The Journal of Infectious Diseases

SUPPLEMENT ARTICLE

Measles in the 21st Century: Progress Toward

Achieving and Sustaining Elimination
1 2 3 1 4 1
Paul A. Gastañaduy, James L. Goodson, Lakshmi Panagiotakopoulos, Paul A. Rota, Walt A. Orenstein, and Manisha Patel

1
Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA,
2
Global Immunization Division, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, 3Immunization Safety Office,
National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, and 4Emory University
and the Emory Vaccine Center, Atlanta, Georgia, USA

The global measles vaccination program has been extraordinarily successful in reducing measles-related disease
and deaths worldwide. Eradication of measles is feasible because of several key attributes, including humans as
the only reservoir for the virus, broad access to diagnostic tools that can rapidly detect measles-infectious
persons, and availability of highly safe and effective measles-containing vaccines (MCVs). All 6 World Health
Organization (WHO) regions have established measles elimination goals. Globally, during 2000– 2018, measles
incidence decreased by 66% (from 145 to 49 cases per million population) and deaths decreased by 73% (from
535 600 to 142 300), drastically reducing global disease burden. Routine immunization with MCV has been the
cornerstone for the control and prevention of measles. Two doses of MCV are 97% effective in preventing
measles, qualifying MCV as one of the most effective vaccines ever developed. Mild adverse events occur in
<20% of recipients and serious adverse events are extremely rare. The economic benefits of measles vaccination
are highlighted by an overall return on investment of 58 times the cost of the vaccine, supply chains, and vacci-
nation. Because measles is one of the most contagious human diseases, maintenance of high (≥95%) 2-dose
MCV coverage is crucial for controlling the spread of measles and successfully reaching measles elimination;
however, the plateauing of global MCV coverage for nearly a decade and the global measles resurgence during
2018–2019 demonstrate that much work remains. Global commitments to increase community access to and
demand for immunizations, strengthen national and regional partnerships for building public health
infrastructure, and implement innovations that can overcome access barriers and enhance vaccine confidence,
are essential to achieve a world free of measles.

Keywords. measles; measles; mumps; rubella vaccine; MMR; elimination; eradication.

Measles is a febrile rash illness that can lead to serious compli- cations and death and one of the world’s most
contagious viral diseases. The basic reproduction number (or average number of secondary cases generated by
an infectious person in a fully sus- ceptible population) for measles is estimated to be 12–18, higher than that of
many other common childhood illness (eg, influenza, pertussis). Under the assumption of a homogenously
mixing population, such high transmissibility means that significantly high population immunity levels of
>92%–94% are needed to impede sustained measles virus transmission. Measles vaccines have been
enormously successful in controlling measles globally, demonstrating the feasibility of reaching a measles
eradication goal (ie, reduction of measles cases globally to zero). In the cur- rent article, we review the
significant impact measles vaccination uptake has had on reducing measles disease burden worldwide, the origin
of measles vaccines and their safety and effectiveness

Correspondence: Paul A. Gastañaduy, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS H24-5, Atlanta, GA 30333 ([email protected]).

The Journal of Infectious Diseases® 2021;224(S4):S420–8

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under
the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and
reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/infdis/jiaa793

profiles, global trends in vaccination coverage, the economic benefits of investing in measles vaccination, the
various setbacks encountered in measles control in recent years, and key challenges that must be overcome to
achieve a world free of measles.
MEASLES DISEASE BURDEN AND IMPACT OF MEASLES VACCINATION

Before the introduction of measles vaccination, measles caused substantial human disease and death worldwide,
infecting nearly everyone by 15 years of age. Measles was common in all parts of the world and caused an
estimated 135 million cases and more than 6 million deaths globally each year [1]. In the United States alone, an
estimated 3–4 million people acquired measles every year (roughly equivalent to a birth cohort), of which
approximately 500 000 cases and nearly 500 deaths were reported annually [2].

