Qdenga Epar Risk Management Plan en

Title Page
EU RISK MANAGEMENT PLAN (RMP)

for
Dengue Tetravalent Vaccine (Live, Attenuated)
RMP Version number: 1.0
Date: 11-October-2022
This document contains confidential information, which is property of TAKEDA PHARMACEUTICAL

COMPANY LIMITED. No use or disclosure outside Takeda is permitted without prior written
authorization from Takeda.
CONFIDENTIAL
Dengue Tetravalent Vaccine (Live, Attenuated) Page 2 of 102
Risk Management Plan / 11-October-2022 Version 1.0
EU Risk Management Plan for Dengue Tetravalent Vaccine (Live,

Attenuated)
Administrative Information
RMP version to be assessed as part of this application:

RMP Version number: 1.0
Data lock point for this RMP: 1-April-2022
Date of final sign off: 11-October-2022
Rationale for submitting an updated RMP:

The rationale of the update of RMP version 0.4 to RMP version 1.0 to remove study DEN-401 from
the RMP and instead, include the study in the list of post-authorization measures. In addition, RMP
was updated to reflect the DEN-303 trial protocol amendment (amendment to protocol version 4.0,
22 February 2021 to version 5.0, 22 August 2022).
Summary of significant changes in this RMP:
RMP Part/Module Significant changes
Part I – Product overview Revision in Brief description of the product: sentence

shortened to remove information which is considered
Commercially Confidential Information
Part II – Safety specifications Revision in Module SVI - Additional EU requirements for the
safety specification:
- to reflect changes made in the updated PI under section 4.6

- sentence shortened to remove information which is
considered Commercially Confidential Information
Module SVII – Identified and Revision in SVII.3.1. Presentation of important identified

potential risks risks and important potential risks and SVII.3.2. Presentation
of the missing information to reflect changes made in the
updated PI under section 4.4 and 4.6
Module SVIII – Summary of the No changes

safety concerns
Part III – Pharmacovigilance III.2. Additional pharmacovigilance activities:

activities
- Trial DEN-303 changes
- Study DEN-401 removed from the additional

pharmacovigilance activities
III.3. Summary table of additional pharmacovigilance
activities revised to reflect changes made for DEN-303 and
DEN-401
Part IV - Plans for post- No changes

authorisation efficacy studies
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RMP Part/Module Significant changes
Part V - Risk minimisation Study DEN-401 removed

measures
Part VI - Summary of the risk II.C.2. Other studies in post-authorisation development plan
management plan updated to remove DEN-401
II.B Summary of important risks - study DEN-401 removed
Part VII – Annexes Annex 2 updated
Other RMP versions under evaluation:

Not applicable
Details of the currently approved RMP:
Not applicable
QPPV name: Dr. Sumit Munjal, Takeda VP EU-QPPV

QPPV signature: Refer to the electronic signature at the end of the document
CONFIDENTIAL
Table of Contents
LIST OF ABBREVIATIONS........................................................................................................................7
PART I: PRODUCT(S) OVERVIEW ...........................................................................................................9
PART II: SAFETY SPECIFICATION ........................................................................................................11
PART II: MODULE SI - EPIDEMIOLOGY OF THE INDICATION(S) AND TARGET POPULATION(S) 11
PART II: MODULE SII - NON-CLINICAL PART OF THE SAFETY SPECIFICATION ...........................18
PART II: MODULE SIII - CLINICAL TRIAL EXPOSURE ........................................................................24
PART II: MODULE SIV - POPULATIONS NOT STUDIED IN CLINICAL TRIALS .................................27
SIV.1. EXCLUSION CRITERIA IN PIVOTAL CLINICAL STUDIES WITHIN THE DEVELOPMENT PROGRAMME ................27
SIV.2. LIMITATIONS TO DETECT ADVERSE REACTIONS IN CLINICAL TRIAL DEVELOPMENT PROGRAMMES ............29
SIV.3. LIMITATIONS IN RESPECT TO POPULATIONS TYPICALLY UNDER-REPRESENTED IN CLINICAL TRIAL
DEVELOPMENT PROGRAMMES ......................................................................................................................30
PART II: MODULE SV - POST-AUTHORISATION EXPERIENCE .........................................................32

PART II: MODULE SVI - ADDITIONAL EU REQUIREMENTS FOR THE SAFETY SPECIFICATION ..33
PART II: MODULE SVII - IDENTIFIED AND POTENTIAL RISKS ..........................................................38
SVII.1. IDENTIFICATION OF SAFETY CONCERNS IN THE INITIAL RMP SUBMISSION ............................................38
SVII.1.1 Risks not considered important for inclusion in the list of safety concerns in the RMP ..............38
SVII.1.2. Risks considered important for inclusion in the list of safety concerns in the RMP ...................38
SVII.2. NEW SAFETY CONCERNS AND RECLASSIFICATION WITH A SUBMISSION OF AN UPDATED RMP ...............39
SVII.3. DETAILS OF IMPORTANT IDENTIFIED RISKS, IMPORTANT POTENTIAL RISKS, AND MISSING INFORMATION..40
SVII.3.1. Presentation of important identified risks and important potential risks .....................................40
SVII.3.2. Presentation of the missing information .....................................................................................47
PART II: MODULE SVIII - SUMMARY OF THE SAFETY CONCERNS .................................................52
PART III: PHARMACOVIGILANCE PLAN (INCLUDING POST-AUTHORISATION SAFETY STUDIES)53
III.1. ROUTINE PHARMACOVIGILANCE ACTIVITIES ...........................................................................................53
III.2. ADDITIONAL PHARMACOVIGILANCE ACTIVITIES .......................................................................................53
III.3. SUMMARY TABLE OF ADDITIONAL PHARMACOVIGILANCE ACTIVITIES.........................................................58
PART IV: PLANS FOR POST-AUTHORISATION EFFICACY STUDIES ...............................................60
PART V: RISK MINIMISATION MEASURES (INCLUDING EVALUATION OF THE EFFECTIVENESS
OF RISK MINIMISATION ACTIVITIES) ...................................................................................................61
V.1. ROUTINE RISK MINIMISATION MEASURES ..............................................................................................61
V.2. ADDITIONAL RISK MINIMISATION MEASURES ..........................................................................................63
V.3. SUMMARY OF RISK MINIMISATION MEASURES .........................................................................................64
PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN - ARTICLE 58 APPLICATION ...............66
I. THE MEDICINE AND WHAT IT IS USED FOR ...................................................................................................66
II. RISKS ASSOCIATED WITH THE MEDICINE AND ACTIVITIES TO MINIMISE OR FURTHER CHARACTERISE THE RISKS66
II.A List of important risks and missing information ..................................................................................67
II.B Summary of important risks ................................................................................................................67
II.C. Post-authorisation development plan ................................................................................................72
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II.C.1. Studies which are conditions of the marketing authorisation .............................. 72

II.C.2. Other studies in post-authorisation development plan ....................................... 72
PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN – EU MAA ...............................................73
I. THE MEDICINE AND WHAT IT IS USED FOR ...................................................................................................73
II. RISKS ASSOCIATED WITH THE MEDICINE AND ACTIVITIES TO MINIMISE OR FURTHER CHARACTERISE THE RISKS73
II.A List of important risks and missing information ..................................................................................74
II.B Summary of important risks ................................................................................................................74
II.C. Post-authorisation development plan ................................................................................................79
II.C.1. Studies which are conditions of the marketing authorisation .............................. 79
II.C.2. Other studies in post-authorisation development plan ....................................... 79
PART VII: ANNEXES ...............................................................................................................................80
ANNEX 1: EUDRAVIGILANCE INTERFACE .......................................................................................................81
ANNEX 2: TABULATED SUMMARY OF PLANNED, ONGOING, AND COMPLETED PHARMACOVIGILANCE STUDY
PROGRAMME ...............................................................................................................................................82
ANNEX 3: PROTOCOLS FOR PROPOSED, ON-GOING AND COMPLETED STUDIES IN THE PHARMACOVIGILANCE PLAN84
ANNEX 4: SPECIFIC ADVERSE DRUG REACTION FOLLOW-UP FORMS ................................................................85
ANNEX 5: PROTOCOLS FOR PROPOSED AND ON-GOING STUDIES IN RMP PART IV ..........................................86
ANNEX 6: DETAILS OF PROPOSED ADDITIONAL RISK MINIMISATION ACTIVITIES .................................................87
ANNEX 7: OTHER SUPPORTING DATA (INCLUDING REFERENCED MATERIAL) .....................................................88
ANNEX 8: SUMMARY OF CHANGES TO THE RISK MANAGEMENT PLAN OVER TIME ..............................................97
ANNEX 9: AD-HOC TABLES REFERENCED IN THE RMP ..................................................................................98
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List of Tables
Table Part I.1: Product Overview ............................................................................................ 9
Table SIII.1: Age group and gender* ..................................................................................... 24
Table SIII.2.A: Number of subjects exposed during completed and ongoing Phase 1, Phase 2 and
Phase 3 trials and overall exposure. ................................................................. 24
Table SIII.2.B: Dose (any TDV formulation, safety set)* ........................................................... 25
Table SIII.2.C: Dose (TDV final formulation, safety set)* .......................................................... 25
Table SIII.3: Ethnic origin (safety set)* .................................................................................. 26
Table SVIII.1: Summary of safety concerns ............................................................................ 52
Table Part III.1: On-going and planned additional pharmacovigilance activities ............................ 58
Table Part IV.1: Planned and on-going post-authorisation efficacy studies that are conditions of the
marketing authorisation or that are specific obligations. ...................................... 60
Table Part V.1: Description of routine risk minimisation measures by safety concern .................... 61
Table Part V.3: Summary table of pharmacovigilance activities and risk minimisation activities by
safety concern ............................................................................................... 64
Table 1 Annex 2: Planned and on-going studies ....................................................................... 82
Table 2 Annex 2: Completed studies....................................................................................... 83
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List of Abbreviations
Abbreviation Definition/Description
ADE Antibody-dependent disease enhancement
AEFI Adverse event following immunisation
AR Assessment report
ATC code Anatomical therapeutic chemical classification system
CFR Case fatality rate
CNS Central nervous system
CSR Clinical study report
CTD Common technical document
DCAC Dengue case adjudication committee
DENV Dengue virus serotype (wild type)
DHF Dengue haemorrhagic fever
DNA Deoxyribonucleic acid
DSS Dengue shock syndrome
ECDC European Centre for Disease Prevention and Control
EEA European economic area
EMA European Medicines Agency
EPAR European public assessment report
EU European Union
FTA Buffer containing Pluronic F127, trehalose and human albumin, used for
stabilization of TDV viruses
GLP Good Laboratory Practice
GMO Genetically modified organism
HAV Hepatitis A virus
HIV Human immunodeficiency virus
ICH International Conference on Harmonisation
Ig Immunoglobulin
INN International non-proprietary names
IR Incidence rate
JE Japanese encephalitis
log Logarithm
MA Marketing Authorization
MAA Marketing Authorization Application
MAH Marketing Authorization Holder
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Abbreviation Definition/Description
MID50 Minimum Infectious Dose 50: Level of viral RNA required to infect half of fed
mosquitoes
ml Millilitre
NCR Noncoding region
NOAEL No-observed-adverse-effect level
NIP National immunisation program
NS Nonstructural
PBRER Periodic benefit-risk evaluation report
PDK Primary dog kidney
PFU Plaque forming units
PI Product information
PIP Paediatric investigation plan
PL Package leaflet
PSUR Periodic safety update report
PV Pharmacovigilance
QPPV Qualified person responsible for pharmacovigilance (in the European Union)
RMP Risk management plan
RNA Ribonucleic acid
SAE Serious adverse event
SC Subcutaneous(ly)
SmPC Summary of product characteristics
TBD To be determined
TDV “Dengue Tetravalent Vaccine (Live, Attenuated)” is referred to as TDV, the Takeda
dengue vaccine candidate also known as TAK-003
TFUQ Targeted follow up questionnaires
US United States
VE Vaccine efficacy
vRNA viral riboNucleic acid
WHO World Health Organization
YF Yellow fever
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Part I: Product(s) Overview

Table Part I.1: Product Overview
Active substance(s) Dengue virus serotype 1 (live, attenuated)*

(INN or common name)
Dengue virus serotype 2 (live, attenuated)#
Dengue virus serotype 3 (live, attenuated)*
Dengue virus serotype 4 (live, attenuated)*
*Produced in Vero cells by recombinant DNA technology. Genes of serotype-
specific surface proteins engineered into dengue virus serotype 2 backbone.
#Produced in Vero cells by recombinant DNA technology.
Pharmacotherapeutic J07BX04 dengue virus vaccines

group(s) (ATC Code)
Marketing Authorisation Takeda GmbH

Applicant
Byk-Gulden-Strasse 2
78467 Konstanz
Germany
Medicinal products to Dengue Tetravalent Vaccine (Live, Attenuated)

which this RMP refers
“Dengue Tetravalent Vaccine (Live, Attenuated)” is referred to as
TDV through this document, the Takeda dengue vaccine candidate
also known as TAK-003.
Invented name(s) in the Qdenga

European Economic Area
(EEA)
Marketing authorisation Centralised procedure

procedure
Brief description of the Chemical class: Vaccines

product
Summary of mode of action:
TDV contains live attenuated dengue viruses. The primary

mechanism of action of TDV is to replicate locally and elicit humoral
and cellular immune responses against dengue disease caused by
any of the four dengue virus serotypes.
Important information about its composition:
Dengue tetravalent vaccine is a live attenuated vaccine. The vaccine

serotype, TDV-2, was derived from attenuated wild type dengue
serotype 2 virus strain (16681) which forms the common genetic
backbone for the other three serotypes. Using recombinant
deoxyribonucleic acid (DNA) technology, the genetic sequence
encoding for pre-membrane (prM) and envelope (E) proteins in the
attenuated TDV-2 genome were replaced with the corresponding
genes of the wild-type serotype 1 (16007), serotype 3 (16562) and
serotype 4 (1036).
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The four viruses are cultured in Vero cells. The purified active
substance is stabilized in a solution containing various salts,
Poloxamer 407, Trehalose, and human serum albumin. There is .no
adjuvant or preservative in dengue vaccine. Each dose of vaccine will
contain a minimum of the specified amount of each serotype
expressed in PFU/dose (TDV-1 ≥3.3 log10 PFU/dose, TDV-2 ≥2.7
log10 PFU/dose, TDV-3 ≥4.0 log10 PFU/dose, TDV-4 ≥4.5 log10
PFU/dose).
Hyperlink to the Product Refer to CTD Module 1.3.1 for proposed PI.
Information (PI)
Indication(s) in the EEA Current (if applicable): Not applicable.
Proposed (if applicable): Qdenga is indicated for the prevention of

dengue disease in individuals from 4 years of age.
Dosage in the EEA Current (if applicable): Not applicable.
Proposed (if applicable):
Qdenga should be administered as a 0.5 ml dose at a two-dose

(0 and 3 months) schedule.
The need for a booster dose has not been established.
Pharmaceutical form(s) Current (if applicable): Not applicable.

and strengths
Proposed (if applicable): Powder and solvent for solution for
injection.
After reconstitution, 1 dose (0.5 ml) contains:
Active ingredients:
Dengue virus serotype 1 (live, attenuated)*: ≥3.3 log10 PFU**/dose
Dengue virus serotype 2 (live, attenuated)#: ≥2.7 log10 PFU**/dose
*Produced in Vero cells by recombinant DNA technology. Genes of serotype-
specific surface proteins engineered into dengue virus serotype 2 backbone.
#Produced in Vero cells by recombinant DNA technology.
**PFU = Plaque-forming units
Is/will the product be Yes
subject to additional
monitoring in the EU?
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Part II: Safety specification

Part II: Module SI - Epidemiology of the indication(s) and
target population(s)
Qdenga is indicated for the prevention of dengue disease in individuals from 4 years of age.
Incidence: Dengue is caused by infection with the wild-type dengue virus serotype (DENV), a
ribonucleic acid (RNA) virus that occurs as 4 recognized serotypes, DENV-1, DENV-
2, DENV-3 or DENV-4. These dengue viruses are transmitted from human to
human by mosquitoes (primarily Aedes aegypti) [1]. The 4 dengue viruses have
spread worldwide and are now endemic in more than 120 countries throughout
Asia, the Pacific Islands, the Caribbean, parts of Africa, Australia, and Central and
South America, with almost 3.9 billion people thought to be at risk [2].
Due to under-recognition, under-reporting, and passive surveillance systems at the

national level, the actual global burden of dengue is difficult to quantify. Access to
and the reliability of national data poses additional challenges for estimating the
dengue burden [3]. The World Health Organization (WHO) frequently cites 50 to
100 million as the annual number of symptomatic cases of dengue [4]. Using
geostatistical methods, modelling groups estimated that 294 million asymptomatic
infections and 96 million symptomatic infections occurred in 2010, of which 70%
were in Asia, 16% were in Africa, and 14% were in the Americas [5].
Over the past 20 years, the number of dengue cases reported to the WHO
increased more than 8-fold [6], from less than 505,430 cases in 2000, to over 2.4
million in 2010, and 4.2 million in 2019. From a sub-regional perspective,
Southeast Asia has the highest age-standardized incidence, estimated at
34.3 cases/1000 people annually. Within Latin America, the Caribbean has the
highest age-standardized incidence, with 18.2 cases/1000 people [3].
Details for some of the highest burdened countries are below:
Indonesia
Indonesia, which is comprised of more than 17,000 islands and 260 million people,
is the most populous country in Southeast Asia. It is hyperendemic for dengue and
is consistently estimated to be among the three countries in the world with the
largest dengue burden [7].
In Indonesia, outbreaks of Dengue haemorrhagic fever (DHF) appear to be cyclical,

occurring every 6 to 8 years. Since 2000, outbreaks of DHF in Indonesia occurred
in 2009 (IR =66/100k) and 2016 (IR = 78/100k), which coincided with a shift in
the dominant serotype from DENV-3 to DENV-1 and DENV-2 [8,9]. In 2017,
Indonesia reported 59,047 DHF cases and 444 DHF-associated deaths
(IR = 23/100k, Case Fatality Rate (CFR) = 0.75%) [8]. However, dengue
surveillance throughout Indonesia is known to be highly variable and incomplete
[10]. A 2013 cartographical based model estimated that 7.6 million dengue cases
occurred in Indonesia in 2010 [5].
A seroprevalence study in 2014 of 30 geographically dispersed clusters found

53.1% of 5 to 9 year olds had previously been exposed to at least one dengue
infection, with a median age of seroconversion estimated at 4.8 years [11].
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Malaysia
Malaysia, a country of 31.6 million inhabitants, is spread across the Malay
Peninsula and Borneo. Over the past 10 years, the burden of dengue in Malaysia
has fluctuated considerably. From 2009 to 2019, there were on average
72,339 suspected cases reported to the national surveillance system annually,
ranging from 19,884 cases in 2011 to 130,101 cases in 2019 [12]. All four dengue
serotypes circulate in Malaysia, with shifts in dominance. Between 2014 and 2017,
DENV-1 and DENV-2 were most prominent [13].
A seroprevalence survey among 9 to 12-years old in Penang and Kuala Lumpur in

2011 found 34% of children had previously been exposed to dengue [14]. While
the majority of dengue cases in Malaysia are among children, in recent years there
has been a shift in the age profile of cases to individuals older than 15 years [15].
A retrospective observational study of dengue mortality in Malaysia in 2013-2014
found 10% of fatal dengue cases to be among children less than 15 years, while
the majority of deaths were adults from the working age group [16].
Singapore
Singapore is an equatorial city-state with approximately 5.6 million inhabitants.

