year-old child developed encephalopathy, convulsions and died.
Should the measles campaign be suspended?
Does the need for action to protect children from possible vaccine-related harm in this situ-
ation outweigh the need for further investigation, or vice versa?
Benefit evaluation begins with an understanding of the epidemiology and natural history of a vaccine-
preventable disease in the unvaccinated population. It involves evaluating the size of the reduction in
risk of morbidity and mortality from the disease in the vaccinated population, which is dependent on the
efficacy of the vaccine used.
The following table may help to break down some of the various aspects when evaluating the benefits
versus the risks.
105
BENEFIT EVALUATION RISK EVALUATION
• Description of implicated vaccine and lots (incl. • Weight of evidence for suspected risk (e.g. fre-
brand, manufacturer, lot, international use). quency, severity, mortality of anaphylaxis).
• Indications for use (e.g. reduce risk of morbidity • Detailed presentation and analysis of data on
and mortality associated with measles or rotavi- new suspected risk (results of case investigation,
rus cases by 80%). incidence in campaign).
• Identification of alternative modalities (if any, e.g. • Probable and possible explanations.
vitamin A supplementation, behaviour modifica-
• Preventability, predictability and reversibility
tion etc).
of new risk (e.g. is it the same as known risk of
• Brief description of safety of vaccine. measles vaccine?).
• Epidemiology and natural history of disease (e.g. • Risks of alternative vaccines.

morbidity and mortality of rotavirus disease).
• Review of complete safety profile of vaccine.
• Known efficacy of vaccine used.
• Estimation of excess incidence of any AEFI com-
mon to alternatives.
• Highlighting of important differences between

alternatives.
Considering the options for action

As a result of the risk/benefit assessment, an options analysis should list all appropriate options for follow-
up action.
EXAMPLE
Options for action could include discontinuing the immunization campaign, withdrawing a vaccine batch, and improv-
ing staff training and communication.
The options analysis should describe the advantages and disadvantages of each option and the likely
consequences.
EXAMPLE
Withdrawing a vaccine lot:
- Advantages: reduces fear of vaccine, renews confidence in the vaccine or the campaign,
- Disadvantages: cost, potential compromise of the campaign, loss of confidence in vaccine quality.
Finally, the options analysis should outline plans or suggestions of studies that could help to determine
the best course of action.
EXAMPLE
Audit injection practices of health workers to identity possible sources of immunization errors; investigate the need for
improved training and education.
It is essential to indicate the quality and quantity of any future evidence necessary to trigger reconsidera-
tion of the issue, and how the outcomes of any actions will be monitored and assessed.
106
Summary
RRThe basic principles of pharmacovigilance, and the special conditions that apply to immunization
programmes.
RRThe interaction and differences between the ADR and the AEFI reporting system.
RRThe different components of AEFI surveillance detection, investigation and causality assessment.
RRThe conducting of risks/benefit assessments for a vaccine.

107
ASSESSMENT 4
ASSESSMENT 4
ASSESSMENT 4
Question 1
Vaccines are considered drugs but require different surveillance systems to monitor adverse events.
Below is a list of differences between vaccines and drugs, which lead to the need for specific ‘immu-
nization safety’, or AEFI surveillance.
Vaccines usually differ from drugs in terms of:
Select one or more.
❒❒ A. Recipient’s age.
❒❒ B. Recipient’s health-status.
❒❒ C. Registration processes in National Regulatory Authorities.
❒❒ D. Staff administrating the vaccine/drug.
❒❒ E. Expectations towards substance’s safety.
Question 2
Effective detection and reporting of adverse events are a cornerstone of efficient AEFI surveillance.
Parents of immunized infants/children, health workers at immunization facilities and staff of acci-
dent and emergency rooms in hospitals are most likely to recognize or detect AEFIs when they first
occur.
Which of the following statements is not correct?
Select one or more.
❒❒ A. Health workers have the responsibility to detect AEFIs and report AEFIs when they first
occur.
❒❒ B. Health workers should be able to detect all cases corresponding to locally suitable AEFI
case definitions.
❒❒ C. Health workers should be trained to detect clusters of AEFI and all other events believed to
be due to immunization.
❒❒ D. Health workers must report serious AEFIs only.

❒❒ E. To support reporting in their countries, immunization programme managers should
establish appropriate criteria for detecting AEFIs by identifying adverse events of importance
to the programme in their country.
109
ASSESSMENT 4
Question 3
Some AEFI reports will need further investigation, some do not.

Which of the following statements are correct? Select one or more:
❒❒ A. Two or more cases of the same, minor adverse event, if related in time, place or the vaccine
administered should be investigated.
❒❒ B. Investigation is limited to the follow-up of serious adverse events following immunization.

❒❒ C. Signals and events associated with newly introduced vaccines should be investigated.
❒❒ D. Investigation is recommended when the events are causing significant parental or commu-
nity concern.
❒❒ E. Following the reporting of an adverse event following immunization, vaccine testing

should be an integral part of its investigations.
Question 4
According to the WHO Aide-memoire on Causality Assessment, which of the following

is not one of the five principles underpinning the causality assessment of vaccine adverse
events? Select one or more.
❒❒ A. Consistency
❒❒ B. Strength of association
❒❒ C. Risk-benefit balance
❒❒ D. Temporal relation
❒❒ E. Biological plausibility
Question 5
During a national immunization programme against measles, if four deaths occur in chil-
dren within one week of vaccination then the programme must be suspended, until further
investigations have taken place.
Is this statement true or false? Select one.
❒❒ True
❒❒ False
110
ASSESSMENT 4
Question 1
Answers A, B, D and E are correct.
Key differences between vaccines and drugs see table on page 93.
Question 2
Any AEFI that is of concern to the parents or to the healthcare worker should be reported.
In particular, health workers must report:
■■ serious AEFIs
■■ signals and events associated with a newly introduced vaccine
■■ AEFIs that may have been caused by an immunization error
■■ significant events of unexplained cause occurring within 30 days after a vaccination
■■ events causing significant parental or community concern.
Question 3
Answers A – D
Reported events requiring the initiation of an investigation are:
■■ Serious AEFIs, i.e. adverse events or reactions that result in death, hospitalization (or prolonga-
tion of existing hospital stay), persistent or significant disability or incapacity (e.g. paralysis), or
are potentially life-threatening,
■■ Clusters of minor AEFIs,
■■ Signals and events associated with newly introduced vaccines,
■■ Other AEFIs recommended by WHO:
–– AEFIs that may have been caused by immunization error (e.g. bacterial abscess, severe local
reaction, high fever or sepsis, BCG lymphadenitis, toxic shock syndrome, clusters of AEFIs),
–– Significant events of unexplained cause occurring within 30 days after a vaccination,
–– Events causing significant parental or community concern.
Answer E
Vaccine testing is not an integral part of an investigation. It is only appropriate if the working hypothesis
about the possible causes of an AEFI suggests there may be a problem with vaccine quality, e.g. bacterial
contamination, damage due to inadequate maintenance of the cold chain, a reconstitution error, etc.
111
ASSESSMENT 4
Question 4
Anwser C is incorrect.
The five principles that underpin the causality assessment of vaccine adverse events are:
Specificity
Strength of Temporal
association relation
CAUSALITY Biological
Consistency
plausibility
Question 5
The correct answer is ‘False’.
Before suspending a programme, it must be established that the deaths are genuinely related to the vac-
cination, and that the number of deaths is higher than expected.
Even if a causal relationship is established between the deaths and the vaccination, a risk/benefit calcula-
tion should be made, to determine if the danger of death from the disease is greater than the risk of the
vaccination. Once this is established, there is a rational basis for deciding whether to suspend the cam-
paign or not.
Keep in mind that during a national campaign a very large number of persons will be vaccinated and some
deaths may occur coincidentally in vaccinated individuals.
112
MODULE 5: Vaccine safety institutions and mechanisms
MODULE 5
Vaccine safety institutions
and mechanisms
Overview
The general principles for the surveillance of adverse events following immunization (AEFIs) are similar
in all countries. However, approaches may differ due to factors such as how immunization services are
organized and the level of resources available.
The first half of the Module describes the central role of the national regulatory authority (NRA) and the
national immunization programme (NIP) along with the role of the AEFI review committee; other par-
ticipants are also briefly introduced.
In the second half of the Module you will look into the international services available to support vaccine
safety in countries. You will understand how national and international agencies work together and how
information flows between countries and them.
Module outcomes
1 List the main functions or services for vaccine safety, including national and international bodies,
as well as manufacturers,
2 Describe the relevant areas of responsibility and (if applicable) the areas of collaboration between
the National regulatory authority and immunization programmes within your own country,
3 Identify the mechanisms by which an AEFI seen in a clinic can be reported to the national regula-
tory authority,
4 Summarize information flows between institutions at national level (immunization clinics, NRAs,
etc.) and international bodies.
114
Overview of functions
Components of a 21st Century global vaccine safety monitoring, investigation, and response system.
Global capacity Global advice and response

building and
harmonized tools Other global or regional
GACVS
advisory bodies
Brighton
Collaboration
CIOMS/WHO National AEFI surveillance, Global signal,

working group investigation and response evaluation and
detection
National regulatory authority
Training
providers National immunization programme WHO PIDM
AEFI review committee

Global Vaccine
Other support groups
Safety DataNet
Other partners
Product monitoring
Vaccine Licensing authorities in Procurement
manufacturers country of manufacture agencies
There are many different organizations serving different purposes in vaccine safety and in the monitoring
and support of national responses to adverse events.
In this module we will first focus on the national institutions displayed in the middle of the graphic. Fol-
lowing this, we will introduce the various international stakeholders and the services they provide to the
national level.
115
NATIONAL LEVEL
National AEFI surveillance systems

The national regulatory authority (NRA) and the national immu-
nization programme (NIP) are responsible for developing and National AEFI surveillance,
investigation and response
maintaining a national AEFI surveillance system. Often an AEFI
review committee and other support groups such as academic National regulatory authority
institutions and technical agencies are linked to the AEFI surveil- National immunization programme
lance system. In countries that produce their own vaccines, vaccine
manufacturers and national control laboratories may be part of the
national AEFI surveillance system. Other support groups
AEFI surveillance addresses the needs of immunization programmes and National regulatory authorities.
The general principles of AEFI surveillance are:24
■■ Detection, correction and prevention of immunization errors,
■■ Identification of potential problems with specific vaccine lots,
■■ Prevention of false blame from coincidental events,
■■ Maintenance of confidence in the programme by properly responding to parent/community
concerns,
■■ Identification of signals for unexpected adverse events and generation of hypotheses to be tested
by controlled studies,
■■ Estimation of AEFI rates in local populations,
■■ Support to formulate and adjust contraindications, risk/benefit equations, and provider and
patient information.
Mass vaccination campaigns

An area of specific need are mass vaccination campaigns. During campaigns, a large number of doses are
administered over a short period. There is a high probability of coincidental adverse events. Immuniza-
tion errors may occur if vaccines are not being given by those who regularly administer vaccine. During
campaigns there is also often increased awareness towards an apparent rise in reported adverse events,
which can undermine the confidence in the vaccine being used and can have a major impact on the suc-
cess of the campaign.
Key point
General principles of AEFI surveillance are similar in all countries. However, approaches may
differ because of factors such as the organizational structure of immunization services and
the amount of resources available.
National AEFI surveillance should be carried out in close collaboration with the NIP, NRA,
AEFI review committee, and other support groups (i.e. technical agencies and academic insti-
tutions). In countries that produce their own vaccines, vaccine manufacturers, and national
control laboratories should be involved in AEFI surveillance.
116

Key point
The safety of vaccines is under the mandate of the National regulatory authority (NRA).
Note: The NIP is also involved in securing the safety of vaccines and their use. Both the role of
the NRA and the NIP should therefore be clearly defined.
All countries should have a National regulatory authority to ensure

that all medicines, including vaccines, used within the country are National AEFI surveillance,
safe, effective and of good quality. NRAs function within the frame-
work of national medicines policy and overall health policy, and as National regulatory authority
with any public entity, must abide by principles of transparency, National immunization programme
fairness and accountability.
After licensure and introduction of a vaccine, the NRA’s respon- Other support groups
sibility to ensure vaccine safety must be met by a strong AEFI
surveillance. It is important to ensure exchange of information
between the NRA and the system of vaccination delivery or the national immunization programme.
Because the NRA may have limited knowledge of the structure and management of the NIP, it is essential
that the immunization programme manager is involved in AEFI surveillance and that everyone’s role in
monitoring and responding to vaccine safety issues is clear.
Core functions specific to vaccines

The NRA is usually the main institution mandated to regulate drugs, including vaccines. It has the aim of
ensuring the quality, efficacy and safety of the product. NRAs function within the framework of national
medicines policy and overall health policy. As with any public body, NRAs must have principles of trans-
parency, fairness and accountability.
Strengthening NRAs
In 1997, WHO launched an initiative to strengthen the capacity of national regulatory systems. These include
institutions such as NRAs, national control laboratories and NIPs, and must operate in close collaboration with
the vaccine manufacturers. The ultimate objective of this initiative was for all countries to have a reliable, properly
functioning NRA. To achieve its objectives, the initiative undertakes a five-step process of capacity development
that is customized to the requirements of each individual country.53
1. Define and regularly update benchmarks and other tools used to assess whether a national regulatory system
is capable of ensuring that the vaccines used or made in its country are of the required standards of quality,
efficacy and safety.
2. Use benchmark indicators and other tools to assess the national regulatory system.
3. Work with the country’s regulators and other health officials in drawing up an institutional development plan
to deal with any shortcomings in the country’s regulatory system, and to build on the existing regulatory
strengths in the country.
4. Implement the institutional development plan, which may involve technical support or staff training to perform
regulatory functions.
5. Re-assess the NRA within 2 years to evaluate progress.
When the initiative started in 1997, only 37 (19%) of WHO’s 190 Member States had reliable, fully functioning
NRAs. By the end of 2010, the number had risen to 60 (31.5%). Priority countries for the initiative are those that
have vaccine manufacturers and thus contribute to the world’s vaccine supply. In 1997, 20 (38%) of the 52 vac-
cine-producing countries had a reliable, functioning NRA. By the end of 2010, the numbers had risen to 34 (77%)
of 44 vaccine-producing countries.
117
NRA functions relating to vaccines 2

FUNCTION 1
Issuing a market authorization, and licensing vaccine production
Marketing authorization
facilities and vaccine distribution facilities.
and licensing activities
FUNCTION 2
Ensuring that post-marketing surveillance is carried out, with a focus
Post-marketing surveillance
on detecting, investigating, and responding to unexpected AEFIs.
(including AEFI surveillance)
FUNCTION 3 Verifying consistency of the safety and quality of different batches

Vaccine lot release of vaccine coming off the production line (lot release).
FUNCTION 4 Accessing, as needed, a national control laboratory in order

Laboratory access to test vaccine samples.
FUNCTION 5
Inspecting vaccine manufacturing sites and distribution channels.
Regulatory inspections
FUNCTION 6
Authorizing and monitoring clinical trials to be held in the country.
Oversight of clinical trials
Functions depending on the source of vaccines

Of the six core functions, all NRAs are responsible for Function 1 (licensing vaccines) and Function 2 (AEFI
surveillance). Both these functions should be coordinated with the National Immunization Programme.2, 54
The NRA’s can be responsible for Functions 3 – 6 depending on how its respective country obtains vaccines.
Countries may:
■■ Obtain vaccines through United Nations procurement agencies, i.e. United Nations Children’s
Fund (UNICEF), WHO, or Pan-American Health Organization (PAHO) Revolving Fund for Vac-
cine Procurement,
■■ Procure vaccines directly on the domestic or the international market,
■■ Manufacture their own vaccines.
The table below shows which responsibilities are taken up by the NRA depending on the source of the vaccine.
NRA functions depending on source of vaccines

Areas of activity by NRA (or WHO) depending on source of vaccines
Vaccine-specific NRA
functions needed Vaccine procured by Vaccine manufactured in
Vaccine procured by NRA
United Nations agency country
FUNCTION 1
Marketing authorization
and licensing activities
FUNCTION 2
AEFI surveillance
FUNCTION 3
NRA lot release
FUNCTION 4 NRA functions

Laboratory access undertaken by WHO
on behalf of United
FUNCTION 5 Nations agencies or
Regulatory inspections NRA functions
producing countries.
undertaken by
FUNCTION 6 producing country.
Oversight of clinical trials
118
The graphic below shows some of the key capabilities enabling a NRA to implement the 6 core functions
listed in the table above.
Review vaccine supplier
release of vaccines
Effectively communicate through

Demonstrate sound regulatory
communication systems informing
competence, with the authority
healthcare workers, patients, and
to enforce regulations
the public through the media
Act based on government NRA Have the epidemiological

commitment (adequate capacity to assess risk
sustained public funding) KEY CAPABILITIES through AEFI surveillance
Conduct research Understand critical

and training components of the
production process
Demonstrate technical Ensure competency

expertise necessary to of inspectors
evaluate documentation (e.g. through trainings)
Vaccine procurement and lot release

There are only about 30 different vaccine types (but many more product formulations) compared with
approximately 20,000 drugs.55 Accordingly, there are relatively few vaccine manufacturers and a limited
number of countries where vaccines are produced. Most countries use vaccines that are imported from
elsewhere.
To support countries with limited national regulatory (NRA) capacity, WHO provides a system of vaccine
prequalification that has been adopted as a standard for procurement by United Nations agencies and some
countries. Alternatively, countries can procure their vaccines directly on the domestic or international
market.
Regardless of how a country obtains vaccines, NRAs are responsible for licensing them i.e. approving their
use within the country. Appropriate licensing of vaccines ensures that quality products are used in immu-
nization programmes by determining that the manufacturer can provide a safe and effective vaccine.
Because vaccines are biological products and quality can vary from lot to lot, NRAs should conduct tests
before a vaccine lot is released for public use. NRAs often delegate testing to a national control laboratory.
NRAs are not responsible for testing vaccine lots when the vaccine is procured through a United Nations
organization i.e. prequalified, which takes responsibility for the testing.
119
Diversification of vaccine manufacture

Over the past decade, there has been substantial diversification in the manufacture of vaccines, including the
growing importance of prequalified vaccines produced by manufacturers in low- or middle-income countries. In
addition to producing vaccines for their own countries, these manufacturers can often provide large volumes at
low prices on the international market and now represent an increasing proportion of the vaccines procured by
UNICEF and the Pan-American Health Organization (PAHO) Revolving Fund for Vaccine Procurement. At the end
of 2008, there were 83 different vaccine products prequalified by WHO, of which 37 were manufactured in low-
or middle-income countries.
Testing of every batch is not done for other drug products. The lot release system is perhaps the greatest
difference between the NRA vaccine functions and NRA functions for other medicines.
Once the NRA releases a vaccine lot, the national immunization programme (NIP) takes responsibility for
its proper storage and handling until it can be administered safely to the target population. Storage and
handling, including maintenance of the cold chain (continuous refrigeration) involves many steps, and
presents opportunities for immunization errors that could result in AEFIs.
Key point
Unlike other drugs, NRAs should test every vaccine lot before public use, unless this is done
by WHO on behalf of United Nations agencies or producing countries. The system of lot
release is probably the greatest difference between vaccines and other medicines.
Once the NRA releases a vaccine lot, the responsibility to keep the vaccine safe and effective is
passed to the NIP.
Regulation of drug safety

NRAs are responsible for ensuring that every pharmaceutical, including vaccines, used within the country is:
1. Of sufficient quality,
2. Effective,
3. Safe for the purpose or purposes for which it is proposed.
There is a possibility that rare, yet severe, adverse events (such as those occurring with a frequency of one
in several thousand) may not be detected during drug development before licensing, because the number
of recipients in the trials is relatively small. It is therefore generally accepted that part of the process of
evaluating drug safety must happen after licensing and marketing. The acceptability of a vaccine shall be
based on its benefit-risk ratio.
Pharmacovigilance is often conducted by national pharmacovigilance centres on behalf of NRAs. These
centres, in collaboration with NRAs, have a significant role in the surveillance of adverse drug reactions
after licensing, including for vaccines and have to be staffed with persons with experience in vaccinology
or training in vaccine vigilance.
120
Influenza A (H1N1) vaccine example