Although most persons fully recover from measles without sequelae, the disease entails significant morbidity
and mortality risks. Common complications of measles in- clude otitis media and diarrhea, but more serious
complica- tions can also occur and include pneumonia, encephalitis, and subacute sclerosing panencephalitis, a
slowly progres- sive neurologic sequela of measles that is universally fatal (estimated risk, 1 subacute sclerosing
panencephalitis case

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per 5000 measles cases) [3]. Secondary bacterial infections related to measles-induced immunosuppression
(inhibition of lymphocyte proliferation and decrease in specific preex- isting antibodies) can further complicate
disease progres- sion and recovery [4–8]. Measles case fatality ratios (CFRs) vary widely, depending on access
to quality healthcare and the underlying nutritional and health status of those in- fected [9]. Measles CFRs in
high-income countries such as the United States can be as low as 0.1% (or lower), but are much higher in other
settings; CFRs have been estimated to be 4%–5% in Africa, and as high as 30% among vulnerable children
during humanitarian crises [10].

After more widespread use of measles vaccines globally in the 1980s, measles incidence and mortality rates
decreased to low levels in all regions of the world [11]. During 2000–2018, the worldwide annual reported
measles incidence per million population decreased by 66%, from 145 to 49 cases, the an- nual number of
reported measles cases decreased by 59%, from 853 479 to 353 236 (Figure 1), and annual estimated measles
deaths decreased by 73%, from 535 600 to 142 300 [11]. In the United States, where measles elimination (ie,
absence of contin- uous endemic measles virus transmission for more than a year) was achieved in 2000, new
measles cases originate through measles introductions from abroad, mainly from unvaccinated

1 000 000 500 000 0

Figure 1. Number of reported measles cases in the United States from 1962 to 2019 (A) and worldwide from 1980 to 2019 (B). Data from
US Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report; global data available at
http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencemeasles. html.
600 000 500 000 400 000

300 000 200 000 100 000

1963
Vaccine licensed

30 000

25 000

1989 - 1991

Resurgence

4 500 000 4 000 000 3 500 000 3 000 000 2 500 000 2 000 000 1 500 000

1989

2nd Dose recommended

1985 1990 1995 2000 2005 2010 2015

2000

Elimination declared

0
1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005 2008 2011 2014 2017

1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018

20 000 1993

15 000 10 000 5000 0

Vaccines for Children program

Progress Toward Measles Elimination • jid 2021:224 (Suppl 4) • S421

Cases, No.

Cases, No.

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US travelers becoming infected and returning home with mea- sles. During 2001–2018, a median of 79 total
cases (range, 37–667), including a median of 28 internationally imported cases (range, 18–82 importations),
were reported annually in the United States, with 3 confirmed measles-related deaths re- ported during that 18-
year period [12, 13]. This low burden of measles equates to more than a 99% decline in the reported number of
cases and deaths due to measles when comparing US prevaccine and postelimination periods (Figure 1) [14].

As of 2019, a total of 83 countries have verified measles elim- ination, paving a path forward for global
eradication. Several key attributes position measles as a prime candidate for eradi- cation: (1) absence of a
nonhuman reservoir (ie, unimmunized humans are essential for the life cycle of the measles virus), (2)
availability of practical and sensitive diagnostic tools, such as immunoglobulin (Ig) M serologic assays and
molecular tests to identify persons with acute measles, and, most importantly, (3) highly effective measles
vaccines. Measles eradication is fea- sible [15]; however, global commitment is essential to sustain longstanding
progress to reduce measles morbidity and mor- tality rates and to achieve regional elimination goals.

GENOTYPIC VARIATION AND PATHOGENESIS OF MEASLES VIRUS

Measles virus is a negative sense, single-stranded RNA virus with a genome size of 15 894 nucleotides [16].
Measles virus is considered monotypic (ie, a genus with only a single species); however, multiple genetically
distinct lineages of wild-type measles virus have been described [17]; the WHO currently recognizes 24
genotypes [18].