For the past 30 years, Singapore has experienced periodic dengue epidemics of
increasing frequency and magnitude, despite a strong vector control program
which has reduced the percentage of houses infested with Aedes larvae to below
1% [17].
Between 2009 and 2019, an average of 9,704 laboratory confirmed dengue cases
were reported in Singapore, ranging from 2,767 in 2017 to a record high of 22,170
in 2013. During this time period, DENV-1 and DENV-2 predominated [18]. In 2020,
Singapore experienced its largest dengue outbreak on record, with more than
35,300 cases reported [19]. This record year was driven in part by a serotype
switch to DENV-3, which had not predominated in Singapore for more than
30 years [20].
A 2017 seroprevalence survey among Singaporean residents 16 to 74 years found
a dengue IgG prevalence of 45.7% among persons sampled. Seropositivity ranged
from 13.8% among residents aged 16 to 20 years to 85% among those over
60 years [21].
Sri Lanka
Sri Lanka is an island nation of 21.4 million inhabitants. From 2010-2016,

Sri Lanka reported an average of 38,802 annual suspected dengue cases. In 2017,
Sri Lanka experienced its largest outbreak on record, with more than 186,000
suspected cases. Before the 2017 epidemic, the largest outbreak that occurred in
Sri Lanka was in 2014, with 47,502 reported suspected cases [22]. All four
serotypes circulate in Sri Lanka annually, but the 2017 outbreak was predominated
by DENV-2 [23]. The majority of cases reported during the 2017 outbreak were
among working-age adults [24].
A 2007 seroprevalence study in Southern Sri Lanka found that dengue
seroprevalence reached 70% by 40 years of age. However, an updated study
conducted in the same area in 2012, found nearly 70% of 20 years olds to be
seropositive, and seropositivity reached 90% among 60 to 65 years olds [25].
Thailand
Across Thailand’s 76 provinces, 13 health regions, and 69.4 million people, there is
considerable geographic and annual variation in the burden of dengue. Between
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2009 and 2019, an average of 89,846 suspected dengue cases were reported in
Thailand annually, ranging from 41,082 in 2014 to 154,000 in 2013 [26]. Dengue
has been hyperendemic in Thailand since 1958 [27], and a recent study found a
high incidence of DENV serotype and genotype co-circulation, particularly in urban
areas [28].
Over the past few decades, the age of first infection has increased in Thailand. This
increase in average age of first infection may in part be due to a significant shift in
the demographics of the Thai population over the past few decades [29]. However,
children are still significantly impacted by dengue in Thailand. A dengue
seroprevalence survey in Ratchaburi and Kamphaeng Phet conducted in 2011
found nearly 80% of 9 to 12 years old had already been exposed to dengue [14].
Argentina
Argentina, a country of 44.5 million inhabitants, remained free from dengue for
more than 80 years before the disease was reintroduced in 1997 in Salta Province.
Since then, locally acquired dengue cases have only been reported from the
northern provinces of the country, though the Aedes aegypti mosquito has spread
southward to latitude 35°S, near Buenos Aires [30].
Between 2009 and 2019 the average number of reported cases in Argentina was
17,413, ranging from 213 cases in 2011 to 79,455 cases (41,211 confirmed) in
2016. In 2020, Argentina reported a record dengue season, with 58,415 confirmed
cases [31]. Three serotypes have cocirculated during 2020, with DENV-1
predominating [32].
During the 2020 outbreak, the 20 to 34-year-old age group had the highest
number of cases and highest incidence rate, followed by 35 to 44 and 10 to 19.
A 2016 seroprevalence survey among 266 affiliates at the Universidad Nacional de
Misiones and Universidad Católica de las Misiones found 6.6% to be seropositive
for dengue [33].
Brazil
Brazil is home to 209.5 million people and is hyperendemic for dengue. Between
2009 and 2019, an average of 986,053 suspected dengue cases were reported
annually, ranging from 252,054 in 2017 to 2.25 million in 2019 [31]. By far, Brazil
has the largest dengue burden in Latin America. Among all dengue cases that were
recorded in the Americas in 2019, more than 70% were from Brazil [31]. Even
still, dengue is under reported in Brazil, with one notification estimated for every
twenty cases of dengue fever [34].
Every year for the past 10 years, Brazil has reported the cocirculation of all four
dengue serotypes.[31] Epidemics occurred in 2010, 2013, 2015, 2016 and 2019,
marked by reintroduction of new serotypes (in 2010 and 2013) as well as the
introduction of new arboviruses (Chikungunya and Zika virus in 2015 and 2016)
[35].
A recent dengue seroprevalence study conducted in Fortaleza, Natal, Vitoria,

Goiania, and Campo Grande found 68% of 9 to 12-year olds to be seropositive for
dengue [14].
Colombia
Colombia has a population of 49.7 million people and has historically been among
the highest dengue burden countries in the Americas. Between 2009 and 2019,
Colombia’s dengue surveillance system reported an average of 79,634 suspected
cases, ranging from 25,284 in 2017 to 138,188 in 2010. During most years,
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multiple dengue serotypes circulate in Colombia. In 2019, DENV-1, DENV-2, and

DENV-3 were detected. DENV-4 was last reported in Colombia in 2016 [36].
A dengue seroprevalence study conducted in Bucaramanga, Armenia, Tebaida,

Calarca, Montenegro, Giarardot, Acacias, Yopal and Aguazul found 91% of 9 to 12-
year olds to be seropositive for dengue [14].
Mexico
Dengue transmission in Mexico, a country of 126.2 million inhabitants, is

heterogenous between and within regions. Sustained dengue transmission occurs
on both coasts, as well as in some central states, namely Morelos and Huasteca
[37]. Between 2009 and 2019, the average number of suspected dengue cases
reported by the national surveillance system was 151,094, ranging from 51,635 in
2010 to 268,458 in 2019 [31]. All four dengue serotypes generally circulate
annually in Mexico. In 2019, all four serotypes were detected, with DENV-2
predominating [38].
A dengue seroprevalence study conducted in Temixco, Veracruz, Valladolid, Ciudad
Mante, and Tizimin Mexico found 48% of 9 to 12-year olds to be seropositive for
dengue [14].
Travellers
Travel-acquired dengue cases have been increasing as the overall global dengue
burden has expanded. Among travellers returning from Southeast Asia, dengue is
a more frequent cause of febrile illness than malaria [39], and accounts for an
estimated 2% of all febrile illnesses in travellers returning from the tropics [16,
40].
However, the true burden of dengue among travellers is likely much higher due to
variability in reporting, misdiagnosis, and the methodological challenges involved
in tracking self-limiting illnesses among travellers [39]. A prospective
seroconversion study of travellers to dengue endemic countries estimated an
incidence of 2.9% in Dutch travellers who spent approximately 1 month in Asia
[41]. Travellers returning home with dengue also contribute to the spread of the
disease to non-endemic areas where Aedes aegypti and Aedes albopictus
mosquitoes are present [42].
Dengue in Europe
Sporadic dengue outbreaks have been recorded over the past decade in
continental Europe, including in Croatia (2010), France (2010, 2013-2015, 2018,
2019), Spain (2018), and Italy (2020) [43-45]. An outbreak on the Madeira island
(Portugal) in 2012 resulted in over 2,000 cases and imported cases were detected
in mainland Portugal and 10 other European countries. In many European
countries, autochthonous cases are observed on an almost annual basis [46].
Dengue in European territories

Several European territories are endemic for dengue:
Reunion Island, a French department in the Indian Ocean of about 840,000

inhabitants, experienced an outbreak of dengue in 2018 with more than 6,000
reported suspected infections. Aedes albopictus, the primary vector of this
outbreak, are also widely established in the European Union [44].
Mayotte is a French territory between Madagascar and Mozambique with 256,000
inhabitants. A representative seroprevalence study of 1,154 inhabitants aged
≥2 years in Mayotte in 2006 found 23% IgG antibody seropositivity, indicating
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substantial prior exposure of dengue among the population of Mayotte [47].

French Guiana is an overseas department of France with nearly 300,000
inhabitants. French Guiana first reported a case of DHF in 1992. Over the past
decade, French Guiana has experienced dengue hyperendemicity, and reported
outbreaks in 2009, 2010, 2013 and 2020 [48].
Madeira, an autonomous region of Portugal with a population of 289,000, reported
2,168 probable dengue cases during its first dengue outbreak from September
2012 to March 2013. Of the suspected cases, 1,080 were confirmed. The dengue
outbreak in Madeira led to many cases of imported cases in other European
countries including 11 in Portugal, 19 in Germany, 7 in Finland, 5 in Sweden, 3 in
France, 2 in Denmark, 2 in Austria, 2 in Norway, 1 in Croatia, 1 in Slovenia, 1 in
Spain, and 1 in Switzerland [43].
In Martinique and Guadeloupe, overseas regions of France, dengue is highly

endemic. A 2011 serosurvey conducted among 783 adult blood donors in
Guadeloupe and Martinique found 93.5% [91.5; 95.1] samples were positive
for dengue antibodies, 90.7% (350 of 386) in Martinique and 96.2% (382 of 397)
in Guadeloupe. Of the adults who tested positive, only 30% recalled having
had dengue [49].
In New Caledonia, a special collectivity of France with a population of 278,000,

dengue occurs regularly. In 2018, 20, 30 dengue cases including two deaths were
reported. DENV-2 was the predominant circulating serotype, comprising 1,149 of
the 1,336 (86%) typed cases [50].
French Polynesia, the only overseas country of France, with 118 islands in the
South Pacific Ocean, has 276,000 inhabitants. A 2014-2015 serosurvey across the
islands using a cluster sampling approach found the majority of the general
population (96%±3%) had been exposed to more than one dengue serotype in
2014. Among schoolchildren, the seroprevalence was 60%±5%. These rates of
seroprevalence are indicative of high transmission rates throughout French
Polynesia [51].
In Wallis and Futuna, a French island collectivity in the South Pacific with about
12,000 people, 225 cases were confirmed since November 2017, putting the
islands above the epidemic threshold. Young people between 5 and 20 years
represented more than half of all confirmed cases. The death of an 8 year old girl
due to dengue was also reported during this epidemic [52].
Saint Barthelemy, an overseas collectivity of France with about 10,000 inhabitants,
is endemic for dengue. In 2015, Saint Barthelemy reported 428 cases of dengue to
PAHO, an incidence rate of 4,280/100,000 [53].
Saint Martin is divided between the French Republic and the Kingdom of the
Netherlands, with about 77,000 inhabitants. The first dengue outbreak identified
on Saint Martin occurred in 1997. Since then, many outbreaks have occurred, most
recently in 2013 and 2014, with 4,020 reported cases, 40 hospitalizations,
2 deaths. In Saint Martin, three serotypes co-circulated during this outbreak:
DENV-1, DENV-2 and DENV-4, with serotype 1 predominating [54].
Aruba is a constituent country of the Kingdom of the Netherlands with 105,000
inhabitants. In 2011, 2,850 cases of dengue were reported. Over the past decade,
outbreaks were reported in 2009 (3,210 reported cases) and 2011 (2,850 cases).
In 2014, 833 cases were reported [55].
Curaçao is a constituent country of the Kingdom of the Netherlands with a
population of 160,000. In 2014, Curacao health authorities reported 194 suspected
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dengue cases (IR = 131/100,000) and 20 confirmed cases. No information on the

number of dengue cases reported in subsequent years has been reported [56].
Prevalence: Dengue is an acute disease and therefore the burden is best characterized by
incidence. Seroprevalence rates, however, are informative as a measure of past
exposure in a specific population at a given time.
Dengue seroprevalence data from studies in Latin America and Asia in 2011 found
more than 75% of 9 to 12-year-old children participating in the study have
previously been exposed to dengue [14]. However, dengue transmission is
spatially heterogenous, and the force of infection can be highly variable within and
across countries. In Singapore, for example, only 16% of 16 to 20 year olds have
previously been exposed, and in Thailand, schools located within the same
municipality have been shown to have significantly different transmission
intensities [29,57].
Demographics Age:
of the target
population in People of all ages are at risk of dengue infection [58]. Though the data are limited,
the indication: the results of some studies suggest that elderly dengue patients have the highest
dengue case-fatality rates [59-61].
In Southeast Asia, dengue has historically been a paediatric disease and clinical
dengue in adults has been rare [62]. Throughout the region, the majority of
children in endemic areas have already had a primary dengue infection before the
age of 9 years [14]. In Asia, DHF and Dengue shock syndrome (DSS) mostly occur
in children aged 2 to 15 years [63]. However, data from Singapore, Malaysia,
Indonesia, Thailand, and Bangladesh point to a recent increase in dengue
incidence among older age groups [29,64-67]. A study from Thailand indicated
that this shift in age profile is, in part, driven by changes in the age structure of
the Thai population over the last 30 years [29,68,69]. Other factors contributing to
this shift in the age burden include increased urbanization, a decrease in mean
household size, improvements in sanitation and water, increases in
socioeconomics, increases in vector control, and educational campaigns against
dengue [70,71].
In Latin America, first infections have generally been among young adults and
severe disease occurs in a significant number of adults [72]. Recently, however,
Latin America has seen an important increase in dengue incidence among children,
leading to an epidemiological shift that is beginning to resemble the historical age
profile seen in Southeast Asia [73].
In Brazil, this shift has been shown to be partly attributed to an increase in
multitypic immunity in adults over time following the re-emergence of DENV-1 in
1986, DENV-2 in 1990, and DENV-3 in 2002. As such, the probability of being
dengue naive into adulthood has been reduced, resulting in a decrease in the
average age of infection [74,75]. Increases in multitypic immunity among adults
may also explain the recent increase in severe dengue observed among children in
Colombia, Venezuela, Nicaragua, and Mexico [76-78].
Gender:
Data regarding differences in dengue vulnerability by gender are mixed and vary
by time, place, and study methodology. Whether differences observed are due to
the pathogenesis process, immune response, exposure to the vector, or related to
treatment seeking behaviour remains unclear [79-82].
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Racial and/or ethnic origin:

Some association has been described for people of African genetic ancestry who
are less affected by severe dengue outcomes [83,84]. No other ethnic groups have
been identified as being at higher or lower risk of severe disease.
Risk factors for Variations in risk of dengue are influenced by rainfall, temperature, population
the disease: density, urbanization, poverty, poor sanitary conditions, domestic water supplies,
and vector control. Globalization, migration, international travel and climate
change also play a role in the geographic expansion of dengue [85,86].
At the individual level, the relative risk of developing severe dengue has been
shown to be significantly higher among persons with a secondary dengue infection
of a heterologous DENV serotype compared to those who have a primary infection
[78,87-92].
Numerous factors are also known to influence the severity of disease, including:
co-morbidities, nutritional status, the two extremes of age, genetic composition,
pregnancy, and the time interval since primary infection [76,90,93-99].
The main There is no specific treatment for dengue. Treatment of dengue is based solely on
existing symptoms and signs, with maintenance of the patient’s body fluid volume critical
treatment for haemorrhagic or shock cases [100].
options:
Dengvaxia is the only dengue vaccine to have been commercialized to date, with
licensure by regulatory authorities in multiple endemic countries [101]. In
December 2018, Dengvaxia received approval in the EU [102].
Natural history Twenty-five percent of dengue infections are thought to be symptomatic [5].
of the Clinically, infection with a dengue virus can result in a range of symptoms, often
indicated with unpredictable clinical progression and outcome [103]. The 2009 WHO clinical
condition in classification for dengue diagnosis and management divides dengue into two
the groups: uncomplicated and severe. Uncomplicated dengue is clinically defined as
unvaccinated an acute febrile illness with two or more manifestations (headache, retro-orbital
population, pain, myalgia, arthralgia, rash, or haemorrhagic manifestations) [100]. Severe
including dengue occurs in a small fraction of cases (<5%), and is associated with severe
mortality and bleeding, severe organ dysfunction, and/or severe plasma leakage [100,104].
morbidity: Illness rarely lasts beyond 10 days, though some symptoms can be persistent and
debilitating [100,105]. Without appropriate treatment, fatality rates can exceed
20%, however, with proper case management, the rate can be less than 1% [46].
The WHO estimates about 500,000 people with severe dengue require
hospitalization annually, and about 2.5% of those affected die [6].
Important co- Everyone in dengue endemic areas is deemed to be susceptible to dengue infection
morbidities: and disease. There are no known risk groups for uncomplicated dengue.
Comorbidities that may predispose individuals to severe forms of dengue include
cardiovascular disease, hypertension, stroke, diabetes, respiratory disease, renal
disease, hepatitis B or C, and Human immunodeficiency virus (HIV) [106-108].
Obesity and advanced age are also associated with more severe forms of dengue
[106,109].
CONFIDENTIAL
Part II: Module SII - Non-clinical part of the safety

specification
Key safety findings from non-clinical studies and relevance to human usage:
Key Safety Findings Relevance to human usage
Toxicity
All toxicity studies were Good Laboratory Practice (GLP) compliant except for the Pilot toxicology
study (DEN-001).
- Single-dose toxicity study (DEN-001) There were no tox-related effects
observed that would be
In a non-GLP pilot toxicology study, toxicity of a single translatable to the human
subcutaneous (SC) dose of TDV was compared with that of population.
wild type DENV-2 virus, vehicle control (vaccine diluent FTA
containing 1% F-127, 15% trehalose, and 0.1% human serum
albumin) or saline placebo. No effect on weight or appearance
was observed in mice dosed with TDV, while mice receiving
DENV-2 had weight loss and poor appearance. Toxicological
findings for both DENV-2 and TDV included a generalized
inflammatory response, reduction in alkaline phosphatase and
splenic extramedullary haematopoiesis. An increase in the
number of platelets was observed on Days 7, 9, and 11 in the
DENV-2 group, and on Days 7 and 9 in the TDV group.
Adverse findings were of lesser severity and shorter duration
in TDV treated animals compared with DENV-2-treated
animals. Viremia was of lower magnitude and shorter duration
in TDV treated animals compared with DENV-2-treated
animals. The results of this pilot toxicology study supported
use of the AG129 mouse model based on susceptibility to the
parental wild type DENV-2 16681 strain and TDV strains.
- Repeat-dose toxicity studies Most treatment-related effects

were reversible as they were no
1/ DEN-004 longer observed on study day 61.
In a GLP study, repeated administration of TDV by SC injection No human safety concerns have
was well tolerated at a target dose (sum of all 4 components) been identified from this study.
of 5.5 log10 PFU/dose (actual minimal dose administered
5.9 log10 PFU per back titration) in AG129 mice. Mice were
administered TDV up to three occasions on Days 1, 31, and
46. Study animals were then observed after dosing to evaluate
the potential toxicity of TDV until scheduled necropsy on day
8/9, 53, or 61.
All 4 vaccine strains replicated after the first TDV dose, but not
after the second or third doses of TDV. A single dose of TDV
resulted in seroconversion to DENV-1, -2 and -3 by Day 16,
while two TDV doses were required for substantial
seroconversion to DENV-4. Transient test article-related
effects, including some changes in clinical chemistry,
hematology, spleen weight and some histopathological effects,
were observed after the first dose. The majority of changes
were no longer observed on Day 61, 15 days after the third
administration of TDV. Minimal increases in the number of
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platelets were observed in the TDV group throughout the

study. No treatment-related or toxicologically significant
findings on any coagulation parameters were observed
throughout the study. Mixed cell infiltrates persisted at the
injection site through study Days 53 and 61 but were deemed
related to the vaccine diluent at these later time points.
Administration of the first dose of TDV did not result in
enhanced infectivity of subsequent doses of the vaccine
viruses.
In contrast, injection with wild type DENV-2 resulted in a
rough fur coat and organ weight changes at necropsy in
addition to histopathology and hematology observations
associated with a more severe generalized inflammatory state.
Injection with wild type DENV-2 resulted in histologic evidence
of dengue virus-associated encephalitis. The observations of
this GLP toxicology study supported the findings of the pilot
toxicology study in supporting tolerability of TDV and
immunogenicity against all 4 DENV serotypes.
2/ Study 5001446 No human safety concerns have