Canada’s national regulatory authority (NRA) is Health Canada. The
Example AEFI reporting form:
Public Health Agency of Canada conducts pharmacovigilance for vac-
cines in collaboration with public health authorities in the provinces and vaccine-safety-training.org/
territories and maintains the national database of reports of AEFIs. tl_files/vs/pdf/aefi_report_
form_canada.pdf
Through the vaccine-safety monitoring system, the Public Health
Agency of Canada identified a higher than normal rate of anaphylaxis
linked to one particular lot (Lot 7A) of a newly released adjuvanted H1N1 flu vaccine. In collaboration with Health
Canada and pending further investigation of serious adverse event reports linked to Lot 7A, unused vaccines from
this lot were withdrawn from use during the investigation.
This document shows an example of an AEFI reporting form that would be used for investigation. This one is
from the Public Health Agency of Canada; the form for your own country may be different. This demonstrates the
importance of clearly defined roles and close coordination between organizations responsible for pharmacovigi-
lance and NRAs.
National immunization programmes (NIP)

A national immunization programme (NIP) is the organizational
component of Ministries of Health charged with preventing disease, National AEFI surveillance,
disability, and death from vaccine-preventable diseases in children
and adults. A NIP is a government programme that operate within National regulatory authority
the framework of overall health policy. National immunization programme
The national immunization programme is used interchange- AEFI review committee

ably with the Expanded Programme on Immunization (EPI) that Other support groups
originally focused on preventing vaccine-preventable diseases in
children. All countries have a national immunization programme
to protect the population against vaccine-preventable diseases.
Key point
Like the NRA, the NIP is responsible for the delivery to the population of safe, effective vac-
cines of high quality.
The NRA releases vaccines for public use (lot release). The NIP assumes responsibility for the
safe storage, handling, delivery and administration of these vaccines. In countries where the
NRA does not have the capacity to act on vaccine safety issues, the NIP may factually have
taken over some of the responsibilities of the NRA.
121
Core functions specific to vaccine safety

When an adverse event following immunization (AEFI) happens, it is the
health staff administering vaccines that often are the first responders. They
assess and treat the adverse event, reporting it, and may be called to con-
tribute to an AEFI investigation. The national immunization programme is
responsible for assuring that health staff respond to adverse events, and act
to minimize the risk of AEFIs in the future.
Given the central role of the national immunization programme in ensur-
ing the safe delivery and administration of vaccines, it is imperative that it
works closely with the NRA and other groups or committees involved in
AEFI surveillance.
The national immunization programme NIP should also work in collabora-
tion with national pharmacovigilance centres on the collection and assessment of AEFI data.
Safety of vaccine administration

NRAs and vaccine manufacturers provide guidance on how to pre-
pare and administer vaccines correctly. The national immunization
programme, as part of the national health delivery system, is
responsible for ensuring that health workers and local vaccinators
are trained to prepare and administer vaccine correctly.
It is vital that health workers or local vaccinators are trained to store
and handle vaccines properly, reconstitute and administer vaccina-
tions correctly, and have the right equipment and materials to do their job.
The correct technique for preparing and administering a vaccine
In WHO’s Immunization in Practice57,
must be followed to ensure that it is effective and does not result Module 4 discusses practices that
in an AEFI caused by immunization errors. Given that immuni- health workers should follow to de-
zations are often administered to a large segment of the healthy liver immunization injections safely.
population, and often are delivered in remote underserved areas, Read the document “Ensuring safe
injections “:
immunization errors are always a concern. To read more about
immunization errors, go to Module 3, chapter “Immunization vaccine-safety-training.org/tl_
error-related reaction” on page 74. files/vs/pdf/Module4_IIP.pdf
The following steps should be taken by the national immunization

programme to avoid immunization errors:
■■ Train immunization workers adequately, provide refresher updates and ensure close supervision
so that proper procedures are being followed.
■■ Do not store other drugs or substances in the refrigerator of the immunization centre. This
will avoid mix-up between vaccine vials and other drug containers and minimize immuniza-
tion errors. If stored together, a drug risks being given instead of a vaccine or an inappropriate
diluent.
■■ Use sterile, preferably single-use, auto-disable syringes for all injections. If only multi-use
syringes are available, sterilize them adequately after each use.
■■ Reconstitute vaccines only with its specific diluent supplied by its manufacturer.
■■ Discard Reconstituted vaccines within 6 hours or at the end of each immunization session
(whichever comes sooner).
122
■■ Carefully conduct epidemiological investigation of an AEFI to pinpoint the cause and how to
improve immunization practices where necessary.
■■ Monitor persons receiving vaccines for 20 minutes after vaccination.
AEFI Review Committee

Every country should establish an AEFI Review Committee to:
National AEFI surveillance,
■■ Review individual serious and unusual AEFIs and other investigation and response
AEFIs referred to it by expert groups (e.g. the national National regulatory authority
immunization technical advisory groups) and/or national
pharmacovigilance centres, National immunization programme

■■ Assess potential causal links between AEFIs and a vaccine
(or vaccine lot), Other support groups
■■ Monitor reported AEFI data for potential signals of previ-

ously unrecognized vaccine-related adverse events,
■■ Provide recommendations for further investigation, education, corrective action and communi-
cation with interested parties, including the media,
■■ Record its deliberations and decisions and feedback on each reviewed case to all relevant
stakeholders.
An AEFI Review Committee should be composed of members that are independent of the immuniza-
tion programme. It should represent a wide range of specialists whose expertise may add to the task of
reviewing the AEFIs. Areas of expertise would include paediatrics, neurology, internist, forensic physician,
pathology, microbiology, immunology and epidemiology. Medical experts in particular should be invited
for the analysis of special clinical events.
To avoid conflict of interest, the national EPI manager, vaccine laboratory scientists, representatives of the
National vaccine regulatory authority, and regional/district EPI officers should not be included as members
in the committee, however, should be available to support it in its functions.

Support for the development, implementation and communication
of vaccine safety policies and procedures is available to immuniza- National AEFI surveillance,
tion programmes from a range of other national, regional and local
organizations. National regulatory authority
National immunization programme

These include National immunization technical advisory groups,
and pharmacovigilance centres. AEFI review committee

Pharmacovigilance centres
The AEFI surveillance functions of pharmacovigilance centres relate to the reporting and investigation
of adverse events associated with vaccines as well as medicinal drugs. Many countries now operate a
decentralized pharmacovigilance system, with a national pharmacovigilance centre functioning as the
123
focal point for a network of regional and/or local centres. These may be located in a range of organizations,
including relevant government departments, hospitals, academic environments, or hosted by a profes-
sional body such as a national medical association.
The provision of a high-quality information service to health workers is a basic tak of pharmacovigi-
lance centres. Continuous and appropriate educational activities improves knowledge, and stimulates and
encourages health workers to report AEFIs.
National immunization technical advisory groups (NITAGs)

The general objective of NITAGs is to guide national governments Evidence-based information is acces-
and policy-makers to develop and implement evidence-based, sible to NITAGs via the online NITAG
locally relevant immunization policies and strategies that reflect Resource Centre. It provides four
national priorities. They support national authorities and empower dedicated services.
them to address issues associated with: NITAG Resource Centre

www.nitag-resource.org
■■ Vaccine quality and safety,
■■ The introduction of new vaccines and immunization
technologies.
NITAGs also serve to:
■■ Reinforce the credibility of national vaccine and immunization policies,
■■ Help governments and national immunization authorities to resist pressure from vested interest
groups,
■■ Enhance the ability to secure government or donor funding for immunization programmes,
■■ Encourage a more comprehensive approach to immunization policy that:
–– Considers the health of vulnerable populations,
–– Integrates various pre-existing vaccine-specific task forces.
124
INTERNATIONAL LEVEL
Global vaccine safety stakeholders

and services
International collaboration is essential to maintain the significant achievements of immunization to
date and to prevent the spread of misinformation about safety concerns from paralysing and damaging
immunization programmes. Vaccine safety is both a priority and a challenge to countries. Examples of
challenges that countries need to address in differing priorities depending on their local contexts include:
■■ Continued prevalence of unsafe injections and injection practices,
■■ Mishandling of rumours and adverse events,
■■ Lack of access to new, safer technologies such as auto-disable syringes,
■■ Growing anti-immunization movements, including anti-vaccination websites,
■■ Inadequate AEFI surveillance,
■■ Globalization and the internet (greater impact of misinformation raising public concerns about
harm from vaccines).
WHO and other partners are supporting various global initiatives that aim to strengthen and support
national AEFI surveillance, investigation and response. The following graphic shows some of the initia-
tives at global level that support countries on vaccine safety issues. Move your mouse over each group to
find out about its overall role.

building and
GACVS
advisory bodies
Brighton
Collaboration

detection
Training

Global Vaccine
Safety DataNet
Other partners
Product monitoring
125
Components of 21st century global vaccine systems39
GACVS
The Global Advisory Committee on Vaccine Safety (GACVS), established in 1999 under WHO’s Immuniza-
tion Safety Priority Project, advises WHO on vaccine-related safety issues and enables WHO to respond
promptly, efficiently and with scientific rigour to issues of vaccine safety with potential global importance.
WHO and partners

Many partners support drug safety activities at global or regional levels, in particular non-governmental
organizations, such as academic, clinical care and public-health institutions.
Brighton collaboration
The Brighton Collaboration, an international voluntary collaboration launched in 2000, provides globally
accepted standard case definitions for assessing AEFIs so that safety data across trials and surveillance
systems can be compared.
Council for International Organizations of Medical Sciences CIOMS/WHO working group

The Council for International Organizations of Medical Sciences (CIOMS) is an international, non-govern-
mental, non-profit organization established jointly by WHO and the United Nations Educational, Scientific
and Cultural Organization (UNESCO) in 1949. CIOMS includes technical working groups (e.g. vaccine
pharmacovigilance).
WHO Programme for International Drug Monitoring (PIDM)

The WHO Programme for International Drug Monitoring (PIDM), established in 1968, consists of a net-
work of national pharmacovigilance centres, WHO headquarters in Geneva, and the WHO Collaborating
Centre for International Drug Monitoring, Uppsala Monitoring Centre, Sweden.

Depending on the countries, other groups such as academic institutions or technical agencies (e.g. national
immunization technical advice groups, NITAGs) provide significant support to drug safety activities.
On the following pages we will introduce some of these initiatives and their respective areas of activity. Fol-
lowing this, we will introduce the Global Vaccine Safety Initiative, an implementation support mechanism
that envisions effective vaccine pharmacovigilance systems to be established in all countries.
126
Global analysis and response

building and
GACVS
advisory bodies
Brighton
Collaboration

detection
Training

Global Vaccine
Safety DataNet
Other partners
Product monitoring
Global Advisory Committee on Vaccine Safety (GACVS)

Established in 1999 under WHO’s Immu-
nization Safety Priority Project, the Global Global advice and response
Advisory Committee on Vaccine Safety Other global or regional
(GACVS)84 advises WHO on vaccine-related GACVS
advisory bodies
safety issues and enables WHO to respond
promptly, efficiently and with scientific
rigour to vaccine safety issues of potential global importance. Outcomes of the deliberations of the GACVS
are reported routinely in WHO’s Weekly Epidemiological Record (www.who.int/wer).
The Committee takes under consideration or makes recommendations regarding all aspects of vaccine
safety that might be of interest and importance to Member States and to WHO, and that are of sufficient
importance to affect WHO or national policies.
The Global Advisory Committee on Vaccine Safety has 14 members.43 They represent a broad range of
disciplines covering immunization activities. These members:
■■ Are independent and unbiased: They take decisions free of vested interests, including the
interests of WHO itself or of other organizations. Each committee member signs a declaration of
interest accordingly.
■■ Offer broad expertise: They have the expertise to evaluate and make decisions in the field of
vaccine safety. They are familiar with drug regulatory processes, with special reference to the
needs of the low-income countries.
■■ Take decisions with scientific rigour: All decisions of the Committee are based on the best
available scientific evidence and expertise. It is authoritative, defensible and explicable in terms
of fact, scientific evidence and process.
127
Since its establishment, GACVS has discussed a broad range of vaccine safety issues either causing, or with
a potential to cause, public concern. These include general issues relevant to all vaccines, such as the safety
of adjuvants, as well as vaccine-specific issues relating to long-standing vaccines and to new vaccines and
vaccines under development.*
GACVS example
The Global Advisory Committee on Vaccine Safety (GACVS) reviewed data from Argentina and South America
confirming in 2007 the significantly high risk of disseminated BCG (dBCG) disease in HIV-positive infants, with
rates approaching 1%. GACVS took into consideration other studies showing that infection with HIV severely im-
pairs the BCG-specific T-cell responses during the first year of life.
Based on evidence available, and considering the significant risk of BCG disease, GACVS advised that routine
BCG vaccination shall no longer recommended for infants known to be HIV-infected with or without symptoms of
HIV infection.
For infants whose HIV status is unknown*, GACVS recommended that BCG vaccination should be administered
regardless of HIV exposure, especially considering the high endemicity of tuberculosis in populations with high
HIV prevalence. Close follow up of infants known to be born to HIV-infected mothers and who received BCG at
birth was also recommended to provide early identification and treatment of any BCG-related complication. In
settings with adequate HIV services that could allow for early identification and administration of antiretroviral
therapy to HIV-infected children, consideration should be given to delaying BCG vaccination in infants born to
mothers known to be infected with HIV until these infants are confirmed to be HIV negative. Infants who dem-
onstrate signs or reported symptoms of HIV-infection and who are born to women known to have HIV infection
should not be vaccinated.
Interactive excercise
Seek advice on the vaccine-specific concerns addressed by GACVS by visiting the GACVS topic list: www.
who.int/vaccine_safety/committee/topics.
* in infants symptoms of HIV-infection rarely appear before several months of age.
128
Question 1*
Based on the information provided in the GACVS example, define, which of the following
statements is correct:
❒❒ A. Infants known to be HIV infected, with or without signs and symptoms should be
immunized with BCG vaccine.
❒❒ B. Infants with unknown HIV status who have signs and symptoms of infection should
be immunized.
❒❒ C. Infants born to women of unknown HIV status should be immunized.
❒❒ D. Infants whose HIV status is unknown and who demonstrate no signs or reported
symptoms suggestive of HIV infection should not be immunized.
Key point
It is essential that concerns about vaccine-related adverse events are responded to in a prompt
and efficient manner. The GACVS is the main global advisory body to provide such advice
with necessary scientific rigour.
Good information practices – Vaccine Safety Net

The internet is a mine of useful information
on various topics, but also contains websites Global advice and response
of dubious quality. Although many quality Other global or regional
GACVS
websites offer science-based information advisory bodies
about vaccine safety, other sites provide
unbalanced and misleading information.
This can lead to undue fears, particularly among parents and patients.*
To assist readers in identifying websites providing information on vaccine safety that comply with good
information practices, the Global Advisory Committee on Vaccine Safety (GACVS) recommended a list of
criteria that sites providing information on vaccine safety should adhere to.45 The recommended criteria
fall into four categories:
■■ Essential criteria, i.e. with respect to credibility,
■■ Important criteria, i.e. with respect to content,
■■ Practical criteria, i.e. with respect to accessibility,
■■ Desired criteria, i.e. with respect to design.
WHO has reviewed a number of sites for adherence to the credibility and content criteria noted above.
Vaccine websites not listed may not appear because:
■■ They have not been reviewed,
■■ They are currently under review,
■■ They have been reviewed and do not meet the credibility and content criteria,
■■ Commercial sites i.e. those supported by vaccine manufacturers are not listed as a matter of policy.
129
From March 2010, more than 30 websites successfully met the GACVS criteria and are listed on the WHO
website. Listed sites are re-evaluated for their adherence to the credibility and content criteria every two
years. Evaluation dates are included within each site description.45
Global Capacity building and

harmonized tools
building and
GACVS
advisory bodies
Brighton
Collaboration

detection
Training

Global Vaccine
Safety DataNet
Other partners
Product monitoring
Brighton Collaboration – setting standards in vaccine safety

The Brighton Collaboration85 is an international voluntary collaboration of sci-
entific experts, launched in 2000. It facilitates the development, evaluation and Global capacity
dissemination of high-quality information about the safety of human vaccines. building and
harmonized tools
The main objectives of the collaboration are.40 Brighton
Collaboration
■■ To raise global awareness of the availability of standardized case defini-
tions and guidelines for data collection, analysis and presentation, and to
CIOMS/WHO
educate about the benefit of and monitor their global use and to facilitate working group
access,
Training
■■ To develop single standardized case definitions86 for specific AEFIs,
providers
■■ To prepare guidelines for data collection, analysis and presentation for
global use,
■■ To develop and implement study protocols for evaluation of case defi-
nitions and guidelines in clinical trials and surveillance systems.
130
Case definitions
In Module 4, chapter “AEFI surveillance: Detection and reporting” (page 99) you have learnt about
the use of standard case definitionsand guidelines. Without globally accepted standard case definitions
for assessing AEFIs, it is difficult, if not impossible, to compare safety data across trials with any validity.
Standard case definitions serve to define the levels of diagnostic certainty or specificity of the reported
AEFI. They also indicate if the AEFI was diagnosed solely on clinical signs and symptoms (lower specific-
ity) or confirmed by laboratory test (higher specificity).
Key point
The Brighton Collaboration provides globally accepted, standard case definitions for assessing
AEFIs so that safety data across trials and surveillance systems can be compared.
CIOMS/WHO working group

The Council for International Organizations of Medical Sciences (CIOMS) is an
international, non-governmental, non-profit organization established jointly by Global capacity
WHO and UNESCO in 1949 to serve the scientific interests of the international building and
harmonized tools
biomedical community.
Brighton
The Council for the International Organizations of Medical Sciences (CIOMS) and Collaboration
WHO established a joint working group on vaccine pharmacovigilance in 2005,
recognizing that vaccines represent a special group of medicinal products with CIOMS/WHO
working group
issues specific to the monitoring and assessment of vaccine safety.
■■ To propose standardized definitions relevant to the monitoring of safety Training
of vaccines intended for the prevention of infectious diseases during providers
clinical trials and for the purposes of vaccine pharmacovigilance after
licensing,
■■ To contribute to the development, review, evaluation and approval of
AEFI case definitions as developed by the Brighton Collaboration process, and to contribute to
their dissemination, including their translation into additional languages,
■■ To collaborate with other CIOMS Working Groups, especially that on Standardized MedDRA
Queries (MedDRA is the Medical Dictionary for Regulatory Activities) and the CIOMS Working
Group VIII on Signal Detection on issues relevant to vaccine safety.
The purpose of developing standardized definitions and terminology,
CIOMS/WHO Report on Vaccine
or other guidance documents relevant to vaccine safety, is to con- Pharmacovigilance:
tribute to the harmonization of vaccine pharmacovigilance among
vaccine-safety-training.org/
different stakeholder groups and bodies. The principal stakeholders
tl_files/vs/pdf/report-of-ci-
are represented among the 22 Joint Working Group members from oms-who-working-group.pdf
the vaccine industry, regulatory agencies, national and international
public health agencies (including WHO and CIOMS) and academia.
A number of subgroups have also been established to carry out specific assigned work.
Additional activities that the CIOMS/WHO Working Group on Vaccine Pharmacovigilance has engaged
in, although not formally incorporated in its terms of reference, have included providing consultations and
expert inputs to other vaccine pharmacovigilance initiatives, such as the Global Vaccine Safety Blueprint
project led by WHO (discussed later in this module), and the development of a vaccine dictionary by the
Uppsala Monitoring Centre.
131
Vaccine safety training opportunities
Global Vaccine Safety Resource Centre