Measles is characterized by a generalized maculopapular skin rash, fever above 38.3°C (101°F), and cough,
coryza, and/ or conjunctivitis. During the incubation period, the virus rep- licates in alveolar macrophages and
dendritic cells before establishing a systemic infection in which infected lympho- cytes disseminate the virus to
major organ systems, peripheral tissues, including the skin, the respiratory tract and epithelial cells. In
uncomplicated measles cases, clinical signs start to sub- side a few days after rash onset, and patients develop a
robust immune response that mediates recovery and provides lifelong immunity [16].

MEASLES VACCINE HISTORY AND DEVELOPMENT

Measles vaccines are attenuated (or weakened) measles vir- uses, so that infection through vaccination of
immunocom- petent persons leads to replication and immunity, but not disease. Data suggest that genotype A
was widely distributed in the prevaccine era when the progenitors of the vaccine strains were first isolated;
however, only a few measles viruses from the 1950s and 1960s have been available for sequencing. All live at-
tenuated vaccine strains used in measles vaccines are members of genotype A.

Most of the measles vaccine strains currently in use were de- rived from the prototype Edmonston strain
(Edmonston wild- type) which was isolated by Enders and Peebles in 1954 [19]. In addition to the live
attenuated vaccine strains, a formalin- inactivated Edmonston vaccine was in use during 1963–1967; however,
use of this vaccine was discontinued because vaccin- ated individuals were at risk for developing atypical
measles after wild-type measles virus infection. Atypical measles is caused by antigen–antibody immune
complex deposition and character- ized by high fever, abdominal pain, myalgias, pneumonitis, and a petechial or
vesicular and edematous rash. The syndrome is preventable by vaccination with a live-attenuated vaccine [20].
To develop live-attenuated vaccines, the Edmonston strain was passaged in human amnion and human kidney
cells be- fore being adapted to chicken embryo fibroblasts to generate the commonly used Moraten and Schwarz
strains. Several vac- cine strains were derived from other wild-type measles virus isolates, including the
Leningrad-16 strain used in Russia, the Shanghai-191 strain used in China, and the CAM-70 strain used in
multiple countries. All measles vaccines are produced in chicken embryo fibroblasts, except the Edmonston-
Zagreb strain (from the Serum Institute of India), which was derived by further passage in human diploid cells,
MRC-5 [20].

Comparison of the genomic sequences of nine measles vac- cine strains with the sequence of the Edmonston
wild-type virus has shown a relatively small amount of genetic heteroge- neity. Although nucleotide
substitutions were found in the non- coding and protein coding regions of the genomes, the overall genetic
organization of the vaccine strains was conserved [21], and there are no clear genetic markers for attenuation.
The bi- ologic basis for attenuation may be the result of use of different cellular receptors by vaccine and wild-
type viruses. Vaccines strains can use both CD46 and human signaling lymphocyte marker for entry, while
wild-type viruses recognize only human signaling lymphocyte marker. Vaccine and wild type viruses use nectin
4 to infect epithelial cells before viral shedding [16, 22]. Importantly, the high attenuation of measles vaccine
vir- uses impedes human-to-human transmission of these viruses; a systematic review of 773 articles including
genotyping of virus strains in close contacts of vaccinated individuals found that all cases of measles in close
contacts were due to wild-type virus [23].

The only wild-type measles viruses currently detected in circulation are members of genotypes D8, D4, B3, and
H1. Although some antigenic variation between wild-type and vac- cine strains has been described [24], the
necessity for conserva- tion of the receptor-binding domains on the viral hemagglutinin (H) protein, the surface
glycoprotein that is the target of neu- tralizing antibodies, constrains antigenic drift (ie, accumulation of
mutations in virus-surface proteins). This conservation of the H protein allows measles vaccines to be highly
effective against all wild-type viruses, directly contributing to overall success of

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the global measles vaccination program, and likely cessation of transmission of 20 of the 24 known genotypes
[25].

Vaccination elicits long-lived humoral and cellular immune responses. Serologic correlates for protection from
measles virus have been established and a titer >120 mUI/mL is con- sidered protective [26]. Most vaccination
studies rely on meas- urement of the concentration of neutralizing antibodies in serum samples as a surrogate for
the immune response [27].