been identified from this study.
In a GLP toxicity study, repeated administration of TDV when
given up to 3 occasions by SC injection to AG129 mice at Based on these results, the NOAEL
levels of 7.0 log10 PFU/dose was well tolerated. was considered to be 1.07 x 107
PFU/dose.
Reversible target organ effects were observed on Day 8 in the
bone marrow (increased myeloid cellularity), spleen (increased The dose level shown to be well
hematopoiesis), thymus (decreased weight), skin and tolerated in this study was 22.8
injections site (mixed cell infiltration, skin times higher than the viral content
degeneration/necrosis and/or hemorrhage) at 7.0 log 10 of the TDV high dose tested in
PFU/dose. Associated changes in organ weights and in clinical clinical studies.
pathology parameters were observed. All changes were
considered expected observations following vaccine
administration and/or non-adverse and reversible based on
nature, relative severity and/or reversibility (or partial
reversibility). Based on these results, the No-observed-
adverse-effect level (NOAEL) was considered to be 7.0 log 10
PFU/dose (1.07 x 107 PFU/dose), which exceeds the maximum
manufacturing release specification for TDV.
3/ Study 5001168 There were no tox-related effects

observed that would be
In a GLP toxicity study, repeated administration of TDV when translatable to the human
given up to 3 occasions by SC injection to AG129 mice at population.
levels of 6.8 log10 PFU/dose was well tolerated.
Based on these results, the NOAEL
Vaccine vRNA from TDV-1, TDV-2 and TDV-3 was detected in was considered to be 5.93 x 106
the serum of animals given TDV at 6.8 log10 PFU/dose after the PFU/dose. The dose level shown to
first vaccination only. Target organ effects were observed in be well tolerated in this study was
the bone marrow (increased myeloid cellularity), spleen 12.6 times higher than the viral
(increased hematopoiesis), thymus (decreased weight), skin content of the TDV high dose
and injection site (mixed cell inflammation) at 6.8 log10 formulation (i.e., 4.7 x 105
PFU/dose. Associated changes in organ weights and in clinical PFU/dose) tested in clinical
pathology parameters were observed. Increases in platelets studies.
were observed in TDV-vaccinated females throughout the
study. In contrast, platelet counts in vaccinated males were
CONFIDENTIAL
not different from control animals. All changes were considered

expected observations following vaccine administration. They
were non-adverse and reversible based on nature, relative
severity, and reversibility or partial reversibility. Based on
these results, the NOAEL was considered to be 6.8 log10
PFU/dose (5.93 x 106 PFU/dose).
- Reproductive and Developmental Toxicity Non-clinical safety data revealed

no special hazard for humans
The objective of this study was to assess the potential toxicity based on toxicity to reproduction
of TDV on fertility, development of the embryo and fetus, and and development.
postnatal development in New Zealand White rabbits. This
study was designed to evaluate International Conference on
Harmonisation (ICH) Harmonised Tripartite Guideline S5
stages A to E of the reproductive process.
F0 generation female rabbits in Groups 1 and 2 were given
2 dose administrations per day (once every 3 weeks) of TDV
(containing 5.4 log PFU/mL; TDV-2: 4.8 log PFU/mL; TDV-3:
5.7 log PFU/mL; TDV-4: 6.2 log PFU/mL) or saline control
article prior to mating on Days 1, 21 and 42 of study, and on
Days 7 and 28 of gestation (GDs 7 and 28). The first day of
dosing was considered Day 1 of study (DS 1).
Administration of TDV on study DS 1, 21 and 42 and GD 7 and
28 did not increase the incidence of clinical signs, dermal
scoring, or maternal gross lesions or have an effect on body
weights, food consumption, and mating, fertility, or
reproduction in the F0 generation, as compared with the group
administered the saline control article. There were no TDV-
related mortalities. In addition, there were no effects on any
ovarian, uterine, or litter parameters following administration
of TDV.
Maternal treatment with TDV did not cause any vaccine-related
effects on clinical observations, body weights, organ weights,
or gross pathology observations in the F1 generation kits.
There were no TDV-related mortalities. There were no fetal
gross external, soft tissue, or skeletal abnormalities attributed
to administration of the vaccine.
TDV elicited an immune response in 100% of the rabbits on DS
48 prior to mating. The F1 generation from Group 2
Caesarean-sectioned fetuses were 100% seropositive while the
natural delivery kits were 95%, 100%, 83% and 93%
seropositive to DENV-1, -2, -3 and -4, respectively.
In summary, TDV was well tolerated and did not produce any
detectable maternal or developmental toxicity in New Zealand
White rabbits.
- Genotoxicity The absence of genotoxicity and

carcinogenicity studies is
Studies investigating genotoxicity have not been conducted. considered acceptable based on
Genotoxicity studies were not conducted as TDV is a live viral the type of product and in line with
vaccine consisting of normal metabolizable components. No current guidelines on non-clinical
novel excipients or compounds of concern are used in the evaluation of vaccines.
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product.
- Carcinogenicity
Studies investigating carcinogenicity have not been conducted.
Carcinogenicity studies were not conducted as TDV consists of
attenuated dengue viruses, which are RNA viruses and are not
oncogenic. TDV consists of normal metabolizable components.
No novel excipients or compounds of concern are used in the
product.
Safety pharmacology
Studies investigating safety pharmacology have not been Separate safety pharmacology
conducted. studies were not conducted, which
is acceptable according to the EMA
As there were no adverse safety issues related to TDV and the WHO guidelines.
identified in the toxicology studies, specific safety
pharmacology studies were not conducted. This type of study
is generally not performed for vaccines. Central nervous
system (CNS) effects were evaluated in the neurovirulence
studies [Report DEN-014,]. CNS-associated organs (brain and
spinal cord) were assessed histopathologically as part of the
biodistribution [Report 5002340] and toxicology [Reports DEN-
004, 5001168 and 5001446] studies with no adverse findings
reported.
Other toxicity-related information or data
- Neurovirulence (DEN-014) Virus replication in the central

As a part of the characterization of the attenuation of TDV nervous system after passage
strains, a mouse neurovirulence study was conducted. through the blood–brain barrier
has been investigated by direct
This study evaluated the neurovirulence of TDV Master Virus intracerebral injection of the
Seeds (MVS) in new-born ICR mice challenged intracranially vaccine in new-born mice brains
with a dose of approximately 103 and/or 104 PFU of TDV MVS, and TDV has showed significantly
recombinant DEN-2 PDK-53-based viruses or wild type dengue lower mortality compared with
viruses. DEN-2 and similar neurovirulence
TDV-1 and TDV-3 MVS exhibited fully attenuated to the original homologues
neurovirulence phenotypes (no illness or mortality) at 104 PFU. recombinant dengue research
At viral dose levels of ~103 PFU, TDV-2 and DEN-2 PDK-53 as strains.
well as TDV-4 and the research grade D2/4 recombinant were
Therefore, TDV is considered to
significantly less neurovirulent than DEN-2 (16681 DEN-2)
have an acceptable neurotoxic
indicating attenuation of the recombinant and MVS stocks
profile and no human safety
compared to DEN-2, albeit at a lower dose than used in earlier
concern has arisen from this
studies. TDV showed significantly lower mortality after
study.
intracranial injection in suckling mice compared with DEN-2
and similar neurovirulence to the original homologue
recombinant dengue research strains.
- Biodistribution and Shedding Biodistribution and shedding

assessment of TDV in AG129 mice
Biodistribution and shedding of TDV by single SC injection was demonstrated that vRNA
assessed in AG129 mice at levels of TDV-1: 5.1, TDV-2: 4.5, distribution could be detected and
TDV-3: 5.4 and TDV-4: 5.9 log10 PFU/dose. RT-qPCR and was cleared from the majority of
histopathology in 16 tissues, saliva, feces, and urine were tissues. There was no shedding of
evaluated at terminal timepoints (Day 2, 6, 14 and 42). TDV TDV vRNA in feces and urine and a
CONFIDENTIAL
was well tolerated (mortality, clinical signs, body weights, food low level of vRNA detected in
consumption, macroscopic findings, organ weights, and saliva of one animal early in the
microscopic findings) and no adverse effects related to TDV study (Day 6), indicating a low risk
administration were observed. On Day 2, viral RNA (vRNA) for vaccine shedding to the
from the four TDV serotypes was detected at low levels at the environment or transmission from
injection site. By Day 6, vRNA was distributed broadly, and vaccinees.
was detectable in most tissues. By Day 14, vRNA had been
reduced to below the level of detection in most tissues,
including serum. By Day 42, most tissues were negative for
vRNA, but low levels of TDV-2 vRNA were detected in one skin
sample from the injection site, one thymus sample, and one
brain sample. There were no TDV-associated clinical
observations or histopathological findings in the brain or
thymus at any timepoint, or in the injection site on Day 42,
including in those animals with detectable vRNA. One
mandibular lymph node was positive for TDV-3 vRNA on Day
42 and minimal increased lymphoid cellularity was present in
the mandibular lymph node in a few animals, including the one
animal with detectable vRNA.
With these data in mind, the potential mechanism of vRNA
distributing to brain of AG129 mice, and potential risk
associated with this finding, was investigated. Review of all
nonclinical studies of TDV in AG129 mice showed no TDV-
related neurological manifestations. TDV was demonstrated to
be less neurovirulent than wild-type DENV-2 in newborn mice.
Both DENV-2 16681 (the wild-type parental strain of PDK-53)
and DENV-2 PDK-53 (the attenuated parental strain of TDV-2)
were reported to have little or no neurovirulence in immune-
competent rhesus macaques when injected into the brain or
spinal cord, and no clinical signs were observed. It may be that
the immunocompromised AG129 mouse model chosen for
biodistribution and shedding assessment may be sensitive to
distribution or persistence of vRNA in brain due to lack of
interferon responses and increased vascular permeability.
Overall, in a single dose TDV nonclinical biodistribution and

shedding study in AG129 mice, the maximal detection of vRNA
in serum was observed on Day 6 and clearance from the
majority of samples was noted by Day 42. TDV was well
tolerated, and there was no measurable level of vRNA in feces
and urine, and a low level of vRNA detected in saliva of one
animal early in the study (Day 6), confirming a low risk for
vaccine shedding to the environment or transmission from
vaccinees.
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- Dengue Antibody-dependent disease enhancement (ADE) Takeda has compiled supportive

immunological data that confirms
Nonclinical studies to evaluate (ADE) were not performed a broad, multicomponent immune
because nonclinical models are not highly predictive of the risk response is generated by TDV,
of severe dengue disease in humans. The available models use which indicates that the risk for
either immunocompromised animals, or if immunocompetent ADE is less than that found in
the animals are not susceptible to symptomatic dengue waning monovalent infections, or
disease. from vaccination with formulations
that are unable to activate multiple
layers of protection (e.g., dengue
specific cellular responses against
all 4 serotypes in addition to that
afforded by antibodies).
CONFIDENTIAL
Part II: Module SIII - Clinical trial exposure

Table SIII.1: Age group and gender*
TDV (final formulation, safety set)
Age (years) Male, n (%) Female, n (%) Total, n (%)
<4 176 (2.1) 178 (2.1) 354 (2.1)
4-11 5176 (60.8) 5049 (59.2) 10225 (60.0)
12-17 2405 (28.3) 2496 (29.3) 4901 (28.8)
18-60 756 (8.9) 807 (9.5) 1563 (9.2)
Total 8513 8530 17043

Source: CTD Module 5.3.5.3, ISA Table 1.1.1.2. for age ≥4 years and Ad-hoc Table SIII.1 for age <4 years.
Note: Studies included: DEN-106, 203, 204, 205, 301, 304, 305 (Group 2), 313, 314 (Group 2), and 315.
*The table presents subjects aged 1.5 to 60 years, limited to those subjects who were eligible for the pooled safety analysis of
phase 2 and phase 3 trials. All phase 1 trials – all in adults - were not included in the safety pooling because they were mainly
designed to explore different doses, schedules, and vaccine formulations, as well as different methods or routes of
administration; subjects who were co-administered YF or Japanese Encephalitis (JE) vaccine were excluded from the pooled
safety analysis to avoid confounding of data interpretation, and their safety data are assessed separately; Trials DEN-307 and
DEN-210 were not included in the pooled analysis as both were ongoing studies with only preliminary safety information available
at the time of the overall safety data cut-off date.
Table SIII.2.A: Number of subjects exposed during completed and ongoing Phase 1,
Phase 2 and Phase 3 trials and overall exposure.
Number of Subjects
Any Other N
TDV Placebo
TDV(c) Vaccines Total(e)
≥1 1 2 ≥1 PBO ≥1 ≥1
Dose Dose(a) Doses(b) Dose Only Dose Dose(d)
Total for Phase 1 Trials
0 0 0 414 41 81 0 455
Total for Phase 2 and Phase 3 Trials
18145 1096 17049 19566 7226 9445 1438 27118
Total Phase 1-Phase 3 Trials (1.5-60 years)
18145 1096 17049 19980 7267 9526 1438 27573
Total for Target Population (4-60 years)
17791 992 16799 19589 7203 9116 1438 27118
Source: CTD Module 2.7.4, Appendix A.
Abbreviations: CSR, clinical study report; NA, not applicable; HAV, hepatitis A virus; PBO, placebo; YF, yellow fever.
Trial DEN-303 data are not included because subjects in this trial have previously participated in the parent Trials DEN-304 or
DEN-315. Therefore, they do not contribute to the overall number of subjects exposed: As of the data cut-off date for the overall
safety data, all 365 subjects enrolled into Trial DEN-303 were still in the 15-month follow-up period (i.e., none has received the
booster dose).
(a) This includes 1 subject of Trial Group 4 from study DEN-204 who received TDV instead of the assigned placebo dose at
Month 12.
(b) 195 subjects from study DEN-204 had final TDV at both Month 0 and Month 3.
(c) Includes any subjects who received any non-final TDV formulation (1 or 2) doses.
(d) Other Vaccines include vaccines for Yellow Fever (YF) and Hepatitis A Virus (HAV).
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(e) DEN-204,305,314 study design allowed administration of either one or two doses of final formulation TDV followed by one
or two placebo or YF/HAV doses to the same subject. Subjects who received more than one IMP are counted under each IMP
they received but are counted only once in the Total column.
Table SIII.2.B: Dose (any TDV formulation, safety set)*
Number of subjects exposed to any TDV formulation
Received Month
12 injection
Received one Received two (DEN-204)(a),
Age (years) dose, n (%) doses, n (%) n (%) Total (b), n (%)
<4 7 (0.8) 384 (2.2) 339 (22.3) 391 (2.1)
4-11 172 (19.8) 10219 (58.1) 901 (59.2) 10391 (56.3)
12-17 88 (10.1) 4829 (27.4) 283 (18.6) 4917 (26.6)
18-60 603 (69.3) 2162 (12.3) NA 2765 (15)
Total 870 17594 1523 18464

Source: CTD Module 5.3.5.3, ISA Table 1.2.1.2. for age ≥4 years and Ad-hoc Table SIII.2.A for age <4 years.
(a) In Trial DEN-204, subjects received a third injection of trial vaccine at Month 12 of either TDV (Group 3; second injection of
TDV) or placebo (Group 1, 2, and 4).
(b) The Total column shows sum of subjects received one doses only and two doses, each of subject is only counted once.
Table SIII.2.C: Dose (TDV final formulation, safety set)*
Number of subjects exposed to TDV final formulation
Received Month
12 injection
Received one Received two (DEN-204)(a),
Age (years) dose, n (%) doses, n (%) n (%) Total(b), n (%)
<4 7 (1.3) 347 (2.1) 339 (22.3) 354 (2.1)
4-11 170 (30.4) 10055 (61.0) 901 (59.2) 10225 (60.0)
12-17 88 (15.7) 4813 (29.2) 283 (18.6) 4901 (28.8)
18-60 295 (52.7) 1268 (7.7) NA 1563 (9.2)
Total 560 16483 1523 17043

Source: CTD Module 5.3.5.3, ISA Table 1.2.1.2. for age ≥4 years and Ad-hoc Table SIII.2.B for age <4 years.
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(a) In Trial DEN-204, subjects received a third injection of trial vaccine at Month 12 of either TDV (Group 3; second injection of
TDV) or placebo (Group 1, 2, and 4).
(b) The Total column shows sum of subjects received one doses only and two doses, each of subject is only counted once.
Table SIII.3: Ethnic origin (safety set)*
Number (%) of TDV

subjects (TDV final
Ethnic origin formulation(b))
American Indian or Alaska native 6274 (36.8)
Asian 6575 (38.6)
Black or African American 2205 (12.9)
White 1425 (8.4)
Multiracial or other(a) 564 (3.3)
Total 17043
Source: CTD Module 5.3.5.3, ISA Table 1.1.1.2. for age ≥4 years and Ad-hoc Table SIII.3 for age <4 years.
(a) Includes subjects of the categories Native Hawaiian or other Pacific Islander, Multiple, Not reported and Unknown.
(b) Include TDV final formulation subjects with age <4 years to 60 years.
*The table presents subjects aged 1.5 to 60 years, limited to those subjects who were eligible for the pooled safety analys is of
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Part II: Module SIV - Populations not studied in clinical

trials
SIV.1. Exclusion criteria in pivotal clinical studies within the development

programme
Females subjects (post-menarche) who were pregnant or breastfeeding.
Females of childbearing potential, who are sexually active, and who have not used any of
the acceptable contraceptive methods for at least 2 months prior to study entry or who
refuse to use an acceptable contraceptive method or avoid donation of ova up to 6 weeks
post second vaccination.
Reason for exclusion These subjects were excluded to ensure vaccinee and fetus safety.
Most live attenuated vaccines are not recommended or contraindicated
during pregnancy as theoretically, live attenuated virus vaccines
administered to pregnant women might, be capable of crossing the
placenta and infecting the foetus [110].
There are conflicting data in the literature regarding the association
between wild type dengue infection during pregnancy and increased risks
of both a more severe course of disease and adverse pregnancy outcomes
[111-113].
Pre-clinical data for TDV were not available when most of the studies
started (including the pivotal Trial DEN-301). Moreover, it was unknown
whether TDV was excreted in human milk and data on excretion of wild
type dengue via breastfeeding are limited.
Is it considered to be Yes
included as missing
information?
Rationale Not applicable. Safety profile of inadvertent use in pregnant or lactating

women is included as missing information.
History of hypersensitivity or allergy to any of the vaccine components.
Reason for exclusion These subjects were excluded to ensure vaccinee safety.
Is it considered to be No
included as missing
information?
Rationale There was no evidence TDV was associated with an increased risk of
serious anaphylactic shock or hypersensitivity events. However, subjects
who are allergic to any vaccine component are at risk to develop
anaphylactic reactions. Anaphylaxis including anaphylactic shock is
classified as an important potential risk. Moreover, hypersensitivity to the
active substances or to any of the excipients of the vaccine or to a
previous dose of TDV are listed as contraindications for TDV in the
Summary of product characteristics (SmPC) in Section 4.3 and Package
Leaflet (PL) Section 2.
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Receipt of any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live
vaccines) prior to study entry or planned receipt of any vaccine within 28 days after study
entry.
Reason for exclusion These subjects were excluded to avoid confounding the assessment of
emerging immune response and safety profile of TDV.
Based on general vaccination guidelines, intervals of 2 or 4 weeks between

administration with inactivated or live vaccines, respectively, should be
respected to avoid interactions with other vaccines.
included as missing
information?
Rationale Not applicable. Safety and immunogenicity of concomitant administration

with other vaccines is included as missing information, except yellow fever
(YF) and Hepatitis A virus (HAV) vaccines for which data from the
development program are included in the marketing authorization
application.
Known or suspected impairment/alteration of immune function:

- Chronic use of oral steroids or receipt of parenteral steroids or immunostimulants
within 60 days before study entry,
- Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy

within the preceding 6 months,
- HIV or HIV-related disease,
- Genetic immunodeficiency
Reason for exclusion These subjects were excluded to ensure vaccinee safety and to not
confound assessment of TDV immunogenicity and safety profile.
Immunocompromised participants may have a higher risk of occurrence of
dengue disease and of impaired immune response to the vaccine limiting
the availability to demonstrate efficacy and safety of TDV during clinical
trials.
included as missing
information?
Rationale Not applicable. Safety and immunogenicity in immunocompromised

individuals is included as missing information.
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Receipt of blood products and/or immunoglobulins within the 6 months before study
entry.
Reason for exclusion These subjects were excluded to avoid confounding the assessment of TDV
immunogenicity in the study population as live-attenuated viruses
contained in TDV may be neutralized by circulating antibodies in
immunoglobulin therapy or blood products (such as blood or plasma).
included as missing
information?
Rationale As per general vaccination guidelines, for patients receiving treatment with
immunoglobulins or blood products containing immunoglobulins, it is
recommended to defer the administration of live attenuated viral vaccines
for at least 6 weeks and preferably for 3 months, following the end of the
treatment before administering TDV, in order to avoid neutralization of the
attenuated viruses contained in the vaccine. This information is mentioned
in the SmPC Section 4.5 and PL Section 2.
Febrile illness (temperature ≥38°C) or moderate or severe acute illness or infection at the
time of randomization.
Reason for exclusion These subjects were excluded to ensure vaccinee safety and not confound
the assessment of emerging immunogenicity and safety profile of TDV.
included as missing
information?
Rationale As per established vaccination guidelines, administration of vaccines must

be postponed in individuals who present febrile illness or moderate to
severe acute disease.
SIV.2. Limitations to detect adverse reactions in clinical trial development

programmes
Overall, data from 27,573 subjects, from 18 ongoing or completed trials, as of the overall safety
data cut-off date, contributed to the safety evaluation of TDV (20,071 subjects from the pivotal Trial
DEN-301). These trials covered an age range from 1.5 to 60 years and safety surveillance up to 36
months after the second dose of trial vaccine in Trial DEN-301. Overall, 19,980 subjects received at
least 1 dose of TDV in these trials. Among all 19,980 subjects exposed to any TDV, 18,145 subjects
(90.8%) received at least 1 SC dose of TDV.
The clinical development program is likely to provide data concerning serious rare adverse events
due to size of population and address long-term risks as the planned follow-up period covers up to
4.5 years after the last TDV injection. Moreover, available follow-up data are 3 years after second
TDV injection for DEN-301 and 4 years after first TDV injection for DEN-204.
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SIV.3. Limitations in respect to populations typically under-represented

in clinical trial development programmes
Table SIV.2: Exposure of special populations included or not in clinical trial development
programs
Type of special Exposure

population
Pregnant women This population was not included in the clinical development program and
is considered as missing information (see SIV.1).
Breastfeeding women
As of 01-October-2020, 34 pregnancies have been identified as exposed to
TDV in clinical trials. These limited data are insufficient to conclude on the
presence or absence of potential effects of TDV on pregnancy, embryo-
foetal development, parturition, and post-natal development.
Immunocompromised This population was not included in the clinical development program and
patients is considered as missing information (see SIV.1).
Patients with hepatic, These conditions were not evaluated during the clinical development
renal or cardiovascular program.
impairment
Population with Populations with different ethnic origin were included in the clinical trials
relevant different (see Table SIII.3). Most of them were Asian, American Indian or Alaska
ethnic origin native (76%). Data for other ethnic origins are limited, however no
clinically significant differences were observed between the different
ethnicities.
Subpopulations This condition was not evaluated during the clinical development program.
carrying relevant
genetic polymorphisms
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Children (<4 years) The overall clinical development of TDV comprised a population aged
1.5 to 60 years; TDV is indicated for the prevention of dengue disease in
individuals from 4 years of age.
Number of subjects aged <4 years in the clinical development program:

- 401 subjects from phase 2 Trial DEN-204
- 54 subjects from phase 2 Trial DEN-203

The evaluation of the safety profile of TDV in children aged <4 years is
limited to 401 subjects aged 2 to 3 years from phase 2 Trial DEN-204,
comprising 354 subjects exposed to TDV and 47 subjects exposed to
placebo only. The 401 children aged <4 years from Trial DEN-204 were
followed up until 48 months after the first vaccine dose. All subjects in
Trial DEN-204 were enrolled in dengue-endemic countries: The Philippines,
Dominican Republic and Panama (Refer to CTD Module 2.7.4).
The 54 subjects aged <4 years from Trial DEN-203, comprise 37 subjects
exposed to HD TDV and 17 subjects exposed to placebo (none received
the final TDV formulation) (Refer to CTD Module 2.7.4).
For children aged <4 years (not part of the proposed age indication), the
evaluation of the long-term safety data of the 401 subjects from Trial
DEN-204 up to 48 months after the first vaccine dose did not identify any
important safety risks.
Elderly (>60 years) This population was not included in the clinical development program.
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Part II: Module SV - Post-authorisation experience

Not applicable (no post-authorisation experience available thus far).
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Part II: Module SVI - Additional EU requirements for the

safety specification
Potential for misuse for illegal purposes
There is no indication that TDV has potential to be a medicinal product of abuse.

TDV is indicated for the prevention of dengue disease in individuals from 4 years of age and there is
no known illegal marketplace. In summary, it is highly unlikely that TDV will be misused for illegal
purposes.
Potential for overdose
TDV is administered by a healthcare professional and using single-dose vials. Therefore, overdosing
is not anticipated. No cases of overdose have been reported in clinical trials with TDV.
Potential for transmission of infectious agents
Transmission of the vaccine viruses to susceptible people or other organisms

A range of organisms may be exposed directly or indirectly to TDV. Vaccinated individuals are
intentionally exposed. Clinical staff administering the vaccine or other staff handling the vaccine
during transport may be unintentionally exposed through a spill or needle stick. During the course of
the release, access to the dengue vaccine will be limited to pharmacy staff, medical practitioners
and health care professionals. Therefore, there is very little potential for unintended exposure to
TDV. Standard blood donation screening practices would prevent vaccine recipients from donating
blood during their expected periods of viremia. However, wild type dengue infections resulting from
needle stick injuries during the care of febrile patients have been reported [114,115]. In the worst
case, a needle stick or other unintended exposure to TDV would be expected to result in the
symptoms seen during intentional vaccination.
Waste management workers, insects, birds and animals may be unintentionally exposed through
inadvertent disposal of unused vaccine to landfill. But due to the instability of dengue viruses and
the vaccine in the environment, there is little risk of waste management workers, insects, birds and
animals being unintentionally exposed to infectious vaccine waste through inadvertent disposal of
unused vaccine.
Theoretically accidental exposure could also occur if a mosquito feeds on a vaccinated subject during
a period of high TDV replication. TDV uptake by the mosquito and subsequent biting of another
person could transmit TDV unintentionally. Takeda has conducted studies in mosquitoes to evaluate
the potential of TDV to be transmitted by these vectors. Dengue virus transmission occurs through
the bite of an infected mosquito vector. TDV monovalent vaccine strains were shown to have a
reduced ability to replicate and disseminate in Aedes aegypti and Aedes albopictus mosquitoes [116].
Environmental escape of TDV by mosquito transmission could only occur if (i) a mosquito vector
feeds on a vaccinee with a sufficient viremia titer to infect the mosquito midgut, (ii) the virus is
capable of replicating in the midgut epithelium, (iii) replicated virus is able to subsequently
disseminate out of the midgut, and (iv) the disseminated virus can replicate in the mosquito salivary
gland and release sufficient virus in saliva for transmission. In the Phase 1 and 2 clinical trials, TDV
(mostly TDV-2) replicated in only a portion of the subjects and, the vaccine viral RNA levels were 1
to 2 logs lower than the wild type dengue MID 50 for both Aedes aegypti and Aedes albopictus
mosquitoes [117,118]. With the very low mosquito infection, dissemination and transmission
capacity of TDV in Aedes aegypti and Aedes albopictus and the low levels of TDV viremia seen in
vaccinees, it is highly unlikely that the vaccine viruses would be transmitted by mosquitoes through
the natural infection route. In addition, TDV has an attenuated phenotype for replication in C6/36
Aedes albopictus mosquito cells. Although very unlikely given the above considerations, it is
expected that TDV transmission from an infected mosquito’s bite would at worst result in the mild
symptoms seen during intentional vaccination.
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The TDV viruses have been shown to be attenuated in humans, non-human primates and mice
[119,120]. In the worst case, unintended exposure to TDV is expected to result in the same
response as intentional inoculation with the vaccine.
Shedding
Dengue viruses are transmitted in blood and are not known to spread to other people by shedding
[10,121]. Although dengue virus RNA and NS1 protein have been found in the urine and saliva in
wild type infections of humans, live dengue viruses have not been isolated [121,122]. In a study,
dengue virus has not been detected in the semen in five patients with acute dengue virus infection
[123]. Cases of likely sexual transmission and cases of presence of dengue virus in semen or vaginal
secretions have been reported but are considered anecdotal [124-126]. There is limited data on the
excretion of wild type dengue via breast milk. In a small study, DENV was detected in breast milk
samples from 9 (75%) of 12 infected breastfeeding mothers [127].
Like other flaviviruses, dengue virus, has low environmental stability. Thus, if TDV would be shed
into the environment, it would likely be unstable. In a single dose TDV nonclinical biodistribution and
shedding study in AG129 mice (Study 5002340), there was no shedding of TDV RNA in feces and
urine. These results suggest a low risk for TDV shedding to the environment or transmission from
vaccinees by shedding.
Maternal-fetal transmission of the vaccine viruses

In studies of dengue in pregnancy, where maternal-fetal transmission of wild type dengue viruses
has been demonstrated by the detection of dengue specific IgM in cord blood, rates of transmission
were low [128,129] (vertical transmission 1.6% and 5.6% respectively). In addition, cases of
dengue disease in neonates following transmission of the virus between an infected mother and the
fetus in utero or as a result of transmission to her infant during labour and delivery, have also been
reported rarely [128-132]. Intrauterine transmission of dengue has been associated with high
maternal serum viremia titers [132] and may be related to endothelial damage and increased
vascular permeability caused by the wild type dengue virus infection [122]. TDV is attenuated and
replication of the vaccine virus is limited relative to wild type dengue viruses.
Pregnant women were not included in the clinical development program (See Part II: Module SIV -
Populations not studied in clinical trials) and therefore there is limited amount of data from the use
of TDV in pregnant women. These data are not sufficient to conclude on the absence of potential
effects of TDV on pregnancy, embryo-fetal development, parturition and post-natal development. A
study in rabbits did not indicate direct or indirect harmful effects with respect to reproductive
toxicity.
Although, live attenuated virus vaccines given to pregnant women might be capable of crossing the
placenta and infecting the fetus, no evidence of increased adverse pregnancy outcomes has been
identified from inadvertent immunisation of women in early pregnancy with the first marketed
dengue vaccine at this time [133].
Potential for infections caused by residuals of biological material used in the
manufacturing process as well as contaminations introduced by the manufacturing
process
The four TDV viruses are purified. The purified active substance is stabilized in a solution containing
various salts, Poloxamer 407, Trehalose, and human serum albumin. Both TDV presentations, vial -
vial presentation or vial - prefilled syringe, are sterile. Therefore, no potential infectious
contaminants from the manufacturing process are expected.
Reversion to virulence
Vaccine viremia and potential reversions in the presence of replication-competent vaccine virus only
were assessed in several Phase 1 and Phase 2 clinical trials conducted in endemic and non-endemic
areas (DEN-101, DEN-102, DEN-103, DEN-104, and DEN-203 Part 1). Furthermore, vaccine viremia
CONFIDENTIAL
and potential reversions independent of the presence of replication-competent vaccine virus was
determined in DEN-205. The proportion of subjects with vaccine viremia varied from one trial to
another likely because of the different trial settings and the different earlier TDV formulations with
different viral content. In the TDV group of Trial DEN-205, vaccine viremia was observed in 30.9%
of subjects and occurred mainly after the first dose and peaked 10 to 12 days after vaccination. In
the vast majority of cases, vaccine viremia occurred for vaccine strain TDV-2.
In total, 423/775 (54.6%) of subjects exposed to TDV had detectable vaccine strain RNA.
Reversions were detected in 67 subjects; all affected only a single attenuation locus. This included
23 reversions detected in Trial DEN-205 for which the presence of replication competent material
was not determined, and 44 reversions detected in Trials DEN-101, DEN-102, DEN-103, DEN-104,
and DEN-203 Part 1. The majority of reversions (n=65) were found in the 5’NCR locus, two affected
the NS1 locus (a single partial reversion in subject from Trial DEN-104 and a single reversion in
subject from HD TDV group of Trial DEN-205)) and none were found for the NS3 locus.
Apart from a numerical increase and temporal association of mostly mild and transient solicited and
unsolicited AEs, no major safety findings were identified for subjects with vaccine viremia. Subjects
with vaccine viremia may develop systemic symptoms such as headache, arthralgia, or myalgia that
can also occur in the absence of viremia, illustrating the non-specific nature of such events. While
rashes were rather infrequent (up to 10.2% in vaccine recipients), their occurrence showed a close
temporal relationship with viremia.
The AE profile in the 67 subjects with reversions was not indicative of an increased severity of
symptoms. The 2 reversions observed in the NS1 locus (partial reversion in subject from Trial
DEN-104, second reversion in subject from the HD TDV group of Trial DEN-205) did not result in
increased virulence: the subject from Trial DEN-104 reported fatigue, rash, and headache (all non-
serious and graded as mild) and no fever; the second subject from Trial DEN-205 did not report any
AEs (refer to CTD Module 2.7.4).
In the pivotal efficacy Trial DEN-301, reversions were determined in subjects who reported a febrile
illness starting within 30 days of vaccination and who had replication competent vaccine virus
detected. Single reversions (all in the 5’NCR locus) were identified in 4 out of 15 subjects with
replication-competent vaccine viremia. All four subjects reported headache; two experienced in
addition rash and vomiting. One of the subjects was hospitalized due to dehydration; however, there
was no evidence of bleeding, low platelet counts or plasma leakage in any of the affected subjects.
Overall, no important safety risk was identified.
The presence of two attenuation determinants is sufficient to maintain the attenuation phenotype of
TDV. Thus, it is unlikely that reversion of only one of the three attenuation loci of TDV would yield
more virulent viruses that persist for a long time and cause dengue disease [2].
Of note, reversion to virulence theoretically may occur by a mechanism other than mutation during
replication: when two dengue viruses infect a single cell, it is theoretically possible for recombination
to occur if the RNA polymerase switches between genomes during viral replication. Since all four of
the TDV viruses share the identical attenuating mutations, recombination between vaccine strains
cannot generate more pathogenic viruses. However, recombination with wild type dengue viruses is
theoretically possible in TDV recipients if that person Recombination between two DENV genomes
has been observed, though at a lower frequency than with other RNA viruses such as poliovirus and
human immunodeficiency virus. In these studies, there was no evidence of recombination leading to
viruses with greater pathogenicity. The life cycle of DENV requires propagation in both humans and
mosquitoes, which may restrict the virus’ ability to mutate [134]. Thus, the genome tends to be
relatively fixed [135-138]. As the attenuated parental virus DENV-2 PDK-53 does not exist in nature,
there are no studies of natural recombination with wild type DENV-2 viruses available. However,
recombination would require co-infection of the same cell with 2 DENVs. The attenuated phenotype
DENV-2 PDK53 results in less replication, reducing the opportunities for co-infection and therefore of
recombination. Even if recombination theoretically occurred, the resulting virus would likely be
attenuated (Refer to CTD Module 1.6.2).
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Potential for immunisation errors

During the clinical trial development of TDV, no systematic immunisation errors were found that
would indicate misinterpretation of the product labelling/handling instructions. However, the ability
to predict post authorization immunisation errors from experience during the clinical phase is limited
and an effect on the safety and/or immunogenicity of TDV cannot be excluded. In order to minimise
immunisation errors in the post-marketing setting, the specific handling, storage and administration
requirements are described in the SmPC Section 6.4 Special precautions for storage and Section 6.6
Special precautions for disposal and other handling and have been taken into account during
packaging design.
The potential sources of immunisation errors with TDV are related to the following elements:
1. TDV must be stored at +2 to +8°C and not frozen.
Drug product stability data indicate that the lyophilized drug product will remain within the potency
specification for at least 18 months when stored at +2 to +8°C, depending on the target starting
potency titer used to manufacture a given lot (refer to SmPC Section 6.3).
After reconstitution with the solvent provided, in general, Qdenga should be used immediately. If
not used immediately the reconstituted vaccine must be used within 2 hours (refer to SmPC Section
6.3).
Safety concerns relating to inappropriate storage are theoretical at this point in time.
The SmPC (Sections 6.3 and 6.4) includes the recommendations to store the vaccine.
2. The vaccine is a lyophilized product that needs to be reconstituted in the appropriate solvent
prior to administration.
Potential errors include use of the wrong solvent, wrong volume of solvent, administration of solvent
alone (without reconstituted vaccine), prolonged storage of reconstituted product before vaccination
or not injecting all 0.5 mL of the reconstituted vaccine. All specific requirements are described in the
instructions for reconstitution (refer to SmPC Section 6.6).
3. TDV is indicated for subcutaneous administration in the deltoid region as two doses, three
months apart.
The SmPC Section 4.2 includes the recommendations to carry out the administration correctly
(Method of administration).
4. Syringes and needles.
The application will include 2 presentations:

• Vial/vial presentation: Vial containing lyophilized vaccine packed with vial containing solvent;
no syringe/needles in the pack
• Vial/pre-filled syringe presentation: Vial containing lyophilized vaccine packed with pre-filled
syringe containing solvent; with or without 2 separate needles in the pack, but none
attached to the syringe
The SmPC Section 6.6 includes the recommendations to carry out the administration correctly.
5. Use of expired vaccine or solvent.
The vaccine should not be used after the expiry date which is stated on the carton.
6. Confusion with another licensed dengue vaccine (i.e. Dengvaxia®) in countries where both
vaccines are licensed which may result in incomplete or wrong vaccination schedules.
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There are no data available on interchangeability of the two vaccines and whether the immune
response may be impacted. In addition, the separate labelling for each product provides instructions
on correct usage.
As recommended by the WHO, errors in immunisation will be considered in the initial evaluation of
all adverse event following immunisation (AEFI) [139]. Correct usage will be monitored within
routine pharmacovigilance activities and any changes in the safety profile of TDV related to
immunisation errors will be followed via periodic safety update reports/periodic benefit-risk
evaluation report (PSURs/PBRERs).
Specific paediatric issues identified in paediatric investigation plans (PIP)

In the current PIP Opinion/EMA Decision for TDV (EMA decision dated 30-Oct-2020), the following
potential long-term safety/efficacy issues were identified as particular causes of concern in the
paediatric population for consideration in the Risk Management Plan/Pharmacovigilance activities:
• Potential Antibody-dependent Disease Enhancement (ADE) in subjects not yet immune to all four
serotypes.
• Possible interaction between the vaccine and other flavivirus vaccines

• Any possible enhancement of severity of other flavivirus diseases.
Assessment of potential ADE in subjects not yet immune to all four serotypes:
The totality of data on virologically confirmed dengue (VCD), hospitalized VCD, and severe forms of
dengue, along with the clinical characteristics of these cases, as assessed in Trials DEN-301, DEN-
313, and DEN-204, did not reveal an identified risk of increased disease severity or disease
enhancement attributable to vaccination in the post-vaccination follow-up period. In baseline
seronegative subjects, an increased risk of hospitalization due to dengue and/or clinically severe
forms of dengue caused by DENV-3 and DENV-4 is considered an important potential safety risk.
This potential risk is under continued monitoring and safety evaluation, based on the ongoing long-
term follow-up in Trial DEN-301. (Refer to CTD Module 2.5 and Module 2.7.4).
Assessment of possible interaction between the vaccine and other flavivirus vaccines:
Co-administration of TDV with yellow fever (YF) and Hepatitis A virus (HAV) vaccines has been
evaluated in two phase 3 trials, DEN-305 and DEN-314. In both trials, the co-administration of TDV
with YF or HAV vaccines was generally well tolerated and had no negative effect on the safety and
reactogenicity of either vaccine. The trials revealed no identified or potential safety risks in case of
co-administration. YF vaccine immunogenicity was not affected when administered concomitantly
with TDV. However, dengue antibody responses were decreased to some extent following
concomitant administration of TDV with the YF vaccine compared with separately administered
vaccines, with non-inferiority shown for DENV-2, DENV-3, and DENV-4, but not for DENV-1. The
clinical significance of this finding is unknown. Co-administration of the HAV vaccine with TDV has no
negative impact on the immune response to either vaccine. The effect of co-administration of TDV
with other vaccines currently remains unknown. (Refer to CTD Module 2.5).
Assessment of any possible enhancement of severity of other flavivirus diseases:
Overall, the data from the TDV clinical development program do not suggest an increased risk for a
possible enhancement in severity of non-dengue flavivirus infections following TDV vaccination.
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Part II: Module SVII - Identified and potential risks