The Global Vaccine Safety Resource Centre (GVS RC)87 is an online platform
GVS RC through which WHO provides learning resources for capacity strengthening
Global Vaccine Safety
Resource Centre
both in form of workshops and online courses. The GVS RC offers learning
opportunities to national public health officials, immunization programme
managers, vaccination staff.
Among the resources available are:
■■ This E-learning course on Vaccine Safety Basics, which complements WHO workshops on Vac-
cine Safety,
■■ Workshops to build minimal capacity for vaccine pharmacovigilance in countries,
■■ Advanced level workshops that focus on causality assessment in particular and mainly aim
at building investigational capacity, for example among members of national AEFI Review
Committees,
■■ Access to training material for national staff that has passed WHO workshops and wishes to
train staff at country level.
Overview of vaccine safety training opportunities for different target groups
BASIC TRAINING BASIC TRAINING ADVANCED TRAINING NATIONAL TRAINERS

NEEDS NEEDS NEEDS (Advanced training
REMOTE AREAS (requiring direct (e.g. AEFI Review participants)
interaction) Committee members)
GVS RC
Global Vaccine Safety
Resource Centre
E-LEARNING COURSE
VACCINE SAFETY VACCINE SAFETY TRAINER
VACCINE SAFETY
BASICS TRAINING ADVANCED TRAINING RESOURCES
BASICS
Go to www.who.int/vaccine_safety/initiative/tech_support to access more information on the Global Vac-

cin Safety Resource Centre.
132
Global signal evaluation and detection

building and
GACVS
advisory bodies
Brighton
Collaboration

detection
Training

Global Vaccine
Safety DataNet
Other partners
Product monitoring
WHO Programme for International Drug Monitoring

Established in 1968, The WHO Programme for International Drug Monitoring
(PIDM)82 provides a forum for WHO Member States to collaborate in the moni- Global signal,
toring of drug safety, and notably, the identification and analysis of new adverse evaluation and
detection
reaction signals from data submitted to the WHO global individual case safety
report (ICSR) database by member countries. WHO PIDM
The programme consists of a three-part network: 42
Global Vaccine
■■ National pharmacovigilance centres from WHO member countries are Safety DataNet
responsible for case reports sent to the WHO ICSR database (managed
by the Uppsala Monitoring Centre (UMC)83 in Sweden),
Other partners
■■ UMC oversees the WHO programme operations, including:
–– Collecting, assessing and communicating information from member
countries about the benefits, harm, effectiveness and risks of drugs,
–– Collaborating with member countries in the development and practice of
pharmacovigilance,
–– Alerting NRAs of member countries about potential drug safety problems via the WHO
signal process.
■■ WHO headquarters in Geneva, Switzerland is responsible for policy issues.
133
Uppsala Monitoring
Centre (UMC) Sweden
REPORTING
ANALYSIS
WHO headquarters
(Geneva)
National
pharmacovigilance centres
from WHO member countries
As of June 2012, more than 100 countries had joined the programme, and more than 30 associate members
were awaiting compatibility between the national and international reporting formats. Member countries
are shown on the map below.42
106 Official Member countries 34 Associate Member countries Countries that are not member of the WHO Pragramme
Global Vaccine Safety DataNet (GVSD)

In 2007, an international meeting was held in France to discuss the establishment
of a Global Vaccine Safety DataNet (GVSD). It was attended by: Global signal,
evaluation and
■■ Experts from developed and developing countries that currently, or will detection
soon, collect computerized information on vaccine exposure and clinical
outcomes, WHO PIDM
■■ Representatives of public health agencies,

Global Vaccine
■■ Pharmaceutical companies. Safety DataNet
The goals of the meeting were to:

Other partners
■■ Assess current capabilities and interest in establishing a global vaccine
safety data network,
134
■■ Explore the infrastructure and funding required to bring such a project to fruition,
■■ Define how to best implement this project.
Several considerations prompted the urgent need for a global

Global Vaccine Safety DataNet
approach to monitoring vaccine safety: meeting:
■■ Vaccine manufacturing is becoming globalized. Many vaccine-safety-training.org/

countries outside North America and Europe are now tl_files/vs/pdf/Global_vac-
cine_safety_DataNet.pdf
producing vaccines,
■■ An increasing number of new vaccines will be first intro-
duced in developing countries that have a limited infrastructure for monitoring vaccine safety,
■■ Future vaccines, such as those against HIV or malaria, will probably make use of newer technolo-
gies with limited safety information, such as DNA vaccines, live virus vectors and new adjuvants.
A globally accessible computerized database for evaluating vaccine safety would allow rapid identification
of possible vaccine safety issues, based on vaccine exposure information, standardized terminology, and
case definitions. Such a database would allow comparison or combination of data from different sites in
collaborating countries.
For example, if a vaccine safety issue is identified and validated in one site or country, the information can
be rapidly communicated via the database to other countries using the same vaccine. Global collaborations
would also enable the experience and expertise of the high-income countries to be extended to immuniza-
tion programmes in the low-income countries, for example:
■■ Training in data management, data sharing, data governance and data protection,
■■ Developing ethical policies and procedures in collecting and reporting data, including guarding
against conflicts of interest,
■■ Sharing protocols, agreements and methods for evaluating local vaccine signals at global level.
The Global Vaccine Safety DataNet GVSD would also enable collaborative studies to be conducted across
several countries and allow results obtained in one geographical area to be tested in different populations
with a different balance of vaccine risk and immunization benefit.*
Question 2*
Think back to the example of the introduction of rotavirus vaccines (page 26) and
detection of the post-licensure incidence of intussusception. How could the pooling of AEFI
data from several countries via a global database have influenced the outcomes of surveil-
lance in this example?
❒❒ A. Pooling of data would have increased the statistical power for identifying intussuscep-
tion following rotavirus vaccination.
❒❒ B. The time to establish a causal association between the AEFI and the vaccine would have
increased.
❒❒ C. Pooling of data would have decreased the statistical power for identifying intussuscep-
tion following rotavirus vaccination.
❒❒ D. The time to establish a causal association between the AEFI and the vaccine would have
decreased.
135
Product monitoring
Procurement agencies
A country that does not produce its own
vaccines acquires them from providers Product monitoring
outside. It is strongly recommended that Vaccine Licensing authorities in Procurement
governments buy their vaccines through a manufacturers country of manufacture agencies
competent procurement body that observes
well-established, internationally recognized
procurement procedures, whether the vaccines are imported or locally produced. International organiza-
tions supporting countries’ procurement efforts are:
■■ UNICEF Supply division – Copenhagen, Denmark,
■■ WHO.
In addition, WHO provides courses in strengthening vaccine procurement skills, which can be accessed
at the Global Learning Opportunities for Vaccine Quality88 website.
Licensing authorities in countries of manufacture

All vaccines used within a national immunization programme must meet WHO prequalification require-
ments for quality and safety. To assure the quality and safety of vaccines, a country must have a competent
and functioning independent National regulatory authority (NRA) that supervises:
■■ Licensing the product and product facilities,
■■ Surveillance for the vaccine performance in field conditions,
■■ Lot release,
■■ Laboratory testing,
■■ Regular inspection,
■■ Compliance with Good Manufacturing Practice (GMP),
■■ Evaluation of clinical trial data in licensing decisions.
Prequalification requirements are rigorous and standardized. Before prequalification is granted, the WHO
conducts quality assurance tests on individual vaccine batches, rigorously inspects manufacturing sites
and evaluates the National regulatory authority of the country where the vaccine will be produced.
Vaccine manufacturers
Marketing authorisation (MA) holders are expected to provide summary of relevant new safety infor-
mation together with a critical evaluation of the risk-benefit balance of the product, in form of periodic
benefit-risk evaluation report (PBRER). The evaluation of such reports should ascertain whether further
investigations need to be carried out or if changes to the marketing authorisation or product information
has to be made.
136
Global Vaccine Safety Initiative

Hundreds of millions of doses of vaccine are used every year in developing countries.
However, assessments of regulatory authorities conducted by WHO demonstrate
that few of these countries’ programmes have the ability to monitor and assure the
safe use of vaccines.
By studying the current performance of vaccine pharmacovigilance systems in
low- and middle-income countries, and of existing inter-country and global sup-
port mechanisms, WHO has developed a Global Vaccine Safety Blueprint Strategy97
in an inclusive drafting process.
Key point
Global Vaccine Safety Blueprint is a strategic framework aiming at the establishment of effec-
tive vaccine pharmacovigilance systems in all countries.
It defines indicators of a minimal capacity for ensuring vaccine safety and proposes a strategic plan for
enhancing global vaccine safety activities by combining the efforts of major pharmacovigilance stakeholders.
The Global Vaccine Safety Blueprint has three main goals: To implement the Global Vaccine
■■ The first goal aims at assisting low- and middle-income Safety Blueprint strategy, a Global
Vaccine Safety Initiative project has
countries to have at least minimal capacity for vaccine been initiated.
safety activities,
who.int/vaccine_safety/
■■ The second goal aims to enhance capacity for vaccine initiative
safety assessment in countries; that introduce newly
developed vaccines; that introduce vaccines in settings
with novel characteristics; that both manufacture and use prequalified vaccines,
■■ The third goal looks to establish a global vaccine safety support structure so that countries can
benefit from international collaboration, training and information exchange.
The 3 main goals run through 8 Strategic Objectives which relate directly to vaccine systems, or are sup-
porting elements to the effectiveness of vaccine safety sytems:
Directly relating to vaccine system (VS) Supporting elements ensuring effectiveness of VS
Establish a legal, regulatory and administrative

1 Strengthen vaccine safety monitoring. 5
framework at all levels.
Strengthen ability to evaluate vaccine Strengthen regional and global technical support
2 safety signals.
6 platforms for vaccine pharmacovigilance.
Develop vaccine safety communication plans,

3 7 Make international expert scientific advice
understand perceptions of risk, and prepare
on vaccine safety issues available.
for managing any AEFI and crises promptly.
Put in place systems for appropriate interaction

Develop internationally harmonized tools
4 and methods for vaccine pharmacovigilance.
8 between national governments, multilateral
agencies, and manufacturers.
137
Summary
RRThe main functions and services that are present for vaccine safety, including national and interna-
tional bodies, and manufacturers.
RRThe relevant areas that the NRA and NIP in your own country are responsible for, and (if appli-
cable) the areas of collaboration between them.
RRThe main actors providing support on vaccine safety to countries at global level, as well as their
areas support:
1. Global capacity building and harmonized tools,
2. Global analysis and response,
3. Global signal evaluation and detection,
4. Product monitoring.
RRThe Global Vaccine Safety Blueprint as the main strategic framework aiming at the establishment
of effective vaccine pharmacovigilance systems in all countries.

138
ASSESSMENT 5
ASSESSMENT 5
ASSESSMENT 5
Question 1
National regulatory authorities are responsible for licensing vaccines and AEFI surveillance,
whereas National Immunization Programmes assume responsibility for the safe storage, handling,
delivery and administration of these vaccines. Both are responsible for the delivery to the popula-
tion of safe, effective vaccines of high quality.
Is this statement true or false? Select one:
❒❒ True
❒❒ False
Question 2
Every country should establish an AEFI Review Committee to review individual serious and
unusual AEFIs and other AEFIs referred to it by expert groups, to assess potential causal links
between AEFIs and a vaccine (or vaccine lot). Furthermore, the AEFI Review Committee should
monitor reported AEFI data for potential signals of previously unrecognized vaccine-related adverse
events, and provide recommendations for further investigation, education, corrective action and
communication with interested parties, including the media.
Which of these people are suitable as members of a national AEFI review committee?
Select one or more:
❒❒ A. National EPI Manager.

❒❒ B. A university professor of epidemiology.
❒❒ C. The director of the National Regulatory Authority.
❒❒ D. A senior investigator in immunology from the national research laboratory.
❒❒ E. A forensic physician.
❒❒ F. The transport manager of the company that distributes the vaccine.
140
ASSESSMENT 5
Question 3
Reporting lines for AEFIs:

Identify one person or organization who should receive information from you, if you have been
alerted to an AEFI, or a cluster of causally related AEFIs, assuming that you are:
A. A pharmacovigilance officer in the NRA
B. A person working in a vaccination centre
C. A Regional Health Officer
a Immunization programme manager

b The National Regulatory Authority
c The vaccine manufacturer
Question 4
Link the organizations listed below to the corresponding areas of expertise.
1. Global Advisory Committee on Vaccine Safety (GACVS)
2. Vaccine manufacturers
3. National advisory body responsible for strengthening evidence-based, locally-relevant policy

and strategy decisions on issues of vaccine quality and safety, including the introduction of,
or need for, new vaccines and immunization technologies.
4. Brighton collaboration
5. Global Vaccine Safety Data Link
a Global signal detection and evaluation

b National Immunization Technical Advisory Groups (NITAGs)
c Product monitoring
d Global capacity building and harmonized tools
e Global analysis and response
141
ASSESSMENT 5
Question 5
The Global Advisory Committee on Vaccine Safety (GACVS) is the main advisory body to
WHO on vaccine-related safety issues. Which of the following actions are in the remit of this
committee? Select one or more:
❒❒ A. Providing advice on vaccine safety alerts that may have a potential to cause, public
concern.
❒❒ B. Develop standard case definitions for specific Adverse Events Following Immunization.
❒❒ C. Providing scientific advice on vaccine safety issues of potential global importance, for
example on the use of BCG vaccine in immunocompromised individuals.
❒❒ D. Review key tools of WHO that support the investigation of adverse events following immu-
nization, for example the WHO Information Sheets on Oberved Rates of Reactions of specific
vaccines.
❒❒ E. Identify and analyse new adverse reaction signals from data submitted to the WHO global
individual case safety report (ICSR) database.
142
ASSESSMENT 5
Question 1
The correct answer is ‘True’.
National regulatory authorities are responsible for licensing vaccines and AEFI surveillance. The NRA is
usually the main institution mandated to regulate drugs, including vaccines. It has the aim of ensuring
the quality, efficacy and safety of the product.
A natses in children and adults. A NIP is a government programme that operate within the framework
of overall health policy. National Immunization Programmes assume responsibility for the safe storage,
handling, delivery and administration of vaccines.
Question 2
Answers B, D and E are correct.
An AEFI Review Committee should be composed of members that are independent of the immuniza-
tion programme. It should represent a wide range of specialists whose expertise may add to the task of
reviewing the AEFIs. Areas of expertise would include paediatrics, neurology, internist, forensic physi-
cian, pathology, microbiology, immunology and epidemiology. Medical experts in particular should be
invited for the analysis of special clinical events.
To avoid conflict of interest, the national EPI manager, vaccine laboratory scientists, representatives of
the national vaccine regulatory authority, and regional/district EPI officers should not be included as
members in the Committee, however, should be available to support it in its functions.
Question 3
Correct answers:
A. The vaccine manufacturer,
B. Immunization programme manager,
C. The National Regulatory Authority.
The National Immunization Programme is a national organisation within Ministry of Health responsible
for protecting children and adults from vaccine-preventable diseases through the correct storage, han-
dling, preparation and administration of safe, effective and high quality vaccines.
The Global Advisory Committee on Vaccine Safety (GACVS) is the multidisciplinary body responsible for
advising WHO on global vaccine safety issues and the prompt, efficient and scientifically rigorous response
to issues of vaccine safety with potential global importance.
The National Regulatory Authority (NRA), is a national institution responsible for the regulatory pro-
cedures governing vaccine lot release and subsequent confirmatory testing, to ensure that all vaccines
released for use within a country are safe, effective and of good quality.
143
ASSESSMENT 5
National Immunization Technical Advisory Groups (NITAGs) are national advisory bodies responsible for
strengthening evidence-based, locally-relevant policy and strategy decisions on issues of vaccine quality
and safety, including the introduction of, or need for, new vaccines and immunization technologies.
Question 4
Correct answers:
1. Global analysis and response,

2. Product monitoring,
3. National Immunization Technical Advisory Groups (NITAGs),
4. Global capacity building and harmonized tools,
5. Global signal detection and evaluation.
Question 5
Established in 1999 under WHO’s Immunization Safety Priority Project, the Global Advisory Committee
on Vaccine Safety (GACVS) advises WHO on vaccine-related safety issues and enables WHO to respond
promptly, efficiently and with scientific rigour to vaccine safety issues of potential global importance.
(http://www.who.int/vaccine_safety)
Answer B
The Brighton Collaboration develops of single standardized case definitions for specific AEFIs. It is an
international voluntary collaboration of scientific experts, launched in 2000. It facilitates the develop-
ment, evaluation and dissemination of high-quality information about the safety of human vaccines.
(https://brightoncollaboration.org/public)
Answer E
The WHO Programme for International Drug Monitoring (PIDM) provides a forum for WHO Mem-
ber States to collaborate in the monitoring of drug safety, and notably, the identification and analysis
of new adverse reaction signals from data submitted to the WHO global individual case safety report
(ICSR) database by member countries.
(www.who.int/medicines/areas/quality_safety/safety_efficacy/National_PV_Centres_Map)
144
MODULE 6: Communication
MODULE 6
Communication
Overview
Every year, billions of doses of vaccine are given in immunization programmes around the world. Vaccines
are designed to provoke an immune response in the body, and it is inevitable that this reaction carries a
small attributable risk to the health of a tiny minority of recipients. This risk is hugely outweighed by the
very significant benefits of immunization in terms of protection from vaccine-preventable diseases and
their wide-ranging consequences.
Explaining risks and benefits of vaccines clearly to parents, guardians and vaccine recipients requires
effective communication and interpersonal skills from trained health professionals in immunization pro-
grammes and educators such as school teachers.
This module will help you to understand public fear and concerns, and how you can improve your com-
munication skills on the subject of vaccine safety.
Module outcomes
1 Understand the need for improved communication on vaccine safety,

2 Critically evaluate and assess new information about vaccines before communicating to the target
audience,
3 Gather information about the various target audiences, who they are, how they perceive vaccine
risk and their knowledge about vaccines and safety,
4 Outline the fears and concerns of different groups associated with, or likely to be affected by, an
immunization programme,
5 Design, simple, clear and tailor-made messages to communicate information about vaccine safety
to your target audience (e.g. parent, vaccinee, clinic staff, media, health professional, drug regula-
tory authority, health minister, etc),
6 Identify the most suitable means and channels of communication to convey information to differ-
ent target groups,
7 Understand the media as being an important ally in vaccine safety.
146
Risk communication
Need for improved communication

Concerns are frequently raised about vaccines
and immunization protocols by members of the Unsafe
general public and in the media. These concerns injections
can be serious and are often misplaced. See the
Evolution Changing
graphic below for some factors that may trigger of program regulations
public concerns.
We need to improve the quantity, quality and tar-
geting of communication about vaccine safety if we
are to increase acceptance of vaccination through Mishandling Vaccine
of rumours campaigns
improved awareness of the risks and benefits.
Challenges to effective Anti-

Inadequate
communication monitoring
immuniza-
tion lobby
Challenges that need to be overcome with effective
communication include among others:
Decline of childhood infections in high-income countries

The impressive decline in the rates and severity of childhood infections in high-income, industrialized
countries during the twentieth century (see diagram) has effectively faded memories of the threats to health
and life posed by once-common diseases such as measles, polio, pertussis, diphtheria and tetanus. The ben-
efits of vaccination are no longer being reinforced by direct experience of the diseases that vaccines prevent.
Crude death rate* for infectious diseases – United States, 1900 – 1996**
§ American Water Works Association. Water chlorination principles and practices: AWWA manual M20. Denver, Colorado:
American Water Works Association, 1973.
* Per 100,000 population per year.
** Adapted from Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the
20th century. JAMA 1999:281; 61–6.
147
Parents view that infectious disease is a thing of the past