MEASLES VACCINE SAFETY

The safety of MCVs, including measles-only, measles-rubella (MR), measles-mumps-rubella (MMR), and
MMR-varicella (MMRV) vaccines is well-established. MCVs have similar safety profiles and are well tolerated,
and common reactions after vaccination are mild [20, 28]. Common adverse events after MMR vaccination
depend on components of the vaccine and include fever (5%–15%), rashes (5%), and lymphadenopathy (5%–
20%), as well as parotitis and transient arthralgias/arthritis [29–32]. These adverse events occur approximately
6–12 days after vaccination, the time period of peak vaccine virus repli- cation. Compared with the first dose of
vaccine, adverse events are less common after the second dose of vaccine, because most children are immune at
the time they receive the second vacci- nation, and therefore, less viral replication occurs [33].

MMR vaccination is only rarely associated with serious ad- verse events, and both precautions and
contraindications to MMR vaccination have been carefully delineated to minimize serious reactions. A review
by the Institute of Medicine assessed whether there was both epidemiologic and mechanistic evi- dence of
serious adverse events associated with MMR vaccine [34]. This review concluded that there is an increased risk
of febrile seizures following MMR vaccine, and that the evidence supported a causal relationship between
MMR vaccine and fe- brile seizures. The review also concluded a causal relationship between MMR vaccine
and anaphylaxis, and MMR vaccine and MIBE in individuals with demonstrated immunodeficiencies.

The attributable risk of febrile seizures after MMR vaccine has been evaluated in multiple large population-
based studies to be approximately 25–34 additional febrile seizures per 100 000 children vaccinated, and occurs
most commonly 7–14 days after vaccination [35]. The risk is approximately twice as high for children aged 12–
23 months who receive the MMRV com- bination vaccine compared with those who receive MMR and varicella
vaccines separately [36]. These studies found that there was 1 additional febrile seizure per every 2300–2600
MMRV vaccine doses given, compared with MMR and varicella vac- cines given separately. There was no
increased risk in individ- uals receiving a second dose of MMRV compared to MMR and varicella separately at
the recommended 4–6-year-old age range [37]. Based on these findings, providers are recommended to discuss
the benefits and risks of vaccination with MMRV versus MMR and varicella separately for the first dose of
measles

vaccine, and to administer MMRV as the first dose only if the parent or caregiver expresses a preference for
MMRV vaccine [28].

Thrombocytopenia can occur after natural measles infec- tion, and a causal relationship between MMR vaccine
and thrombocytopenia has been established based on observational studies, case reports, and biologic
plausibility [34]. A large US study evaluating the risk of immune thrombocytopenic pur- pura (ITP) in children
aged 12–23 months in the 6 weeks after MMR vaccination [38] found that 76% of ITP cases in children in this
age-group were attributable to the MMR vaccine, and estimated a rate of 1 case of ITP per 40 000 vaccine doses
given. Thrombocytopenia associated with vaccination was generally mild and resolved within 7 days, on
average. In addition, the risk for thrombocytopenia after MMR vaccination is several- fold lower than after
wild-type rubella (estimated as 1 case per 3000 infections) [39]. Persons with a history of thrombocyto- penia or
thrombocytopenic purpura might be at increased risk for clinically significant thrombocytopenia after MMR
vaccina- tion; thus, a history of these conditions is a precaution for MMR vaccination.

Anaphylaxis and other immediate hypersensitivity reactions can occur after MMR vaccination, and are likely
related to al- lergies to the gelatin or neomycin components of the vaccine [40–42]. In a large population-based
study, the risk of anaphy- laxis following MMR vaccine was estimated to be 5.14 per mil- lion vaccine doses
(95% confidence interval, 1.06–15.01) [43]. History of severe allergic reaction to any component of the vac-
cine is a contraindication to MMR vaccination [28].