SVII.1. Identification of safety concerns in the initial RMP submission
SVII.1.1 Risks not considered important for inclusion in the list of safety concerns in the
RMP
Reason for not including an identified or potential risk in the list of safety concerns in the
RMP:
Risks with minimal clinical impact on patients (in relation to the severity of the indication
treated): upper respiratory tract infection, nasopharyngitis, pharyngotonsillitis, bronchitis, rhinitis,
decreased appetite, irritability, headache, somnolence, dizziness, diarrhoea, nausea, abdominal pain,
vomiting, rash, pruritus, urticaria, angioedema, myalgia, arthralgia, injection site pain, injection site
erythema, malaise, asthenia, fever, injection site swelling, injection site bruising, injection site
pruritus, influenza like illness, injection site haemorrhage, fatigue and injection site discolouration.
Adverse reactions with clinical consequences, even serious, but occurring with a low
frequency and considered to be acceptable in relation to the severity of the indication
treated: not applicable
Known risks that require no further characterisation and are followed up via routine
pharmacovigilance namely through signal detection and adverse reaction reporting, and
for which the risk minimisation messages in the product information are adhered by
prescribers (e.g. actions being part of standard clinical practice in each EU Member state
where the product is authorised): not applicable
Known risks that do not impact the risk-benefit profile: not applicable
Other reasons for considering the risks not important: not applicable
SVII.1.2. Risks considered important for inclusion in the list of safety concerns in the RMP
Important Identified Risks Risk-benefit impact
No important risk identified Not applicable
Important Potential Risks Risk-benefit impact
Anaphylaxis including There were no TDV-related anaphylactic reactions or anaphylactic

anaphylactic shock shock events reported during the clinical development program.
However, anaphylaxis is a severe and potentially fatal systemic
reaction which has been reported for most vaccines [140].
Dengue disease due to waning Vaccines are not anticipated to be 100% efficacious. In addition,
protection against dengue over most vaccines are not anticipated to provide lifelong immunity.
time Vaccine effectiveness may wane with increasing time since
vaccination. Waning immunity may lead to a risk for wild type
dengue infection unless there is pre-existing immunity for the
serotype/prior natural infection.
Severe and/or hospitalized For TDV, the data assessed in clinical Trials DEN-301, DEN-313
dengue following vaccination and DEN-204, the totality of clinical data did not reveal an
caused by dengue virus identified risk of increased disease severity or disease
serotype 3 or 4 in individuals enhancement attributable to vaccination in the post-vaccination
not previously infected by follow-up period. An exploratory subgroup analysis of Trial
dengue virus DEN-301, in baseline dengue seronegative subjects suggests a
potential risk of hospitalization due to dengue caused by DENV-3
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and/or clinically severe forms of dengue.
The evaluation of the VE against VCD caused by DENV-4 in

baseline seronegatives subjects was limited by the overall small
number cases reflective of the generally lowest prevalence for this
dengue serotype worldwide.
Missing Information Risk-benefit impact
Safety profile of inadvertent Theoretically the live attenuated virus in the vaccine could cross
use in pregnant or lactating the placenta and result in viral infection of the foetus. Owing to
women this concern, most live attenuated vaccines are either
contraindicated or not recommended during pregnancy.
There is limited amount of data from the use of TDV in pregnant

women. These data are not sufficient to conclude on the absence
of potential effects of TDV on pregnancy, embryo-foetal
development, parturition and post-natal development.
It is not known whether TDV is excreted in human milk.
Safety and immunogenicity in Immunocompromised individuals may not respond adequately to

immunocompromised vaccination and potentially the live attenuated virus in the vaccine
individuals may become pathogenic. Therefore, as per guidelines on
vaccination, live-attenuated virus vaccines are not recommended
for use in severely immunocompromised individuals. The safety of
TDV in immunocompromised individuals is not known as they were
excluded from the clinical development program.
Safety and immunogenicity of Potential interactions between concomitantly administered vaccines

concomitant administration may compromise the effectiveness and/or safety.
with other vaccines other than
HAV and YF
Safety and reactogenicity of a A protective immune response with TDV may decline over time. It
booster dose is currently unknown whether a lack of protection could result in an
increased severity of dengue. The effect of a booster dose is being
investigated in 2 ongoing clinical trials (DEN-301 and DEN-303).
SVII.2. New safety concerns and reclassification with a submission of an

updated RMP
Not applicable (initial marketing authorisation application).
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SVII.3. Details of important identified risks, important potential risks,

and missing information
SVII.3.1. Presentation of important identified risks and important potential risks
Important Potential Risk: Anaphylaxis including anaphylactic shock
Potential mechanisms: Anaphylaxis is a Type 1 immediate hypersensitivity reaction (Geland

Coombs classification) mediated by the interaction of IgE antibodies
against a particular vaccine component. Therefore, previous exposure
and sensitization to the triggering substance or a cross reactive allergen
is necessary. When a vaccine component (allergen) binds to the IgE
receptors on the surface of mast cells and basophils this results in cellular
activation and release of preformed mediators such as histamine and
tryptase that elicit the signs and symptoms of anaphylaxis [141].
Evidence source(s) and Case descriptions of anaphylaxis for other vaccines exist in the literature
strength of evidence: [140].
TDV contains human serum albumin which has been associated with
urticarial hypersensitivity reactions to rabies vaccine [142, 143]. Persons
with prior allergic reactions to albumin containing products may be at
higher risk of an allergic reaction to TDV. No published evidence for a
potential hypersensitivity potential of other constituents of TDV was
identified.
Characterisation of the Anaphylaxis is an acute hypersensitivity reaction with multi-organ-system

risk: involvement (≥2) that can present as, or rapidly progress to, a severe
life-threatening reaction. It may occur following exposure to the different
components of the vaccine. Anaphylactic shock is the most severe
manifestation of anaphylaxis [141].
Anaphylaxis after vaccination in general occurs very rarely but is a
potentially life-threatening medical emergency [144-148]. It has been
estimated to occur at a rate of approximately one to ten per 1,000,000
doses for most commonly administered vaccines [149-151]. The true
rate of allergic reactions is unknown because most reactions are not
reported [152].
No cases of anaphylaxis have been observed in the TDV pre-clinical

development program. There were no TDV-related anaphylactic reactions
or anaphylactic shock events reported during the clinical development
program. TDV was not associated with an increased risk for serious
anaphylactic shock or severe hypersensitivity events.
Risk factors and risk Clinical risk factors that have been identified for anaphylaxis are [153-
groups: 155]:
- History of allergies to the active substances or any of the other

components of the TDV vaccine.
- History of an allergic reaction after a previous immunisation with TDV.
- Coexisting atopic disease, particularly asthma.

However, allergic reactions may occur in patients without known risk
factors [156].
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Preventability: Predictability/prevention for new onset anaphylaxis is not possible due to

it being idiosyncratic.
The best practice to prevent anaphylactic reactions is to identify at-risk

individuals by obtaining the history of severe allergic reactions to any
component of the vaccine or to previous vaccinations that might indicate
an underlying hypersensitivity and avoid their vaccination.[157]
The SmPC Section 4.3 contains the following contraindication:

“Hypersensitivity to the active substances or to any of the excipients
listed in Section 6.1. or hypersensitivity to a previous dose of Qdenga”.
As per general recommendations on immunisation, individuals should be

observed after vaccination and appropriate medical treatment of
anaphylaxis should always be readily available. Early recognition of
symptoms and intervention can minimise the reaction sequalae/severity.
The SmPC Section 4.4 contains the following Special warnings and
precautions for use: “As with all injectable vaccines, appropriate medical
treatment and supervision must always be readily available in the event
of a rare anaphylactic reaction following administration of the vaccine.”
Impact on the risk- A severe anaphylactic reaction can be life threatening. When promptly
benefit balance of the treated, the prognosis is good.
product:
Public health impact: Currently, 18,273 doses of TDV were administered with no anaphylactic
reactions to TDV reported. This potential risk is not expected to have a
serious impact on public health.
Important Potential Risk: Dengue disease due to waning protection against dengue over
time
Potential mechanisms: Waning protection against dengue over time may leave the vaccinee
susceptible to wild type dengue infection, a potentially life-threatening
illness. Waning protection also may render vaccinees at risk for ADE of
infection.
Evidence source(s) and Efficacy analyses in pivotal Trial DEN-301 demonstrated the Vaccine
strength of evidence: Efficacy (VE) of TDV in the primary endpoint of preventing VCD fever
caused by any dengue serotype from 30 days to 12 months post second
vaccine dose, i.e., until end of Part 1 (VE: 80.2%; 95% CI: 73.3%,
85.3%) and also for the secondary endpoint period from 30 days to 18
months post second vaccine dose (VE: 73.3%; 95% CI: 66.5%, 78.8%).
VE was also seen for hospitalizations due to VCD by all dengue serotypes
combined. From 30 days to 18 months post second vaccine dose, the VE
for VCD leading to hospitalization was 90.4% (95% CI: 82.6%, 94.7%).
From first dose to 4.5 years after second dose, the VE in preventing VCD
fever by any serotype was 62.5% (95% CI: 56.0%, 65.8%) and
hospitalization due to VCD fever caused by any serotype was 84.1%
(95% CI: 77.8%, 88.6%).
In an exploratory analysis at 54 months post second dose (end of
Part 3), VE in preventing VCD was shown for all four serotypes in
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baseline dengue seropositive subjects. In baseline seronegative subjects,

VE was shown for DENV-1 and DENV-2, but not suggested for DENV-3
and could not be shown robustly for DENV-4 due to lower incidence of
cases.
VE varied in exploratory analysis by study intervals: during the third
year, although some decline in efficacy compared with Year 2 was
observed, largely driven by non-hospitalized VCD cases, efficacy against
VCD was demonstrated overall, as well as in both baseline seronegative
and seropositive subjects. Efficacy against VCD leading to hospitalization
remained robust with little change compared with Year 2. The data
obtained in the last 18 months of follow-up following Year 3 showed
continued long-term protection against overall VCD and a sustained high
level of protection against hospitalized VCD regardless of baseline
serostatus.
Waning immunity resulting in a loss of protection over time is applicable
to all vaccines. The maximum duration of protection with TDV is not
known currently.
Characterisation of the In the Trial DEN-301, the exploratory year-by-year analysis of efficacy by
risk: serotype and serostatus, TDV efficacy against DENV-3 was seen in
baseline seropositive subjects in Year 1, Year 2 and Year 3, while in
baseline seronegative subjects, the efficacy against DENV-3 was not
suggested. There is not enough data to make an assessment against
DENV-4 in baseline seronegative subjects. The relative risk of VCD (TDV
versus placebo, irrespective of hospitalization) caused by DENV-3 in
baseline seronegative subjects up to 54 months after the second vaccine
dose was close to 1 (1.11 [95% CI: 0.62, 1.99]). The relative risk of VCD
caused by DENV-3 in baseline seronegative subjects declined over time,
with a relative risk point estimate of <1 during Year 3 (relative risk 0.91
[95% CI: 0.34, 2.45]) and Year 4 (relative risk 0 [95% CI: not
estimable]); no VCD caused by DENV-3 occurred after Year 4 up to the
end of Part 3.
Over the years, a meaningful long-term protection was observed against
VCD despite a pattern of some waning driven by outpatient cases.
However, protection against hospitalized VCD was high and sustained.
The data obtained in the last 18 months of follow-up up to Month 54
showed continued long-term protection against overall VCD and a
sustained high level of protection against hospitalized VCD regardless of
baseline serostatus.
In year-by-year analysis until four years after the second dose, VE in

preventing VCD was shown for all four serotypes in baseline dengue
seropositive subjects. In baseline seronegative subjects, VE was shown
for DENV-1 and DENV-2, but not suggested for DENV-3 and could not be
shown for DENV-4 due to lower incidence of cases.
The long-term persistence of neutralising antibodies was shown in study

DEN-301, with titers remaining well above the pre-vaccination levels for
all four serotypes, up to 51 months after the first dose.
Risk factors and risk In general, lack of response to vaccination can occur in subjects with
groups: immunodeficiency (leading to suboptimal or even absent immune
response), elderly age and related senescence of immune
responsiveness, interference due to wild type infectious agents, acute or
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chronic disease and suboptimal health and nutritional status,

immunological interference (e.g., administration of immunoglobulins, or
immunosuppressive medications). In addition, there may be failure to
respond due to the normal expected variation in immune response across
healthy individuals (i.e., a “low responder” or “non-responder) [159].
A comprehensive subgroup analysis showed efficacy across the evaluated
subgroups by age group, region, country and prior vaccination against YF
or JE, with the varying magnitude of VE per subgroup to a large extent
attributable to the serotype distribution in the respective subgroup. No
risk factors have been identified for TDV vaccination failure.
In general, vaccine effectiveness may wane with increasing time since
vaccination. Depending on the vaccine, rates of decline may vary across
antigens. A number of variables, including subject age, serostatus at
vaccination, presence or absence of exposures to circulating wild type
virus (natural boosting), possible evolution of the wild type virus away
from the targets of vaccine antigens, as well as unknown factors,
influence duration of vaccine protection.
Preventability: The SmPC includes in Section 4.4 the following Special warning and
Precaution for use: “A protective immune response with Qdenga may not
be elicited in all vaccinees against all serotypes of dengue virus and may
decline over time (see Section 5.1). It is currently unknown whether a
lack of protection could result in an increased severity of dengue. It is
recommended to continue personal protection measures against
mosquito bites after vaccination. Individuals should seek medical care if
they develop dengue symptoms or dengue warning signs. There are no
data on the use of Qdenga in subjects above 60 years of age and limited
data in patients with chronic medical conditions”. Information is also
provided in PL Section 2.
Impact on the risk- The impact of waning protection against dengue over time on the risk-
benefit balance of the benefit balance is expected to be minimal.
product:
Public health impact: This potential risk is not expected to have a serious impact on public
health.
Important Potential Risk: Severe and/or hospitalized dengue following vaccination caused by
dengue virus serotype 3 or 4 in individuals not previously infected by dengue virus
Potential mechanisms: The 2009 WHO criteria classify dengue infection according to levels of
severity: dengue without warning signs, dengue with warning signs and
severe dengue. Severe dengue is defined by one or more of the following
criteria: severe plasma leakage that may lead to shock and/or fluid
accumulation with or without respiratory distress and/or severe bleeding
and/or severe organ impairment [100]. The most severe forms of dengue
infection, dengue haemorrhagic fever (DHF) and dengue sock syndrome
(DSS) [58], are life threatening. Primary infection with any of the
4 dengue serotypes is thought to result in life-long protection from
re-infection by the same serotype but does not protect against a
secondary infection by 1 of the 3 other dengue serotype and may lead to
an increased risk of severe disease over the course of secondary infection
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(DHF/DSS) [160].
In wild type dengue, severe disease is mainly observed after secondary

infections, typically with a different serotype.
There are 4 distinct, but closely related, serotypes of the virus that cause
dengue. Following a primary infection with one dengue virus (DENV)
serotype, protection against the infecting serotype (homotypic
protection) is considered long-lasting. Temporary cross-protection is
induced to the other serotypes (heterotypic protection), lasting 2 years
on average. Following waning of cross-neutralizing antibodies, the host-
immune response may increase the severity of subsequent DENV
infections with different serotypes. Following recovery from a second
infection, broadly cross-neutralizing antibodies are induced (multitypic
protection), such that severe disease with tertiary and quaternary
infections is considered rare [161].
The mechanism for more severe disease associated with a second
infection is not well understood although ADE [162], cytokine storm
[163,164] or cross-reactive T cells are hypothesized [165].
The mechanism for a higher risk of severe and hospitalized dengue in
seronegative subjects after Dengvaxia vaccination is currently not
understood but has been compared to the phenomenon of secondary
dengue infection in the wild type situation [166]. Younger children may
be more susceptible to this phenomenon as this group includes a high
proportion of subjects who are dengue seronegative.
The recombinant construct of TDV is different from the licensed dengue
vaccine Dengvaxia in that the four vaccine viruses use the replicative
genetic backbone of a dengue virus (DENV-2; PDK 53) instead of the YF
vaccine virus 17D. These differences result in an immunogenicity profile
that is unique to TDV. TDV is expected to elicit CD8 + T-Cell response
directed at the structural and non-structural proteins of dengue virus
rather than the structural proteins of the dengue virus and non-structural
proteins of the YF virus. Generally, virus specific cytotoxic T-Cell
responses are thought to be important for the rapid clearance of viral
infections and cytotoxic T-Cell responses directed against dengue
antigens have been associated with sub-clinical second dengue infections
in children [167].
Evidence source(s) and Today, severe dengue in the absence of dengue vaccination affects most
strength of evidence: Asian and Latin American countries and has become a leading cause of
hospitalization and death among children and adults in these regions [6].
Efficacy results by baseline dengue serostatus (determined for all
subjects), demonstrated overall VE against VCD and VCD leading to
hospitalization regardless of prior exposure to dengue. Efficacy against
individual dengue serotypes varied. The totality of data on VCD,
hospitalized VCD, and severe forms of dengue, along with the clinical
characteristics of these cases, as assessed in Trials DEN-301, DEN-313,
and DEN-204, did not reveal an identified risk of increased disease
severity or disease enhancement attributable to vaccination in the post-
vaccination period.
Trial DEN-301: Virologically Confirmed Dengue and hospitalised VCD
from baseline up to 54 months after the Second Vaccine Dose (Safety
Set), irrespective of baseline serostatus and for all serotypes combined:
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• Relative risk of VCD (95% CI): 0.40 (0.36, 0.46)

• Relative risk of hospitalised VCD (95% CI): 0.16 (0.12, 0.23)
Trial DEN-301: Severe forms of dengue (Dengue Case Adjudication
Committee [DCAC]-defined severe dengue and DHF) from baseline up to
54 months after the last vaccine dose (safety set), irrespective of
baseline serostatus and for all serotypes combined:
• Relative risk of DCAC-defined severe dengue (95% CI): 0.30 (0.07,
1.25)
• Relative risk of DHF (95% CI): 0.30 (0.13, 0.68)
Exploratory efficacy analyses at 54 months after the second vaccine dose
did not suggest efficacy for VCD caused by serotype DENV-3 in baseline
seronegative subjects (RR: 1.11 [95% CI: 0.62, 1.99]). An imbalance in
hospitalized VCD caused by DENV-3 was noted in baseline seronegative
subjects, with 11 cases in the TDV group (0.3%) compared with 3 cases
in placebo group (0.2%), with a relative risk of 1.81 (95% CI: 0.51,
6.48).
In the baseline seronegative subgroup, a total of 2 subjects with VCD
were assessed as DCAC defined severe dengue (both in the TDV group;
0.05% of 3714 subjects). Both cases occurred early in the trial during
Parts 1 and 2 (i.e., before 18 months post second dose). Five subjects
experienced DHF as per programmed algorithm, WHO 1997 DHF criteria),
4 of 3714 subjects (0.11%) in the TDV group and 1 of 1832 subjects
(0.05%) in the placebo group. Of note, 1 of these 4 DHF cases in the
TDV group was also classified as DCAC-defined severe dengue. All of
these cases in baseline seronegative subjects were caused by DENV-3.
The assessment of whether TDV may be associated with an increased
risk of severe forms of dengue in baseline seronegative subjects who
experience VCD caused by serotype DENV-3 remained inconclusive; the
data are limited by the small number of cases.
In baseline seronegative subjects, an increased risk of hospitalization
and/or severe forms of dengue caused by serotype DENV-3 following
vaccination in baseline seronegative subjects is considered an important
potential safety risk.
The evaluation of VE against VCD caused by DENV-4 in baseline
seronegative subjects up to 54 months after the second dose was limited
by the overall small number cases (n=15) reflective of the generally
lowest prevalence for this dengue serotype worldwide. Additionally, most
of the DENV-4 cases occurred in the later part of the trial when data
indicated waning efficacy against other serotypes, which also precluded a
robust conclusion. For instance, the VE in Year 1 post second dose could
not be ascertained for DENV-4 in baseline seronegative subjects because
no cases were reported in that period. Importantly, none of the DENV-4
cases in the TDV group in baseline seronegative subjects required
hospitalization or were a severe form of dengue, which suggested no
change in the severity of presentation.
Conservatively, risk of hospitalization and/or clinically severe forms of
dengue caused by serotype DENV-4 is considered an important potential
safety risk in individuals not previously infected by dengue virus.
Characterisation of the WHO estimated that in the absence of vaccination about 3.9 billion
risk: people, in more than 128 countries, are at risk of dengue infection, with
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approximately 390 million dengue infections occurring annually of which