Some parents in countries such as the USA and western Europe may feel that exposing a child to even a
small potential risk from vaccination is unnecessary because they assume that infectious diseases are ‘a
thing of the past’. Parents have to be made aware of the consequences of their decisions not to vaccinate
their children – if herd immunity falls, the disease may re-emerge and spread through the population.
This is what happened when concerns about the safety of the vaccine against measles, mumps and rubella
(MMR) in the 1990s led to a sharp decline in vaccine uptake in the UK, followed by an increase in cases
of measles, mumps and rubella.
Introduction of new vaccines

New vaccines are being introduced and a wider range of ages is being targeted for routine immunization.
For example, teenagers in some countries are offered vaccines against human papillomavirus and bacterial
meningitis. Likewise, elderly people are encouraged to seek vaccination against influenza. In the develop-
ing world, women of childbearing age are targeted for vaccination with at least two doses of tetanus toxoid
to protect themselves and their newborns from the disease.
Communication with different age groups requires different skills and the use of age-appropriate language.
Staff needs to be prepared and trained to deal with the different target groups and to expect different
adverse events (e.g. immunization anxiety may occur at a different frequency in different age groups).
Transparency and accountability

Finally, good communication to all relevant stakeholders is essential to keep the trust of the public towards
a transparent and accountable immunization service.
Communicate only reliable information

Before beginning a consultation or leading a training/education ses-
sion, all health workers must carefully evaluate the reliability and
validity of the information they give to clients, patients or professional
colleagues.
The national AEFI coordinator is responsible for ensuring that a critical
review of the vaccine literature is available to health workers.
Ensuring that the literature, library or database is accurate, and up to date, supports effective communica-
tion in several ways:
■■ It ensures that up-to-date vaccination policies and procedures are applied at national level,
■■ It facilitates effective management of rumours and community concerns arising from poor sci-
ence or misleading reports in the media,
■■ It supports the detection, investigation and decision-making about actions needed in response
to new safety concerns. These may originate from other places/countries or may occur during
the introduction of new vaccines.
Before acting on new information about vaccine safety in the scientific literature, ensure that you critically
review the published material yourself if this is within your expertise.
You can also seek advice from an expert who is qualified and trained to conduct an evaluation. Such
experts can be persons from the National immunization programme (NIP) or the National regulatory
authority (NRA). If appropriate expertise is limited or inaccessible, obtain guidance from international
148
sources, such as the Global Advisory Committee on Vaccine Safety (GACVS) or WHO’s Vaccine Safety
Net. The WHO evaluation of whether MMR vaccine increases the incidence of autism is a good example
of an expert evaluation by the Global Advisory Committee on Vaccine Safety, responding to information
needs of the public.
WHO evaluation of whether MMR vaccine increases the incidence of autism
In 1998, a researcher claimed that MMR vaccine increases the incidence of autism. Parents expressed their con-
cerns and media reported widely on this statement. Global scientific advice on this issue was needed for profes-
sional staff to take informed decision on this issue.
WHO, based on the recommendation of its advisory body the Global Advisory Committee on Vaccine Safety
(GACVS) (who.int/vaccine_safety/committee), commissioned a literature review by an independent researcher
of the risk of autism associated with MMR vaccine. The existing studies did not show evidence of an association
between the risk of autism or autistic disorders and MMR vaccine.
Based on the extensive review presented, GACVS concluded that no evidence existed of a causal association be-
tween MMR vaccine and autism or autistic disorders. The Committee expressed its belief that the matter would
likely be clarified by an improved understanding of the causes of autism.
GACVS also concluded that there was no evidence to support the routine use of monovalent vaccines against
measles, mumps and rubella vaccines over the combined vaccine, a strategy which would put children at in-
creased risk of incomplete immunization.
GACVS recommended that there should be no change in current vaccination practices with MMR.
Simplified and key messages

In earlier modules and in the previous case study, we described
and illustrated how you communicate complex detailed infor-
mation about AEFIs accurately and systematically, using the
approved procedures for reporting adverse events to higher levels
(e.g. the NRA). The focus of this module is to support your ability
to communicate appropriately targeted and simplified messages
about vaccine safety to
Encoding communication.
Photo credit: WHO/Christopher Black relevant audiences.
It is important to be clear about key messages and simple mes-

sages. To frame your communication simply and clearly, while
covering all the essential points, you first need to know:
■■ Who is your intended audience?
■■ What is their background knowledge, attitudes and
beliefs about vaccination?
Source: wikipedia.org
149
KEY MESSAGES  SIMPLE MESSAGES 

w Key messages give the most w Simple messages are "jargon
important information that you free" and easy for the general
want the public to know. One or public to understand.
two sentences get to the heart of
the matter. w They "translate" complex
concepts and information into
w Key messages help you to take readily accessible ideas and
charge of a situation that requires examples.
firm, unambiguous communication,
e.g. to refute a misleading rumour w They may be short (e.g. slogans
or inaccurate report in the media. used in a campaign poster), or
much longer (e.g. an article in a
magazine or on a website).
Question 1*
Example key messages of a statement developed to respond to a public concern about a
cluster of fatal AEFIs:
• Three children died after immunization with measles vaccine at a Central Clinic,
• Investigations found the cause of death is not due to the vaccine, but to problems
arising from unsterile needles,
• Measles causes 750,000 deaths and debilitating disease in children worldwide every
year,
• The measles vaccine is the only effective measure in the world for the control of
measles,
• Staff training in injection safety and infection control will be prioritized to prevent
similar adverse events from occurring.
Look at the example key messages. Which of the five categories of AEFI that you have learnt
in Module 1 is the cause of the problem here?
Refrain from over-simplifying or withholding information*

Vaccination clinic staff may fear that raising the topic of vaccine-associated risks with members of the
public may cause alarm and generate concerns about vaccination where none existed previously. Some
health workers may also be tempted to omit certain information about vaccine safety to parents, guardians
or vaccinees, assuming a lack of understanding on their part. In particular, health workers may believe
that members of the public cannot absorb complex scientific information, for example, about how the
immune system responds to a vaccine and why vaccine reactions sometimes occur. For the same reason,
health workers may be hesitant to explain the risks and benefits of a vaccine using the background rate
of an adverse event, the rate of the same event in the vaccinated population, and how the population risk
relates to the risk of an AEFI occurring in a vaccinated individual.
150
DO DO NOT
Inform vaccinees or their families. Do not leave the vaccinees or their
They deserve to know the details families uninformed. It is unethical to
about the vaccine: conduct an invasive procedure without
informed consent.
1. Name of the vaccine,
Do not assume parents or the public
2. What the vaccine protects against,
will not understand information about
3. Expected or potential adverse vaccine safety.
events,
4. What to do if they or their child
experience an adverse event.
As a Healthcare provider, communicate

this information in understandable
terms, ideally in written form ahead of
the time of vaccination.
Key point
It is important to emphasize that it is unethical to conduct an invasive procedure such as
immunization without first obtaining informed consent from the vaccinee or from a respon-
sible adult in the case of a child.
True consent cannot be given unless the essential information has been communicated to the tar-
get audience in simple, accessible language that enables the listener to reach an informed decision.
Risk perception
Health experts do not view the risks associated with a medical pro-
cedure (such as vaccination) in the same way as members of the
public (parents, patients and vaccinees).
Experts understand risks in terms of numerical values and rates:
for example, this table compares the risks of death due to three vac-
cine-preventable diseases and the risks of adverse events following
immunization with the approved vaccines.
Risks of illnesses and risks associated to the corresponding vaccines

Death:
Measles • 1 in 3,000 cases in high income industrialized countries.
• As much as 1 in 5 cases during outbreaks in low- to middle-income countries.
Diphtheria Death: 1 in 20 cases.
Death: 25 – 70 in 100 cases overall.

Tetanus
(10 – 20 in 100 cases with good intensive care management.)
Measles vaccine Encephalitis or severe allergic reaction: 1 in 1,000,000 cases.
DTP vaccine Continuous crying, then full recovery: 1 in 100 cases.
• Convulsions or shock (full recovery): 1 in 1,750 cases.

Tetanus toxoid vaccine
• Acute encephalopathy: 0 – 10.5 in 1,000,000 cases.
151
Public perception
In contrast to the perception of experts, parents, guardians and vaccinees rather want to know whether
they or their child could be the “one in a million” who develops encephalitis following immunization with
measles vaccine.
The public sees risk in terms of:

Voluntariness of exposure,
Familiarity of risk,
Control over risk,
Catastrophic potential,
Fatal outcomes,
Unequal balance between risk &
benefit,
Unequal distribution of risk.
Experts see risk in terms of:

Morbidity and mortality levels
Other factors that may influence the way public tends to see risk, include:
Negligence of the danger of the disease

Most adults in high-income countries with high vaccination coverage have never seen a case of measles or
any of the other vaccine-preventable childhood diseases. As a consequence, they may underestimate the
probability of harm if the disease does develop.
Influence by individual context

The public is likely to perceive risk in broad religious, social or personal contexts. For example, some will
distrust the medical system due to a personal prejudice against “experts” and a desire not to be influenced
by them; others will uncritically accept all instructions from health workers because they feel intimidated
or inferior.
Aversion to medicine
Adverse personal experiences from the past (e.g. the memory of a painful injection or a sore/swollen arm)
may also negatively influence attitudes to vaccine-associated risk. The thought of being injected with a
foreign substance derived from disease-causing organisms can induce fear and dread. Clients may feel
reluctant to come to a clinic or other health facility, or to bring their children if the environment feels
intimidating and the health workers are not reassuring or welcoming.
For all these reasons, it is important to understand the concerns of your target audience and the different
approaches required to communicate effectively with persons planning to receive a vaccine, the public and
your expert colleagues.
152
Personal perspectives influence perception
Fear over being injected

with substance derived Technical concerns over
Religious beliefs
from disease-causing distance or probability
organisms
Social contexts, including

Past adverse experiences Financial concerns
experience from media
Prejudice or distrust Feelings of intimidation

of the medical system
Concerns of the target audience

There are some common misconceptions about vaccination that are often cited by concerned parents as rea-
sons not to get their children vaccinated. If staff can respond to these with accurate rebuttals perhaps they
may not only ease parents’ minds but discourage them from taking other anti-vaccine “facts” at face value.
Sources of information
Lack of information, or inadequate or misleading information about vaccine safety increases the risk
of the erosion of trust and confidence in health experts, immunization programmes and governments.
Ultimately it can result in lost opportunities to protect health. WHO estimates that two million additional
lives could be saved every year by the effective use of readily available vaccines.
Be aware of the different sources of information in your country. Even in remote rural locations in develop-
ing countries, the knowledge, attitudes and beliefs of the population towards vaccine safety are influenced
by an increasingly wide range of information sources. Roll your mouse over the images to see what the
main information sources might be.
Video or DVD
Printed material Mobile phone

messages
Radio and Local health

television workers
MAIN SOURCES
FOR INFORMATION
Parents, guardians ABOUT VACCINE Health education
and vaccines SAFETY campaigns
Religious and/or Visiting experts

community leader
Online resources
and communication
networks
153
Question 2*
Select from the below sources of online information that may help you as immunization
manager to powerfully share information with colleagues and the public on the safety of
vaccines and immunization?
❒❒ Facebook ❒ Blogs ❒ Website
❒❒ Twitter ❒ Wikipedia ❒ Newsletters
The World Wide Web is a mine of useful information on various topics, but also contains websites of dubi-
ous quality. Many quality websites contain science-based information about vaccine safety. Others provide
unbalanced and misleading information, which can lead to undue fears, particularly among parents and
patients. At WHO’s Vaccine Safety Net website (www.who.int/vaccine_safety/initiative/communication/
network/vaccine_safety_websites/) you can find Websites providing information on vaccine safety which
adhere to good information practices.*
Should you be seeking information on vaccine safety that you want to communicate in your country or
region, consider the advice of the Global Advisory Committee on Vaccine Safety (GACVS) on how to iden-
tify good information practices for vaccine safety websites.89
Communicating in public
The most effective method of communicating an important message depends on many factors – including
how the communicator gets the message across. Some people are gifted at presenting a message verbally
to a large audience (e.g. in a lecture or meeting). Others may find large audiences intimidating, but may be
excellent communicators in small groups or one-to-one interviews.
Whatever the setting or means of communication you choose, there are some general principles to keep
in mind. These apply both when the communication is with one (interpersonal communication) or with
many people:
Target audience
Gather as much information as possible about your target audience to ensure you design messages they
will hear.
■■ Reflect on the capabilities and concerns of your target audience – what do they need to under-
stand to make informed decisions?
FOR EXAMPLE
Providing reassurance to concerned parents, differs from communicating newly available evidence
to experts at a conference.
■■ Consider the age range of your audience.

FOR EXAMPLE
Informing teenagers learning about papilloma virus and HPV vaccination at school versus talking to elderly
people learning about influenza and flu vaccination at a community centre.
■■ Take into account differing educational levels.
154
FOR EXAMPLE
Talking to preschool children versus qualified nurses at an immunization clinic.
■■ Mind language problems.

FOR EXAMPLE
Speaking to someone with the same local language versus speaking to someone who has difficulties
understanding your language.
■■ Respect gender differences.

FOR EXAMPLE
Talking to female patients may differ from communicating to a male audience depending on your cultural
contexts.
■■ Take differing religious contexts into account.
Communication objective
■■ What is your single overarching communications objective?
■■ What key messages are necessary to achieve that objective and consider the best ways to com-
municate them (for example, verbally, in writing or in pictures).
Structured communication
■■ Communicate in a logical sequence.
■■ Sum up the key points at the end.
Interactive communication
■■ Encourage the audience to ask questions.
■■ Thank the target audience for its attention.*
Question 3*
Imagine that during an immunization campaign you have to communicate information in
your country about vaccine safety and the benefits of immunization to either nervous par-
ents and their child, or to teachers in a secondary school. Which of the following statements
is correct? Several answers possible.
❒❒ A. Conduct an interview with a nervous young mother with her first baby choosing a quiet
room to enable an atmosphere of trust.
❒❒ B. Be aware of your time schedule when interviewing concerned parents. You should not
take more than a few minutes to look into their concerns.
❒❒ C. When communicating to teachers at a large secondary school, group them to get your
message across to them at the same time and allow time for discussion to resolve potential
information gaps in your audience.
❒❒ D. Provide information material (posters, videos, slides) to target audiences that supports
your key messages and provides additional information.
155
Responding to vaccine safety crises
Rumours and crises

Allegations regarding vaccine-related adverse events that are not rapidly and effectively dealt with can
undermine confidence in a vaccine and ultimately have dramatic consequences for immunization cover-
age and disease incidence.
Some situations that encourage rumour include:
■■ Serious social conflict,
■■ Economic and political uncertainty,
■■ Social transition and clashes of culture and beliefs,
■■ A history of discrimination and manipulation,
■■ Lack of transparency in a distant or authoritarian organization.
What is a vaccine safety crisis?

You may not be able to define it, but you certainly know when you are in one!
Crises in vaccine safety are characterized by an unexpected series of events that initially seem to be out
of control. The outcome is usually uncertain when the crisis is first identified, and there is a threat to the
success of a vaccine or immunization programme.
A crisis may have a “real” basis arising from genuine vaccine reactions or immunization errors, or it may
have no foundation in reality and be triggered entirely by mistaken rumours. Often a crisis in vaccine
safety originates in the identification of AEFIs, but is aggravated by negative rumours.
Whether a rumour triggers a series of events that build into a crisis depends on the nature of the rumour,
how fast it spreads and whether prompt and effective action is taken to address it.
When approaching a crisis, keep in mind that this may not only be a challenge, but also an opportunity
to improve the communication on immunization issues. You have the opportunity to dispel negative
rumours, to take action to upgrade policies and procedures if required, and to correct any errors or lapses
in best practice.
EVERY CRISIS IS ALSO

CRISIS CAN ENTAIL:
AN OPPORTUNITY TO:
w Unexpected series of event. w Improve communication.
w Events are out of control. w Dispel negative rumours.
w The outcome is uncertain. w Take any required action to upgrade
policies and procedures.
w Threat to existing situation.
w Correct any errors or lapses in best
practice.
156
Question 4*
Consider the following scenarios. A new vaccine is introduced in a country and a cluster of
serious AEFIs occurs including the death of a child.
Which of the following statements address(es) failures in communication that could
increase the risk of these adverse events “exploding” into a national crisis and putting the
immunization programme at risk?
Several answers possible.
❒❒ A. No one took responsibility for managing the event locally - the correct actions were not
taken, or not taken quickly enough.
❒❒ B. Local communication about the event was poor, adding to the uncertainty and insecu-
rity about what actually went wrong and whether it was being addressed. The parents of
the dead child were not counselled, neither was empathy shown to them.
❒❒ C. The event was inaccurately reported in the media before you could deal with it.
❒❒ D. Rumours started circulating on social media sites.
❒❒ E. Someone involved in the original event was not truthful when interviewed about it and
the lie was later exposed, adding to the perception that there was a conspiracy to hide the
problem and that the health authorities could not be trusted.
Impact of rumours and crises

The history of immunization is not only characterized by its unique success at achieving huge reductions
in mortality (deaths) and morbidity (illness and disability) from vaccine-preventable infections and the
global eradication of smallpox. It is also notable for the emergence of vaccine sceptics who firmly believe
that vaccines are harmful and lobby against them. This – often very vocal – opposition has been a persis-
tent challenge to immunization programmes since they first began over two centuries ago.90
Example 1: Whole-cell pertussis “scare”

Many recent immunization programmes have suffered setbacks from immunization scares. Children have
been needlessly put into danger by frightened parents that refused immunization for their children after
“scare stories” about particular vaccines.
The graphs illustrate the impact of rumours about the pertussis whole-cell vaccine from about 1960
onwards in four different locations. Note how affected the vaccine coverage entails a rise in the incidence
of pertussis.
These examples also show how negative beliefs about a particular vaccine can spread around the world and
reduce public confidence in its safety.
157
Incidence of pertussis in countries affected by active anti-vaccine movements.
Example 2: MMR and autism controversy in the UK

In 2008, 14 years after the local transmission of measles was halted in the UK, the Health Protection Agency
for England and Wales declared it had once again become endemic, i.e. continuously circulating in the
population. This was seen as a result of almost a decade of low MMR vaccination coverage across the UK.
Burgess, Burgess and Leask54 (2006) analysed how a report of a hypothesised link between measles-mumps-
rubella vaccination and autism in 1998 became a major public health issue in the United Kingdom, leaving
most experts surprised by its overwhelming influence on public opinion about MMR vaccination. Effec-
tively communicating with parents of autistic children and members of the general public who believed
that the truth about the vaccine was being concealed would have been critical to avoid the reduction of
vaccination coverage.
1995: Uptake of MMR vaccine peaks at 92% of eligible infants.

1998: Research studies claiming an association between MMR and autism are published in 1998
by a group led by Andrew Wakefield
1999: Wakefields claims prompt huge coverage in the media and a crisis of confidence in the vaccine,
which leads to a rapid decline in its uptake.
2000: Confidence in the vaccine continues to decline. Outbreaks of measles occur in the UK
and in some other countries as the MMR coverage rate declines.
2001: Tony Blair, the Prime Minister at the time, is placed under extreme pressure to say whether his young son Leo
has been given the MMR vaccine. Blair’s refusal to answer the question adds to public concerns.
2002: Vaccine uptake continues to decline. Further outbreaks of measles occur.
2003: Vaccine uptake continues to decline.
2004: Evidence from large-scale studies begins to prove that there is no casual association between autism and MMR,
and Wakefield’s research is eventually exposed as without foundation. Vaccine confidence starts to grow again.
158
Health-damaging outcomes of negative rumours are not confined to high-income countries. There are
many other cases from all over the world. For example, in 2009, the death of a 7-year-old child in Taiwan,
following his vaccination against the H1N1 strain of influenza virus, led to rumours that the vaccine was
responsible. These rumours were followed by a 30% drop in the number of children receiving it.
Question 5*
Which of the following statements would you think to be the main reason for less tolerance
towards vaccines, making them more likely to be the subject of negative rumours and “scare
stories” than is the case for medical drugs?
❒❒ A. Vaccines are more expensive than many drugs which creates less tolerance in the pub-
lic’s perception.
❒❒ B. Public tolerance towards adverse reactions is lower compared to side-effects of drugs
as vaccines are given to healthy people.
❒❒ C. Parents consenting to vaccinating their child, perceive a harm possibly linked to a vac-
cine as more grave because it could have been avoided.
❒❒ D. The public awareness towards vaccine preventable diseases in industrialized countries
is high, leading to a resentment towards vaccines.
Responding to rumours and crises
Preparatory work*
Key point
Expect crises! They will happen. Be prepared.
When planning your communication to effectively deal with rumours and crises, consider the following
three questions:
■■ Who are your “allies” in dealing with a crisis in public confidence in vaccine safety?
■■ What are the main elements of your communication plan to deal with rumours and crises effectively?
■■ Why could your crisis communication plan fail?
Particularly knowing the persons available to support you during a crisis is important. Think of who is best
positioned to support you in developing and implementing your crisis communication plan. Professionals
working in your post-marketing surveillance system may be well positioned to resolve a crisis swiftly by
providing facts and information and supporting the communication. Also think about possible alliances
outside your usual contacts, who could add their expertise or support; for example, an organization that
might fund aspects of your communication strategy such as printing leaflets, or a scientific journalist
who might write an evidence-based article counteracting unfounded information arising from a rumour.
DEFINE THE NATURE OF THE CRISIS DEFINE THE NATURE OF THE RUMOUR
• Is the crisis linked to immunization or not? • Where does it come from?
• How soon will facts be available? • Is it based on facts?
• What is the damage potential? • Who is likely to be affected by it?
• How is it spread and by whom?
159
Before you begin work on your crisis communication plan, also make sure that you have clear information
and understanding of the crisis or rumour.
Developing a crisis communication plan

CHECKLIST OF POSSIBLE
Communication in the context of a vaccine-related crisis INTERVENTIONS
follows the same steps as any other planning process, but Mass media
because of the urgency of the situation, compressed time Are they open to your message?
scales apply and you must be able to implement the plan What are risks of further distortion?
quickly. Inclusive planning and action are critical – all stake-
holders should be involved as soon as possible. Remember Advocacy
Target key opinion leaders?
that communication is not an isolated exercise, but part of a
broader action plan for handling the crisis. Advertising
Will this increase credibility?
Key point Community mobilization

Do you have time and resources?
Do not hesitate in taking essential actions if some
Support the health community:
stakeholders cannot be contacted immediately or seek collaboration and maintain
do not respond quickly. contact with them.
There are four basic elements of a communication plan.
Decide on
your overarching
objectives
Select CRISIS Define

the channels COMMUNICATION your target
of communication audience
PLAN
Choose your
key messages
Decide on your overarching objectives

What are the overarching objectives of your communication strategy? It may be, for example:
■■ Within 1 year, to reverse the 10% drop in immunization coverage caused by adverse rumours
about the vaccine,
■■ To demonstrate increased public confidence in the vaccine and the immunization programme
within 6 months, through surveys of knowledge, attitudes and beliefs.
160
Define your target audiences
■■ The people most affected by the rumour or crisis,

■■ The most influential people to communicate your vaccine safety messages to,
■■ Internal to the immunization programme or the organizations that govern its operation: e.g.
health workers, government ministers, national or international vaccine safety committees,
■■ External to the immunization programme: e.g. patients/clients, the public, community organi-
zations, pressure groups or the media.
Choose your key messages

■■ What do you want the audience to hear and retain?
Select the channels of communication

■■ Choose methods that will reach the largest possible number in your target audience and have
highest impact – based on the funding and other resources you have available,
■■ Be creative about the “how” – effective communication channels may be neglected by opting for
the obvious routes,
■■ Do not underestimate “people power”, for example, by using social media to counteract mislead-
ing rumours.
*
Question 6*
“Patients die after being given measles vaccine in Bukkala.” Imagine that a crisis was trig-
gered by a report in a mainstream newspaper. A paper has alleged that several children died
due to a measles vaccine in a local immunization clinic. You have been asked to formulate a
statement on the situation.
Which of the following suggested actions is/are correct (several statements possible)?
❒❒ A. Provide a simple explanation of the situation.

❒❒ B. State if there is no evidence that the death was caused by the vaccine itself.
❒❒ C. Inform if there is an investigation ongoing.
❒❒ D. Provide information on the safety profile of the vaccine.
❒❒ E. Provide information on the risk posed by the disease that the vaccine prevents.
❒❒ F. If you do not have sufficient information to respond to a journalist’s request available,
answer with “No comment”.
161
Communicating with the media

“The media” have already been mentioned, referring to a wide range of communication organizations,
methods and technologies. In the final part of this module, the focus is on how someone like you can:
■■ Communicate your key messages about vaccine safety to the mass media – including the coun-
teracting of negative rumours,
■■ Deal effectively with questions from journalists working for newspapers, television, radio and
(increasingly) the authors of online blogs and internet news services,
■■ Design a press release or prepare for an interview by following some simple principles.
There are positive and negative aspects of media coverage.
Positive aspects of media coverage

Well-researched, responsible journalism is important. It can help:
■■ Communicate public health messages,
■■ Expose malpractice and negligence, and
■■ Highlight controversy and inconsistencies in policies and strategies affecting the public.
Negative aspects of media coverage

The news media have to make a profit, e.g. by selling newspapers or advertising space on television. If some
journalists are only interested in features of your story that boost sales figures, the task of communicating
is becoming more difficult.
Journalists decide on what the news agenda is and cover news that interest their target audience:
■■ Newsworthy stories are more likely to be dramatic, are targeted at affecting many people, and
may focus on famous people or young children,
■■ Stories could be controversial (e.g. the MMR vaccine and autism), or involve conflict between
individuals or organizations and often focus on scandal, corruption and fraud.
Adverse events following immunization are likely to be reported as they involve children and possibly
prevalent negative rumours. They can result in sensationalist reporting, especially if the journalist did not
fully understand the issue.
AEFI coverage can be extremely negative if you are not prepared to answer media questions and to get on
top of the news before journalists do. Understanding the media, how they work and what they want and
establishing good relations with specific media and journalists will help to ensure fair coverage.
CAN HELP YOUR WORK CAN HARM YOUR WORK

w Communicating public health w Inaccurate or unbalanced news
messages keeping the public coverage.
informed.
w Gearing conflicts by publishing
w Exposing malpractice and negligence. dramatic stories.
w Helping improve inconsistencies in w Publishing sensational stories

policies and strategies affecting the (implying conspiracies, scandal,
public. corruption and fraud).
162
Preparing a press release

Frequent press releases from the authorities concerned in investigating the death ensure that journalists
are kept informed of the facts as they become known. This prevented adverse and ill-informed specula-
tion from growing about the cause of the tragedy. In preparing an appropriate press release, you should
consider two aspects: the title and the content. The title should be short and to the point – but it should
also arouse interest, as in this example. The content of the press release should be clear and simple – short
sentences are best.
Present all the relevant facts in a logical sequence, getting your main points in at the begin-
ning – get help from your colleagues to design your press release.
Include a quote if you can get one from a well-known person or someone with a prestigious
job title.
If the press release is in response to “bad news” (e.g. a cluster of AEFIs) – do not avoid
the negative or controversial issues; if you do not deal with them, you will leave room for
misinterpretation.
Two pages of text are the most you should write (less is better) – anything longer risks get-
ting cut back by an editor who may change the intended message when your press release is
shortened.
At the end, give your name, title, organization, telephone number(s) and email address if you
have one for journalists to contact you for interview requests or more information.
Interactive excercise
Below are various parts of a press release which have been mixed up by your assistant. Bring the informa-
tion units into the right sequential order by entering numbers 1 – 4 in the corresponding boxes beside the
press release.
Try to describe the situation, outline which follow up action has been taken, provide additional back-
ground information and close with an action statement by the Ministry of Health.
163
Question 7*
AEFI death in Lukurna, Lisusistan: Initial findings
Following standard procedures, the Ministry of Health of Lisusistan

appointed a high level team of experts to investigate promptly the child’s
cause of death.
A.
The investigation revealed no link between the death of the child and the
vaccination. According to the experts, the probable cause of death was
asphyxia.
So far, no other serious adverse event was reported. Our officials will
B. continue to monitor ongoing immunization activities to ensure the safety
of children in Lisusistan.
Every day, an estimated 20 children die from non-vaccine related

causes in Lisusistan. Consequently it can be expected that a some death
C.
cases can coincidentally occur in short temporal relationship following
vaccination.
Pentavalent vaccination was introduced 2 months ago and about 50,000

doses have been administered by today.
Two days ago, the death of a three month old boy from Lukurna Health
D. Centre has been reported.
This child had received a dose of pentavalent vaccine 4 days ago
together with 23 other children. Of these other children, none had an
untoward reaction to the vaccine.
Preparing for an interview

Preparing for an interview is comparable to preparing a
press release, but it is even more important that you find
out who is conducting the interview and which organiza-
tion they work for. The individual or their organization
may have a particular point of view (e.g. a bias in favour of
or against vaccination), or they may have a reputation for
fairness in news reporting. Another consideration might be
whether the interviewer has medical or scientific training
that will influence the kind of questions you could be asked.
Above all consider the emphasis you need to place on the
key messages you want to get across.*
During the interview, follow these simple rules.
■■ Maintain eye contact with the interviewer,
■■ Dress in a professional manner,
■■ Think before you speak and take time to frame your answers,
■■ Speak clearly and audibly in simple conversational language,
■■ Stick to the facts and avoid speculation or personal opinions,
■■ Make sure you get your key message into the dialogue – more than once if possible,
164
■■ Be enthusiastic and engaged in the conversation – try not to look nervous, even if you feel
uncomfortable about being interviewed,
■■ Never say “No comment!”,
■■ Remember that there is no such thing as an “off the record” statement that you can be certain
the interviewer will keep confidential.
Most of all – try to imagine how the interview will appear to members of your target audience. Will they
be persuaded by your message?
Build professional relationships with journalists

you trust to maintain high standards.
Contact trusted journalists quickly if a rumour start

to circulate- before a crisis develops – so you can
give them the facts.
Keep your messages simple and to the point.
Be willing to answer questions and be completely

honest. Refer to someone who knows the answer
if you don't.
Give contact information so the journalist can

follow up on the story or check facts with you later.
Remain polite and professional at all times –

never lose your temper, even if provoked.
Know your work and be prepared.
Remember that journalists are not interested

in destroying your reputation or tricking you!
165
Summary
RRClear communication is needed to dispel rumours and misconceptions about vaccine safety.
RRPrepare your key messages so that they address the issues in a clear, simple way and that reach
your specific audience.
RRKnow who your audience is, and understand their concerns and their perception of risk.
RRChoose the most appropriate means of communicating as this will affect your success.
RRDevelop a plan for communicating, especially in the event of a crisis.
RRWhen communicating with the media, understand their perspective and how it can affect you.

166
ASSESSMENT 6
ASSESSMENT 6
ASSESSMENT 6
Question 1
Read each of the points listed below and choose the correct option from the list below to indi-
cate whether the information is:
■■ more likely to influence how health experts evaluate vaccine risks
or
■■ more likely to influence how members of the public evaluate vaccine risks.
1. Simplified key messages about vaccine safety and the risk of adverse events.
2. Morbidity and mortality rates following immunization with specific vaccines.
3. Adverse personal experiences of vaccination in the past.
4. Rumours of adverse events following immunization.
5. Population data on the incidence of AEFIs relative to the incidence of disease-related harm.
6. Research studies on vaccine safety in specialist journals.
7. Information that supports informed consent to vaccination.
8. Information in accessible language about the symptoms and complications of vaccine-pre-

ventable diseases.
a General public
b Health experts
Question 2
Is this statement true or false?

More parents in developing countries compared to industrialized countries may feel that exposing
a child to even a small potential risk from vaccination is unnecessary because they assume that
infectious diseases are ‘a thing of the past’.
Select one:
❒❒ True
❒❒ False
168
ASSESSMENT 6
Question 3
Which of the following general principles of communication should be kept in mind when
informing a community group about the local vaccination programme?
Select one or more:
❒❒ A. The messages about vaccination should be kept positive at all times and any unhelpful
questions should be discouraged.
❒❒ B. The age range in the audience should be considered, so that age-appropriate language,
information and diagrams can be used.
❒❒ C. Decide what your key messages are, the most important information you want your audi-
ence to hear, and state the points simply.
❒❒ D. Avoid mentioning anything that might concern parents and stop them from giving con-
sent for their children to be vaccinated.
❒❒ E. Reflect on the fears and concerns your audience may have about vaccination and ensure
that you give them all the information they need in order to make informed choices.
Question 4
Which of the following are helpful suggestion to get your message across with journalists?
Select one or more:
❒❒ A. Build professional relationships with journalists who you think you can trust to maintain
high standards.
❒❒ B. Be proactive and contact journalists if a rumour about vaccine safety starts to circulate.
❒❒ C. Keep your messages simple and to the point.
❒❒ D. Journalists want to hear complex scientific information. Make sure to use academic jargon
or complex arguments.
❒❒ E. Remain polite but authoritative – if you feel not confident to respond to a difficult ques-
tion, respond with ‘No comment’.
❒❒ F. Give contact phone numbers and/or email addresses so the journalist can follow up on the
story or check facts with you later.
169
ASSESSMENT 6
Question 5
Below find the press statement of the interactive exercise in Module 6. Link the paragraph of
the press statement to its corresponding main message from the list below.
AEFI death in Lukurna, Lisusistan: Initial findings.
1. Pentavalent vaccination was introduced 2 months ago and about 50,000 doses have been
administered by today.
2. Two days ago, the death of a three month old boy from Lukurna Health Centre has been
reported. This child had received a dose of pentavalent vaccine 4 days ago together with 23
other children. Of these other children, none had an untoward reaction to the vaccine.
3. Following standard procedures, the Ministry of Health of Lisusistan appointed a high level
team of experts to investigate promptly the child’s cause of death. The investigation revealed
no link between the death of the child and the vaccination. According to the experts, the
probable cause of death was asphyxia.
4. Every day, an estimated 20 children die from non-vaccine related causes in Lisusistan.
5. Consequently it can be expected that a some death cases can coincidentally occur in short
temporal relationship following vaccination.
6. So far, no other serious adverse event was reported. Our officials will continue to monitor
ongoing immunization activities to ensure the safety of children in Lisusistan.
a Response undertaken to respond to this event

b Future Follow-up actions
c Supporting scientific facts
d Information on the event
e Information on possible cause
f Introduction
170
ASSESSMENT 6
Question 1
Correct answers are: 1–a, 2–b, 3–a, 4–a, 5–b, 6–b, 7–a, 8–a.
Perception of risk varies strongly depending on the audience.
Health experts do not view the risks associated with a medical procedure (such as vaccination) in the same
way as members of the public. They understand risks in terms of numerical values and rates: for example,
this table compares the risks of death due to three vaccine-preventable diseases and the risks of adverse
events following immunization with the approved vaccines.
Parents, guardians and vaccinees, however, rather want to know whether they or their child could be the
“one in a million” who develops encephalitis following immunization with measles vaccine.
Question 2
The correct answer is ‘False’.
The impressive decline in the rates and severity of childhood infections in industrialized countries has
effectively faded memories of the threats to health and life posed by once-common diseases such as mea-
sles, polio, pertussis, diphtheria and tetanus. The benefits of vaccination are no longer being reinforced by
direct experience of the diseases that vaccines prevent.
Question 3
Answers B, C and E are correct.
Answer A
Discouraging questions will prevent you from responding to concerns of the audience. Questions should
be encouraged and negative attitudes and concerns should be openly discussed.
Answer D
Trust in vaccine safety can easily be eroded if you attempt to disguise or conceal the possible adverse
effects that may follow immunization. Everyone, either the person receiving a vaccine or his/her parents,
deserves to know the name of the vaccine, what the vaccine is protecting against, any what adverse event
can be expected from it. They should also be informed on what to do if they or their child experience an
adverse event. It is up to the health care provider to communicate information in understandable terms
for each individual. Ideally, this would happen in written form ahead of the time of vaccination.
171
ASSESSMENT 6
Question 4
Answer A, B, C and F are correct.
Answer D
Do not use academic jargon or complex arguments – this may lead to misunderstanding and frustration
among your audience.
Answer E
Responding to journalists with ‘No comment’ may lead to acrimonies. Be willing to answer questions
and be completely honest. If you are not sure of the facts, do not be evasive or speculate., but offer get
back to journalists with this information shoertly after the interview.
Question 5
Correct answers:
1. Introduction,
2. Information on the event,
3. Response undertaken to respond to this event,
4. Supporting scientific facts,
5. Information on possible cause,
6. Future Follow-up actions.
172
A General Assessment is available online to test the

knowledge you acquired in this course and to provide you
with a certificate upon successful completion.
Visit the General Assessment at:

http://assessments.vaccine-safety-training.org
Glossary
A
Acellular pertussis (aP) vaccine

A preparation of subunit proteins from pertussis bacteria, used to immunize against pertussis.
Adjuvant
A pharmacological agent (e.g., aluminum salt, oil-in-water emulsions) that modifies the effect of other
agents, such as a drug or vaccine, while having few if any direct effects when given by itself. Adjuvants are
often included in vaccines to enhance the recipient’s immune response to a supplied antigen, while keeping
the injected foreign material to a minimum.
ADR surveillance
A surveillance system designed to collect adverse drug reactions following administration of a drug used
for prophylaxis, diagnosis, or therapy of diseases, or for the alteration of a physiological process. This type
of surveillance typically relies on health professionals associating an adverse reaction in an individual as
a possible consequence of the drug and reporting it to the national pharmacovigilance centre, NRA or
appropriate authority.
Adrenaline
A drug used to treat severe allergic reaction (anaphylaxis). Also a hormone produced by the adrenal gland.
Adverse drug reaction (ADR)

A response to a drug that is noxious and unintended and occurs at doses normally used in man for the
prophylaxis, diagnosis or therapy of disease, or for modification of physiological function.
Adverse event (or adverse experience)

Any untoward medical occurrence that may appear during treatment with a pharmaceutical product but
which does not necessarily have a causal relationship with the treatment.
Adverse event following immunization (AEFI)

Any untoward medical occurrence which follows immunization and which does not necessarily have a
causal relationship with the usage of the vaccine. The adverse event may be any unfavourable or unin-
tended sign, abnormal laboratory finding, symptom or disease.
Adverse event of special interest (AESI)

A relatively new AEFI classification that started with pandemic vaccine development. AESI refers to
adverse events of significant scientific, medical, and public interest among pandemic vaccines.
AEFI surveillance (also known as vaccine safety surveillance)

A surveillance system designed to collect adverse events temporally associated with receipt of vaccines.
This type of surveillance typically relies on health professionals associating an adverse event in an indi-
vidual as a possible consequence of vaccination and reporting it to the NRA or appropriate authority.
Anaphylaxis
An acute, multi-system, allergic reaction (IgE mediated) to a substance, such as vaccination, drugs, and
food. Symptoms of anaphylaxis may include breathing difficulties, loss of consciousness, and a drop in
blood pressure. This condition can be fatal and requires immediate medical attention.
Antibiotic
A substance that kills or inhibits the growth of bacteria. Antibiotics (in trace amounts) are used during
the manufacturing phase of some vaccines to prevent bacterial contamination of the tissue culture cells.
174
Glossary
Antibody
A special protein produced by plasmocytes in response to antigens (foreign substances, e.g., bacteria or
viruses). Antibodies bind with antigens on microorganisms as one of the initial steps of the body’s protec-
tion against infection.
Antigen
A foreign substance in the body that triggers the production of antibodies.
Asthma
Chronic respiratory disease characterized by constriction of the bronchial tubes to the lungs, which causes
sudden and recurring breathing problems, coughing, chest tightness and wheezing.
Asymptomatic carriage
An infection or colonization by a pathogen that does not cause symptomatic disease.
Atopy
A genetic predisposition toward the development of immediate hypersensitivity reactions against com-
mon environmental antigens (atopic allergy), most commonly manifested as allergic rhinitis but also as
bronchial asthma, atopic dermatitis, or food allergy.
Attenuated vaccine – See Live attenuated vaccine.

Autism
A chronic neural development disorder usually diagnosed between 18 and 30 months of age. Symptoms
include problems with social interaction and communication as well as repetitive interests and activities.
At this time, the cause of autism is not known.
Auto-disable (AD) syringes

AD syringes are self-locking syringes that can be used only once. AD syringes are the preferred equipment
for immunizations requiring injections.
Autoimmune disorders
A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
There are more than 80 different types of autoimmune disorders.
Bacillus Calmette-Guérin (or Bacille Calmette-Guérin, BCG) – See Tuberculosis vaccine.

Bacteria
Single-celled life-forms that can reproduce quickly on their own. Some bacteria cause disease.
Bacterial carriage
A bacterial infection or colonization that does not cause symptomatic disease.
Bacterial meningitis
Inflammation of the membranes that surround the brain and spinal cord; caused by a bacterial infection.
BCG osteitis
A rare reaction from BCG vaccination, causing inflammation of the bone.
Bell’s palsy
Paralysis of one of the facial nerves (the nerves that supply muscles on the face), due to unknown cause.
It is characterized by an asymmetric facial expression, due to the paralysis of one side. Several conditions
can cause a facial paralysis, e.g., viral infections, brain tumor, stroke, and Lyme disease. However, if no
specific cause can be identified, the condition is known as Bell’s palsy.
175
Glossary
Biologicals
A medical product prepared from biologic material of human, animal, or microbiologic origin (e.g., blood
products, vaccines, insulin).
Biosynthetic technology
A method for producing a chemical compound using a living organism.
Booster injection
An additional vaccine dose needed to “boost” (increase) antibody levels after completion of the primary
immunization, which may be a series of up to three doses.
Brachial neuritis (also known as brachial plexus neuropathy or neuralgic amyotrophy)

A neuropathy that presents as a deep, steady, often severe aching pain in the shoulder and upper arm and
may include muscular weakness.
Bradycardia
Abnormally slow heartbeat.
Brighton Collaboration
An international voluntary collaboration to facilitate the development, evaluation, and dissemination of
high quality information about the safety of human vaccines. For more information, see http://http://www.
brightoncollaboration.org.
Buffers
Substances that minimize changes in the acidity of a solution when an acid or base is added to the solution.
Buffers are used in the manufacturing process of some vaccines.
Burden of disease
The impact of a disease in a defined population, usually expressed in terms of mortality or morbidity rates,
or some other measure such as years of healthy life lost or disability adjusted life years (DALYs).
Carrier protein
A protein linked to a weak antigen to increase its immunogenicity when used as a vaccine.
Case control study

Study that compares a group of persons with an outcome of interest (e.g., a disease, health condition,
unintended drug response) to a control group of people without it. The two groups are compared for dif-
ferences in past exposures (e.g., drugs, vaccines) or other pre-existing conditions that might explain the
difference in outcome.
Causality assessment (or causality association)

The systematic review of data about an AEFI case to determine the likelihood of a causal association
between the event and the vaccine(s) received.
Cell-mediated immunity
An immune response not involving antibodies, in which specific blood cells, leukocytes, and lymphocytes
attack and remove antigens.
Challenge, dechallenge and rechallenge

A testing protocol in which a medicine or drug is administered, withdrawn, then re-administered, while
being monitored for adverse effects at each stage. It is one of the standard means of assessing adverse drug
reactions but is usually not possible in vaccine trials or AEFI investigations.
176
Glossary
Cholera
An acute infectious disease of the small intestine, caused by the bacterium Vibrio cholerae and char-
acterized by profuse watery diarrhea, vomiting, muscle cramps, severe dehydration, and depletion of
electrolytes.
Chronic fatigue syndrome (CFS)

A debilitating and complex disorder characterized by profound fatigue of six months or longer duration
that is not improved by bed rest and that may be worsened by physical or mental activity. Persons with
CFS most often function at a substantially lower level of activity than they were capable of before the onset
of illness. In addition to these key-defining characteristics, patients report various nonspecific symptoms,
including weakness, muscle pain, impaired memory and/or mental concentration, insomnia, and post-
exertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years.
Clinical efficacy
The ability of a medical intervention (e.g., vaccine, drug, procedure) to produce the desired clinical effect
(e.g., protection, cure, symptomatic relief).
Clinical trial
A systematic study of a medical intervention in human subjects (including patients and other volunteers)
in order to discover or verify the effects of and/or identify any adverse reaction to the intervention. Clinical
trials also study the absorption, distribution, metabolism, and excretion of the products with the objective
of ascertaining their efficacy and safety. Clinical trials are generally classified into Phases I to IV. Phase
IV trials are studies performed after the licensure and introduction of pharmaceutical products. They are
carried out to expand the evidence base of the product characteristics for which the marketing authoriza-
tion was granted.
Cluster
Two or more instances of an event related in time, place, population subgroup, or common exposure (e.g.,
vaccine). AEFI clusters are usually associated with a particular provider, health facility, and/or a vial of
vaccine that has been inappropriately prepared or contaminated.
Coincidental event
An AEFI classification referring to an adverse event that occur after a vaccination has been given but are
not caused by the vaccine or its administration.
Cold chain
A system used to transport vaccines at a constant temperature involving a chain of refrigerators and por-
table cool boxes. Most vaccines and diluents need to be transported and stored in a cold chain between
2°C to 8°C.
Combination or combined vaccine

A vaccine that consists of two or more antigens in the same preparation (e.g., MMR, DTP).
Confounding factor
A confounding factor is anything that is coincidentally associated with an event (for example, an AEFI),
which may mislead the investigator into wrongly concluding that it is influencing the rate of an adverse
vaccine reaction.
Congenital
A condition that is present at birth, though not necessarily hereditary.
Conjugated vaccine
A vaccine in which two compounds (usually a protein and polysaccharide) have been joined together to
increase the vaccine’s effectiveness.
177
Glossary
Conjugation technology
A vaccine technology in which two compounds (usually a protein and polysaccharide) are joined together
to increase the vaccine’s effectiveness.
Contraindication
A condition that makes a particular treatment or procedure, such as vaccination with a particular vac-
cine, inadvisable. Contraindications can be permanent, such as known allergies to a vaccine component,
or temporary, such as an acute febrile illness.
Controlled study
A study that compares a group with an exposure or outcome of interest with a group that does not have the
exposure or outcome. When study subjects are randomly assigned to exposed or unexposed groups by the
study researcher (e.g., are assigned to receive or not receive a vaccine or drug) and subsequent differences
in outcomes measured, the study is called a randomized clinical trial. Studies in which exposure status is
not controlled by researchers are called ‘observational’ and include cohort and case-control studies.
Convulsion – See Seizure.

Cost-effective
This refers to a type of economic analysis that allows comparison of different intervention options by
estimating the cost per health outcome for each alternative intervention. It indicates which interventions
provide the greatest impact for a given cost.
Cost-saving
The case in which the cost of an intervention (e.g., the cost of delivering a vaccine) is less than the cost of
not intervening (e.g., the cost of disease in the absence of vaccination). In this example, the intervention
saves money.
Crohn’s disease
A chronic medical condition characterized by inflammation of the bowel. Symptoms include abdominal
pain, diarrhea, fever, loss of appetite, and weight loss. The cause of Crohn’s disease is not yet known, but
genetic, dietary, and infectious factors may play a part.
Depot effect
Some adjuvants used in injectable vaccine formulations act as a storage depot for the antigen, allowing its
slow release and gradual absorption into the body; this depot effect maximizes the immune response to
the vaccine.
Diabetes
A chronic health condition in which the body is unable to produce insulin and properly break down sugar
(glucose) in the blood. Symptoms include hunger, thirst, excessive urination, dehydration, and weight loss.
Treatment of diabetes requires daily insulin injections or other diabetes medication, proper nutrition, and
regular exercise. Complications can include heart disease, stroke, neuropathy, poor circulation leading to
loss of limb, vision problems, and death.
Diluent
A fluid provided in a vial or ampoule that is mixed with lyophilized vaccine powder before the vaccine can
be injected. Diluents are not interchangeable. Vaccines have different diluents; mixing and administering
the wrong diluent with a vaccine has led to serious adverse events including death.
178
Glossary
Diphtheria
A disease caused by toxigenic strains of Corynebacterium diphtheriae. Often marked by the formation of
a false membrane in the throat, diphtheria is a serious vaccine-preventable disease that can cause death
in unvaccinated children.
Diphtheria toxoid vaccine

A vaccine containing diphtheria toxoid, used to immunize against diphtheria.
Disseminated BCG infection

Tuberculosis (BCG) vaccine-induced infection that is spread over a large area of the body, a tissue, or an
organ. This can result in death (referred to as Fatal disseminated BCG infection).
Dose-response
The relationship between the dose of an active substance (e.g. a vaccine or drug) or radiation exposure,
and the response in the body of exposed individuals.
Drug (or medicine)

Any substance in a pharmaceutical product that is used to modify or exploit physiological systems or
pathological states for the benefit of the recipient. The term drug/medicinal product is used in a wider
sense to include the whole formulated and registered product, including the presentation and packaging,
and the accompanying information. Vaccines are drugs/medicines.
DT vaccine
A preparation of diphtheria and tetanus toxoids together in one vaccine, used to immunize children and
adolescents against diphtheria and tetanus. The DT vaccine given to adults contains a reduced amount of
diphtheria toxoid.
DTaP vaccine
A combination of diphtheria and tetanus toxoids with acellular pertussis vaccine together in one vaccine,
used to immunize against diphtheria, tetanus, and pertussis.
DTP vaccine
A combined preparation of diphtheria and tetanus toxoids with pertussis vaccine together in one vaccine,
used to immunize against diphtheria, tetanus, and pertussis (also sometimes referred to as DPT vaccine).
When an acellular pertussis vaccine is used, the combination is usually abbreviated DTaP. When the whole
cell pertussis vaccine is used, the combination is usually abbreviated DTwP.
DTwP vaccine
A combination of diphtheria and tetanus toxoids with whole cell pertussis vaccine together in one vaccine,
used to immunize against diphtheria, tetanus, and pertussis.
Effectiveness – See Vaccine effectiveness.

Efficacy – See Vaccine efficacy.
Elimination
Reduction to zero (or a very low defined target rate) of new cases of an infectious disease in a defined
geographical area as a result of deliberate efforts; continued measures to prevent re-establishment of trans-
mission are required.
Emulsion
A mixture of two liquids that do not mix resulting in one of the liquids dispersed throughout the other in
small droplets.
179
Glossary
Encephalitis
Refers to an encephalopathy caused by an inflammatory response in the brain. This is usually manifested
with systemic constitutional symptoms, particularly fever and pleocytosis of the cerebrospinal fluid. How-
ever, the terms encephalopathy and encephalitis have been used imprecisely and even interchangeably in
the literature.
Encephalopathy
Refers to a variety of conditions affecting the brain resulting in alterations in the level of consciousness,
ranging from stupor to coma. At times, febrile seizures, afebrile seizures, and epilepsy have been consid-
ered components of encephalopathy. However, the terms encephalopathy and encephalitis have been used
imprecisely and even interchangeably in the literature.
Endotoxin
A toxin contained in the cell walls of some microorganisms, especially gram-negative bacteria, that is
released when the bacterium dies and is broken down in the body. Fever, chills, shock, and a variety of
other symptoms may result, depending on the particular organism and the condition of the infected person.
Epidemic
The occurrence of disease within a geographical area and/or population that is in excess of what is nor-
mally expected for a given period of time.
Epidemiology
The study of the distribution and determinants of health and disease in human populations.
Equine-derived
A substance extracted from horses, e.g. some antibodies used in passive immunization are extracted from
the serum of horses exposed to the target antigen.
Eradication
The complete and permanent worldwide reduction to zero new cases of an infectious disease through
deliberate efforts; no further control measures are required.
Evidence-based
Research based on systematic investigation of the outcomes of controlled interventions; the results have
been verified by other researchers using the same methods.
Expanded Programme on Immunization (EPI)

An international programme launched by WHO in 1974 to increase immunization of the world’s children.
EPI originally targeted vaccines for six diseases: measles, diphtheria, pertussis, tetanus, tuberculosis and
poliomyelitis. EPI and national immunization programme (NIP) are used interchangeably.
Fatal dissemination of BCG infection

Tuberculosis (BCG) vaccine-induced infection that is spread over a large area of the body, a tissue, or an
organ, and results in death.
Febrile
Relating to fever; feverish. A febrile seizure is a seizure or convulsion that occurs during a high fever. Com-
mon in children under five years of age, rarely resulting in long term injury.
Freund’s adjuvant
A water-in-oil emulsion added to some vaccines to increase the immune response to the vaccine antigen.
180
Glossary
Global Advisory Committee on Vaccine Safety (GACVS)

Established in 1999, the GACVS advises the WHO on vaccine-related safety issues and enables WHO to
respond promptly, efficiently, and with scientific rigor to issues of vaccine safety with potential global
importance. The committee also assesses the implications of vaccine safety for practice worldwide and for
WHO policies. For more information, see http://http://www.who.int/vaccine_safety/en/.
Good manufacturing practice (GMP)

Guidelines that outline the aspects of production that would affect the quality of a product. Many coun-
tries have legislated that pharmaceuticals, biologicals, and medical device companies must follow GMP
procedures, and have created their own GMP guidelines that correspond with their legislation to assure
the quality of those products. WHO also proposes GMP guidelines that are used by many countries.
Guillain-Barré Syndrome (GBS)

A rare neurological disease characterized by loss of reflexes and temporary paralysis. Symptoms include
weakness, numbness, tingling, and sensitive disorders that spreads over the body. Muscle paralysis starts
in the feet and legs and moves upwards to the arms and hands. Sometimes paralysis can result in the
respiratory muscles causing breathing difficulties. Symptoms usually appear over the course of one day
and may continue to progress for three or four days up to three or four weeks. Recovery begins within two
to four weeks after the progression stops. While most patients recover, approximately 15 to 20% experience
persistent symptoms. GBS is fatal in 5% of cases.
Haemophilus influenzae type b (Hib)

Bacteria that can cause serious invasive illnesses, such as pneumonia and meningitis; most common in
children and persons who are immune compromised (less able to fight off infections). Hib is one of six
types of bacteria that are major causes of bacterial meningitis in unimmunized infants.
Haemophilus influenzae type b (Hib) vaccine

A subunit polysaccaride-conjugate vaccine used to immunize against invasive Hib disease.
Hepatitis B
A viral infection of the liver that is transmitted through contact with blood or other body fluids that are
infected with the hepatitis B virus. Some infections, especially those acquired in infancy, can become
chronic and result in cirrhosis and primary liver cancer in adulthood.
Hepatitis B vaccine (HepB)

A subunit protein-based recombinant vaccine used against hepatitis B infection.
Herd effect
The resistance of a group to invasion and spread of an infectious agent, based on the resistance to infection
of a high proportion of individual members of the group. The resistance results from a small proportion
of susceptible individuals in a population making it difficult for the infectious agent to sustain circulation.
Herd immunity
A population with a high proportion of individuals with immunity to a particular pathogen, as a con-
sequence of immunization or infection and recovery, may confer protection from infection on the small
proportion of its non-immune members because there are too few susceptible people in the ‘herd’ for the
infection to circulate.
181
Glossary
Herpes zoster
An inflammatory disease, also known as the shingles, caused by the same virus that causes chicken pox.
Some people exposed to this virus during childhood develop partial immunity. After the primary infec-
tion as chicken pox the virus becomes dormant, reactivating years or decades later as herpes zoster. It is
characterized by painful skin lesions that occur mainly on the trunk (back and stomach) of the body but
which can also develop on the face and in the mouth.
HIV/AIDS
Acquired immune deficiency syndrome (AIDS) is a collection of symptoms and infections resulting from
the specific damage to the immune system caused by the human immunodeficiency virus (HIV).
Holistic
All embracing, taking into account all aspects of a situation; in healthcare, holistic usually refers to a com-
mitment to consider all aspects of the patient’s situation, including social and psychological states as well
as medical conditions.
Hypersensitivity
An excessive or abnormal sensitivity in a body tissue to an antigen or foreign substance.
Hypertension
High blood pressure.
Hypotension
Low blood pressure.
Hypothesized associations
Low blood pressure.
Hypotonic hyporesponsive episode (HHE)

A recognized serious reaction to immunization, especially pertussis-containing vaccine. It is defined as
an acute loss in sensory awareness or loss of consciousness accompanied by pallor and muscle hypotonic-
ity. No long-term sequelae have been identified in the small number of children who have had long term
follow-up. HHE is not a contraindication for further doses of pertussis vaccine.
I
Immune response
The body’s defense against foreign objects or organisms, such as bacteria, viruses or transplanted organs
or tissue.
Immune system
A complex system of organs and processes in the body responsible for fighting disease. Its primary function
is to identify foreign substances in the body (including bacteria, viruses, fungi, parasites or transplanted
organs and tissues) and develop a defense against them. This defense is known as the immune response.
Immunity
The body’s response mechanism for fighting against bacteria, viruses and other foreign substances. If a cell
or tissue (such as bacteria or a transplanted organ) is recognized as not belonging to the body, the immune
system will act against the “invader.” The immune system is the body’s way to fight external invasions.
Immunization
The process by which a person or animal becomes protected against a disease through an enhancement of
their immune response. This term is different from vaccination which is a form of immunization where the
body learns to recognize a particular foreign object (active immunization). Passive immunization can be
provided by administering external antibodies that will temporarily help strengthen the body’s response
without inducing memory against a specific foreign object.
182
Glossary

Immunization error
An AEFI classification that refers to events caused by errors in vaccine preparation, handling, or
administration.
Immunization safety
The process of ensuring and monitoring the safety of all aspects of immunization, including vaccine qual-
ity, vaccine storage and handling, vaccine administration, disposal of sharps, and management of waste.
Immunocompromised (also immunosuppression)

Unable to mount a normal immune response. This condition can be genetic, or caused by disease (like
HIV infection or cancer) by certain drugs (such as those used in chemotherapy and organ transplantation).
Individuals whose immune systems are severely compromised should not receive LAV vaccines.
Immunogenicity
The power of an antigen to induce an immune response.
Inactivated polio vaccine (IPV)

An inactivated (killed) polio vaccine, developed in 1955 by Dr. Jonas Salk. Unlike oral polio vaccine (OPV),
a LAV vaccine, IPV must be injected to produce the desired immune response.
Inactivated vaccine (also known as killed vaccine)

A vaccine made from microorganisms (viruses, bacteria, other) that have been killed through physical or
chemical processes. These killed organisms cannot cause disease.
Incidence
The number of new cases (e.g., of a disease, adverse event) occurring in a defined population during a given
time interval, often one year.
Individual case safety report (ICSR)

A report received by a company or agency that describes an adverse event.
Infammatory bowel disease

A general term for any disease characterized by inflammation of the bowel; examples include colitis and
Crohn’s disease. Symptoms include abdominal pain, diarrhea, fever, loss of appetite, and weight loss.
Influenza
A highly contagious viral infection characterized by sudden onset of fever, aches and pains, and inflam-
mation of mucous membranes.
Informed consent
An ethical requirement that an idividual who gives consent for an invasive medical procedure (e.g. a vac-
cination) is fully informed of all relevant risks and benefits of the procedure before making the decision
to consent.
Inoculation
The practice of intentionally exposing someone to matter from smallpox pustules in order to initiate a
mild, protective response to the disease.
Insulin
A hormone secreted by the islets of Langerhans and functioning in the regulation of the metabolism of
carbohydrates and fats, especially the conversion of glucose to glycogen, which lowers the blood glucose
level. It is also available as a pharmaceutical for the treatment of diabetes.
183
Glossary
Intramuscular (IM) injection

Administration of vaccine into the muscle mass. Vaccines containing adjuvants should be injected IM to
reduce the depot effect and formation of granulomas.
Intranasal influenza
A live attenuated influenza vaccine, administered through the nose. Advantages of this vaccine include
easier and more acceptable administration than injection and possibly the stimulation of a broader
immune response in some age groups.
Intussusception
A potentially life threatening obstruction of the bowel. When the first rotavirus vaccine was licensed in
1999, it was withdrawn from the market following evidence linking it to a small increase in the risk of
intussusception.
Japanese encephalitis (JE)

A mosquito-borne viral infection, the leading cause of viral encephalitis in Asia.
Japanese encephalitis (JE) vaccine

Two vaccines against JE are currently available internationally: the inactivated, mouse-brain derived JE
vaccine and the live attenuated SA-14-14-2 JE vaccine.
Key message
A key message gives the most important information that you want the public to know, for example in
relation to a health education campaign on the benefits of vaccination.
Killed vaccine – See Inactivated vaccine.
Large linked databases (LLDBs)

Administrative databases of relatively large size that were created separately from each other and linked to
enable the sharing of data across platforms. Such linked databases have become popular in vaccine safety
surveillance where specific disease’s occurrence can be linked to a person’s vaccination history.
Leukemia
Any of a group of neoplastic diseases of the blood-forming organs, resulting in an abnormal increase in
the production of leukocytes, often accompanied by anemia and enlargement of the lymph nodes, spleen,
and liver.
Licensure
The granting of a license to conduct a regulated procedure, for example, to conduct a trial of a new vaccine
or to approve a vaccine for routine delivery to the public in a vaccination programme.
Live attenuated vaccine (LAV)

A vaccine prepared from living micro-organisms (viruses, bacteria currently available) that have been
weakened under laboratory conditions. LAV vaccines will replicate in a vaccinated individual and produce
an immune response but usually cause mild or no disease.
184
Glossary
Local (or localized)

Restricted or limited to a specific body part or region.
Lot (or lot-release)

Vaccines are produced in “lots” or batches. Prior to releasing a “lot” of vaccine for public use, the NRA
provides a vital check on the manufacturer’s performance. As a minimum, lot release should be based
on review of the summary lot protocols, which contain details of that particular lot. In addition, selected
laboratory testing can be carried out. Lot release should be included in the regulations that cover biologi-
cal products.
Lymphadenitis
Lymphadenitis is the inflammation and/or enlargement of one or more lymph nodes. Most cases indicate
an immune response in the node to local infection or antigen stimulation, for example in a vaccine. Gen-
eralised lymphadenitis is a widespread inflammation of the lymph nodes due to systemic (circulating)
infection.
Lyophilized
Freeze-dried; e.g. measles and BCG vaccines are transported as lyophilized powders which must be
reconstituted with specific liquid diluents before use as injectable vaccines. Lyophilised vaccines must be
discarded within 6 hours of reconstitution, or at the end of a vaccination session, whichever comes first.
Macrophagic myofasciitis
A disease causing muscle pain, joint pain, muscle weakness, fatigue, fever, and muscle tenderness. It is
characterized by microscopic muscular infiltration with macrophages. Specific causes are unknown, but
the disease has been associated with the persistence of aluminum hydroxide used in some vaccines. The
diagnosis can only be confirmed through a muscle biopsy.
Malaria
An infectious disease caused by a parasite (plasmodium) that is transmitted from human to human by
the bite of infected female Anopheles mosquitoes. Malaria is a leading cause of morbidity and mortality
in sub-Saharan Africa.
Measles
A contagious viral disease marked by fever, the eruption of red circular spots on the skin that can be deadly
to young and weakened individuals.
Measles vaccine
A preparation of live attenuated measles virus used to immunize against measles.
Meningococcal disease
Bacterial diseases caused by the meningococcus (Neisseria meningitidis). Meningococcal diseases include
clinical forms of the disease, in particular meningitis, sepsis and pneumonia.
Microorganisms
Tiny organisms (including bacteria and viruses) that can only be seen with a microscope.
Minor (or mild) vaccine reaction

Vaccine reactions that usually occur within a few hours of injection, resolve after a short period of time,
and pose little danger.
185
Glossary
MMR vaccine
A preparation of live attenuated measles, mumps, and rubella viruses together in one vaccine, used to
immunize against measles, mumps, and rubella.
Monovalent vaccine
A monovalent vaccine is designed to immunize against a single antigen or single microorganism whereas
polyvalent vaccines aim to immunize against several strains of the same microorganism, or against several
microorganisms.
MR vaccine
A preparation of live attenuated measles and rubella viruses together in one vaccine, used to immunize
against measles and rubella.
Multiple Sclerosis (MS)

A disease of the central nervous system characterized by the destruction of the myelin sheath surround-
ing neurons, resulting in the formation of “plaques.” The cause of MS is unknown, although it appears
to require a genetic susceptibility combined with an environmental ‘trigger’, possibly a viral infection.
While extensively investigated, there is no epidemiologic evidence to support a link between vaccination
and onset or recurrence of MS.
Mumps
An acute contagious viral illness marked by swelling, especially of the parotid glands.
National immunization programme (NIP)

The organizational component of government Ministries of Health charged with preventing disease, dis-
ability, and death from vaccine-preventable diseases in children and adults. NIP is used interchangeably
with the Expanded Programme on Immunization (EPI) that originally focused on preventing vaccine-
preventable diseases in children.
National immunization technical advisory groups (NITAGs)

Advisory groups whose general objective is to guide national governments and policy-makers to develop
and implement evidence-based, locally relevant immunization policies and strategies that reflect national
priorities.
National pharmacovigilance centre

A governmentally recognized centre (or integrated system) within a country with the clinical and scientific
expertise to collect, collate, analyze, and give advice on all information related to drug safety.
National regulatory authority (NRA)

The regulatory body that approves procedures to ensure that medicines, including vaccines, are of ade-
quate safety and potency. The vaccine manufacturer is responsible for demonstrating that the vaccine
batch produced meets the requirements, based on the test specifications given by the NRA. The NRA is also
responsible both for the official vaccine lot release process, based on the data and information provided by
the manufacturer and, eventually, for confirmatory testing.
Necrosis
The death of living cells or tissues.
Neisseria meningitidis (aka meningococcus)

A bacterium that causes meningitis, as well as infections elsewhere in the body.
186
Glossary
Neomycin
A broad-spectrum antibiotic that is used in the manufacture of some vaccines.
Neonatal tetanus
Tetanus that occurs in a newborn infant.
Neuritis
Inflammation of the nerves.
Neurodevelopmental disorders
A disorder of neural development, an impairment of the growth and development of the brain or central
nervous system.
Neuropathy
A general term for any dysfunction in the nervous system. Symptoms include pain, muscle weakness,
numbness, loss of coordination, and paralysis. This condition may result in permanent disability.
Oedema
The presence of an excessive amount of fluid in or around cells, tissues, or serous cavities of the body.
Options analysis
A system for ranking multiple options in order to decide the best course of action in the prevailing
circumstances.
Oral polio vaccine (OPV)

A preparation of live attenuated polio virus, used to immunize against polio and developed by Dr. Albert
Sabin in 1961. OPV is administered orally (by mouth).
Otitis media
An inflammation of the middle ear usually caused by a virus or a bacteria. This condition usually occurs in
conjunction with an upper respiratory infection. Symptoms include earache, high fever, nausea, vomiting,
and diarrhea. In addition, hearing loss, facial paralysis, and meningitis may result.
Oxytocin
A hormone secreted by the posterior pituitary gland that stimulates contractions of the uterus and ejection
of milk. As a pharmaceutical it is used in childbirth and lactation to cause muscles to contract in the uterus
(womb) and mammary glands in the breast.
Pan-American Health Organization (PAHO) Revolving Fund for Vaccine Procurement

A mechanism developed by PAHO in 1979 for the purchase of vaccines, syringes/needles, and cold chain
equipment for countries in Latin America and the Caribbean. Through a system of bulk purchasing, the
Fund has secured for the past 30 years a supply of high quality vaccines for national immunization pro-
grams at affordable prices, and it has also allowed for the orderly planning of immunization activities.
Pandemic
An epidemic occurring over a very large area and affecting a large number of people.
Paracetamol (also known as acetaminophen)

A widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer).
187
Glossary
Passive reporting – See Passive surveillance.

Passive surveillance (also known as spontaneous reporting)
A surveillance system designed to collect adverse events that follow vaccination. This type of surveillance
typically relies on health professionals noticing and reporting adverse events in individuals after vaccina-
tion to the NRA or appropriate authority.
Pathogen
Any disease-causing substance. Most commonly used for organisms (e.g., bacteria, viruses) and their
biological products (e.g. toxins).
Pertussis (also known as whooping cough)

An infectious bacterial disease caused by Bordetella pertussis that produces violent, spasmodic coughing;
also called whooping cough.
Pertussis vaccine
Two types of pertussis vaccines are currently available: the inactivated whole-cell vaccine (wP) and subunit
protein-based vaccine (aP).
Pharmacovigilance
The science and activities relating to the detection, assessment, understanding, and prevention of adverse
effects or any other drug-related problem.
Placebo controlled
A randomized clinical trial may include controls in which some of the subjects receive a product which
has no active ingredients, referred to as a placebo, e.g. a sugar pill or an injection of normal saline. None
of the people in the clinical trial nor the clinical team administering the intervention know who was given
the placebo, or the test product, or the best performing existing product. A placebo controlled trial enables
researchers to evaluate whether the simple act of being given a pill or an injection has a beneficial effect.
Plague
A serious, potentially life-threatening infectious disease that is usually transmitted to humans by the bites
of rodent fleas. It was one of the scourges of early human history.
Pneumococcal conjugate vaccine (PCV-7, PCV-10, PCV-13)

Three subunit polysaccarhide-conjugate vaccines exist against pneumococcus. PCV-7 vaccine protects
against seven serotypes and PCV-10 protects against ten serotypes of Streptococcus pneumoniae, and
PCV-13 protects agains 13 serotypes serotypes of Streptococcus pneumoniae most commonly isolated
from young children.
Pneumococcal disease
Bacterial diseases caused by Streptococcus pneumoniae. Pneumococcal diseases include meningitis, sep-
sis, and pneumonia, all of which cause significant illness and death.
Poliomyelitis (also known as polio)

An acute infectious viral disease characterized by fever, paralysis, and atrophy of skeletal muscles. The
Global Polio Eradication Initiative was launched in 1988 with the goal of eradicating polio from the earth
through routine and mass polio vaccination programs.
Polysaccharide vaccine
A vaccine that is composed of long chains of sugar molecules that resemble the surface of certain types of
bacteria. Polysaccharide vaccines are available for pneumococcal disease, meningococcal disease, and Hib.
Post-licensure surveillance (also known as post-marketing surveillance)

Pharmacovigilance conducted after a product has been licensed and introduced for use in a population.
Potency
A measure of strength or immunogenicity in vaccines.
188
Glossary
Prequalified vaccine
A vaccine that has been approved as acceptable, in principle, for purchase by United Nations agencies, such
as WHO, after full assessment of all procedures involved in its production. The purpose of the assessment
is to verify that prequalified vaccines: (a) meet the specifications of the relevant UN agency; and (b) are
produced and overseen in accordance with the principles and specifications recommended by WHO, for
good manufacturing practice (GMP), and for good clinical practice (GCP). This is to ensure that vaccines
used in national immunization services in different countries are safe and effective for the target popula-
tion at the recommended schedules and that they meet particular operational specifications for packaging
and presentation.
Preservatives
Compounds that are added to multi-dose vaccine vials to prevent bacterial and fungal growth. The most
commonly used product is called thiomersal, a mercury-containing compound.
Priming
The process of artificial induction of immunity, in order to protect against infectious disease. Priming the
immune system involves sensitizing or stimulating an immune response with an antigen that can produce
immunity to a disease-causing organism or toxin (poison). Vaccinations involve the administration of one
or more of these antigens, which can be administered in several forms.
Programme for International Drug Monitoring (PIDM)

This programme, established in 1968, consists of a network of national pharmacovigilance centres, WHO
Headquarters in Geneva, and the WHO Collaborating Centre for International Drug Monitoring, the
Uppsala Monitoring Centre, in Uppsala, Sweden. For more information, see https://www.who-umc.org/
global-pharmacovigilance/who-programme/.
Rabies
A potentially fatal viral infection spread through the bite of certain warm-blooded animals. It attacks the
central nervous system and, if left untreated, is highly fatal in animals.
Randomized clinical trials

A systematic study of medical interventions in human subjects (including patients and other volunteers) in
which study subjects are randomly assigned to treatment and control groups. Used to discover or verify the
effects of and/or identify any adverse reactions to investigational products, and/or to study the absorption,
distribution, metabolism and excretion of the products with the objective of ascertaining their efficacy
and safety. Studies in which neither the investigator nor the study subjects know to which group, treat-
ment or control, they have been assigned until the conclusion of the study are referred to as ‘double-blind
randomized clinical trials’ and are considered the gold standard for drug and vaccine efficacy research.
Reactogenicity
Being able to produce adverse reactions.
Reassortant vaccine
A live attenuated vaccine in which attenuation is achieved by using virus strains in which some gene
sequences have been rearranged (reassorted); for example, RotaTeq vaccine contains five reassortant rota-
virus strains.
Recombinant DNA
A vaccine technology that uses genetic material from a disease-causing organism into a live vector, often
a yeast cell, in order to replicate a protein antigens of the disease-causing organism. The proteins are then
purified and used as vaccine.
189
Glossary
Reconstituted vaccine
The mixing of a powdered (usually lyophilized) form of a vaccine with a fluid called a diluent prior to injection.
Retrovirus
An RNA virus (a virus composed not of DNA but of RNA). Retroviruses have an enzyme called reverse
transcriptase that gives them the unique property of transcribing RNA (their RNA) into DNA. The retroviral
DNA can then integrate into the chromosomal DNA of the host cell to be expressed there. HIV is a retrovirus.
Risk
The probability that an individual will experience a certain event during a defined period of time.
Risk-benefit analysis
Evaluation and assessment of the relative risks and benefits of an intervention, e.g. the potential benefit of
protection from measles and its complications due to vaccination, relative to the potential risk of adverse
reactions to the vaccine.
Rotavirus
A group of viruses that cause diarrhea (rotaviral gastroenteritis) in children.
Rotavirus vaccine
A preparation of live attenuated rotavirus used to immunize against infant rotaviral gastroenteritis.
Rubella (German measles)

A viral infection that is usually milder than measles but can cause serious damage or death to a fetus when
a pregnant woman is infected.
Rubella vaccine
A preparation of live attenuated rubella virus used to immunize against rubella.
Safety profile
A summary of the evidence on the safety of a medical product, such as a vaccine or drug, under ideal
conditions of use, including the incidence of any adverse reactions relative to the number of doses given.
Sciatic nerve
The largest nerve in the human body providing both motor and sensory control for much of the lower
limbs. Vaccination of infants and children in the buttock is not recommended because of concern about
potential injury to the sciatic nerve, which is well documented after injection into the buttock.
Second opportunity
WHO recommends that all children receive two doses of measles vaccine, either through routine services
or mass vaccination campaigns. Often when the second dose is delivered through campaigns, it is consid-
ered the second opportunity for measles vaccination.
Seizure
Uncontrolled electrical activity in the brain, resulting in convulsion, physical signs, thought disturbances,
or a combination of symptoms.
Sensitivity
In the context of public health surveillance, the proportion of all incident cases of a health condition
detected by a surveillance system.
190
Glossary
Sepsis (also known as “blood stream infection”)

The presence of bacteria (bacteremia) or other infectious organisms or their toxins in the blood (septice-
mia) or in other tissue of the body.
Serious adverse event

A regulatory term defined as any untoward medical occurrence that at any dose: results in death; requires
inpatient hospitalisation or prolongation of existing hospitalization; results in persistent or significant dis-
ability/incapacity; or, is life-threatening. For more information, see http://www.fda.gov/safety/medwatch/
howtoreport/ucm053087.htm.
Severe vaccine reaction

This is not a regulatory term. It refers to vaccine reactions that usually do not result in long-term problems,
but can be disabling and, rarely, life threatening. Severe reactions include serious reactions but also include
other severe reactions.
Side effect
Any unintended effect of a pharmaceutical product (including vaccines) occurring at a dose normally used
in man.
Signal
Reported information on a possible causal relationship between an adverse event and a drug, the relation-
ship being previously unknown or incompletely documented. Usually more than a single report is required
to generate a signal, depending upon the seriousness of the event and the quality of the information.
Simple message
A simple message is ‘jargon free’ and easy for the general public to understand – it ‘translates’ complex
concepts and information into readily accessible ideas and examples.
Smallpox
An acute, highly infectious, often fatal disease caused by a variola virus and characterized by high fever
and aches with subsequent widespread eruption of pimples that blister, produce pus, and form pockmarks.
Declared eradicated by the World Health Assembly in 1980.
Sorbitol
An alcohol used in the manufacture of some vaccines.
Specificity
In the context of surveillance, the measure of the degree to which cases detected through a surveillance
system actually have the disease.
Spontaneous reporting – See Passive surveillance.

Stabilizers
Compounds that are used to help vaccine maintain its effectiveness during storage. Vaccine stability is
essential, particularly where the cold chain is unreliable. Factors affecting stability are temperature and pH.
Standard case definition

A common, formal definition for the health-related event under surveillance. The case definition of a
health-related event can include clinical manifestations (i.e., symptoms), laboratory results, epidemiologic
information (e.g., person, place, and time), and/or specified behaviors, as well as levels of certainty (e.g.,
confirmed/definite, probable/presumptive, or possible/suspected). The use of a standard case definition
increases the specificity of reporting and improves the comparability of the health-related event reported
from different sources of data, including geographic areas.
191
Glossary
Strain
A specific genetic grouping of an organism. Many organisms, such as viral influenza, pneumococcus and
meningococcus, have multiple strains that cause disease.
Stridor
A whistling sound generated when breathing (usually heard on inspiration) that indicates obstruction of
the trachea or larynx.
Subcutaneous (SC) injection

Administration of vaccine into the subcutaneous layer above the muscle and below the skin.
Subunit conjugate vaccine

A vaccine in which two compounds (usually a protein and polysaccharide) are joined together to increase
the vaccine’s effectiveness.
Subunit polysaccharide vaccine

A vaccine that uses portions of bacteria that are composed of long chains of sugar. Polysaccharide vaccines
are available for pneumococcal disease, meningococcal disease and Hib.
Subunit protein-based vaccine

A vaccine made from fragments of viruses or bacteria that involve a protein to increase the vaccine’s
effectiveness.
Subunit vaccine
A vaccine made from components of viruses or bacteria instead of the whole organism.
Sudden Infant Death Syndrome (SIDS) (also known as “crib” or “cot” death)
The sudden and unexpected death of a healthy infant under one year of age. A diagnosis of SIDS is made
when an autopsy cannot determine another cause of death. The cause of SIDS is unknown.
Suppurative lymphadenitis
This is a common adverse reaction to tuberculosis (BCG) vaccine and involves the inflammation of the
lymph nodes associated with skin ulceration.
Surfactant
A chemical agent capable of reducing the surface tension of a liquid in which it is dissolved.
Surveillance
The systematic collection, analysis, interpretation, and dissemination of health data on an ongoing basis,
to gain knowledge of the pattern of disease occurrence and potential in a community, in order to control
and prevent disease in the community.
Surveillance system
The systematic collection, analysis, interpretation, and dissemination of health data on an ongoing basis,
to gain knowledge of the pattern of disease occurrence and potential in a community, in order to control
and prevent disease in the community.
Synthetic vaccine
A vaccine consisting mainly of synthetic peptides or carbohydrates as antigens. They are often considered
to be safer than vaccines from bacterial cultures.
Systemic
Relating to a system, or affecting the entire body or an entire organism (e.g., fever).
192
Glossary
Tachycardia
A heart rate that exceeds the normal range for a resting heart.
Td vaccine
A preparation of tetanus and diptheria toxoids together in one vaccine used to immunize adults against
diphtheria and tetanus. This vaccine contains a reduced amount of diphtheria toxoid used in the DT prepa-
ration for children. When given to women of childbearing age, vaccines that contain tetanus toxoid (TT or
Td) not only protect women against tetanus, but also prevent neonatal tetanus in their newborn infants.
Temporal association
Two or more events that occur around the same time. The preceding event may or may not be causally
related to the later one.
Tetanus
A disease caused primarily by toxigenic C. tetani. The rare but often fatal disease affects the central ner-
vous system by causing painful muscular contractions.
Tetanus toxoid (TT) vaccine

A preparation of tetanus toxoid used to immunize against tetanus. When given to women of childbear-
ing age, vaccines that contain tetanus toxoid (TT or Td) not only protect women against tetanus, but also
prevent neonatal tetanus in their newborn infants.
Thiomersal
Thiomersal is a mercury-containing preservative that has been used in some vaccines and other products
since the 1930’s. While there is no evidence that the low concentrations of thiomersal in vaccines have
caused any harm other than minor reactions like redness or swelling at the injection site, in July 1999 the
US Public Health Service, the American Academy of Pediatrics, and vaccine manufacturers agreed that
thiomersal should be reduced or eliminated from vaccines as a precautionary measure. Today, all routinely
recommended childhood vaccines manufactured for the US market contain either no thiomersal or only
trace amounts.
Thrombocytopenia
A severe decrease in the number of blood platelets, the cells involved in clotting. Thrombocytopenia may
stem from failure of platelet production, splenic sequestration of platelets, increased platelet destruction,
increased platelet utilization, or dilution of platelets.
Thrombocytopenic purpura
Severe thrombocytopenia characterized by mucosal bleeding and bleeding into the skin in the form of
multiple petechiae (small purlish spot), most often evident on the lower legs, and scattered small bruises
at sites of minor trauma. In children, idiopathic thrombocytopenic purpura is usually self-limited and
follows a viral infection.
Time to onset
The period of time between an intervention (in this case, a vaccination) and the onset of an adverse reac-
tion to the vaccine.
Toxic shock syndrome

A rare serious adverse event resulting from improper vaccine preparation and injection practices. It is a
life-threatening illness that is caused by toxins (poisons) that circulate in the bloodstream. Bacteria that
have infected some part of the body release these toxins. People with toxic shock syndrome develop high
fever, rash, low blood pressure, and failure of multiple organ systems in the body.
193
Glossary
Toxoid
Inactivated or killed toxin (poison) used in vaccine production.
Toxoid vaccine
A vaccine made from a toxin (poison) that has been made harmless but that elicits an immune response
against the toxin.
Tuberculosis (TB)
A disease caused by the bacterium Mycobacterium tuberculosis. The bacteria usually attack the lungs. But,
TB bacteria can attack any part of the body such as the kidney, spine, and brain. If not treated properly,
TB disease can be fatal.
Tuberculosis vaccine (Bacillus Calmette-Guérin, BCG vaccine)

A vaccine against tuberculosis that is prepared from a strain of the live attenuated bovine tuberculosis bacillus.
Tuberculosis vaccine is used in many countries with a high prevalence of tuberculosis to prevent childhood
tuberculous meningitis and miliary disease. It is administered intradermally and often leaves a scar.
Typhoid (typhoid fever)

A serious disease caused by a bacteria called Salmonella Typhi. Typhoid causes a high fever, weakness,
stomach pains, headache, loss of appetite, and sometimes a rash. If it is not treated, it can kill up to 30% of
people who get it. There are different vaccines to prevent typhoid: inactivated vaccines that require injec-
tion, and live attenuated vaccines that are taken orally (by mouth).
Uppsala Monitoring Centre (UMC)

An independent centre which receives adverse drug reactions from national pharmacovigilance centres in
WHO member countries and generates signals of possible side-effects. For more information, see http://
http://www.who-umc.org.
Urticaria (also known as hives)

The eruption of red marks on the skin that are usually accompanied by itching. This condition can be
caused by an allergy (e.g., food, vaccine, drugs), stress, infection, or physical agents (e.g., heat, cold).
Vaccination
Inoculation with a vaccine for the purpose of inducing immunity.
Vaccine
A material containing live attenuated or inactivated (killed) microorganisms, or constituents of microor-
ganisms, capable of eliciting protection against infection.
Vaccine Adverse Event Reporting System (VAERS)

A passive surveillance system in the US intended to collect reports of reactions to vaccines. Under the aegis
of the US Centers for Disease Control and Prevention and the US Food and Drug Administration.
Vaccine effectiveness
The probability that a vaccine, when used in the field under routine vaccination circumstances, confers
immunity in a population. Expressed as a percent.
Vaccine efficacy
The potential of a vaccine to protect from a disease in controlled clinical trials. Expressed as a percent.
194
Glossary
Vaccine pharmacovigilance
The science and activities relating to the detection, assessment, understanding and communication of
adverse events following immunization and other vaccine- or immunization-related issues, and to the
prevention of untoward effects of the vaccine or immunization
Vaccine reaction (also referred to as adverse vaccine reaction or adverse reaction)

A classification of AEFI referring to events caused or precipitated by the vaccine when given correctly,
caused by the inherent properties of the vaccine.
Vaccine safety
The process of ensuring and monitoring the safety of vaccines through their life cycle.
Vaccine safety surveillance – See AEFI surveillance.

Vaccine-associated neurotropic disease
A very rare disease of the nervous system that follows vaccination against yellow fever.
Vaccine-associated paralytic poliomyelitis (VAPP)

A very rare risk of paralytic polio resulting from oral poliomyelitis vaccine (OPV). Associated with approx-
imately one in every 2.5 million doses of OPV. VAPP is not a risk with IPV.
Vaccine-associated risk
The probability of an adverse or unwanted outcome occurring, and the severity of the resultant harm to
the health of vaccinated individuals in a defined population, following immunization with a vaccine under
ideal conditions of use.
Vaccine-associated viscerotropic disease

A disease that presents with fever, liver damage and blood disorders that very rarely results from vaccina-
tion against yellow fever.
Vaccine-derived poliovirus (VDPV)

Where polio vaccine coverage rates decline but OPV use continues, person-to-person spread of vaccine
polioviruses can lead to increased virulence that resemble the wild virus.
Vaccine-preventable diseases
Diseases for which vaccines exist that can confer partial or complete protection.
Vaccinee
The individual receiving a vaccine.
Valent
The number of types of a microorganism that are covered in a vaccine product (e.g. seasonal influenza
vaccines that typically cover three virus types are called tri-valent).
Validity
The degree to which an estimate reflects the true value of what it purports to measure.
Varicella (also known as chickenpox)

An acute contagious disease characterized by papular and vesicular lesions.
Vasculitis
Refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood
vessels that cause a visible rash.
Vasovagal syncope
A neurovascular reaction that leads to fainting.
195
Glossary
Virus
An ultramicroscopic infectious agent that consists of genetic material surrounded by a protein coat. A
virus can replicate themselves only within cells of living hosts.
Whole cell pertussis (wP) vaccine

A preparation of inactivated whole cell pertussis bacterium, used to immunize against pertussis.
Wild poliovirus
A strain of poliovirus that occurs naturally, as opposed to vaccine-related strains.
World Health Organization (WHO)

A United Nations specialized agency established to coordinate international health activities and to help
governments improve health services.
Yellow fever
An infectious viral tropical disease transmitted by mosquitoes and characterized by high fever, jaundice,
and gastrointestinal bleeding.
Yellow fever vaccine

A preparation of live attenuated yellow fever virus, used to immunize against yellow fever. A single dose
provides protection against the disease for at least ten years and often for 30 years or more.
196
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201
Questions solutions
Module 1
Question 1
Answer A and D are correct.
Eradication refers to the complete and permanent worldwide reduction to zero new cases of the disease
through deliberate efforts.
If a disease has been eradicated, no further control measures are required.
Elimination refers to the reduction to zero (or a very low defined target rate) of new cases in a defined
geographical area.
Elimination requires continued measures to prevent re-establishment of disease transmission.
Question 2
All the answers are correct.
The initial EPI goals were to vaccinate every child against tuberculosis, polio, diphtheria, per-
tussis, tetanus and measles by the time they were one year of age, and to give tetanus toxoid
vaccinations to women to protect them and their newborns against tetanus.
Question 3
Answers A and D are correct.
An AEFI is any adverse event observed following immunization. Some may be due to the
vaccine, some due to error in the administration of the vaccine, and some are the result of
unrelated coincidence.
An adverse vaccine reaction is a subset of AEFI. It refers to a vaccine-related event caused or
precipitated by a vaccine when given correctly. Note that the rate of adverse vaccine reactions
is very much lower than the rate of health-damaging complications resulting from the disease
in unvaccinated individuals.
Question 4
All answers are correct.
All of the listed components can contribute to the risk of an adverse reaction.
Question 5
Answer D is wrong.
An event that occurs in 2 out of a thousand persons is regarded as uncommon (infrequent).
Please compare the frequency and the Percentage of persons vaccinated in the table above.
202
Questions solutions
Module 2
Question 1
Answer B: Allergic anaphylactic reactions are more likely to occur after receipt of the second dose of
measles vaccine.
Answer C: Pertussis (wP) is an inactivated vaccine. Live vaccines include:
■■ Tuberculosis (BCG),
■■ Oral Polio Vaccine,
■■ Measle,
■■ Rotavirus,
■■ Yellow Fever.
Question 2
Answer C is incorrect.
Inactivated vaccines can be considered safer than live vaccines, which, however, comes with a
reduced effectiveness of the vaccine. Inactivated vaccines should not be seen as ineffective – the
immunization schedule foresees repeated doses to ensure adequate immune responses in patients.
Live vaccines on the other hand should not be seen as unsafe – their production is usually
done with meticulous quality checks ensuring their safety. It is rather important to have well
trained health staff screening patients for counter indications to the vaccines.
Question 3
Measles vaccine is a live vaccine, not a conjugate vaccine.
Question 4
This pentavalent vaccine combines five (‘penta’) antigens in one formulation: diphtheria toxoid, tetanus
toxoid, whole-cell pertussis, hepatitis B and Haemophilus influenzae type b.
Question 5
Answer B is incorrect.
Aluminium salts primarily slow the escape of the antigen from the site of injection. As the
exposure between the antigen and the immune system, they increase the effectiveness of the
vaccine.
203
Questions solutions
Module 3
Question 1
This statement is true.
Events that are life-threatening or result in the death of a patient are defined as “serious”.
Question 2
Answer C is correct.
Incorrect storage can lead to reconstitution errors: The drug may be given to the client in mis-
take for a vaccine or may be used instead of the correct diluent to reconstitute a freeze-dried
powder vaccine.
Question 3
Answer A is correct.
The number of expected infant deaths occurring the day after DTP immunization
would total 2,421.
Question 4
Answer B is correct.
The vaccine attributable rate is 0.2:1,000 or 2 additional cases of convulsions in infants in every
10,000 vaccinations, compared with the background rate.
Module 4
Question 1
Parents may be anxious about immunization because they are voluntarily exposing their
healthy children to the risk of an adverse reaction. Any benefit from the vaccination is not
immediate and can only be imagined in terms of protection from future disease.
Question 2
Pharmacovigilance authorities concluded that the original clinical trial contained too few vac-
cinees to detect the real incidence of such a rare adverse event. As a consequence, subsequent
rotavirus vaccines were subject to clinical trials containing at least 60,000 infants. This example
illustrates why signal detection, hypothesis generation and testing are vital in post-licensure
pharmacovigilance of vaccines.
Question 3
Answers B and C are correct.
Answer A: According to the Brighton Case definition, fever higher than 40.5 degrees Celsius
is “extreme”.
Answer D: To be due to DTP vaccination, encephalopathy symptoms should occur within 48
hours of vaccination.
204
Question 4
The case was isolated and clinical & laboratory investigations were carried out. A brain biopsy was col-
lected immediately after the child’s death and sent for culture, microscopy and electronic microscopy. It
was determined that herpes virus was responsible for the clinical picture. This example shows, that it is
critical to take additional information into account.
Apart from the additional information that was made available, one has to be aware, that the nature of the
problem is also a potential factor:
–– Disease level and incidence – is this a common vaccine-preventable condition (e.g. measles)
or relatively rare (e.g. diphtheria)?
–– Is this a crisis situation – for example, a life-threatening vaccine reaction or a threat to the
continuation or success of the immunization programme?
–– Is the risk caused by an immunization error that can be identified and corrected, or is it an
unavoidable and inherent risk?
–– Why has concern been raised about the risk and by whom?
Module 5
Question 1
Answer C is correct.
For infants known to be HIV infected, the risks linked to the vaccination outweigh its benefits with or
without signs and symptoms.
They should not be immunized.
For infants with unknown HIV status who have signs and symptoms of infection and are born to infected
mothers the risks usually outweighs benefits.
They should not be immunized. If infection status can be established early (virology), BCG may
be administered once HIV infection ruled out.
For infants born to women of unknown HIV status the benefits outweigh the risks.
These infants should be immunized.
For infants whose HIV status is unknown and who demonstrate no signs or reported symptoms suggestive
of HIV infection but who are born to known HIV-infected women benefits usually outweigh the risks.
These infants should be immunized after consideration of local factors (details in guideline79).
Question 2
Pooling and analysing data from several countries provides additional statistical power for
identifying rare adverse events, such as intussusception following rotavirus vaccination. It
could reduce the time taken to investigate and establish a causal association between the AEFI
and the vaccine and take appropriate action.
Questions solutions
Module 6
Question 1
The AEFIs are due to an immunization error as the investigation revealed that unsterile needles had been
used.
To avert this practice, WHO recommends the use of sterile, disposable auto-disable (AD) syringes with
attached needles for all vaccine injections; AD syringes cannot be used a second time because the plunger
“locks” when it has been pushed forward to deliver the vaccine and it cannot be pulled back.
Note how the key messages are listed to support the main message of the statement:
■■ Information specifying the event,
■■ Possible cause of the AEFI,
■■ Scientific evidence on the disease,
■■ Scientific evidence on the vaccine,
■■ Response undertaken to respond to the event.
Question 2
All of the statements above are correct.
Relevant tools include discussions on social media channels, e.g. Facebook, Twitter; blogs (diaries, opinion
pieces and commentaries on news and events written by members of the general public as well as journal-
ists and all kinds of experts); or Wikipedia, the online encyclopaedia, with content freely created by its
worldwide contributors.
All these forms of communication can be harnessed to deliver correct health messages on vaccine safety
and to counteract misleading or health-damaging information that is causing concern locally or nationally.
Question 3
A, C and D are correct.
The best means of communicating with a nervous young mother may be a one-to-one interview in a room
where you will not be disturbed and the conversation is private. Take time to listen to her concerns and
reassure her that they are understandable. Use simplified messages in language that she can understand
and do not overload her with too much technical detail. Leaflets that provide additional information to
read later may serve well to reinforce your messages.
Communication with teachers at a large school can take place in a group meeting, so that your message
can influence many of them at the same time. The room should be large enough to seat everyone comfort-
ably, so they can all see you. Make, however, sure that the group is small enough that they can be heard by
everyone if they ask questions. Use display materials (e.g. posters, video, slides) and provide hand-outs to
read later to reinforce your messages.
Question 4
All of the statements above are correct.
206
Questions solutions
Question 5
Statements B and C are correct.
A vaccine reaction or immunization error means that a previously healthy person was subjected to some
form of harm as a result of the immunization. By contrast, medical drugs are given to people who are
already sick, to make them better. This difference results in a much lower public tolerance to adverse reac-
tions of vaccines than there is to the side-effects of drugs.
Most vaccine recipients are babies and young children who were vaccinated with their parents’ consent;
any harm that occurs following an immunization is seen as “avoidable” by parents because the vaccine
could have been refused. There is much less tolerance for instances of avoidable harm than there is for
adverse events that could not be avoided.
Due to a decline of childhood infections in industrialized countries the threats to health and life posed by
once-common vaccine preventable diseases (measles, polio, pertussis, diphtheria and tetanus) is low. The
benefits of vaccination are no longer being reinforced by directly experiencing the diseases that vaccines
prevent.
Question 6
Statements A, B, C, D, and E are correct.
Your key message should be a simple explanation of the situation: If there is no evidence that the
death was caused by the vaccine itself, state this. If there is an investigation ongoing, say this.
As with any new vaccine, health authorities closely monitor adverse events following the vaccination, so
that any safety issues are quickly identified and followed up. State how many people have been vaccinated
with this vaccine, how many serious adverse events have been reported, and how many of those have
proven to be related to the vaccine itself, to put this particular event into perspective. For example, state
how many people die or are seriously ill each year as a result of influenza.
If you do not have information to respond to a journalist’s request, offer the journalists to share the
information with them later, or refer them to the specialist who has this information available. After the
interview, provide the offered information to the journalist in a timely manner.
Question 7
Sequence: D: 1, A: 2, C: 3, B: 4.
(other sequences are possible).
207

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VACCINE

OVERALL COORDINATION (WHO)

DESIGN AND TECHNICAL IMPLEMENTATION

© World Health Organization 2013

MODULE 1: Introduction to vaccine safety................................................................................. 9

MODULE 2: Types of vaccine and adverse reactions.............................................................. 38

MODULE 3: Adverse events following immunization.............................................................. 67

ASSESSMENT 4............................................................................................................................ 108

MODULE 5: Vaccine safety institutions and mechanisms................................................... 113

ASSESSMENT 5............................................................................................................................ 139

MODULE 6: Communication....................................................................................................... 145

ASSESSMENT 6............................................................................................................................ 167

Adverse events Vaccine safety

MODULE 1: Introduction to vaccine safety ASSESSMENT

MODULE 2: Types of vaccine and adverse reactions ASSESSMENT

MODULE 3: Adverse events following immunization ASSESSMENT

MODULE 4: Surveillance ASSESSMENT

MODULE 5: Institutions and mechanisms ASSESSMENT

MODULE 6: Communication ASSESSMENT

1 Explain the importance of Vaccination in the control of infectious diseases,

Importance of immunization programmes

History of vaccine development

1955 Polio (IPV)

1800 – 1899 1900 – 1949 1950 – 1979 1980 – 1999 2000

Strengthening immunization: WHO’s Expanded Programme on Immunization

1974 1990 1999

Expectations towards safety of vaccines

Low public tolerance requires safe vaccination

General public has low tolerance to adverse events

Expectation to safety standard is higher with

National regulatory authorities (NRAs) ensure with rigor the quality,

Once introduced, NRAs monitor Before being

How the immune system works

Primary and secondary immune response. Source: wikipedia.org

Primary and secondary immune responses to the same pathogen

How vaccines work

Vaccines reproduce a natural infection with less complications

Natural infection IMMUNITY Vaccination

Immunization triggers an immune ☑ Vaccinee does not endure

Tubercle bacillus Bacillus Calmette-Guérin (BCG) vaccine

Oral polio vaccine (OPV) vaccine, I

Clostridium tetani (Tetanus)** Tetanus toxoid (TT) vaccine

Whole-cell pertussis (wP) vaccine,

Measles virus Measles vaccine

Hepatitis B virus Hepatitis B vaccine

Rotavirus Rotavirus vaccine

Haemophilus influenzae type B (Hib) Hib conjugate vaccine

Yellow fever virus Yellow fever vaccine

Live attenuated (LAV)

Inactivated (killed antigen)

– Whole-cell pertussis (wP)

Subunit (purified antigen)

– Acellular pertussis (aP),

Toxoid (inactivated toxins)

– Tetanus toxoid (TT),

Vaccine manufacturers strive to develop vaccines that:

Vaccine product-related reaction

Vaccine quality defect-related reaction

Immunization error-related reaction