Immunocompromised patients should also not receive the MMR vaccine. Potential fatal adverse events in
immunocom- promised hosts include measles pneumonia, MIBE, and dis- seminated measles infection [44–47].
This recommendation is inclusive of persons with human immunodeficiency virus (HIV) infection who are
severely immunocompromised. However, a systematic review of 28 safety studies of MMR vacci- nation among
HIV-infected children found that adverse events and deaths after measles vaccines were uncommon in this pop-
ulation [48]; thus, persons with HIV infection should receive MMR vaccine if they are not severely
immunosuppressed (eg, T-lymphocyte percentage >15% at any age or CD4 cell count >200/μL for those >5
years of age) [28].

MMR vaccine is contraindicated in pregnancy owing to the- oretical concerns of fetal harm including congenital
rubella syndrome [28]. Nevertheless, a systematic review of vaccines given to pregnant women found that
among 4918 pregnant women who inadvertently received MMR vaccine while preg- nant, no cases of
congenital rubella syndrome were reported [49]. Similarly, a safety review of 131 reports to the Vaccine
Adverse Event Reporting System of MMR vaccine adminis- tered to pregnant women found that most vaccines
were given to women early in pregnancy (when they were unaware of their
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pregnancy), and in the majority of reports, no adverse events were reported [50]. The highly favorable safety
profile of MCV has been an essential component of the global measles eradica- tion strategy.

MEASLES VACCINE USE AND EFFECTIVENESS

All 194 countries have added MCV into their routine child- hood immunization programs, a critical step toward
global measles eradication. MCV is usually delivered as a combined multiantigen vaccine, either MR or MMR
vaccine. Combination vaccines are cost-effective, in that the addition of other antigens increases cost by much
smaller margins compared with the sub- stantial costs incurred by administration, delivery, and wastage of
multiple vaccines. Currently, 122 countries have intro- duced MMR into their routine immunization schedules,
with MMR being used solely in most countries in the European and Americas regions [51].

The effectiveness of the measles component of the MMR vac- cine is high, 93% after 1 dose and 97% after 2
doses in persons aged ≥12 months. Duration of immunity is likely lifelong after 2 doses [28]. Although the
incremental vaccine effectiveness between 1 and 2 doses may seem small, the measles herd im- munity
threshold is high (>92%), necessitating implementation of a second dose for optimal measles control and
elimination to be successfully achieved. As a result of numerous measles outbreaks occurring in vaccinated
school-aged children in the United States during the 1980s, a second dose of MMR was re- commended for
school-aged and college students in 1989. The assimilation of a 2-dose recommendation into the US child- hood
immunization schedule, in addition to school-entry im- munization requirements, the introduction of the
Vaccines for Children program in 1993 to improve vaccine access, and con- certed efforts in the 1990s by other
countries in the Americas region to reduce measles cases and outbreaks (which limited the number of
introductions of measles from these countries), ul- timately led to the elimination of measles in the United States
by 2000.

Timing and delivery strategies for MCV vaccination vary by country and are contingent on multiple factors,
including the infrastructure to implement routine immunizations and mass vaccination campaigns, the capacity
and preparedness for rapid outbreak response, and the local epidemiology of mea- sles based on surveillance
data. Overall disease burden and age at highest risk of disease is often a primary consideration when
establishing an immunization schedule. Currently, 41% of countries with measles vaccination programs begin
vaccinating infants before 1 year of age (usually at 9 months), owing to the high disease burden in infants.

The chance of exposure to measles for infants and young children in each country must be carefully weighed
against the age-specific immunogenicity of each dose of measles vac- cine in order to define the optimal age for
routine vaccination.
Although infants are at risk of severe disease and serious compli- cations, studies have suggested that
vaccination at <12 months of age can lead to suboptimal immune responses that continue to be low despite
additional doses [52, 53, 54]. In the United States, where exposure to measles is rare, the first dose is re-
commended at 12–15 months of age and the second dose at 4–6 years, in order to effectively protect young
children and to ensure they are fully vaccinated before school entry. Other countries that have achieved measles
elimination recommend different schedules (eg, both Canada and Australia recom- mend the first dose of MMR
at 12 months and the second at 18 months of age), highlighting that even in countries with sim- ilar measles
epidemiology, country-specific healthcare delivery systems play a critical role in establishing the optimal timing
for vaccination [39].