96 million manifests clinically (with any severity of disease). About
500,000 persons require hospitalization due to warning signs or severe
dengue, and about 20,000 deaths are estimated to occur due to severe
dengue every year [148]. Patients with severe dengue require immediate
emergency treatment to avert death and those with warning signs should
be assessed and treated without delay.
In Trial DEN-301, the incidence and relative risk of VCD overall and
hospitalized VCD up to 54 months after the second vaccine dose (all
4 serotypes combined) were lower in the TDV group than in the placebo
group. Overall, 442 VCD cases (0.7 cases per 100 person-years) were
identified in the TDV group compared with 547 cases (1.9 cases per 100
person-years) in the placebo group. The incidence of severe forms of
dengue (DCAC-defined severe dengue and DHF) in the TDV group was
<0.1 cases per 100 person-years.
Up to 54 months after the second dose, the incidences of hospitalised
VCD caused by DENV-3 were low (3 cases in the placebo group and 12
cases in the TDV group; 2:1 randomization ratio to be considered) and
fluctuated over time depending on local epidemiology and hospitalisation
practices. There was no worsening over time in terms of potentially
increased severity of cases caused by DENV-3 in the baseline
seronegative subpopulation: two cases in TDV recipients that were
assessed as severe by the independent adjudication committee occurred
early in the trial during Parts 1 and 2 (ie, before 18 months post second
dose). No hospitalized or severe forms of dengue caused by DENV-4
occurred in the TDV group.
The relative risk of VCD caused by DENV-3 in baseline seronegative
subjects declined over time, with a relative risk point estimate of <1
during Year 3 (relative risk 0.91 [95% CI: 0.34, 2.45]) and Year 4
(relative risk 0 [95% CI: not estimable]); no VCD caused by DENV-3
occurred after Year 4 up to the end of Part 3. This is reflected in the
declining trend of cumulative relative risks assessed at 12, 24, 36
months after second dose (refer to CTD Module 2.7.4); the data obtained
in the last 18 months of follow-up up to month 54 is consistent with this
trend (refer to CTD Module 5.3.5.1: DEN-301 M54 Data Tables and
Graphs).
Risk factors and risk Risk factors for severe dengue in unvaccinated subjects are described in
groups: section Epidemiology of the indication(s) and target population(s) (see
Part II Module SI) and include persons with a secondary dengue infection
of a heterologous DENV serotype, co-morbidities, nutritional status, the
two extremes of age, genetic composition, pregnancy, and the time
interval since primary infection.
The main risk factor found for severe dengue following vaccination with
Dengvaxia was a seronegative baseline status [168]. The risk of severe
dengue following vaccination of seronegative subjects seemed to be
related to the speed of the waning immunity in combination with the local
dengue epidemiology [169].
In the Trial DEN-301 for TDV, efficacy results by baseline dengue
serostatus, which was determined for all subjects, demonstrate overall
VE against VCD. The trial also showed high overall efficacy against DHF.
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Preventability: In Trial DEN-301, TDV was shown to be efficacious in prevention of

symptomatic dengue manifesting as outpatient fever, febrile illness
requiring hospitalisation or DHF in subjects 4 to 16 years of age.
The SmPC includes in Section 4.4 the following Special warning and
Precaution for use: “A protective immune response with Qdenga may not
be elicited in all vaccinees against all serotypes of dengue virus and may
decline over time (see SmPC Section 5.1). It is currently unknown
whether a lack of protection could result in an increased severity of
dengue. It is recommended to continue personal protection measures
against mosquito bites after vaccination. Individuals should seek medical
care if they develop dengue symptoms or dengue warning signs”.
Information is also provided in PL Section 2.
Impact on the risk- In Trial DEN-301, TDV was shown to be efficacious in prevention of
benefit balance of the symptomatic dengue manifestations as outpatient fever, febrile illness
product: requiring hospitalisation or DHF in subjects 4 to 16 years of age. There
was rapid onset of efficacy after the first dose, and efficacy was seen in
varied epidemiological settings od Asia and Latin America in both dengue
seropositive and seronegative subjects, while no additional risk of severe
forms of dengue was identified. TDV has a positive benefit-risk balance in
the indication proposed and TDV could play an important role as a
component of a multimodal approach to reducing the global burden of
dengue.
Public health impact: This potential risk is not expected to have a serious impact on public
health. The overall public health impact of severe dengue is provided in
Part II Module SI.
SVII.3.2. Presentation of the missing information
Safety profile of inadvertent use in pregnant or lactating women
Evidence source: Population in need of further characterisation:

A study in rabbits did not indicate direct or indirect harmful effects
insufficient of TDV with respect to reproductive toxicity (Module
4.2.3.5.1, Study Report 20129939). TDV has not been studied in
pregnant women because pregnancy was an exclusion criterion in all
clinical trials. There are limited data on pregnancy outcomes following
vaccine dose administration; these are based on TDV or placebo
inadvertently administered to women who were pregnant or who became
pregnant shortly after vaccination (“exposed pregnancies”). These data,
however, are not sufficient to conclude on the absence of potential
effects of TDV on pregnancy, embryo-fetal development, parturition, and
postnatal development.
There are conflicting data in the literature regarding the association
between wild type dengue infection during pregnancy and increased risks
of both a more severe course of disease and adverse pregnancy
outcomes [111-113].
As with other live attenuated vaccines, women of childbearing potential
should avoid pregnancy for at least 1 month following vaccination.
Women who intend to become pregnant should be advised to delay
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vaccination.
As of 01 October 2020, 34 pregnancies were identified as exposed to

TDV: 27 had normal outcomes, 4 spontaneous abortion and 3 elective
termination. There were no clinically important differences regarding the
frequencies of spontaneous abortions or elective terminations between
women exposed to TDV and women exposed to placebo only. In addition,
one neonatal death occurred after an exposed pregnancy. However, the
death was considered not causally related to TDV.
It is unknown whether TDV is excreted in human milk. There are limited
data on the excretion of wild-type dengue via breast milk. In a small
study, dengue virus was detected in breast milk samples from 9 (75%) of
12 infected breastfeeding mothers [127].
Qdenga is contraindicated in pregnant and breast-feeding women (see

SmPC Section 4.3 Contraindications and PL Section 2).
The SmPC Section 4.4 contains also Special warnings and precautions for
use: “As with other live attenuated vaccines, women of childbearing
potential should avoid pregnancy for at least one month following
vaccination.” Information is also provided in SmPC Section 4.6 and PL
Section 2.
In addition to the impact of maternal dengue infection, concerns have

been raised on the effect of maternal infection on subsequent infections
in the infant. Declining levels of maternal antibodies have been shown to
sensitize infants born to dengue-immune mothers to severe disease
during primary infection, through the process of antibody-dependent
enhancement of infection [170,171].
Safety and immunogenicity in immunocompromised individuals
Generally, live-attenuated virus vaccines are contraindicated or not

recommended for use in severely immunocompromised individuals due to
a potential risk of impaired immune response, uncontrolled replication of
the attenuated vaccine virus or vaccine reversion to natural virulence
resulting in uncontrolled wild type disease [172].
Published data on dengue virus infection and immunocompromised

patients come from case reports or small case series [173-178] often
with mixed patient populations (for example variability in underlying
conditions or interventions, differing degrees of immunocompromised,
different ethnic and geographical backgrounds).
From the limited data available, overall clinical outcomes for dengue virus
infection in immunocompromised patients appear to be similar to those
for dengue virus infection in immunocompetent patients.
For wild type DENV, there is a theoretical risk of prolonged dengue
viremia in profoundly immunocompromised patients, and it is not clear
whether dengue virus could persist in certain organs after becoming
undetectable in serum or plasma.
Ng et al. [179] reported a case of persistent DENV infection in a
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lymphopenic renal transplant recipient who was therapeutically

immunosuppressed to prevent organ rejection. Authors showed that low
CD8+ T cell count contributes to the persistence of DENV—longer in
podocytes and coincidence of rising CD8+ T cell count with viruria
clearance suggests that cytotoxic T cells are needed for sterilizing DENV
infection. Their role in the clearance of acute human DENV infection has
remained unclear although CD8+ T cell epitopes have been characterized
in DENV patients [180] and animal models [165,181,182]. Delayed DENV
clearance has been observed previously in a renal and bone marrow
transplant patients, although the duration of viral persistence lasted only
19 and 80 days, respectively [183,184]. The patient remained RNAemic
and viruric despite consistently detectable levels of DENV-3 neutralizing
antibodies. Moreover, the IgG subclass composition would also not
prevent IgG antibodies from being secreted into the urine.
These observations suggest that an effective DENV vaccine needs to

stimulate both humoral and cellular response.
There are no reliable data available from any immunocompromised
patient group to assess duration of viral RNA detection in blood, semen
or other compartments. It is possible that severe immunosuppression
could be associated with more severe illness following flavivirus
infections, but conclusive data are lacking.
Immunocompromised international travellers are potentially at risk
because the vaccine may not elicit a protective immune response and the
risk of disease acquisition would be high [185].
Vaccination with TDV was not studied in subjects with primary or
secondary immune deficiencies and is contraindicated in individuals with
congenital or acquired immune deficiency, including immunosuppressive
therapies such as chemotherapy or high doses of systemic corticosteroids
within 4 weeks prior to vaccination and in individuals with symptomatic
HIV infection or with asymptomatic HIV infection when accompanied by
evidence of impaired immune function (SmPC Section 4.3)
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Safety and immunogenicity of concomitant administration with other vaccines other than
HAV and YF
Simultaneous or concomitant administration of vaccines is defined as

administering more than one vaccine on the same clinic day, at different
anatomic sites, and not combined in the same syringe [186].
Potential interactions between concomitantly administered vaccines may
compromise the immunogenicity/effectiveness (e.g., vaccination failure
from interference) and/or safety (e.g., increased rates or severity of
adverse events).
Recent reviews on the simultaneous administration of the most widely
used live and inactivated vaccines has produced seroconversion rates and
rates for adverse reactions similar to those observed when the vaccines
are administered separately [187-190].
Co-administration of TDV with YF and HAV vaccines was evaluated in two
phase 3 trials conducted in non-endemic areas (DEN-305 and DEN-314
respectively).
TDV may be administered concomitantly with an HAV vaccine.

Coadministration has only been studied in adults.
TDV may be administered concomitantly with a YF vaccine. In a clinical

study involving approximately 300 adult subjects who received TDV
concomitantly with YF 17D vaccine, there was no effect on YF
seroprotection rates. Dengue antibody responses were decreased
following concomitant administration of TDV and YF 17D vaccine. The
clinical significance of this finding is unknown. (SmPC Section 4.5).
Co-administration data with other vaccines, other than YF and HAV, are
missing.
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Safety and reactogenicity of a booster dose

Although a generally consistent overall efficacy and continued protection
against hospitalised dengue is observed after a 2-dose vaccination
regimen with TDV (two single doses 3 months apart), data also indicate a
trend of declining efficacy over time, as reflected in lower vaccine efficacy
estimates in Years 2 and 3 compared with the preceding period. This
observation suggests a waning in vaccine efficacy and therefore the
effect of a booster dose is being investigated in 2 ongoing clinical trials
(DEN-301 and DEN-303).
Currently, the need for a booster dose has not been established (SmPC
Section 4.2).
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Part II: Module SVIII - Summary of the safety concerns

Table SVIII.1: Summary of safety concerns
Summary of safety concerns
Important identified risks None
Important potential risks Anaphylaxis including anaphylactic shock
Dengue disease due to waning protection against dengue over time

Severe and/or hospitalized dengue following vaccination caused by
dengue virus serotype 3 or 4 in individuals not previously infected
by dengue virus
Missing information Safety profile of inadvertent use in pregnant or lactating women

Safety and immunogenicity of concomitant administration with
other vaccines other than HAV and YF
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Part III: Pharmacovigilance Plan (including post-

authorisation safety studies)
III.1. Routine pharmacovigilance activities
Routine pharmacovigilance activities beyond adverse reaction reporting and signal detection are in
place for several safety concerns as described below.
Other forms of routine pharmacovigilance activities for the following safety concerns:
Cumulative reviews will be conducted for the following safety concerns: Anaphylaxis including
anaphylactic shock, vaccination failure, hospitalized including severe forms of dengue, Safety in
pregnant and lactating women, Safety and efficacy in immunocompromised individuals and, Safety
and immunogenicity of concomitant administration with other vaccines.
The objectives of these activities are to closely monitor the safety concerns mentioned above. These
analyses will be done every 6 months.
Any spontaneous reports in the post-marketing setting of inadvertent exposure during pregnancy or
lactation will be followed as required to ensure adequate and timely collection of case information,
collation, follow-up, assessment and reporting in accordance with regulations. In addition,
information on inadvertent exposure during pregnancy or lactation will be provided in
PBRERs/PSURs.
III.2. Additional pharmacovigilance activities

Efficacy, Safety and Immunogenicity of TDV in Trial DEN-301 (Part 4 and 5)
Study short name and title:

DEN-301 - Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial to Investigate the Efficacy,
Safety and Immunogenicity of TDV Administered Subcutaneously in Healthy Children Aged 4 - 16
Years Old.
Part 4 and 5 assess VE of a booster dose of TDV against symptomatic dengue illness due to any
serotype and will provide data on the effect of a booster dose on VE after a 2-dose vaccination
regimen with TDV (2 single doses 3 months apart).
Rationale and study objectives:

The WHO recommends a long-term follow-up to evaluate safety of dengue vaccines for 3 to 5 years.
The total follow-up period including Parts 1, 2 and 3 of this study last 4 to 4.5 years after the second
dose. Part 3 fulfils the WHO recommendation of long-term follow-up to evaluate safety. The booster
phase of this phase III trial is comprised of 2 parts (Parts 4 and 5). Part 4 includes modified active
surveillance post-booster vaccination and lasts a minimum of 13 months for each subject. Part 5
includes modified active surveillance following the completion of Part 4 and lasts 1 year for each
subject.
Secondary safety objectives include:

• To describe the safety of TDV
Exploratory objectives include:

Parts 1, 2, and 3
Efficacy:
• To describe the efficacy of TDV in preventing virologically confirmed dengue fever between first
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and second vaccinations.
• To describe the efficacy of TDV in preventing virologically confirmed dengue fever from first
vaccination until end of Part 2.
• To describe virologically confirmed and hospitalized dengue fever identified during Part 3.
• To describe virologically confirmed dengue fever identified during Part 3.

• For the correlate of protection, a threshold antibody titer value may be evaluated to predict VE
using descriptive methodology.
• To describe the profiles of IgG, IgM, and NS1 antigen during episodes of febrile illness.
Booster phase (Parts 4 and 5)
Efficacy:
• To assess the efficacy of a TDV booster dose in preventing symptomatic dengue fever of any
severity induced by any dengue serotype.
• To assess the efficacy of a TDV booster dose in preventing symptomatic dengue fever of any
severity by dengue exposure status at baseline.
• To assess the efficacy of a TDV booster dose in preventing hospitalization due to virologically
confirmed dengue fever induced by any dengue serotype.
• To assess the efficacy of a TDV booster dose in preventing severe dengue induced by any dengue
serotype.
Safety:
• To describe the safety of a TDV booster dose.
• To describe the reactogenicity of a TDV booster dose in a subset of subjects.

Booster immunogenicity:
• To assess the immunogenicity of a TDV booster dose in a subset of subjects.
Study design:
This is a phase 3, double-blind, randomized, placebo-controlled trial with 2 parallel groups. 20,099
participants were enrolled and randomly assigned 2:1 to receive two doses of TAK-003 or two doses
of placebo. The trial includes 3 time periods (Parts 1, 2 and 3) for surveillance of febrile illness with
potential dengue aetiology. The trial includes 2 additional time periods (Parts 4 and 5) for
surveillance of febrile illness with potential dengue aetiology for subjects participating in the booster
phase of the trial.
Part 1 constitutes the primary analysis period, including primary efficacy analysis.
Part 2 constitutes a period of additional active surveillance for secondary efficacy analyses.
Part 3 constitutes modified active surveillance for the assessment of long-term safety. Part 3 is a
modified active surveillance for the assessment of safety in all subjects following the completion of
Part 2 and lasting 2.5 to 3 years for each subject. The modified surveillance during Part 3 will
maintain at least weekly contacts through Part 3 of the trial, but the intensity of investigation will be
modified based on the need for hospitalization. Surveillance will identify febrile illness of any severity
that could potentially be due to dengue. All virologically confirmed hospitalized dengue cases are
adjudicated to identify cases of severe dengue.
Part 4 and 5 constitute a period of modified active surveillance for exploratory efficacy,
CONFIDENTIAL
immunogenicity, and safety analyses post-booster vaccination.
Part 4 is a modified active surveillance post-booster vaccination and lasting minimum 13 months for
each subject. Part 5 is a modified active surveillance following the completion of Part 4 and lasting 1
year for each subject.
Study population:
Healthy subjects aged 4 to 16 years inclusive (Part 1 to 3) and aged 4 to 11 (Part 4 to 5) years, at
the time of randomization, living in dengue-endemic countries.
Milestones:
Interim Reports:
End of Part 4 CSR: Q4 2024 (planned)

Final Report (Final CSR Parts 1, 2, 3, 4 and 5): Q1 2026 (planned)
Long-term safety and antibody persistence of TDV and the impact of a booster dose in
Trial DEN-303
DEN-303 - A Phase 3, Follow-up Trial to Evaluate Long-term Safety and Antibody Persistence, and
the Impact of a Booster Dose of TDV in Healthy Adolescents and Adults in Areas Non-Endemic for
Dengue.