MEASLES VACCINATION COVERAGE

During 2000–2019, estimated coverage with the routine first- dose MCV (MCV1) increased globally from 72%
to 85% (Figure 2), and the number of countries with ≥90% MCV1 coverage increased from 86 (45%) to 122
(63%) [55]. Among countries with ≥90% MCV1 coverage nationally, those that also had ≥80% MCV1
coverage in all districts increased from 1% in 2003 to 22% in 2019. From 2000 to 2019, the number of countries
providing a second dose of MCV (MCV2) nation- ally through routine immunization services increased from 95
(50%) to 177 (91%), and estimated global MCV2 coverage in- creased from 18% to 71%. However, as of 2019,
17 countries had yet to introduce MCV2 nationally, and MCV1 coverage has remained at 84%–85% globally
since 2010. Therefore, mass vaccination campaigns remain a necessary strategy for eliminating measles in many
countries. In 2019, approximately 204 million persons received MCV during supplementary immunization
activities in 55 countries, and an additional 9 million received MCV during measles outbreak response activities.

Countries that have achieved measles elimination have in- vested heavily in routine immunization programs to
ensure consistently high vaccination coverage against measles and other vaccine-preventable diseases. In the
United States, after the first licensure of measles vaccine in 1963 and MMR in 1971, MCV coverage steadily
increased, with almost 20 million doses distributed in 1989 alone [20]. National vaccination coverage surveys
including MMR were implemented beginning in 1994 for young children and 2006 for adolescents; estimates
have remained steady at ≥90% for both 1 and 2 doses since 2010 (Figure 2). In 2017, MMR vaccination
coverage was reported to be 91.5% for children aged 19–35 months vaccinated with ≥1 dose and 94.3% for
children in kindergarten with ≥2 doses [56, 57]. Similarly, in Canada and Australia, the estimated MCV1
coverage among 2-year-olds in 2017 was 90% and 90.5%, re- spectively [58, 59].

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A
100
90

80

B 100

50

MMR 1+ (19–35 mo)

MMR 2+ (13–17 y)

Figure 2.

ECONOMIC BENEFITS OF MEASLES VACCINATION

The economic benefits of investing in vaccines, particularly measles vaccines, are well established [60–64].
Even in coun- tries with low disease incidence, periodic measles outbreaks continue to occur, causing costly
disruptions to society and requiring resource-intensive outbreak response activities [65]. A review of cost
estimates of 11 measles outbreaks during the postelimination era in the United States, found that measles costs
public health and healthcare institutions a median of ap- proximately $33 000 (US dollars) per case, and $4000
per day of investigation [66]. Furthermore, after accounting for broad

MCV1

MCV2

A, Estimated measles-mumps-rubella (MMR) vaccination coverage among children aged 19–35 months or 13–17 years. (Data from National
Immunization Surveys, United States, 1995–2019; available at https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/data-
reports/mmr/trend/index.html and https:// www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/data-reports/mmr/trend/index.html).
B, Estimated measles-containing-vaccine (MCV) first dose (MCV1) and MCV second dose (MCV2) coverage (worldwide data from World
Health Organization, 1980–2019; available at http://www.who.int/immunization/monitoring_surveillance/ data/en). A, B, Horizontal dashed
lines represent 90% vaccination coverage.

economic benefits, the overall societal return on investment for 10 vaccines is 44 (range, 27–67) times the cost
of the vaccines, supply chains, and vaccine delivery [60]; the measles vaccine has the highest return on
investment, 58 (28–105) times the cost [60]. In the United States, it has been estimated that routine measles
vaccination of the 2009 birth cohort prevented 3.8 mil- lion measles illnesses and >3000 measles-related deaths,
a net savings of more than >$3 billion in direct costs and $8 billion in societal costs [67]. Achieving an eventual
measles eradica- tion goal would have massive economic implications and could save current ongoing annual
costs of >$2 billion in measles

Progress Toward Measles Elimination • jid 2021:224 (Suppl 4) • S425

1980 1982

2011

1984 1986

2013

1988 1990

2017
2019

1992 1994

1996 1998

2000 2002

1995
1997

2004 2006

2008 2010

1999
2001

2012 2014

2003
2005

2016 2018

2007
2009

2015

Coverage, % Coverage, %

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treatment and >15 million disability-adjusted life-years, valued at >$63 billion globally each year [68].

BARRIERS TO ACHIEVING AND MAINTAINING MEASLES ELIMINATION AND FUTURE

CONSIDERATIONS

Despite significant progress in decreasing measles incidence and mortality rates globally since 2000, measles
elimination efforts have encountered setbacks in recent years. Estimated MCV1 coverage worldwide has
plateaued at 84%–85% for nearly a decade and reported global measles cases increased from a historic low of
132 490 in 2016 to 869 770 in 2019 (556% increase) [55]. Among persons with confirmed measles cases
reported to WHO during 2013–2018, 45% were reported to have never received MCV, and 30% had an
unknown vaccina- tion history [69].

Several countries lost their elimination status in 2019. In the Americas, the first region of the WHO to have been
declared free of measles in 2016, recent reestablishment of endemic virus transmission in Venezuela and Brazil
led to a loss of regional elimination. The United States has similarly experienced sev- eral sizeable outbreaks
following measles importations, mostly in settings with low vaccination coverage, including communi- ties in
Ohio [70], Minnesota [71], and Washington [72]. During 2018 and 2019, prolonged outbreaks of almost 1-year
duration in undervaccinated communities in New York threatened the measles elimination status of the United
States. The 1282 mea- sles cases reported in the United States in 2019 was the highest annual number of
reported cases since 1992 [73, 74]. Since 2001, 88% of US residents with confirmed measles cases are ei- ther
unvaccinated or have an unknown vaccination status [12].

The Measles & Rubella Initiative (M&RI), a global partner- ship formed in 2001, coordinates efforts to achieve
a world without measles and rubella. The M&RI is led by the American Red Cross, the United Nations
Foundation, WHO, United Nations Children’s Fund (UNICEF), and the US Centers for Disease Control and
Prevention. Since 2001, it has invested >$1.2 billion for measles and rubella elimination efforts. In 2012, a
Measles and Rubella Strategic Plan was released cov- ering the period 2012–2020 and was endorsed by the
M&RI [75]. Among its goals were reaching measles elimination in ≥5 of the 6 WHO regions, establishing a
target date for measles eradication, and achieving a ≥95% coverage with MCV in all districts of all countries no
later than 2020. While considerable progress in measles control has been made, none of those tar- gets have
been met.

There are multiple challenges to achieving and maintaining the measles herd immunity threshold needed for
measles erad- ication, estimated generally to be >92%–94%. Achieving such immunity levels requires
substantial political will, elimination of financial and physical access barriers to measles vaccination,
strengthening of public health infrastructure (eg, inconvenient

clinic locations and hours), and combating dissemination of misinformation eroding trust and confidence in
vaccines [11, 76, 77]. A midterm review of the Measles and Rubella Strategic Plan concluded that measles
could be eradicated and offered a number of recommendations to try to support eradication [78]. Notably,
vaccine hesitancy was listed by WHO in 2019 as among the top 10 challenges to global health [79]. Both the
Centers for Disease Control and Prevention and WHO have established comprehensive initiatives to address
vaccine hesitancy [80, 81].

Intensified efforts and resource commitments by global part- ners and countries are needed to get back on track
toward mea- sles elimination. A new immunizations guidance document, the Immunization Agenda 2030
(IA2030) [82], cocreated by WHO and partners and to be endorsed by the World Health Assembly, builds on
lessons learned and progress made toward the Global Vaccine Action Plan goals. The IA2030 aims to use
measles, a proven effective surrogate or marker for the performance of Expanded Programmes on Immunization
[83], to drive efforts to strengthen immunizations and primary healthcare systems [82].

Focusing on measles elimination strategies can enhance de- livery of routine immunization for other vaccine-
preventable diseases, help identify unvaccinated or undervaccinated com- munities and close immunity gaps,
lead to improvements in surveillance and expansion of cold-chain capacity, create op- portunities to provide
refresher training on vaccination to healthcare workers, and advance the adoption of strategies used for measles
elimination to ensure high coverage for vaccines against other diseases (eg, school-entry requirements) [84].
The IA2030 thus provides an opportunity to strengthen vaccination programs, build on public health
partnerships, and leverage data-driven approaches that use disease surveillance to increase vaccination coverage
and equity in all communities [65, 85].

KEY INNOVATIONS FOR MEASLES CONTROL IN RESOURCE-LIMITED COUNTRIES

Innovative approaches for measles diagnostics and vaccination methods, principally to address challenges in
resource-limited settings lacking strong healthcare infrastructures, could facili- tate the control of measles and
help overcome critical barriers to achieving measles elimination.

New Rapid Diagnostic Test

Because many of the typical clinical signs of measles can also be caused by other infectious agents, including
rubella virus, labora- tory confirmation of measles is a critical component of the measles control strategy but
may not always be feasible in resource-limited settings. Detection of measles-specific IgM antibodies by
enzyme immunoassay is the most common method used for case confir- mation, though detection of viral RNA
by reverse-transcription polymerase chain reaction is increasing in many countries. While most of the IgM tests
are performed with serum samples, the use of

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alternative samples, such as dried blood spots and oral fluid sam- ples, has helped to expand laboratory
surveillance. The recent de- velopment of a rapid diagnostic test that can provide results in <20 minutes to
detect measles IgM in field settings, will facilitate rapid detection of cases and response activities in resource-
limited set- tings where the logistics of sample transport and storage are often challenging [86, 87].

Alternative Vaccine Delivery Approaches

Alternative vaccine delivery methods that eliminate the need for cold-chain transportation and hypodermic
needle and sy- ringe subcutaneous injection could improve vaccine delivery in resource-limited settings and
increase vaccination coverage and equity. Several routes of administration have been evalu- ated. A measles
vaccine delivered by the respiratory route as an aerosol was immunogenic but the seroconversion rate was
inferior to the rate observed after subcutaneous injection [88]. A dry powder was immunogenic in nonhuman
primates, but work was discontinued after a phase I clinical trial [89, 90]. Measles vaccination via the
intradermal route produced lower seroresponses because efficient and reliable delivery methods were not
available [91]. However, the recent success in devel- opment and testing of dissolving microneedle patches for
the delivery of measles and rubella vaccine shows that intradermal vaccination by this method is a promising
way to improve the efficiency of delivery of vaccination [92, 93].

CONCLUSIONS

Although measles is one of only a handful of human pathogens that could be eradicated, and despite the broad
availability of an intervention tool that could make this possible—an effec- tive and inexpensive measles
vaccine with decades of use and an excellent safety track record—the disease remains a leading cause of
childhood disease and death globally. Several tough challenges to increasing measles vaccination coverage
remain, including poor access to immunization services and dissemina- tion of misinformation eroding vaccine
confidence.

Exacerbating these challenges are the recent diversions of public health resources to combat the novel
coronavirus dis- ease 2019 pandemic, which have affected routine immunization services and vaccine-
preventable disease surveillance in many countries, thereby increasing the risk for outbreaks of measles during
or after the pandemic. Yet, the notable successes of mea- sles vaccination in the control and elimination of
measles in var- ious regions across the globe undoubtedly demonstrate that these barriers can be overcome, and
that measles eradication is attain- able. With renewed efforts and resource commitments to achieve elimination,
and the implementation of strategies that improve primary health delivery systems, decrease missed
opportunities for vaccination and counteract vaccine hesitancy, and incorpo- rate innovative approaches for
measles diagnostics and vaccine delivery, a world without measles could be within our grasp.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided
by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the
authors, so questions or comments should be addressed to the corresponding author.

The complete references are available as online Supplemental Material.

Notes

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent
the official position of the Centers for Disease Control and Prevention, US Department of Health and Human
Services.

Supplement sponsorship. This supplement is sponsored by the Bill and Melinda Gates Foundation.

Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form
for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the
manuscript have been disclosed.

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