This Phase 3 trial will evaluate long-term antibody persistence and safety data in healthy subjects in
areas non-endemic for dengue who have previously received a primary TDV vaccination in either
DEN-304 and DEN-315 trials (termed here as “parent trials”). The immunogenicity and safety of a
TDV booster dose in this population will then be assessed.
The primary objectives are:
• To describe antibody persistence for each of the 4 dengue serotypes for up to 63 months after
the first vaccination in the primary vaccination series for subjects from parent Trial DEN-315
(Mexico) and for up to 36 months after the first vaccination in the primary vaccination series for
subjects from parent Trial DEN-304 (United States).
• To describe the impact of a TDV booster dose vs placebo on antibody response for each of the
4 dengue serotypes at 1 month and 6 months post administration of the TDV booster or
placebo.
The secondary objectives are:
Immunogenicity
Antibody Persistence
• To describe the overall trend in antibody decay for all 4 dengue serotypes from values obtained
after the primary vaccination series in the parent trials through 63 months after the first
vaccination in the primary vaccination series for subjects from parent Trial DEN-315 (Mexico)
and through 36 months after the first vaccination in the primary vaccination series for subjects
from parent Trial DEN-304 (United States).
Impact of a TDV Booster Dose
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• To describe the impact of a TDV booster on antibody response for each of the 4 dengue
serotypes for up to 69 months following the first vaccination in the primary vaccination series for
subjects from the parent Trial DEN-315 (Mexico) and for up to 42 months following the first
vaccination in the primary vaccination series for subjects from parent Trial DEN-304 (United
States).
Safety
• To describe the long-term safety of TDV for up to 63 months in previously vaccinated subjects
from parent Trial DEN-315 (Mexico) and for up to 36 months in previously vaccinated subjects
from parent Trial DEN-304 (United States).
• To assess safety for 6 months following administration of the TDV booster or placebo in Group 1
and 2, respectively*.
*Group 1 = TDV, Group 2 = Placebo
Exploratory Objectives:
Applicable to subjects from parent trial DEN-315 (Mexico only):

• To evaluate aspects of the long-term humoral immune response to Takeda’s TDV in all subjects
at 63 months after the first vaccination in the primary vaccination series in the parent trials; this
is inclusive of, but not restricted to, an assessment of the anti-dengue Non-Structural Protein 1
(NS1) antibody response.
Applicable to subjects from parent Trial DEN-304 (United States only):

• To evaluate aspects of the long-term humoral immune response to Takeda’s TDV in all subjects
at 36 months after the first vaccination in the primary vaccination series in the parent trial
(DEN-304), and in the CMI subset at 1 month and 6 months post booster in the current trial;
this is inclusive of, but not restricted to, an assessment of the antidengue NS1 antibody
response.
• To evaluate aspects of the long-term cell-mediated immune response to Takeda’s TDV up to
36 months after the first vaccination in the primary vaccination series in the parent trial (DEN-
304) and at 1 month and 6 months post booster in the current trial; this is inclusive of, but not
restricted to, the magnitude (Interferon-gamma Enzyme-Linked Immunospot [IFN-γ ELISpot])
of the long-term T cell-mediated immune response to TDV (CMI subset only).
Study design:
This is a Phase 3 follow-up trial that will evaluate the long-term antibody persistence and safety of
Takeda’s TDV in healthy adolescents and adults in areas non-endemic for dengue in addition to
assessing the impact of a booster dose in this population. . Subjects who previously received TDV in
two parent trials, DEN-304 and DEN-315, are invited to participate in this follow-up trial. DEN-303
will include up to 600 healthy subjects aged ≥13 to ≤63 years at trial entry. To enable the
assessment of a booster dose, the trial will be double-blinded, randomized, and placebo-controlled
from Visit 3 onwards.
Study population:
Healthy subjects aged ≥13 and ≤63 years at trial entry in areas non-endemic for dengue who
received at least one dose of Takeda’s TDV in the parent trial.
Milestones:
Final CSR: Q1 2025
CONFIDENTIAL
Immunogenicity and safety of TDV and 9vHPV in subjects aged ≥9 to <15 years in Trial
DEN-308

DEN-308 – A phase 3 open-label, randomised trial to investigate the immunogenicity and safety of
the co-administration of a subcutaneous dengue tetravalent vaccine (live, attenuated) and
intramuscular recombinant 9-valent human papillomavirus (9vHPV) vaccine in subjects aged ≥9 to
<15 years in endemic country for dengue.

The WHO recommends that new vaccines should be introduced according to existing national
immunisation programs. Recombinant 9-valent human papillomavirus (HPV) vaccine is
recommended either in a 2-dose or 3-dose schedule 6 to 12 months apart in subjects 9 through
14 years of age. Further, if the second dose is administered earlier than 5 months after the first
dose, then a third dose should be administered at least 4 months after the second dose. Many
similarities exist between the proposed vaccination schedule for TDV and the approved schedule for
9-valent HPV (9vHPV) vaccine, including the overlapping target age group and the potential delivery
through school immunisation programs.
In order to avoid barriers to the inclusion of TDV in routine national vaccination programs, the effect
of adding TDV to such programs needs to be examined. This is particularly relevant for low-income
countries where the cost of a standalone vaccination could be too high, and potentially undermine
TDV uptake, if inclusion in routine vaccine schedules were not possible.
Study design:
This is a phase 3, open-label, randomised, multicentre trial in 614 healthy subjects aged ≥9 to
<15 years in endemic areas for dengue to investigate the immunogenicity and safety of the
co-administration of TDV and 9vHPV vaccine versus 9vHPV vaccine alone. Subjects will be
randomized equally to 1 of 2 groups (307 subjects per trial group):
Group 1: first doses of 9vHPV vaccine + TDV co-administered on Day 1 (Month 0 [M0]), second
dose of TDV administered on Day 90 (M3), second dose of 9vHPV vaccine administered on Day 180
(M6).
Group 2: first dose of 9vHPV vaccine administered on Day 1 (M0), second dose of 9vHPV vaccine
administered on Day 180 (M6).
The primary objective is:
• To demonstrate the non-inferiority (NI) of the immune response (in terms of geometric mean
titers [GMTs]) to 2 doses of 9vHPV vaccine, 1 co-administered with TDV, compared with 2 doses
of 9vHPV vaccine administered alone.
The secondary objectives are:

Immunogenicity
• To describe the immune response to HPV (in terms of seroresponse) in subjects administered
2 doses of 9vHPV vaccine, 1 co-administered with TDV, compared with subjects administered
2 doses of 9vHPV vaccine alone.
• To describe the immune response to TDV at 1 month following a second dose of TDV given
3 months after the first dose of TDV administered concomitantly with 9vHPV vaccine.
Safety
• To describe the safety profile after administration of TDV concomitantly with 9vHPV vaccine.
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Study population:
Healthy subjects (male or female) aged ≥9 and <15 years in endemic areas for dengue.
Milestones:
Final CSR: Q4 2023
III.3. Summary table of additional pharmacovigilance activities

Table Part III.1: On-going and planned additional pharmacovigilance activities
Summary of Safety concerns Due

Study Status objectives addressed Milestones dates
Category 3 - Required additional pharmacovigilance activities
Efficacy, Safety To evaluate the Dengue disease due to Interim Q4 2024

and efficacy, waning protection against report: End (planned)
Immunogenicity immunogenicity dengue over time Part 4 CSR
of TDV in Trial and safety of a TDV
DEN-301 (Part 4 booster dose Severe and/or
and 5) hospitalized dengue
following vaccination Final Report Q1 2026
Study status: caused by dengue virus (Final CSR (planned)
ongoing serotype 3 or 4 in Parts 1, 2, 3,
individuals not previously 4 and 5)
infected by dengue virus
Safety and reactogenicity
of a booster dose
Long-term safety To assess the Dengue disease due to Final CSR Q1 2025
and antibody immunogenicity waning protection against
persistence of and safety of a TDV dengue over time
TDV and the booster dose in
impact of a Healthy Severe and/or
booster dose Adolescents and hospitalized dengue
(Trial DEN-303) Adults. following vaccination
caused by dengue virus
Study status: serotype 3 or 4 in
ongoing individuals not previously
infected by dengue virus
Safety and reactoge-
nicity of a booster dose
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Summary of Safety concerns Due

Study Status objectives addressed Milestones dates
Category 3 - Required additional pharmacovigilance activities
Immunogenicity To investigate the Safety and Final CSR Q4 2023

and safety of TDV immunogenicity immunogenicity of
and 9vHPV in and safety of the concomitant
subjects aged ≥9 co-administration administration with other
to <15 years of a subcutaneous vaccines other than HAV
(Trial DEN-308) dengue tetravalent and YF
vaccine and
Study status: intramuscular
ongoing recombinant
9-valent human
papillomavirus
(9vHPV) vaccine in
subjects aged ≥9
to <15 years in
endemic country
for dengue
CONFIDENTIAL
Part IV: Plans for post-authorisation efficacy studies
Table Part IV.1: Planned and on-going post-authorisation efficacy studies that are
conditions of the marketing authorisation or that are specific obligations.
Efficacy
Study Status Summary of objectives uncertainties Milestones Due Date
addressed
Efficacy studies which are conditions of the marketing authorisation
None Not applicable Not applicable Not Not

applicable applicable
Efficacy studies which are Specific Obligations in the context of a conditional marketing authorisation
or a marketing authorisation under exceptional circumstances
None Not applicable Not applicable Not Not

applicable applicable
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Part V: Risk minimisation measures (including evaluation of

the effectiveness of risk minimisation activities)
Risk Minimisation Plan
V.1. Routine Risk Minimisation Measures
Table Part V.1: Description of routine risk minimisation measures by safety concern
Safety concern Routine risk minimisation activities
Anaphylaxis including Routine risk communication:

anaphylactic shock
SmPC Section 4.3 Contraindications and Section 4.4 Special Warnings and
Precautions for Use
PL Section 2
Routine risk minimisation activities recommending specific clinical
measures to address the risk:
Not applicable
Other routine risk minimisation measures beyond the Product
Information:
Not applicable
Dengue disease due to Routine risk communication:

waning protection
against dengue over SmPC Section 4.4 Special Warnings and Precautions for Use
time PL Section 2
Not applicable
Information:
Not applicable
Severe and/or Routine risk communication:

hospitalized dengue
following vaccination SmPC Section 4.4 Special Warnings and Precautions for Use
caused by dengue virus PL Section 2
serotype 3 or 4 in
individuals not Routine risk minimisation activities recommending specific clinical
previously infected by measures to address the risk:
dengue virus Not applicable
Information:
Not applicable
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Safety profile of Routine risk communication:

inadvertent use in
pregnant or lactating SmPC Section 4.3 Contraindications, Section 4.4 Special warnings and
women precautions for use and Section 4.6 Fertility, pregnancy and lactation
PL Section 2
Not applicable
Information:
Not applicable
Safety and Routine risk communication:

immunogenicity in
immunocompromised SmPC Section 4.3 Contraindications, Section 4.5 Interactions with
individuals Medicinal Products and other forms of interactions
PL Section 2
Not applicable
Information:
Not applicable

immunogenicity of
concomitant SmPC Section 4.5 Interaction with other medicinal products and other
administration with forms of interaction
other vaccines other PL Section 2
than HAV and YF
Not applicable
Information:
Not applicable

reactogenicity of a
booster dose SmPC Section 4.2
Not applicable
Information:
Not applicable
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V.2. Additional Risk Minimisation Measures

Routine risk minimisation activities as described in Part V.1. are sufficient to manage the safety
concerns of the vaccine.
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V.3. Summary of risk minimisation measures

Table Part V.3: Summary table of pharmacovigilance activities and risk minimisation
activities by safety concern
Safety concern Risk minimisation measures Pharmacovigilance activities
Anaphylaxis including Routine risk minimisation Routine pharmacovigilance

anaphylactic shock measures: activities beyond adverse
reactions reporting and signal
SmPC Section 4.3 and Section 4.4 detection:
PL Section 2 Cumulative review
No additional risk minimisation No additional pharmacovigilance
measures activities
Dengue disease due Routine risk minimisation Routine pharmacovigilance

to waning protection measures: activities beyond adverse
against dengue over reactions reporting and signal
time SmPC Section 4.4 detection:
No additional risk minimisation Additional pharmacovigilance
measures activities:
Efficacy, Safety and Immunogenicity
of TDV in Trial DEN-301 (includes
administration of a booster dose)
DEN-303 – Long-term immunogenicity

trial (includes administration of a
booster dose)
Severe and/or Routine risk minimisation Routine pharmacovigilance

hospitalized dengue measures: activities beyond adverse
following vaccination reactions reporting and signal
caused by dengue SmPC Section 4.4 detection:
virus serotype 3 or 4 PL Section 2
in individuals not Cumulative review
previously infected by No additional risk minimisation Additional pharmacovigilance
dengue virus measures activities:

booster dose)
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Safety concern Risk minimisation measures Pharmacovigilance activities
Safety profile of Routine risk minimisation Routine pharmacovigilance

inadvertent use in measures: activities beyond adverse
pregnant or lactating reactions reporting and signal
women SmPC Section 4.3, Section 4.4 and detection:
Section 4.6
Cumulative review
PL Section 2
No additional pharmacovigilance
No additional risk minimisation activities
measures
Safety and Routine risk minimisation Routine pharmacovigilance

immunogenicity in measures: activities beyond adverse
immunocompromised reactions reporting and signal
individuals SmPC Section 4.3 and Section 4.5 detection:
No additional risk minimisation No additional pharmacovigilance
measures activities

immunogenicity of measures: activities beyond adverse
concomitant reactions reporting and signal
administration with SmPC Section 4.5 detection:
other vaccines other PL Section 2
than HAV and YF Cumulative review
No additional risk minimisation Additional pharmacovigilance
measures activities:
Coadministration with 9vHPV vaccine

Trial (DEN-308)

reactogenicity of a measures: activities beyond adverse
booster dose reactions reporting and signal
SmPC Section 4.2 detection:
No additional risk minimisation None
measures
Additional pharmacovigilance
activities:

booster dose)
CONFIDENTIAL
Part VI: Summary of the risk management plan - Article 58

Application
Summary of risk management plan for Dengue Tetravalent
Vaccine (Live, Attenuated) Takeda (Dengue tetravalent vaccine
(live, attenuated)) – Article 58 Application
This is a summary of the risk management plan (RMP) for Dengue Tetravalent Vaccine (Live,
Attenuated) Takeda. The RMP details important risks of Dengue Tetravalent Vaccine (Live,
Attenuated) Takeda, how these risks can be minimised, and how more information will be obtained
about Dengue Tetravalent Vaccine (Live, Attenuated) Takeda risks and uncertainties (missing
information).
Dengue Tetravalent Vaccine (Live, Attenuated) Takeda summary of product characteristics (SmPC)
and its package leaflet give essential information to healthcare professionals and patients on how
Dengue Tetravalent Vaccine (Live, Attenuated) Takeda should be used.
This summary of the RMP for Dengue Tetravalent Vaccine (Live, Attenuated) Takeda should be read
in the context of all this information including the assessment report of the evaluation and its plain-
language summary, all which is part of the European Public Assessment Report (EPAR).
Important new concerns or changes to the current ones will be included in updates of Dengue
Tetravalent Vaccine (Live, Attenuated) Takeda RMP.
I. The medicine and what it is used for

Dengue tetravalent vaccine (Live, Attenuated) is authorised for the prevention of dengue disease
caused in individuals from 4 years of age (see SmPC for the full indication). It contains Dengue virus
serotype 1 (live, attenuated), Dengue virus serotype 2 (live, attenuated), Dengue virus serotype 3
(live, attenuated) and Dengue virus serotype 4 (live, attenuated) as the active substances and it is
given by subcutaneous injection.
Further information about the evaluation of Dengue Tetravalent Vaccine (Live, Attenuated) Takeda
benefits can be found in Dengue tetravalent vaccine (Live, Attenuated) EPAR, including in its plain-
language summary, available on the EMA website, under the medicine’s webpage:
[ENTER LINK TO THE EPAR SUMMARY LANDING PAGE].
II. Risks associated with the medicine and activities to minimise or

further characterise the risks
Important risks of Dengue Tetravalent Vaccine (Live, Attenuated) Takeda, together with measures
to minimise such risks and the proposed studies for learning more about Dengue Tetravalent
Vaccine (Live, Attenuated) Takeda risks, are outlined below.
Measures to minimise the risks identified for medicinal products can be:
• Specific information, such as warnings, precautions, and advice on correct use, in the package
leaflet and SmPC addressed to patients and healthcare professionals;
• Important advice on the medicine’s packaging;

• The authorised pack size — the amount of medicine in a pack is chosen so to ensure that the
medicine is used correctly;
CONFIDENTIAL
• The medicine’s legal status — the way a medicine is supplied to the patient (e.g. with or without
prescription) can help to minimise its risks.
Together, these measures constitute routine risk minimisation measures.

In addition to these measures, information about adverse reactions is collected continuously and
regularly analysed, including PSUR assessment so that immediate action can be taken as necessary.
These measures constitute routine pharmacovigilance activities.
If important information that may affect the safe use of Dengue Tetravalent Vaccine (Live,
Attenuated) Takeda is not yet available, it is listed under ‘missing information’ below.
II.A List of important risks and missing information

Important risks of Dengue Tetravalent Vaccine (Live, Attenuated) Takeda are risks that need special
risk management activities to further investigate or minimise the risk, so that the medicinal product
can be safely administered. Important risks can be regarded as identified or potential. Identified
risks are concerns for which there is sufficient proof of a link with the use of Dengue Tetravalent
Vaccine (Live, Attenuated) Takeda. Potential risks are concerns for which an association with the use
of this medicine is possible based on available data, but this association has not been established
yet and needs further evaluation. Missing information refers to information on the safety of the
medicinal product that is currently missing and needs to be collected (e.g. on the long-term use of
the medicine).
List of important risks and missing information
Important potential risks Anaphylaxis including anaphylactic shock

Dengue disease due to waning protection against dengue over time

dengue virus serotype 3 or 4 in individuals not previously infected by
dengue virus
Missing information Safety profile of inadvertent use in pregnant or lactating women

Safety and immunogenicity of concomitant administration with other
vaccines other than HAV and YF
II.B Summary of important risks
Important potential risk: Anaphylaxis including anaphylactic shock
Evidence for linking the There were no TDV-related anaphylactic reactions or anaphylactic
risk to the medicine shock events reported during the clinical development program.
Anaphylaxis is a rare, severe allergic reaction and can occur with
vaccines.
CONFIDENTIAL
Risk factors and risk Clinical risk factors that have been identified for anaphylaxis are:
groups
- history of allergies to the active substances or any of the other
components of the Dengue Tetravalent Vaccine (Live, Attenuated)
Takeda referred to as TDV vaccine,
- history of an allergic reaction after a previous immunisation with
TDV,
- coexisting atopic disease, particularly asthma.

factors.
Risk minimisation Routine risk minimisation measures:

measures
- Summary of product characteristics (SmPC) Section 4.3 and
Section 4.4
- Package Leaflet (PL) Section 2

No additional risk minimisation measures
Important potential risk: Dengue disease due to waning protection against dengue over time
Evidence for linking the In a year-by-year analysis until 4.5 years after the second dose in
risk to the medicine Trial DEN-301, VE in preventing VCD was shown for all four serotypes
in baseline dengue seropositive subjects. In baseline seronegative
subjects, VE was shown for DENV-1 and DENV-2, but not suggested
for DENV-3 and could not be shown robustly for DENV-4 due to lower
incidence of cases. During the third year of Trial DEN-301, although
some decline in efficacy compared with Year 2 was observed, largely
driven by non-hospitalized VCD cases, efficacy against VCD was
demonstrated overall, as well as in both baseline seronegative and
seropositive subjects. Efficacy against VCD leading to hospitalization
obtained in the last 18 months of follow-up up to Month 54 showed
continued long-term protection against overall VCD and a sustained
high level of protection against hospitalized VCD regardless of baseline
serostatus.
Waning immunity resulting in a loss of protection over time is
applicable to all vaccines. The maximum duration of protection with
TDV is not known currently.
CONFIDENTIAL
Risk factors and risk In general, lack of response to vaccination can occur due to
groups immunodeficiency, elderly age, interference due to wild type infectious
agents, acute or chronic disease and suboptimal health, as well as
nutritional status, immunological interference. In addition, there may
be failure to respond due to the normal expected variation in immune
response across healthy individuals (i.e., a “low responder” or “non-
responder).
Additionally, vaccine effectiveness may wane with increasing time
since vaccination. Depending on the vaccine, rates of decline of
vaccine effectiveness may vary across antigens. A number of variables
influence duration of vaccine protection, including age, serostatus at
virus (natural boosting), possible evolution of the wild type virus, as
well as unknown factors.
No risk factors have been identified for TDV vaccination failure.

measures
- SmPC Section 4.4
- PL Section 2
Additional Efficacy, Safety and Immunogenicity of TDV in Trial DEN-301

pharmacovigilance (includes administration of a booster dose)
activities
DEN-303 – Long-term immunogenicity trial (includes administration of
a booster dose)
See Section II.C of this summary for an overview of the post-
authorisation development plan.
CONFIDENTIAL
Important potential risk: Severe and/or hospitalized dengue following vaccination caused by
Evidence for linking the Efficacy results by baseline dengue serostatus (determined for all
risk to the medicine subjects), demonstrated overall VE against VCD and VCD leading to
hospitalization regardless of prior exposure to dengue. Efficacy against
individual dengue serotypes varied. The totality of data on VCD,
hospitalized VCD, and severe forms of dengue, along with the clinical
characteristics of these cases, as assessed in Trials DEN-301, DEN-
313, and DEN-204, did not reveal an identified risk of increased
disease severity or disease enhancement attributable to vaccination in
the post-vaccination period.
Exploratory efficacy analyses at 54 months after the second vaccine
dose did not suggest efficacy for VCD caused by serotype DENV-3 in
baseline seronegative subjects (RR: 1.11 [95% CI: 0.62, 1.99]). For
hospitalized VCD caused by DENV-3 there were with 11 cases in the
TDV group (0.3%) compared with 3 cases in placebo group (0.2%),
with a relative risk of 1.81 (95% CI: 0.51, 6.48).
were assessed as severe dengue as defined by the Adjudication
Committee (both in the TDV group; 0.05% of 3714 subjects). Both
cases occurred early in the trial during Parts 1 and 2 (i.e., before
18 months post second dose). Five subjects experienced DHF as per
programmed algorithm, WHO 1997 DHF criteria), 4 of 3714 subjects
(0.11%) in the TDV group and 1 of 1832 subjects (0.05%) in the
placebo group. Of note, 1 of these 4 DHF cases in the TDV group was
also classified as DCAC-defined severe dengue. All of these cases in
baseline seronegative subjects were caused by DENV-3. The
assessment of whether TDV may be associated with an increased risk
of severe forms of dengue in baseline seronegative subjects who
experience VCD caused by serotype DENV-3 remained inconclusive;
the data are limited by the small number of cases. In baseline
seronegative subjects, an increased risk of hospitalization and/or
clinically severe forms of dengue caused by serotype DENV-3 following
vaccination in subjects not previously infected by dengue virus is
considered an important potential safety risk.
Conservatively, due to limited data for DENV-4, risk of hospitalization
due to dengue and/or clinically severe forms of dengue caused by
serotype DENV-4 in baseline seronegative subjects is considered an
important potential safety risk, although up the 54 months after the
second vaccine dose no hospitalisations caused by DENV-4 occurred in
TDV recipients.
Risk factors and risk No risk factors for severe dengue with TDV have been identified.
groups

measures
- SmPC Section 4.4
- PL Section 2
CONFIDENTIAL
Additional Efficacy, Safety and Immunogenicity of TDV in Trial DEN-301 (includes

pharmacovigilance administration of a booster dose).
activities
a booster dose)
Missing Information: Safety profile of inadvertent use in pregnant or lactating women

measures
SmPC Section 4.3, Section 4.4 and Section 4.6
PL Section 2
Missing Information: Safety and immunogenicity in immunocompromised individuals

measures
SmPC Section 4.3 and Section 4.5
PL Section 2
Missing Information: Safety and immunogenicity of concomitant administration with other


measures
SmPC Section 4.5
PL Section 2
Additional Coadministration with 9vHPV vaccine Trial (DEN-308)

pharmacovigilance
activities See Section II.C of this summary for an overview of the post-
Missing Information: Safety and reactogenicity of a booster dose

measures
SmPC Section 4.2
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Additional Efficacy, Safety and Immunogenicity of TDV in Trial DEN-301 (includes

pharmacovigilance administration of a booster dose)
activities
a booster dose)
II.C. Post-authorisation development plan

II.C.1. Studies which are conditions of the marketing authorisation
There are no studies which are conditions of the Scientific Opinion or specific obligation of Dengue
Tetravalent Vaccine (Live, Attenuated) Takeda.
II.C.2. Other studies in post-authorisation development plan

Purpose of the study:

WHO recommends long-term follow-up to evaluate the safety of dengue vaccines for 3 to 5 years.
dose. For those participants in the booster phase, Parts 4 and 5, there is approximately 2 years of
additional follow-up.
Long-term safety and antibody persistence of TDV and the impact of a booster dose (Trial
DEN-303)
DEN-304 and DEN-315 trials (termed here as “parent trials”). It will then go on to assess the
immunogenicity and safety of a TDV booster dose in this population.
Immunogenicity and safety of TDV and 9vHPV in subjects aged ≥9 to <15 years (Trial
DEN-308)
recommended either in a 2-dose or 3-dose schedule 6 to 12 months apart in subjects 9 through 14
years of age. Further, if the second dose is administered earlier than 5 months after the first dose,
then a third dose should be administered at least 4 months after the second dose. Many similarities
exist between the proposed vaccination schedule for TDV and the approved schedule for 9-valent
HPV (9vHPV) vaccine, including the overlapping target age group and the potential delivery through
school immunisation programs.
CONFIDENTIAL
Part VI: Summary of the risk management plan – EU MAA

Summary of risk management plan for Qdenga (Dengue
tetravalent vaccine (live, attenuated)) – EU MAA
This is a summary of the risk management plan (RMP) for Qdenga. The RMP details important risks
of Qdenga, how these risks can be minimised, and how more information will be obtained about
Qdenga's risks and uncertainties (missing information).
Qdenga's summary of product characteristics (SmPC) and its package leaflet give essential
information to healthcare professionals and patients on how Qdenga should be used.
This summary of the RMP for Qdenga should be read in the context of all this information including
the assessment report of the evaluation and its plain-language summary, all which is part of the
European Public Assessment Report (EPAR).
Important new concerns or changes to the current ones will be included in updates of Qdenga's RMP.
I. The medicine and what it is used for

Qdenga is authorised for the prevention of dengue disease in individuals from 4 years of age (see
SmPC for the full indication). It contains Dengue virus serotype 1 (live, attenuated), Dengue virus
serotype 2 (live, attenuated), Dengue virus serotype 3 (live, attenuated) and Dengue virus serotype
4 (live, attenuated) as the active substances and it is given by subcutaneous injection.
Further information about the evaluation of Qdenga’s benefits can be found in Qdenga’s EPAR,
including in its plain-language summary, available on the EMA website, under the medicine’s
webpage:
[ENTER LINK TO THE EPAR SUMMARY LANDING PAGE].
II. Risks associated with the medicine and activities to minimise or

further characterise the risks
Important risks of Qdenga, together with measures to minimise such risks and the proposed studies
for learning more about Qdenga's risks, are outlined below.
Measures to minimise the risks identified for medicinal products can be:
• Specific information, such as warnings, precautions, and advice on correct use, in the package
leaflet and SmPC addressed to patients and healthcare professionals;
• Important advice on the medicine’s packaging;
• The authorised pack size — the amount of medicine in a pack is chosen so to ensure that the
medicine is used correctly;
• The medicine’s legal status — the way a medicine is supplied to the patient (e.g. with or without
prescription) can help to minimise its risks.
Together, these measures constitute routine risk minimisation measures.
In addition to these measures, information about adverse reactions is collected continuously and
regularly analysed, including PSUR assessment so that immediate action can be taken as necessary.
These measures constitute routine pharmacovigilance activities.
If important information that may affect the safe use of Qdenga is not yet available, it is listed under
‘missing information’ below.
CONFIDENTIAL
II.A List of important risks and missing information

Important risks of Qdenga are risks that need special risk management activities to further
investigate or minimise the risk, so that the medicinal product can be safely administered.
Important risks can be regarded as identified or potential. Identified risks are concerns for which
there is sufficient proof of a link with the use of Qdenga. Potential risks are concerns for which an
association with the use of this medicine is possible based on available data, but this association has
not been established yet and needs further evaluation. Missing information refers to information on
the safety of the medicinal product that is currently missing and needs to be collected (e.g. on the
long-term use of the medicine).
List of important risks and missing information
Important potential risks Anaphylaxis including anaphylactic shock.
Dengue disease due to waning protection against dengue over time.

dengue virus serotype 3 or 4 in individuals not previously infected by
dengue virus.
Missing information Safety profile of inadvertent use in pregnant or lactating women.
Safety and immunogenicity in immunocompromised individuals.

Safety and immunogenicity of concomitant administration with other
vaccines other than HAV and YF.
Safety and reactogenicity of a booster dose.
II.B Summary of important risks
Important potential risk: Anaphylaxis including anaphylactic shock
Evidence for linking the risk There were no TDV-related anaphylactic reactions or anaphylactic
to the medicine shock events reported during the clinical development program.
Anaphylaxis is rare, severe allergic reaction and can occur with
vaccines.
Risk factors and risk groups Clinical risk factors that have been identified for anaphylaxis are:
- History of allergies to the active substances or any of the other
components of Dengue Tetravalent Vaccine (live, Attenuated)
referred to as TDV.
- History of an allergic reaction after a previous immunisation with

TDV.
- Coexisting atopic disease, particularly asthma.

factors.
CONFIDENTIAL
Risk minimisation measures Routine risk minimisation measures:

- Summary of Product Characteristics (SmPC) Section 4.3 and
Section 4.4
- Package Leaflet (PL) Section 2
Important potential risk: Dengue disease due to waning protection against dengue over time
Evidence for linking the risk In a year-by-year analysis until 4.5 years after the second dose in
to the medicine Trial DEN-301, VE in preventing VCD was shown for all four serotypes
in baseline dengue seropositive subjects. In baseline seronegative
subjects, VE was shown for DENV-1 and DENV-2, but not suggested
for DENV-3 and could not be shown robustly for DENV-4 due to lower
incidence of cases. During the third year of Trial DEN-301, although
some decline in efficacy compared with Year 2 was observed, largely
driven by non-hospitalized VCD cases, efficacy against VCD was
demonstrated overall, as well as in both baseline seronegative and
seropositive subjects. Efficacy against VCD leading to hospitalization
obtained in the last 18 months of follow-up up to Month 54 showed
continued long-term protection against overall VCD and a sustained
high level of protection against hospitalized VCD regardless of
baseline serostatus.
Waning immunity resulting in a loss of protection over time is

applicable to all vaccines. The maximum duration of protection with
TDV is not known currently.
Risk factors and risk groups In general, lack of response to vaccination can occur due to
immunodeficiency, elderly age, interference due to wild type infectious
agents, acute or chronic disease and suboptimal health, as well as
nutritional status, immunological interference. In addition, there may
be failure to respond due to the normal expected variation in immune
response across healthy individuals (i.e., a “low responder” or “non-
responder).
Additionally, vaccine effectiveness may wane with increasing time

since vaccination. Depending on the vaccine, rates of decline of
vaccine effectiveness may vary across antigens. A number of variables
influence duration of vaccine protection, including age, serostatus at
virus (natural boosting), possible evolution of the wild type virus, as
well as unknown factors.
No risk factors have been identified for TDV vaccination failure.
CONFIDENTIAL

- SmPC Section 4.4
- PL Section 2
No additional risk minimisation measures.

activities
a booster dose)
CONFIDENTIAL
Important potential risk: Severe and/or hospitalized dengue following vaccination caused by
Evidence for linking the risk Efficacy results by baseline dengue serostatus (determined for all
to the medicine subjects), demonstrated overall VE against VCD and VCD leading to
hospitalization regardless of prior exposure to dengue. Efficacy
against individual dengue serotypes varied. The totality of data on
VCD, hospitalized VCD, and severe forms of dengue, along with the
clinical characteristics of these cases, as assessed in Trials DEN-301,
DEN-313, and DEN-204, did not reveal an identified risk of increased
disease severity or disease enhancement attributable to vaccination in
the post-vaccination period.
Exploratory efficacy analyses at 54 months after the second vaccine
dose did not suggest efficacy for VCD caused by serotype DENV-3 in
baseline seronegative subjects (RR: 1.11 [95% CI: 0.62, 1.99]). For
hospitalized VCD caused by DENV-3 there were with 11 cases in the
TDV group (0.3%) compared with 3 cases in placebo group (0.2%),
with a relative risk of 1.81 (95% CI: 0.51, 6.48).
were assessed as severe dengue as defined by the Adjudication
Committee (both in the TDV group; 0.05% of 3714 subjects). Both
cases occurred early in the trial during Parts 1 and 2 (i.e., before
18 months post second dose). Five subjects experienced DHF as per
programmed algorithm, WHO 1997 DHF criteria), 4 of 3714 subjects
(0.11%) in the TDV group and 1 of 1832 subjects (0.05%) in the
placebo group. Of note, 1 of these 4 DHF cases in the TDV group was
also classified as DCAC-defined severe dengue. All of these cases in
baseline seronegative subjects were caused by DENV-3. The
assessment of whether TDV may be associated with an increased risk
of severe forms of dengue in baseline seronegative subjects who
experience VCD caused by serotype DENV-3 remained inconclusive;
the data are limited by the small number of cases. In baseline
seronegative subjects, an increased risk of hospitalization due to
dengue and/or clinically severe forms of dengue caused by serotype
DENV-3 is considered an important potential safety risk.
Conservatively, due to limited data for DENV-4, risk of hospitalization
due to dengue and/or clinically severe forms of dengue caused by
serotype DENV-4 in baseline seronegative subjects is considered an
important potential safety risk, although up the 54 months after the
second vaccine dose no hospitalisations caused by DENV-4 occurred in
TDV recipients.
Risk factors and risk groups No risk factors for severe dengue with TDV have been identified.

- SmPC Section 4.4
- PL Section 2

activities
a booster dose)
CONFIDENTIAL

Missing Information: Safety profile of inadvertent use in pregnant or lactating women

- SmPC Section 4.3, Section 4.4 and Section 4.6
- PL Section 2
Missing Information: Safety and immunogenicity in immunocompromised individuals

SmPC Section 4.3 and Section 4.5
PL Section 2
Missing Information: Safety and immunogenicity of concomitant administration with other


- SmPC Section 4.5
- PL Section 2
Additional Coadministration with 9vHPV vaccine Trial (DEN-308)

pharmacovigilance
activities See Section II.C of this summary for an overview of the post-
Missing Information: Safety and reactogenicity of a booster dose

- SmPC Section 4.2

activities
a booster dose)
CONFIDENTIAL
II.C. Post-authorisation development plan

II.C.1. Studies which are conditions of the marketing authorisation
There are no studies which are conditions of the marketing authorisation or specific obligation of
Qdenga.
II.C.2. Other studies in post-authorisation development plan

WHO recommends long-term follow-up to evaluate the safety of dengue vaccines for 3 to 5 years.
dose. For those participants in the booster phase, parts 4 and 5, there is approximately 2 years of
additional follow-up.
Long-term safety and antibody persistence of TDV and the impact of a booster dose
(study DEN-303)
DEN-304 and DEN-315 trials (termed here as “parent trials”). It will then go on to assess the
immunogenicity and safety of a TDV booster dose in this population.
Immunogenicity and safety of TDV and 9vHPV in subjects aged ≥9 to <15 years (study
DEN-308)
recommended either in a 2-dose or 3-dose schedule 6 to 12 months apart in subjects 9 through 14
years of age. Further, if the second dose is administered earlier than 5 months after the first dose,
then a third dose should be administered at least 4 months after the second dose. Many similarities
exist between the proposed vaccination schedule for TDV and the approved schedule for 9-valent
HPV (9vHPV) vaccine, including the overlapping target age group and the potential delivery through
school immunisation programs.
CONFIDENTIAL
Part VII: Annexes

Annex 1: EudraVigilance Interface ......................................................................................... 81
Annex 2: Tabulated summary of planned, ongoing, and completed pharmacovigilance study
programme ................................................................................................... 82
Annex 3: Protocols for proposed, on-going and completed studies in the pharmacovigilance plan... 84
Annex 4: Specific adverse drug reaction follow-up forms........................................................... 85
Annex 5: Protocols for proposed and on-going studies in RMP Part IV ......................................... 86
Annex 6: Details of proposed additional risk minimisation activities ............................................ 87
Annex 7: Other supporting data (including referenced material) ................................................ 88
Annex 8: Summary of changes to the risk management plan over time ...................................... 97
Annex 9: Ad-hoc Tables Referenced in the RMP ....................................................................... 98
CONFIDENTIAL
Annex 4: Specific adverse drug reaction follow-up forms
Not applicable.
CONFIDENTIAL
Annex 6: Details of proposed additional risk minimisation activities
Not applicable.
CONFIDENTIAL

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Title Page

EU RISK MANAGEMENT PLAN (RMP)

RMP Version number: 1.0

This document contains confidential information, which is property of TAKEDA PHARMACEUTICAL

EU Risk Management Plan for Dengue Tetravalent Vaccine (Live,

RMP version to be assessed as part of this application:

Rationale for submitting an updated RMP:

Part I – Product overview Revision in Brief description of the product: sentence

- to reflect changes made in the updated PI under section 4.6

Module SVII – Identified and Revision in SVII.3.1. Presentation of important identified

Module SVIII – Summary of the No changes

Part III – Pharmacovigilance III.2. Additional pharmacovigilance activities:

- Study DEN-401 removed from the additional

Part IV - Plans for post- No changes

RMP Part/Module Significant changes

Part V - Risk minimisation Study DEN-401 removed

Part VII – Annexes Annex 2 updated

Other RMP versions under evaluation:

Details of the currently approved RMP:

QPPV name: Dr. Sumit Munjal, Takeda VP EU-QPPV

PART II: MODULE SV - POST-AUTHORISATION EXPERIENCE .........................................................32

II.C.1. Studies which are conditions of the marketing authorisation .............................. 72

Part I: Product(s) Overview

Active substance(s) Dengue virus serotype 1 (live, attenuated)*

#Produced in Vero cells by recombinant DNA technology.

Pharmacotherapeutic J07BX04 dengue virus vaccines

Marketing Authorisation Takeda GmbH

Medicinal products to Dengue Tetravalent Vaccine (Live, Attenuated)

Invented name(s) in the Qdenga

Marketing authorisation Centralised procedure

Brief description of the Chemical class: Vaccines

TDV contains live attenuated dengue viruses. The primary

Important information about its composition:

Dengue tetravalent vaccine is a live attenuated vaccine. The vaccine

Indication(s) in the EEA Current (if applicable): Not applicable.

Proposed (if applicable): Qdenga is indicated for the prevention of

Dosage in the EEA Current (if applicable): Not applicable.

Proposed (if applicable):

Qdenga should be administered as a 0.5 ml dose at a two-dose

Pharmaceutical form(s) Current (if applicable): Not applicable.

Part II: Safety specification

Due to under-recognition, under-reporting, and passive surveillance systems at the

Details for some of the highest burdened countries are below:

In Indonesia, outbreaks of Dengue haemorrhagic fever (DHF) appear to be cyclical,

A seroprevalence study in 2014 of 30 geographically dispersed clusters found

A seroprevalence survey among 9 to 12-years old in Penang and Kuala Lumpur in

Singapore is an equatorial city-state with approximately 5.6 million inhabitants.

Sri Lanka is an island nation of 21.4 million inhabitants. From 2010-2016,

A recent dengue seroprevalence study conducted in Fortaleza, Natal, Vitoria,

multiple dengue serotypes circulate in Colombia. In 2019, DENV-1, DENV-2, and

A dengue seroprevalence study conducted in Bucaramanga, Armenia, Tebaida,

Dengue transmission in Mexico, a country of 126.2 million inhabitants, is

Dengue in European territories

Reunion Island, a French department in the Indian Ocean of about 840,000

substantial prior exposure of dengue among the population of Mayotte [47].

In Martinique and Guadeloupe, overseas regions of France, dengue is highly

In New Caledonia, a special collectivity of France with a population of 278,000,

dengue cases (IR = 131/100,000) and 20 confirmed cases. No information on the

Racial and/or ethnic origin: