A Prospective Study to Estimate the Incidence of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Infants and Young Children in Sub-Saharan Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine
Conditions: Malaria
Sponsor: GlaxoSmithKline

Protocol 
Study ID:  115055
Official Title of Study: A prospective study to estimate the incidence of diseases 
specified as adverse events of special interest, of other adverse events leading to 
hospitalisation or death, and of meningitis in infants and young children in sub-Saharan 
Africa prior to implementation of the RTS,S/AS01E candidate vaccine. 
Date of Document: 13 May 2020

CONFIDENTIAL 
115055 (EPI-MALARIA-002 VS AME) 
Protocol Amendment 7 Final 
5-MAY-2020 
1 
 
Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89 
1330 Rixensart, Belgium 
1. 
PROTOCOL INFORMATION 
This protocol is formatted as “PASS protocol” proposed by the European Medicines 
Agency (EMA) pharmacovigilance guidance [European Medicines Agency, 2012]. 
However, this study is not a safety study but will serve to collect baseline information 
necessary to prepare the PASS study EPI-MALARIA-003 VS AME (115056) (referred to 
as EPI-MAL-003 in the remainder of the document) that will start upon the 
implementation of the RTS,S/AS01E vaccine in Sub-Saharan Africa. 
Title: 
A prospective study to estimate the incidence of 
diseases specified as adverse events of special 
interest, of other adverse events leading to 
hospitalisation or death, and of meningitis in infants 
and young children in sub-Saharan Africa prior to 
implementation of the RTS,S/AS01E candidate 
vaccine. 
Protocol version identifier: 
115055 (EPI-MALARIA-002 VS AME) 
Date of last version of the 
protocol:  
Amendment 7 Final: 5 May 2020 
EU PAS Register No: 
NA (Not applicable) 
Active substance: 
NA (Not applicable) 
Medicinal product: 
NA (Not applicable) 
Product reference: 
H0002300 
Procedure number: 
Not allocated 
Opinion Holder: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89 
1330 Rixensart, Belgium 
Research question and 
objectives: 
Co-Primary Objectives: 
• 
To estimate the incidence of adverse events of 
special interest, and of other adverse events 
leading to hospitalisation or death, in children, 
prior to implementation of RTS,S/AS01E. 
• 
To estimate the incidence of aetiology-
confirmed meningitis, in children, prior to 
implementation of RTS,S/AS01E. 
Objectives related to malaria are considered as 
secondary objectives. 
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Countries of study: 
Sites in sub-Saharan Africa (SSA) countries have 
been selected for EPI-MAL-002 based on the 
existence of a health and demographic surveillance 
system (HDSS) from the International Network for 
the Demographic Evaluation of Populations and 
Their Health (INDEPTH) or equivalent surveillance 
system census and of vaccine registries.  
Following the World Health Organization (WHO)’s 
Strategic Advisory Group of Experts (SAGE) on 
Immunization and the Malaria Policy Advisory 
Committee (MPAC) recommendations of pilot 
implementations of RTS,S/AS01E in 3-5 distinct 
settings in SSA restricted to moderate-to-high 
transmission of malaria, sites in SSA countries with 
moderate-to-high transmission of malaria have 
started enrolment (Ghana [Kintampo and 
Navrongo], Kenya [Kombewa], and Burkina Faso 
[Sapone, Nouna]). 
In April 2017, the WHO Regional Office for Africa 
announced that the RTS,S/AS01E vaccine will be 
first introduced in 3 countries (Ghana, Kenya and 
Malawi) through a WHO-coordinated pilot 
implementation programme, referred to as the 
Malaria Vaccine Implementation Programme 
(MVIP) in the remaining sections of this document. 
In order to align with the MVIP, the study sites for 
the GSK Phase IV studies have been, or will be, 
selected from the 3 countries where the 
RTS,S/AS01E vaccine will be implemented As a 
consequence, Burkina Faso sites, that had already 
started EPI-MAL-002, early terminated the follow-
up activities in active surveillance and enrolment in 
enhanced hospitalisation surveillance since 06 June 
2018, with the exception of the follow-up check-ups 
at the hospital for children diagnosed with 
meningitis, cerebral malaria or with an AESI. All 
study activities are planned to be terminated by Q2 
2019. A description of data from these sites will be 
presented in the progress reports up to Q4 2019, but 
none of these data will be part of the statistical 
analyses for the interim and final reports.  
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Authors: 
(Amended 5 May 2020) 
Coordinating authors: 
• 
 (GSK Biologicals) 
• 
, Lead Scientific Writer 
(GSK Biologicals) 
Main GSK Biologicals contributing authors: 
• 
, Data Management (Business 
and Decision Life Sciences for GSK 
Biologicals) 
• 
/ 
, Oversight 
Data Manager (GSK Biologicals) 
• 
, 
, Head of Global 
Epidemiology (GSK Biologicals) 
• 
, 
, Global 
Epidemiology (GSK Biologicals) 
• 
, Senior Manager, 
Epidemiologist (GSK Biologicals) 
• 
, Senior Epidemiology Lead – 
Malaria (GSK Biologicals) 
• 
, Statistician (4Clinics 
for GSK Biologicals) 
• 
, Lead Statistician (GSK 
Biologicals) 
• 
, Epidemiology lead (GSK 
Biologicals) 
• 
, Epidemiology Lead –Malaria 
(previously Statistician) (GSK Biologicals) 
• 
, Clinical and Epidemiological 
Project Lead (GSK Biologicals) 
Other GSK contributing authors: 
• 
, 
, Global Study 
Management (GSK Biologicals) 
• 
, 
, Safety 
Physician (GSK Biologicals) 
• 
, Safety Scientist (GSK 
Biologicals) 
• 
/ 
, 
Senior Manager, Safety Physician (GSK 
Biologicals) 
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• 
 / 
 
Delivery Lead (GSK Biologicals) 
• 
, Clinical Laboratory 
Sciences (CVO Europe for GSK Biologicals) 
• 
, Clinical Laboratory 
Sciences (Altran for GSK Biologicals) 
• 
, Local Delivery Lead (GSK 
Biologicals) 
• 
, Epidemiologist (consultant 
for GSK Biologicals) 
• 
, 
, Global 
Regulatory Lead Malaria Vaccines (GSK 
Biologicals) 
• 
, CLS Clinical Read-out Leader 
(GSK Biologicals) 
• 
, Senior Manager, Global 
Regulatory Affairs, Malaria Vaccines (GSK 
Biologicals) 
• 
, Local Delivery Lead (GSK 
Biologicals) 
• 
, Clinical Operations Head, 
Africa and Middle East (GSK Biologicals) 
Other non-GSK Biologicals contributors: 
• 
Representatives of the Principal Investigators 
and co-chairs of the Safety Post Approval 
Program Partnership Committee.  
Other non-GSK Biologicals partners: 
• 
Réseau en Afrique Francophone pour la 
Télémédecine (RAFT) (represented by 
Professor 
, Geneva, 
Switzerland) 
• 
Agence de Médecine Préventive (AMP) 
Regional Office for Africa (represented by Dr. 
, Abidjan, Ivory Coast) 
• 
PATH (represented by 
, Seattle, 
United States of America) 
• 
IQVIA (represented by 
, 
Project Manager)  
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CONFIDENTIAL 
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• 
Second line laboratory: Clinical Laboratory 
Services (represented by 
, 
Johannesburg, South Africa) 
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2. 
OPINION HOLDER  
Opinion holder: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
© 2012 GSK group of companies or its licensor (Amended 5 May 2020) 
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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL INFORMATION ................................................................................... 1 
2. 
OPINION HOLDER .................................................................................................. 6 
LIST OF ABBREVIATIONS ........................................................................................... 15 
3. 
RESPONSIBLE PARTIES ...................................................................................... 18 
4. 
ABSTRACT ............................................................................................................ 19 
5. 
AMENDMENTS AND UPDATES ............................................................................ 26 
6. 
MILESTONES ........................................................................................................ 27 
7. 
BACKGROUND AND RATIONALE ........................................................................ 27 
7.1. 
Background ................................................................................................ 27 
7.2. 
Safety results of the clinical development of RTS,S/AS01E ......................... 29 
7.3. 
Efficacy results of the clinical development of RTS,S/AS01E ....................... 35 
7.4. 
Rationale for the study ................................................................................ 36 
8. 
RESEARCH QUESTION AND OBJECTIVES ........................................................ 38 
8.1. 
Co-primary objectives ................................................................................. 38 
8.2. 
Secondary objectives .................................................................................. 38 
9. 
RESEARCH METHODS ......................................................................................... 39 
9.1. 
Study design ............................................................................................... 39 
9.1.1. 
Rationale for the study design ...................................................... 42 
9.2. 
Setting ........................................................................................................ 44 
9.2.1. 
Study population .......................................................................... 46 
9.2.1.1. 
Participant recruitment ................................................ 47 
9.2.2. 
Inclusion criteria for enrolment ..................................................... 49 
9.2.3. 
Exclusion criteria for enrolment .................................................... 50 
9.2.4. 
Study period ................................................................................ 50 
9.2.5. 
Case definitions ........................................................................... 50 
9.2.5.1. 
AESI ........................................................................... 50 
9.2.5.2. 
Hospitalisations for an AE other than an AESI, 
meningitis, any malaria or severe malaria 
(including cerebral malaria) ........................................ 56 
9.2.5.3. 
Meningitis ................................................................... 56 
9.2.5.4. 
Febrile convulsions ..................................................... 57 
9.2.5.5. 
Malaria ....................................................................... 57 
9.2.5.6. 
Anaemia ..................................................................... 58 
9.2.5.7. 
Hospitalisation ............................................................ 59 
9.2.5.8. 
Deaths ........................................................................ 59 
9.2.6. 
Surveillance quality indicators ...................................................... 59 
9.2.6.1. 
Case definition for abscess at injection site ................ 60 
9.2.6.2. 
Case definition for foot positional deformations .......... 60 
9.2.7. 
Study procedures ......................................................................... 60 
9.2.7.1. 
Active surveillance ...................................................... 60 
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9.2.7.1.1. 
Informed consent .................................... 61 
9.2.7.1.2. 
Check inclusion and exclusion 
criteria .................................................... 61 
9.2.7.1.3. 
Assign subject study number .................. 62 
9.2.7.1.4. 
Collect demographic data ....................... 62 
9.2.7.1.5. 
Health history.......................................... 62 
9.2.7.1.6. 
Check and record vaccinations ............... 62 
9.2.7.1.7. 
Record information about health 
care seeking behaviour, malaria 
control measures, drug use and 
exposure to environmental 
hazards................................................... 62 
9.2.7.1.8. 
Record health care facility visits 
and hospitalisations ................................ 62 
9.2.7.1.9. 
Physical examination, record of 
signs and symptoms, record any 
serious delay in developmental 
milestones or physical disability .............. 63 
9.2.7.1.10. Refer sick children or children with 
disabilities to outpatient clinic or 
hospital ................................................... 63 
9.2.7.1.11. Record cases of death ............................ 63 
9.2.7.1.12. Study conclusion .................................... 64 
9.2.7.1.13. Outline of study procedures .................... 65 
9.2.7.2. 
Enhanced hospitalisation surveillance ........................ 69 
9.2.7.2.1. 
Informed consent (for subjects not 
enrolled previously, i.e. for 
previous hospitalisation or for 
active surveillance) ................................. 69 
9.2.7.2.2. 
Check inclusion and exclusion 
criteria (for subjects not enrolled 
previously) .............................................. 69 
9.2.7.2.3. 
Assign subject study number (for 
subjects not enrolled previously) ............. 69 
9.2.7.2.4. 
Collect demographic data (for 
subjects not enrolled previously) ............. 69 
9.2.7.2.5. 
Record type of health care facility ........... 70 
9.2.7.2.6. 
Record any serious delay in 
developmental milestones or 
physical disability (for subjects not 
enrolled previously and at study 
conclusion) ............................................. 70 
9.2.7.2.7. 
Health history.......................................... 70 
9.2.7.2.8. 
Record information about health 
care seeking behaviour, malaria 
control measures, drug use and 
exposure to environmental 
hazards................................................... 70 
9.2.7.2.9. 
Record standard vaccinations ................. 70 
9.2.7.2.10. Record diagnosis .................................... 70 
9.2.7.2.11. Record haemoglobin 
measurement.......................................... 71 
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9.2.7.2.12. Record deaths ........................................ 71 
9.2.7.2.13. Record cases of suspected AESI, 
other AE leading to hospitalisation 
or death, meningitis cases, 
malaria episodes diagnosed by 
RDT and/or microscopy, abscess 
at injection site and foot positional 
deformations ........................................... 71 
9.2.7.2.14. Record serious adverse events 
related to a study procedure ................... 71 
9.2.7.2.15. Study conclusion .................................... 72 
9.2.7.2.16. Outline of study procedures .................... 72 
9.2.7.3. 
Biological sample handling and analysis ..................... 74 
9.2.7.3.1. 
Biological samples .................................. 74 
9.2.7.3.2. 
Laboratory assays .................................. 75 
9.2.7.4. 
Management of AESI, other AE leading to 
hospitalisation or death, meningitis cases, 
malaria episodes, abscess at injection site and 
foot positional deformations ........................................ 75 
9.2.7.4.1. 
Case ascertainment for meningitis .......... 76 
9.2.7.4.2. 
Case ascertainment for AESI .................. 77 
9.2.7.4.3. 
Children suspected of having a 
serious adverse event (SAE) .................. 78 
9.2.7.4.4. 
Case ascertainment for other AE 
leading to hospitalisation or death........... 78 
9.2.7.4.5. 
Case ascertainment for malaria .............. 78 
9.2.7.4.6. 
Children with abscess at injection 
site .......................................................... 79 
9.2.7.4.7. 
Children with foot positional 
deformations ........................................... 79 
9.2.7.5. 
Package for standard of care ...................................... 79 
9.2.7.6. 
Capacity building ........................................................ 80 
9.2.8. 
Study procedures during special circumstances ................................. 81 
9.3. 
Variables..................................................................................................... 81 
9.3.1. 
Co-primary endpoints................................................................... 81 
9.3.2. 
Secondary endpoints ................................................................... 81 
9.3.3. 
Patient characteristics and potential confounding variables ......... 82 
9.3.3.1. 
Recorded in EPI-MAL-002 and EPI-MAL-003 ............. 82 
9.3.3.2. 
Recorded in EPI-MAL-005 .......................................... 83 
9.4. 
Data Sources .............................................................................................. 83 
9.4.1. 
Health Demographic Surveillance System (or equivalent 
surveillance system) .................................................................... 83 
9.4.2. 
Active surveillance and enhanced hospitalisation 
surveillance of study EPI-MAL-002 .............................................. 84 
9.4.3. 
Study EPI-MAL-005 ..................................................................... 85 
9.5. 
Study size ................................................................................................... 86 
9.6. 
Data management ...................................................................................... 88 
9.7. 
Data analysis .............................................................................................. 88 
9.7.1. 
Total cohort .................................................................................. 89 
9.7.2. 
According-to-protocol (ATP) cohort .............................................. 89 
9.7.3. 
Derived and transformed data ...................................................... 89 
9.7.4. 
Conduct of analyses .................................................................... 90 
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9.7.4.1. 
Sequence of analyses ................................................ 90 
9.7.5. 
Analysis of co-primary objectives ................................................. 90 
9.7.5.1. 
Analysis population..................................................... 90 
9.7.5.2. 
Statistical approach .................................................... 90 
9.7.5.2.1. 
Incidence of AESI, and other AE 
leading to hospitalisation or death........... 90 
9.7.5.2.2. 
Incidence rate of aetiology-
confirmed meningitis ............................... 92 
9.7.6. 
Analysis of secondary safety objectives ....................................... 92 
9.7.6.1. 
Analysis population..................................................... 92 
9.7.6.2. 
Statistical approach .................................................... 92 
9.7.7. 
Analysis for other secondary objectives ....................................... 94 
9.7.7.1. 
Analysis population..................................................... 94 
9.7.7.2. 
Statistical approach .................................................... 94 
9.7.8. 
Statistical considerations ............................................................. 96 
9.7.8.1. 
Handling of missing data ............................................ 96 
9.7.8.2. 
Descriptive statistics ................................................... 97 
9.7.9. 
Statistical models ......................................................................... 97 
9.7.10. 
Statistical analyses during special circumstances ........................ 98 
9.8. 
Quality Control ............................................................................................ 98 
9.8.1. 
Monitoring by GSK Biologicals ..................................................... 98 
9.8.2. 
Archiving of data at study sites .................................................... 99 
9.8.3. 
Audits ........................................................................................ 100 
9.9. 
Limitations of the research methods ......................................................... 100 
10. PROTECTION OF HUMAN SUBJECTS .............................................................. 103 
10.1. 
Regulatory and ethical considerations, including the informed 
consent process........................................................................................ 103 
11. MANAGEMENT AND REPORTING OF SERIOUS ADVERSE EVENTS 
RELATED TO STUDY PROCEDURE .................................................................. 104 
11.1. 
Safety definition ........................................................................................ 105 
11.1.1. 
Definition of a serious adverse event ......................................... 105 
11.2. 
Detecting and recording serious adverse events....................................... 106 
11.2.1. 
Time period for detecting and recording serious adverse 
events ........................................................................................ 106 
11.2.2. 
Evaluation of serious adverse events ......................................... 106 
11.2.2.1. Assessment of intensity ............................................ 106 
11.2.2.2. Assessment of outcomes.......................................... 106 
11.3. 
Reporting of serious adverse events ......................................................... 107 
11.3.1. 
Prompt reporting of serious adverse events to GSK 
Biologicals ................................................................................. 107 
11.3.2. 
Contact information for reporting serious adverse events 
to GSK Biologicals ..................................................................... 107 
11.3.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................. 107 
11.3.3.1. Back-up system in case the electronic SAE 
reporting system does not work ................................ 108 
11.3.3.2. Updating of SAE information after removal of 
write access to the subject’s eCRF ........................... 108 
11.4. 
Follow-up of serious adverse events ......................................................... 108 
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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ............................................................................................................ 109 
13. REFERENCES ..................................................................................................... 109 
 
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LIST OF TABLES 
PAGE 
Table 1 
Meningitis cases observed in MALARIA-055 over 20 months post 
first dose (MedDRA preferred terms including meningitis and 
meningitis with any aetiologies) .............................................................. 31 
Table 2 
Cases of severe malaria disease (secondary case definition 1) 
classified by syndrome, group and time period including fatal 
cases by syndrome (ITT population; 5-17 month age category; 
from MALARIA-055 study) ..................................................................... 33 
Table 3 
Summary of adverse events of special interest (AESI) by body 
system ................................................................................................... 52 
Table 4 
List of study procedures to be conducted at each visit, and study 
visit schedule (active surveillance) ......................................................... 65 
Table 5 
List of study procedures to be conducted in the event of 
hospitalisation ........................................................................................ 72 
Table 6 
Estimation of the lower (LL) and upper (UL) limits of observed 
incidences of events following dose administration based on 
10,000 subjects, different numbers of detected events, and 
different risk periods ............................................................................... 87 
Table 7 
Estimation of the lower (LL) and upper (UL) limits of observed 
incidences of events among all children less than 5 years of age 
based on 11,500 birth cohort, and different numbers of detected 
events .................................................................................................... 88 
Table 8 
Incidence rate and prevalence calculations for other objectives 
(children enrolled in active surveillance) ................................................. 95 
Table 9 
Timeframes for submitting SAEs related to blood sampling in 
case of a suspected AESI or meningitis to GSK Biologicals ................. 107 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 41 
 
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LIST OF ANNEXES 
PAGE 
Annex 1 
LIST OF STAND-ALONE DOCUMENTS.............................................. 116 
Annex 2 
LIST OF PRINCIPAL AND COORDINATING INVESTIGATORS ......... 117 
Annex 3 
GLOSSARY OF TERMS ...................................................................... 118 
Annex 4 
TRADEMARKS .................................................................................... 122 
Annex 5 
CASE DEFINITIONS FOR PROTOCOL-DEFINED ADVERSE 
EVENTS OF SPECIAL INTEREST (AESI) AND 
SURVEILLANCE INDICATORS ........................................................... 123 
Annex 6 
STUDY SPECIFIC GUIDANCE DOCUMENT ...................................... 142 
Annex 7 
AMENDMENTS TO THE PROTOCOL ................................................. 144 
Annex 8 
PROTOCOL AMENDMENT 7 SPONSOR SIGNATORY 
APPROVAL .......................................................................................... 182 
Annex 9 
PROTOCOL AMENDMENT 7 INVESTIGATOR AGREEMENT ............ 183 
 
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LIST OF ABBREVIATIONS 
ADEM 
Acute Disseminated Encephalo-Myelitis 
AE 
Adverse Event 
AESI 
Adverse Event Of Special Interestw 
AMP 
Agence de Médecine Préventive 
AS01 
GSK’s proprietary Adjuvant System containing MPL, QS-21 
and liposome  
ATP 
According To Protocol 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CLS  
Clinical Laboratory Services 
CRP 
C-Reactive Protein 
CS 
Circumsporozoite 
CSF 
Cerebrospinal Fluid 
DNA 
Deoxyribonucleic Acid 
DTP 
Diphtheria, Tetanus, Pertussis trivalent vaccine 
DTP-HepB 
DTP-Hepatitis B tetravalent vaccine 
DTPw/HepB/Hib 
Diphtheria-tetanus-whole-cell pertussis-hepatitis B- 
Haemophilus influenza type b pentavalent vaccine 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EPI 
Expanded Program on Immunization 
EU PAS 
European Union Post-Authorisation Studies 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices 
GSK 
GlaxoSmithKline 
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HBsAg 
Hepatitis B surface antigen 
HDSS 
Health and Demographic Surveillance System 
HHE 
Hypotonic Hyporesponsive Episode 
HIV 
Human Immunodeficiency Virus 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INDEPTH 
International Network for the Demographic Evaluation of 
Populations and Their Health 
IRB 
Institutional Review Board 
LAR 
Legally Acceptable Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPAC 
Malaria Policy Advisory Committee 
MPL 
3-O-desacyl-4’- monophosphoryl lipid A (produced by GSK) 
MTI 
Malaria Transmission Intensity 
MVIP 
Malaria Vaccine Implementation Programme 
OPV 
Oral Poliovirus Vaccine 
P. falciparum 
Plasmodium falciparum 
PATH REC 
Program for Appropriate Technology in Health Research 
Ethics Committee  
PCR 
Polymerase Chain Reaction 
PCV 
Pneumococcal Conjugate Vaccine  
pIMD 
potential Immune-Mediated Disorders 
PT 
Preferred Term 
PY 
Person-Years 
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QS-21  
QS-21 QS-21 = Quillaja saponaria Molina, fraction 21 
(Licensed by GSK from Antigenics Inc, a wholly owned 
subsidiary of Agenus Inc., a Delaware, USA corporation) 
RAFT 
Réseau en Afrique Francophone pour la Télémédecine 
RDT 
Rapid Diagnostic Test 
RMP 
Risk Management Plan 
RR 
Relative Risk 
RTS 
Hybrid protein comprising HBs (hepatitis B surface antibody) 
and CS protein portions 
RTS,S 
Particulate antigen, containing both RTS and HBs antigen (S) 
proteins 
SAE 
Serious Adverse Event 
SAGE 
Strategic Advisory Group of Experts 
SAP 
Statistical Analysis Plan 
SDV 
Source Document Verification 
SOC 
System Organ Class 
SPM 
Study Procedures Manual 
SSA 
Sub-Saharan Africa 
WHO 
World Health Organization 
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3. 
RESPONSIBLE PARTIES 
GSK Biologicals has the overall responsibility for the conduct of the study. 
 (DVM, MSc, PhD; Senior Epidemiology Lead - Malaria) and 
 
 (PhD; Epidemiology Lead – Malaria) are the GSK Biologicals designated contact 
persons for this study. 
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4. 
ABSTRACT 
Title 
A prospective study to estimate the incidence of diseases 
specified as adverse events of special interest, of other adverse 
events leading to hospitalisation or death, and of meningitis in 
infants and young children in sub-Saharan Africa prior to 
implementation of the RTS,S/AS01E candidate vaccine. 
115055 (EPI-MALARIA-002 VS AME), 
Amendment 7: 05 May 2020 
Main author 
 
, Senior Epidemiology Lead – Malaria and 
, Epidemiology Lead - Malaria 
Rationale and 
background 
 
GSK Biologicals has developed a pre-erythrocytic Plasmodium 
(P.) falciparum malaria vaccine, RTS,S/AS01E, for routine 
immunisation of infants and children living in malaria-endemic 
countries of sub-Saharan Africa (SSA). RTS,S/AS01E will be 
the first vaccine to be implemented for the prevention of 
malaria and it will be the first AS01-adjuvanted vaccine used in 
the paediatric population. 
In July 2015, the European Medicines Agency (EMA) issued a 
positive opinion for the RTS,S/AS01E vaccine, and in October 
2015 recommendations about RTS,S/AS01E were issued by the 
World Health Organization (WHO)’s Strategic Advisory Group 
of Experts (SAGE) on Immunization and the Malaria Policy 
Advisory Committee (MPAC). In April 2017, the WHO 
Regional Office for Africa announced that the RTS,S/AS01E 
vaccine will be first introduced in 3 countries (Ghana, Kenya 
and Malawi) through a WHO-coordinated pilot implementation 
programme, referred to as the Malaria Vaccine Implementation 
Programme (MVIP) in the remaining sections of this document. 
The safety and efficacy of RTS,S/AS01E have been evaluated 
during pre-authorisation clinical trials conducted mainly in 
SSA. 
The RTS,S/AS01E vaccine will be implemented only in malaria 
endemic countries of SSA. Most of these countries have no 
baseline incidence data on rare diseases such as those that may 
be reported as adverse events (AE) following vaccination.  
Data generated from EPI-MALARIA-002 VS AME (115055) 
(referred to as EPI-MAL-002 in the remainder of the document) 
will fill this gap and provide data that serve as baseline data for 
the post-implementation safety study (EPI-MAL-003) that will 
evaluate the safety of RTS,S/AS01E as reflected in the 
co-primary and secondary objectives. Therefore, the primary 
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aims of the EPI-MAL-002 study are to provide reliable 
estimates of the rates of occurrence of diseases specified as 
adverse events of special interest (AESI), of other AE leading 
to hospitalisation or death, and of meningitis cases (reported as 
a potential risk in the MALARIA-055 Phase III study) in 
preparation for the post-implementation safety study 
EPI-MAL-003. Additionally, vaccine impact measures 
(indirect, total and overall effects) are included in 
EPI-MAL-002 and EPI-MAL-003. Therefore, all malaria 
events (morbidity, mortality and hospitalisation) will be 
monitored throughout the study. Background incidence rates of 
any malaria and severe malaria, including cerebral malaria, will 
be collected. The mortality rate, overall and by gender, will also 
be estimated. 
Research question 
and objectives 
 
Co-primary objectives 
• 
To estimate the incidence of AESI1, and of other AE 
leading to hospitalisation or death, in children, prior to 
implementation of RTS,S/AS01E. 
• 
To estimate the incidence of aetiology-confirmed 
meningitis, in children, prior to implementation of 
RTS,S/AS01E. 
 
Secondary objectives 
In children living in the study area, prior to implementation of 
RTS,S/AS01E: 
• 
To estimate the incidence of aetiology-confirmed, and/or 
probable meningitis (final classification). 
• 
To estimate the incidence of probable meningitis (final 
classification). 
• 
To estimate the incidence of aetiology-confirmed, probable 
and/or clinically suspected meningitis (final classification). 
• 
To monitor trends over time of meningitis cases identified 
at site level (first line laboratory). 
• 
To describe risk factors for AESI, other AE leading to 
hospitalisation or death, meningitis and malaria. 
• 
To describe the causes of hospitalisation (including AESI, 
other AE, meningitis and malaria). 
                                                 
1 Acute disseminated encephalomyelitis, encephalitis, Guillain-Barre Syndrome, hypotonic hyporesponsive episode, 
generalised convulsive seizure. 
Intussusception, hepatic failure, renal insufficiency. 
Juvenile chronic arthritis, Stevens-Johnson syndrome/toxic epidermal necrolysis, Henoch-Schonlein purpura, Kawasaki 
disease. 
Diabetes mellitus type I, thrombocytopenia, anaphylaxis. 
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• 
To describe the causes of death, overall and by gender. 
• 
To assess the risk of febrile convulsions during the 7-day 
period and 1-month period following administration of 
routine EPI vaccines. 
• 
To estimate the incidence of any malaria (including 
P. falciparum malaria) using rapid diagnostic test (RDT) 
and/or microscopy. 
• 
To estimate the incidence of severe malaria (including 
P. falciparum malaria) using RDT and/or microscopy. 
• 
To estimate the incidence of cerebral malaria (malaria 
diagnosed by RDT and/or microscopy). 
• 
To estimate the prevalence of anaemia among hospitalised 
children. 
• 
To estimate the incidence of all-cause hospitalisations and 
hospitalisations attributed to malaria (including 
P. falciparum). 
• 
To estimate the mortality rate (all-cause mortality and 
deaths attributed to malaria [including P. falciparum]), 
overall and by gender. 
Study design 
 
• 
A disease surveillance study with prospective cohort event 
monitoring among infants and young children living in a 
demographic census in SSA countries.  
• 
The design will include active surveillance (home visits 
and continuous monitoring of outpatient visits and 
hospitalisations at all health care facilities) and enhanced 
hospitalisation surveillance (continuous monitoring of 
hospitalisations). 
• 
The study targets enrolling 30,000 children in active 
surveillance, with about 20,000 children enrolled where the 
RTS,S/AS01E vaccine will be implemented. Among the 
30,000 children, approximately 15,000 children (with 
about 10,000 children in sites where the vaccine will be 
implemented) will be enrolled in the 6-12 weeks group (to 
collect background data in this age group) and 
approximately 15,000 children (with about 10,000 children 
in sites where the vaccine will be implemented) will be 
enrolled in the 5-17 months group (to mimic administration 
of RTS,S/AS01E in the 5-17 months age group). 
• 
For EPI-MAL-002 and EPI-MAL-003, the study sites were 
chosen based on existing infrastructure to identify the 
study population. 
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• 
The diseases under surveillance for safety include AESI, 
other AE leading to hospitalisation or death, and 
meningitis, and will be monitored among children enrolled 
in active surveillance and in enhanced hospitalisation 
surveillance. To estimate vaccine impact, several measures 
of malaria burden will be monitored among children in the 
active surveillance. The mortality rate, overall and by 
gender, will also be estimated. 
• 
Active surveillance will last 44 months for each subject 
(mimicking 24 months of active follow-up after the 
4th dose of RTS,S/AS01E in EPI-MAL-003), except for 
subjects enrolled from Burkina Faso sites for whom their 
participation in the study has been early terminated. 
Population, 
including the 
setting and study 
population 
 
Subjects < 5 years of age living in a geographically limited area 
with a health and demographic surveillance system (HDSS) or 
equivalent surveillance system in place, and an existing 
infrastructure to monitor population health and vaccination 
programmes. Sites in SSA countries have been selected for 
EPI-MAL-002 based on the existence of a HDSS from the 
International Network for the Demographic Evaluation of 
Populations and Their Health (INDEPTH) or equivalent 
surveillance system census and of vaccine registries.  
Following the SAGE/MPAC recommendations of pilot 
implementations of RTS,S/AS01E in 3-5 distinct settings in 
SSA restricted to moderate-to-high transmission of malaria, 
sites in SSA countries with moderate-to-high transmission of 
malaria have started enrolment (Ghana [Kintampo and 
Navrongo], Kenya [Kombewa], and Burkina Faso [Sapone and 
Nouna]). 
In April 2017, the WHO Regional Office for Africa announced 
that the RTS,S/AS01E vaccine will be first introduced in 3 
countries (Ghana, Kenya and Malawi) through the MVIP. In 
order to align with the MVIP, the study sites for the GSK Phase 
IV studies have been, or will be, selected from the 3 countries 
where the RTS,S/AS01E vaccine will be implemented. As a 
consequence, Burkina Faso sites, that had already started EPI-
MAL-002, stopped the follow-up activities in active 
surveillance and enrolment in enhanced hospitalisation 
surveillance on 06 June 2018, with the exception of the follow-
up check-ups at the hospital for children diagnosed with 
meningitis, cerebral malaria or with an AESI. All study 
activities are planned to be terminated by Q2 2019. A 
description of data from these sites will be presented in the 
progress reports up to Q4 2019, but none of these data will be 
part of the statistical analyses for the interim and final reports.  
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Variables 
 
Co-primary endpoints 
In children living in the study area, prior to implementation of 
RTS,S/AS01E: 
• 
Occurrence of AESI. 
• 
Occurrence of other AE leading to hospitalisation or death. 
• 
Occurrence of aetiology-confirmed meningitis. 
Secondary endpoints 
In children living in the study area, prior to implementation of 
RTS,S/AS01E: 
• 
Occurrence of probable meningitis (final classification). 
• 
Occurrence of clinically suspected meningitis (final 
classification). 
• 
Occurrence of meningitis cases identified at site level (first 
line laboratory). 
• 
Occurrence of hospitalisation (including those attributed to 
an AESI, other AE, meningitis, or malaria) or death. 
• 
Occurrence of febrile convulsions during the 7-day period 
(Days 0-6) and 1-month period (Days 0-29) following 
administration of routine EPI vaccines. 
• 
Occurrence of two events used as surveillance quality 
indicators: abscess at injection site during the 7-day period 
(Days 0-6) following any routine vaccination and foot 
positional deformation. 
• 
Occurrence of episodes of malaria using RDT and/or 
microscopy 
– 
Any malaria (including P. falciparum malaria). 
– 
Severe malaria (including P. falciparum malaria). 
– 
Cerebral malaria. 
• 
Occurrence of anaemia at hospital entry among 
hospitalised children. 
• 
Occurrence of hospitalisation 
– 
All causes and hospitalisations for any malaria 
(including P. falciparum malaria), severe malaria 
(including P. falciparum malaria) and cerebral 
malaria. 
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• 
Occurrence of death 
– 
All causes and malaria attributed deaths (including 
P. falciparum malaria attributed death). 
– 
AE attributed deaths. 
Data sources 
 
HDSS (or equivalent surveillance system) 
• 
Listings of all children living in the study area based on the 
demographic census; 
• 
Total number of children < 5 years of age recorded at the 
beginning of the study, at least once a year during the study 
duration, and at the end of the study;  
• 
Other demographic data (cause and date of deaths, 
migrations); 
• 
Information related to vaccination. 
Active surveillance (enrolment) 
• 
Socio-demographic data; 
• 
Active participation in any trial with an investigational 
product. 
Active surveillance (home visits) 
• 
Vaccination types and dates; 
• 
Health history; 
• 
Malaria control measures, health care seeking behaviour, 
drug use and exposure to environmental hazards; 
• 
Verbal autopsy report. 
Active surveillance (outpatient visits and hospitalisations at 
all health care facilities) 
• 
Data on visits at primary health care facilities and hospitals 
since enrolment or last home visit. 
Enhanced hospitalisation surveillance (hospitalisations) 
• 
Socio-demographic data; 
• 
Active participation in any trial with an investigational 
product; 
• 
Health history; 
• 
Malaria control measures, health care seeking behaviour, 
drug use and exposure to environmental hazards; 
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• 
Type of health care facility; 
• 
Final diagnosis for the hospitalisation visit on discharge for 
all children; 
• 
Data relevant to the diagnosis of AESI, other AE leading to 
hospitalisation or death, meningitis and malaria (including 
cerebral malaria); 
• 
Vaccination types and dates; 
• 
Autopsy report. 
Study conclusion (home visit) 
• 
Vital status; 
• 
Verbal autopsy report; 
• 
Vaccination types and dates; 
• 
Health history since last visit. 
Malaria Transmission Intensity Study EPI-MALARIA-005 
BOD AME (116682) (referred to as EPI-MAL-005 in the 
remainder of the document) 
• 
Estimation of annual parasite prevalence; 
• 
Changes in diagnostic practices; 
• 
Malaria control and prevention measures on the 
community and individual level. 
Study size 
 
The study targets enrolling 15,000 children per group (i.e. 
6-12 weeks group and 5-17 months group; with about 
10,000 children of 15,000 in each group enrolled where the 
RTS,S/AS01E vaccine will be implemented), for a total of 
30,000 children (about 20,000 children enrolled where the 
vaccine will be implemented). For some of the AESI the 
incidence could be very rare (around 1/100,000 person years 
[PY]) and the period at-risk considered could be from 2 weeks 
till 6 months for AESI, and 12 months for meningitis. The 95% 
confidence interval (CI) around an observed incidence of 25.2 
per 100,000 PY (corresponding to 1 event detected, in a risk 
period of 6 weeks following each dose [censored at the 
administration of the following dose], based on 10,000 
subjects) will be [0.6, 140.2]. 
Data analysis 
 
• 
The incidence rate of each AESI and other AE leading to 
hospitalisation or death will be calculated by dividing the 
number of subjects reporting at least one event over the 
follow-up period by the total person-time. A 95% CI will 
be computed using an exact method for a Poisson variable. 
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• 
The person-time for an event of interest (e.g. juvenile 
chronic arthritis) will be calculated as the time between the 
reference date (date of first administration of 
Diphtheria-tetanus-whole-cell pertussis-hepatitis B- 
Haemophilus influenza type b pentavalent vaccine 
[DTP/HepB/Hib] or date of first virtual vaccination, 
corresponding to the week before first visit) and the end of 
the at-risk period or the earliest of the followings: 
– 
Date of first diagnosis of event of interest (e.g. first 
episode of juvenile chronic arthritis). 
– 
Date of end of study period. 
– 
Date of enrolment in EPI-MAL-003 (when 
applicable). 
– 
Date when child reaches 5 years. 
– 
Date of last contact (Lost-to follow-up). 
– 
Date of death. 
• 
Each AESI will be grouped after case ascertainment (for 
both confirmed and non-confirmed cases). 
• 
The incidence rate of aetiology-confirmed meningitis and 
of cerebral malaria will be computed with 95% CI using 
the same approach as described above. 
Milestones  
The study started in Q4 2015, and is planned to end in Q1 2022. 
Progress reports will be generated every 6 months. An interim 
report is planned to be written by Q3 2019 
5. 
AMENDMENTS AND UPDATES 
Final: 31 May 2012 
Amendment 1 Final: 22 October 2013 
Amendment 2 Final: 03 June 2014 
Amendment 3 Final: 19 March 2015 
Amendment 4 Final: 11 December 2015 
Amendment 5 Final: 11 October 2017 
Amendment 6 Final: 06 July 2018 
The rationale for the protocol amendments 1, 2, 3, 4, 5 6 and 7, and the summary of 
changes are provided in Annex 7 
(Amended 5 May 2020) 
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6. 
MILESTONES  
Milestone 
Planned date 
Start of data collection 
Q4 2015*  
End of data collection 
Q1 2022 
Study progress report  
1 progress report every 6 months  
Interim report 
Q3 2019 
Final report of study results 
Q4 2022 
*Actual date 
7. 
BACKGROUND AND RATIONALE 
7.1. 
Background 
The devastating morbidity and mortality, particularly in children under five years of age, 
that results from malaria in sub-Saharan Africa (SSA) is well documented [WHO World 
Malaria Report, 2012]. In 2010 there were approximately 174 million cases of malaria in 
the African region, 98% due to Plasmodium (P.) falciparum, causing approximately 
596,000 deaths, 91% of which were in children under five years of age [WHO World 
Malaria Report, 2012]. During the past decade, renewed international commitment and 
increased funding to scale-up proven malaria control interventions have resulted in 
morbidity and mortality reductions in several African countries [Steketee, 2010]. The 
development of efficacious malaria vaccines has been identified by national and 
international health authorities as a key component of a sustainable malaria control 
programme which will consequently have significant benefits in terms of health and the 
economy [Malaria Vaccine Technology Roadmap, 2013]. 
GSK Biologicals has developed a pre-erythrocytic P. falciparum malaria vaccine, 
RTS,S/AS01E, for routine immunisation of infants and children living in malaria-endemic 
countries of SSA. RTS,S/AS01E will be the first vaccine to be implemented for the 
prevention of malaria and it will be the first AS01-adjuvanted vaccine used in the 
paediatric population. 
The vaccine antigen, RTS,S, consists of sequences of the P. falciparum circumsporozoite 
(CS) protein and hepatitis B surface antigen (HBsAg) adjuvanted with AS01E that 
consists of two immune enhancers MPL (3’-O-desacyl-4’-monophosphoryl-lipid A) and 
QS-21 (Quillaja saponaria Molina, fraction 21), in a liposomes suspension. 
The pre-authorisation clinical development has been conducted mainly in SSA countries. 
The main clinical study supporting efficacy and safety is the large Phase III study, 
MALARIA-055, conducted at 11 study sites in seven countries across SSA, which 
enrolled 15,459 children. This clinical trial was conducted in two age categories. Infants 
aged 6-12 weeks at first dose received RTS,S/AS01E, in co-administration with other 
childhood vaccinations (diphtheria-tetanus-whole-cell pertussis-hepatitis B/Haemophilus 
influenza type b pentavalent vaccine [DTPwHepB/Hib] and oral poliovirus vaccine 
[OPV]), within the context of the Expanded Program on Immunization (EPI). The 
comparator group received meningococcal C conjugate vaccine in co-administration with 
the same EPI vaccines. At Month 20, infants vaccinated with RTS,S/AS01E in co-
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administration with other childhood vaccinations received either a fourth dose of 
RTS,S/AS01E with OPV, or meningococcal C conjugate vaccine with OPV. Infants in the 
comparator group received meningococcal C conjugate vaccine with OPV. Children aged 
5-17 months at first dose received RTS,S/AS01E without co-administration of other 
vaccines. The comparator group received human diploid-cell rabies vaccine. At 
Month 20, children vaccinated with RTS,S/AS01E received either a fourth dose of 
RTS,S/AS01E or meningococcal C conjugate vaccine. Children in the comparator group 
received meningococcal C conjugate vaccine at the time of the fourth dose. Children aged 
5 to 17 months at first dose were followed for approximately 48 months after Dose 1 and 
infants aged 6 to 12 weeks at first dose for approximately 38 months after Dose 1. 
In July 2015, the European Medicines Agency (EMA) issued a positive opinion for the 
RTS,S/AS01E vaccine [European Medicines Agency, 2015(a); European Medicines 
Agency, 2015(b)], and in October 2015 recommendations about RTS,S/AS01E were 
issued by the World Health Organization (WHO)’s Strategic Advisory Group of Experts 
(SAGE) on Immunization and the Malaria Policy Advisory Committee (MPAC) [WHO, 
2015(a)] (see Section 9.1.1). 
The EMA issued a positive opinion for the RTS,S/AS01E vaccine with the following 
indication: “Mosquirix is indicated for active immunisation of children aged 6 weeks up 
to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. 
The use of Mosquirix should be based on official recommendations considering 
Plasmodium falciparum malaria epidemiology in different geographical areas” [European 
Medicines Agency, 2015(a); European Medicines Agency, 2015(b)]. These policy 
recommendations will be defined by the WHO and public health authorities in the 
malaria endemic SSA countries where the vaccine would be used.  
The WHO’s SAGE and MPAC recommended pilot implementations of RTS,S/AS01E in 
children of 5–17 months of age, in parts of 3-5 sub-Saharan African countries, 
administering 3 doses of the vaccine to children aged 5-9 months of age in areas of 
moderate-to-high transmission of malaria with a fourth dose 15-18 months later. They did 
not recommend the use of the malaria vaccine in the 6–12 weeks age group [WHO, 
2015(a)]. In April 2017, the WHO Regional Office for Africa announced that the 
RTS,S/AS01E vaccine will be first introduced in 3 countries (Ghana, Kenya and Malawi) 
through a WHO-coordinated pilot implementation programme [WHO, 2017], referred to 
as the Malaria Vaccine Implementation Programme (MVIP) in the remaining sections of 
this document (see section 9.2). 
The study protocol has been adapted to take into account implementation of a 4th dose of 
RTS,S/AS01E 18 months after the 3rd dose. Although SAGE/MPAC recommended the 
use of the RTS,S/AS01E vaccine in the 5-17 months age group only, the study will enrol 
children in the two age groups in which the Phase III study MALARIA-055 was 
conducted (6-12 weeks at first dose and 5-17 months at first dose). This will allow 
collection of background data in both age groups. In the post-implementation safety study 
EPI-MAL-003, only the 5-17 months age group will be kept. 
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7.2. 
Safety results of the clinical development of RTS,S/AS01E 
In the large, pivotal Phase III study (MALARIA-055), adverse events (AEs) including 
serious adverse events (SAEs) were collected throughout the trial in all subjects. Seizures 
occurring within 7 days after vaccination were collected proactively and were analysed 
according to Brighton Collaboration Guidelines. Potential immune-mediated disorders 
(pIMDs) were collected as SAEs throughout the trial. Information was collected on all 
unsolicited reports of AEs that occurred within 30 days after vaccination and on 
reactogenicity within 7 days after vaccination among the first 200 children in both age 
categories at each study site. This study was overseen by an Independent Data 
Monitoring Committee. Safety results are shown below for the intention-to-treat 
population. 
In the 5-17 month old group at Month 20 post Dose 1, at least one SAE was reported in 
1,108 children out of 5,949 vaccinated with RTS,S/AS01E (18.6%; 95% confidence 
interval [CI]: 17.6, 19.6) and in 676 children out of 2,974 who received the rabies vaccine 
(control group) (22.7%; 95% CI: 21.1, 24.3) [The RTS,S Clinical Trials Partnership, 
2014]. At least one SAE related to vaccination (judged by the study investigator) was 
reported in 10 children (0.2%) vaccinated with RTS,S/AS01E and in one child (0.0%) 
receiving the rabies vaccine. 
Over the same surveillance period in the 6-12 week old group, at least one SAE was 
reported in 959 infants among 4,358 who were vaccinated with RTS,S/AS01E (22.0%; 
95% CI: 20.8, 23.3) and in 503 infants among 2,179 who received the meningococcal C 
conjugate vaccine (control group) (23.1%; 95% CI: 21.3, 24.9) [The RTS,S Clinical 
Trials Partnership, 2014]. SAEs were judged to be related to vaccination by the study 
investigator for 4 children (0.1%) vaccinated with RTS,S/AS01E and 3 infants (0.1%) 
receiving the meningococcal C conjugate (control group). 
Pneumonia, gastroenteritis, malaria, anaemia and febrile convulsions were the most 
frequently reported SAEs in both study groups. 
Up to study end, in the 5-17 month old group, at least one SAE was reported in 
720 children out of 2,976 vaccinated with RTS,S/AS01E and receiving a 4th dose of 
RTS,S/AS01E (24.2%; 95% CI: 22.7, 25.8), in 752 children out of 2,972 vaccinated with 
RTS,S/AS01E and receiving meningococcal C conjugate vaccine at the time of the 
4th dose (25.3%; 95% CI: 23.7, 26.9) and in 846 children among 2,974 who received the 
rabies vaccine followed by meningococcal C conjugate vaccine at the time of the 4th dose 
(control group) (28.4%; 95% CI: 26.8, 30.1). At least one SAE related to vaccination was 
reported in 8 children vaccinated with RTS,S/AS01E and receiving a 4th dose of 
RTS,S/AS01E, in 4 children vaccinated with RTS,S/AS01E and receiving meningococcal 
conjugate vaccine at the time of the 4th dose, and in one child receiving the rabies vaccine 
followed by meningococcal C conjugate vaccine at the time of the 4th dose [The RTS,S 
Clinical Trials Partnership, 2015]. 
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In the 6-12 week old group, over the same surveillance period, at least one SAE was 
reported in 580 infants among 2,180 who were vaccinated with RTS,S/AS01E and 
receiving a 4th dose of RTS,S/AS01E (26.6%; 95% CI: 24.8, 28.5), in 602 children among 
2,178 who were vaccinated with RTS,S/AS01E and receiving meningococcal C conjugate 
vaccine at the time of the 4th dose (27.6%; 95% CI: 25.8, 29.6), and in 619 infants among 
2,179 who received meningococcal C conjugate vaccine for primary vaccination and at 
the time of the 4th dose (control group) (28.4%; 95% CI: 26.5, 30.4). At least one SAE 
related to vaccination was reported in 6 infants vaccinated with RTS,S/AS01E and 
receiving a 4th dose of RTS,S/AS01E, in one infant vaccinated with RTS,S/AS01E and 
receiving meningococcal C conjugate vaccine at the time of the 4th dose, and in 3 infants 
receiving the meningococcal C conjugate vaccine for primary vaccination and at the time 
of the 4th dose [The RTS,S Clinical Trials Partnership, 2015]. 
Potential immune-mediated disorders (pIMDs): 
In the 5-17 month old group and up to Month 20 post Dose 1, 3 cases of pIMDs were 
reported among children vaccinated with RTS,S/AS01E (2 cases of encephalitis, one case 
of erythema multiforme) and 2 cases among children receiving the rabies vaccine 
(2 cases of encephalitis). In the 6-12 week old group, 3 cases were reported among 
infants vaccinated with RTS,S/AS01E (encephalitis, glomerulonephritis acute, 
Langerhans’ cell histiocytosis) and 2 cases among children receiving the 
meningococcal C conjugate vaccine (encephalitis, glomerulonephritis). 
Post 4th dose of RTS,S/AS01E / meningococcal C conjugate vaccine, no case of 
pIMD was reported in the 6-12 week old group, and 6 cases were reported in the 
5-17 month old group: 3 cases among children vaccinated with RTS,S/AS01E and 
receiving a 4th dose of RTS,S/AS01E (2 cases of encephalitis and one case of 
encephalomyelitis), 1 case among children vaccinated with RTS,S/AS01E and receiving 
meningococcal C conjugate vaccine at the time of the 4th dose (encephalitis), and 2 cases 
among children receiving the rabies vaccine followed by meningococcal C conjugate 
vaccine at the time of the 4th dose (vitiligo, Stevens-Johnson syndrome). 
Meningitis:  
• 
An imbalance was observed for meningitis in the 5-17 month category (Table 1). 
During the 20 months period post Dose 1, in children aged 5-17 months, 
16 meningitis cases (9 no aetiology, 4 meningitis meningococcal, 1 meningitis viral, 
1 meningitis pneumococcal, 1 Haemophilus influenza meningitis) occurred in the 
RTS,S/AS01E group and 1 (no aetiology) in the control vaccine group (Relative Risk 
[RR] = 8.0 [95% CI: 1.1, 60.3]). Among infants aged 6-12 weeks, 9 meningitis cases 
(3 no aetiology, 3 meningitis pneumococcal, 3 meningitis due to salmonella) 
occurred in the RTS,S/AS01E group and 3 (2 no aetiology, 1 meningitis 
pneumococcal) in the control group (RR = 1.5 [95% CI: 0.4, 5.5]) [The RTS,S 
Clinical Trials Partnership, 2014]. Most of the meningitis cases were observed 
during the 12 months period post-Dose 3 (23 out of 29 cases, 79.3%), no clear risk 
window was identified in study MALARIA-055. The meningitis cases were mainly 
observed in 2 trial sites, Lilongwe in Malawi and Kombewa in Kenya. 
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Table 1 
Meningitis cases observed in MALARIA-055 over 20 months post 
first dose (MedDRA preferred terms including meningitis and 
meningitis with any aetiologies)  
Analysis 
available 
Follow up 
(post dose 3) 
Age 
category 
Number of cases in 
RTS,S/AS01E 
(Number of 
RTS,S/AS01E study 
participants) 
Number of cases 
in control 
(Number of 
control study 
participants) 
RR 
95% CI 
June 2014 
18 months 
6-12w 
9 (4358) 
3 (2179) 
1.5 
0.4-5.5 
5-17m 
16 (5949) 
1 (2974) 
8.0 
1.1-60.3 
Between administration of the 4th dose of RTS,S/AS01E / meningococcal C conjugate 
vaccine and study end, in children aged 5-17 months, 2 meningitis cases occurred among 
children vaccinated with RTS,S/AS01E and receiving a 4th dose of RTS,S/AS01E, and 3 
cases among children vaccinated with RTS,S/AS01E and receiving meningococcal C 
conjugate vaccine at the time of the 4th dose. No case occurred in the control vaccine 
group (rabies vaccine for primary vaccination and meningococcal C conjugate vaccine at 
the time of the 4th dose). In infants aged 6-12 weeks, 2 meningitis cases occurred among 
infants vaccinated with RTS,S/AS01E and receiving meningococcal C conjugate vaccine 
at the time of the 4th dose, and 3 cases among infants receiving meningococcal C 
conjugate vaccine for primary vaccination and at the time of the 4th dose [The RTS,S 
Clinical Trials Partnership, 2015]. Therefore, meningitis was considered as a potential 
risk. 
Febrile convulsions: 
• 
Among children aged 5-17 months, the occurrence of generalised convulsive 
seizures with fever within 7 days following primary vaccination in RTS,S/AS01E 
recipients was 1.04 case/1000 doses compared to recipients of control vaccine 
(0.57 case/1000 doses). Among infants aged 6-12 weeks, the incidence of febrile 
convulsions was 0.16 case/1000 doses of RTS,S/AS01E vaccine versus 
0.47 case/1000 doses of control vaccine. Although the increase in febrile convulsions 
was observed within 7 days of vaccination in children, the overall rate of febrile 
convulsions reported as a SAE was not increased in the RTS,S/AS01E group 
compared to the control group over 30 days post vaccination (0.8%% in 
RTS,S/AS01E versus 0.8% in control) and over 18 months of follow-up (3.8% in 
RTS,S/AS01E versus 3.8% in controls) [The RTS,S Clinical Trials Partnership, 
2011]. The incidence of febrile convulsions after administration of the 4th dose of 
RTS,S/AS01E / meningococcal C conjugate vaccine was 2.5 cases/1000 doses in 
children aged 5-17 months, vaccinated with RTS,S/AS01E and receiving a 4th dose of 
RTS,S/AS01E, 1.2 case/1000 doses in children vaccinated with RTS,S/AS01E and 
receiving meningococcal C conjugate vaccine at the time of the 4th dose, and 
0.4 case/1000 doses in the control vaccine group (rabies vaccine for primary and 
meningococcal C conjugate vaccine at the time of the 4th dose). Among infants aged 
6-12 weeks, the incidence of febrile convulsions was 2.2 cases/1000 doses in infants 
vaccinated with RTS,S/AS01E and receiving a 4th dose of RTS,S/AS01E, no 
case/1000 doses in infants vaccinated with RTS,S/AS01E and receiving 
meningococcal C conjugate vaccine at the time of the 4th dose and 
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0.5 case/1000 doses in the control vaccine group [The RTS,S Clinical Trials 
Partnership, 2015]. Therefore, febrile convulsions were considered as an identified 
risk. 
Severe malaria including cerebral malaria: 
In the MALARIA-055 study, there was a higher susceptibility to severe malaria in 
5-17 months recipients of a primary course of RTS,S/AS01E without a 4th dose (R3C) 
relative to the control group (C3C) after Month 20. This finding was considered to be 
related to a potential rebound effect and has been included in the Risk Management Plan 
(RMP) as a potential risk. In order to further investigate this finding, an additional 
analysis was conducted in MALARIA-055 to examine clinical syndromes and outcomes 
of cases of severe malaria.  
The cases of severe malaria disease according to the secondary case definition 1 
(P. falciparum > 5000 parasites per μL AND with one or more marker(s) of disease 
severity including co-morbidities: pneumonia, meningitis, sepsis, gastroenteritis) were 
classified by syndrome using the markers of severe malaria disease. GSK Biologicals has 
considered the definition for cerebral malaria cases as: parasitaemia > 5000 per μL, 
Blantyre Coma Score ≤ 2 and haemoglobin level of ≥ 5 g/dL. It should be noted that 
whereas this is a commonly used definition, low coma score can be the outcome of many 
diseases processes and is not pathognomic of sequestration of parasitized red cells in the 
cerebral microvasculature. 
In a post-hoc analysis of the Phase III study MALARIA-055, the distribution of the 
markers of severity used in the case definition of severe malaria were analysed by study 
group. Of the 1038 severe malaria cases according to the secondary case definition 1, 73 
cases met the definition of cerebral malaria (parasitaemia > 5000 per μL, Blantyre Coma 
Score ≤ 2 and haemoglobin level of ≥ 5 g/dL) in both age categories over the entire study 
period. An imbalance was observed for cerebral malaria in the 5-17 month category 
(Table 2). 
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Table 2 
Cases of severe malaria disease (secondary case definition 1) classified 
by syndrome, group and time period including fatal cases by syndrome 
(ITT population; 5-17 month age category; from MALARIA-055 study)  
Time 
Period 
Syndrome 
RTS,S group (R3C + R3R) N=5948 
Control group (C3C) N=2974 
N 
Died 
N 
Died 
M0-M20 
All Cases 
205 
6 
158 
2 
Cerebral 
16 
3 
5 
1 
Cerebral + 
Anaemia 
6 
1 
1 
0 
Anaemia 
25 
0 
29 
1 
Other 
157 
2 
123 
0 
Missing 
1 
0 
0 
0 
Time 
period 
Syndrome 
3-dose schedule (R3C) 
N=2719 
4-dose schedule (R3R) 
N=2681 
Control (C3C) 
N=2702 
N 
Died 
N 
Died 
N 
Died 
M21-SE 
All Cases  
103 
6 
76 
3 
76 
2 
Cerebral 
9 
4 
11 
2 
2 
0 
Cerebral + 
Anaemia 
0 
0 
1 
0 
2 
1 
Anaemia 
18 
1 
11 
0 
17 
0 
Other 
75 
1 
53 
1 
54 
1 
Missing 
1 
0 
0 
0 
1 
0 
R3C group: children and infants to receive 3 doses of RTS,S/AS01E on a 0-1-2-month schedule + a dose of a 
meningococcal C conjugate vaccine at study month 20 
R3R group: children and infants to receive 3 doses of RTS,S/AS01E on a 0-1-2-month schedule + a 4th dose of 
RTS,S/AS01E at study month 20 
C3C group: children and infants to receive 3 doses of a control vaccine on a 0-1-2-month schedule + a dose of a 
control vaccine at study month 20 
SE = Study end (Month 48) 
All cases: Secondary case definition 1 (> 5000 parasites/µL and at least 1 marker of severe disease, including 
comorbidities) 
Cerebral: > 5000 parasites/µL and BCS ≤ 2 and a haemoglobin level of ≥ 5 g/dL 
Anaemia: > 5000 parasites/µL and BCS > 2 and a haemoglobin level of < 5 g/dL 
Cerebral+Anaemia: > 5000 parasites/µL and BCS ≤ 2 and a haemoglobin level of < 5 g/dL 
Other severe disease: > 5000 parasites/µL, a BCS >2, a haemoglobin level of ≥ 5 g/dL and another marker of severe 
disease (prostration, respiratory distress, seizures, hypoglycemia [< 2.2 mmol/L], acidosis [BE ≤ -10.0 mmol/L], lactate 
≥ 5.0 mmol/L) 
Missing: Haemoglobin or BCS unavailable so syndrome classification could not be determined 
• 
During the 20 months period post Dose 1, in children aged 5-17 months, 16 cerebral 
malaria cases (parasitaemia > 5000 per μL, Blantyre Coma Score ≤ 2 and 
haemoglobin level of ≥ 5 g/dL) occurred in the RTS,S/AS01E group, among 5948 
children, and 5 cerebral malaria cases occurred in the control vaccine group, among 
2974 children. In addition, cerebral malaria and anaemia (parasitaemia > 5000 per 
μL, Blantyre Coma Score ≤ 2 and haemoglobin level of < 5 g/dL) were observed for 
6 subjects in the RTS,S/AS01E group and 1 subject in the control vaccine group. 
• 
Between administration of the 4th dose of RTS,S/AS01E / meningococcal C 
conjugate vaccine and study end, in children aged 5-17 months, 9 cerebral malaria 
cases occurred among 2719 children vaccinated with RTS,S/AS01E and receiving 
meningococcal C conjugate vaccine at the time of the 4th dose. No cerebral malaria 
with anaemia was observed in this group. 11 cerebral malaria cases occurred among 
2681 vaccinated with RTS,S/AS01E and receiving a 4th dose of RTS,S/AS01E (plus 
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one case of cerebral malaria with anaemia), and 2 cerebral malaria cases occurred 
among 2702 children receiving rabies vaccine for primary and meningococcal C 
conjugate vaccine at the time of the 4th dose (plus 2 cases of cerebral malaria with 
anaemia). 
Taking into consideration the fact that the numbers were small, that no clinical diagnosis 
was performed by the investigators (no clinical case definition used), that there is no 
known biological plausibility of a pre-erythrocytic vaccine to directly cause cerebral 
malaria, the most likely explanation of the imbalance is a possible rebound effect and/or 
shift of age linked to the efficacy of the intervention. Therefore GSK Biologicals 
considers cerebral malaria as a safety concern that requires further evaluation, and has 
therefore categorized it as an important potential risk in the RMP. 
Overall mortality by gender: 
Ad-hoc analysis of mortality by gender based on the completed Phase III study 
MALARIA-055 data was performed at the request of WHO, in the context of their policy 
making pertaining to the potential use of Mosquirix in SSA [WHO, 2016(a); WHO, 
2016(b)]. 
In this analysis all-cause mortality in the girls who received RTS,S/AS01E was ≈2-fold 
higher than in the girls who received the control vaccine (123/5091 [2.4%] versus 
33/2603 [1.3%]; for both age categories pooled); while in boys, all-cause mortality was 
slightly lower in the group that received RTS,S/AS01E compared to the boys in the 
control group (95/5215 [1.8%] versus 55/2550 [2.2%]). 
It is GSK’s position that this should not be considered a safety signal because: 
• 
Low fatality rate overall in study MALARIA-055 compared to what could be 
expected: 1 to 2% in each group, while in real-life setting under 5 mortality in SSA is 
estimated to be 3% (WHO) to 5% (World bank); 
• 
An investigator-initiated case control study in one site showed a 70% reduction in 
all-cause mortality in children enrolled in the study, as compared to children living in 
the same area but not enrolled in MALARIA-055; 
• 
Background mortality rates per gender vary significantly across SSA countries. 
Under circumstances where boys and girls have the same access to resources such as 
food and medical care, boys have higher mortality rates than girls during childhood. 
Western Africa had the most countries (five) with evidence of excess female child 
mortality in the 2000s as well as several countries of Eastern Africa and Middle 
Africa [United Nations, 2011]. 
• 
The overall trend for differences in mortality rates in girls between the RTS,S/AS01E 
and control groups is also observed in the subgroup analyses of the potential 
confounding factors including administration of recommended EPI vaccines 
(measles, yellow fever, etc), human immunodeficiency virus (HIV) status and 
different access to medical care and/or proper nutrition. These differences are in-line 
with the observed imbalance in overall mortality and it is difficult to understand 
whether they actually contributed to the overall mortality differences between girls in 
the RTS,S/AS01E treatment groups and girls in the control group. Therefore, these 
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additional analyses only seem to support the hypothesis that the observed imbalance 
in mortality in girls (i.e. active versus control) is likely to be a chance finding (given 
the small numbers involved and the fact that clinical trials are not designed to 
evaluate impact on mortality, especially for a disease like malaria that is perfectly 
treatable). 
However, GSK Biologicals considers that gender-specific mortality requires further 
evaluation, and has therefore categorized it as missing information in the RMP. 
In summary, meningitis is considered/reported as a potential risk in the RMP of 
RTS,S/AS01E. The occurrence of febrile convulsions is considered/reported as an 
identified risk associated during the 7 days following vaccination with RTS,S/AS01E. 
The imbalance observed for cerebral malaria following a post-hoc analysis of the 
MALARIA-055 study is considered as a safety concern that requires further evaluation 
and is therefore categorized as an important potential risk in the RMP. At present, GSK 
Biologicals does not consider excess/increased mortality in females as a potential risk. 
Additional data need to be generated; for now it has been categorized in the RMP as 
missing information.  
7.3. 
Efficacy results of the clinical development of RTS,S/AS01E 
Efficacy results of the Phase III study, MALARIA-055, are shown below for the 
intention-to-treat population. Efficacy against all episodes of clinical malaria in children 
aged 5 to 17 months over 12 months after Dose 3 was estimated to be 55.1% (95% CI: 
50.5, 59.3) [The RTS,S Clinical Trials Partnership, 2011]. Over 18 months after Dose 3 it 
was estimated to be 45.1% (95% CI: 41.4, 48.7) [The RTS,S Clinical Trials Partnership, 
2014]. In infants aged 6-12 weeks, efficacy against all episodes of clinical malaria over 
12 months was 32.9% (95% CI: 26.3, 38.8) [The RTS,S Clinical Trials Partnership, 
2012] and over 18 months was 27.0% (95% CI: 21.1, 32.5) [The RTS,S Clinical Trials 
Partnership, 2014].  
In both age groups, vaccine efficacy for clinical malaria waned over time (Schoenfeld 
residuals p<0. 001). In children 5-17 months, the reduction in malaria by 6 month time 
intervals following Dose 3 was reported as: 68% (95% CI: 64, 72) over the first 6 months 
of follow-up; 41% (95% CI: 36, 46) over the subsequent 6 months of follow-up; and 26% 
(95% CI: 19, 33) over the last 6 months of follow-up [The RTS,S Clinical Trials 
Partnership, 2014]. In infants 6-12 weeks, the corresponding reduction was reported to be 
47% (95% CI: 39, 54), 23% (95% CI: 15, 31), and 12% (95% CI: 1, 21), respectively 
[The RTS,S Clinical Trials Partnership, 2014].  
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Long-term follow-up efficacy data and data following administration of a 4th dose of 
RTS,S/AS01E 18 months post Dose 3 show a decline in efficacy against clinical and 
severe malaria with time in both children and infants who did not receive a 4th dose of the 
RTS,S/AS01E vaccine. Administration of a 4th dose of RTS,S/AS01E enhanced protection 
against clinical malaria in infants and children as well as the efficacy against severe 
malaria in children. In children aged 5 to 17 months who did not receive a 4th dose of 
RTS,S/AS01E, efficacy against all episodes of clinical malaria over 30 months post Dose 
3 was estimated to be 35.2% (95% CI: 30.5, 39.5). In children who were administered a 
4th dose of RTS,S/AS01E, efficacy against all episodes of clinical malaria over 30 months 
was 43.9% (95% CI: 39.7, 47.8). For severe malaria, efficacy over 30 months in children 
aged 5 to 17 months was 4.5% (95% CI: -20.6, 24.5) when no 4th dose of RTS,S/AS01E 
was administered and 34.9% (95% CI: 15.6, 50.0) when a 4th dose of RTS,S/AS01E was 
administered. In infants aged 6-12 weeks, efficacy against all episodes of clinical malaria 
over 30 months was 20.3% (95% CI: 13.6, 26.5) without administration of a 4th dose of 
RTS,S/AS01E and 27.8% (95% CI: 21.7, 33.4) with administration of a 4th dose of 
RTS,S/AS01E. Efficacy against severe malaria over 30 months was 7.9% (95% CI: -23.3, 
31.2) without administration of a 4th dose of RTS,S/AS01E and 11.9% (95% CI: -18.3, 
34.5) with administration of a 4th dose of RTS,S/AS01E [The RTS,S Clinical Trials 
Partnership, 2015]. These data support the benefit of a 4th dose of RTS,S/AS01E 
administered 18 months post Dose 3. 
A potential rebound effect was observed in children aged 5-17 months. Throughout the 
period 18 months post Dose 3 to study end, an increased incidence of severe malaria was 
observed in children who did not receive a 4th dose of RTS,S/AS01E, compared to 
controls: efficacy was -41.0% (95% CI: -98.5, -0.8). Among children who were 
administered a 4th dose of RTS,S/AS01E efficacy against severe malaria throughout the 
same period was -4.0% (95% CI: -50.0, 27.8). In infants aged 6-12 weeks, efficacy 
against severe malaria during the period 18 months post Dose 3 to study end was 11.2% 
(95% CI: -31.3, 40.2) when no 4th dose of RTS,S/AS01E was administered and 32.4% 
(95% CI: -3.2, 56.2) when a 4th dose of RTS,S/AS01E was administered. In contrast, 
clinical malaria disease showed no period of increased incidence compared to controls. 
The impact of RTS,S/AS01E against clinical malaria and severe malaria varied 
substantially by study site and the rebound effect was mainly observed in medium and 
high transmission settings [The RTS,S Clinical Trials Partnership, 2015]. 
7.4. 
Rationale for the study 
The RTS,S/AS01E vaccine will be implemented only in malaria endemic countries of 
SSA. Most of these countries have no baseline incidence data on rare diseases such as 
those that may be reported as AE following vaccination. Lack of baseline data would 
compromise the interpretation of any AE detected following the implementation of the 
RTS,S/AS01E vaccine in the paediatric population.  
GSK Biologicals has developed a set of studies to address this paucity of data, and to 
ensure optimal collection of information related to the occurrence of those events before 
and after implementation of the RTS,S/AS01E vaccine. EPI-MAL-002, a 
pre-implementation study (i.e. before vaccine implementation), is intended primarily as a 
surveillance study to collect background incidence rates of protocol-defined events of 
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special interest, other events leading to hospitalisation or death, and meningitis cases in 
preparation for EPI-MAL-003. In the post-implementation study EPI-MAL-003, the 
events of special interest have been defined as adverse events of special interest (AESI), 
and events leading to hospitalisation or death have been defined as AE leading to 
hospitalisation or death. The events measured in EPI-MAL-002 and EPI-MAL-003 are 
based on results from MALARIA-055 or are events that have historically been associated 
with vaccines other than RTS,S/AS01E, or may hypothetically be associated with 
RTS,S/AS01E due to the fact that this vaccine has components which are new compared 
to current widely used vaccines. They will be monitored the same way in EPI-MAL-002 
and EPI-MAL-003. In order to harmonize the terminology between the two studies, the 
terms AESI and AE will be used even for EPI-MAL-002.  
Additionally, vaccine impact measures (indirect, total and overall effects) are included in 
EPI-MAL-002 and EPI-MAL-003 to take advantage of the capacity developed for the 
safety component in the study sites and of the data collected on any malaria and severe 
malaria, including cerebral malaria, during EPI-MAL-002. Therefore malaria morbidity 
and mortality will also be monitored. The mortality rate, overall and by gender, will also 
be estimated. 
The EPI-MAL-002 study started in Q4 2015 and will last for approximately 5 years 
(depending on recruitment timelines). EPI-MAL-003 started in Q1 2019 when the 
vaccine became available in the study sites that are exposed clusters after its 
implementation according to WHO guidelines in the framework of the MVIP (first 
vaccine introduction was foreseen in 2018, see section 9.2). 
(Amended 5 May 2020) 
In parallel with both EPI-MAL-002 and EPI-MAL-003, a third study (EPI-MAL-005) is 
conducted to measure malaria transmission intensity (MTI) and other malaria control 
interventions at community level in the study site areas. This study began in Q4 2014, at 
the first malaria transmission peak season in the West African sites with peak malaria 
transmission in the second half of the year, and will run through the completion of EPI-
MAL-003. It is taking place in similar if not identical settings as EPI-MAL-002 and EPI-
MAL-003.  
Finally, describing the overall morbidity and mortality in this population is thought to 
have broader utility beyond these malaria studies, and could serve as baseline data for 
other disease control and prevention studies.  
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8. 
RESEARCH QUESTION AND OBJECTIVES 
8.1. 
Co-primary objectives 
• 
To estimate the incidence of AESI2, and of other AE leading to hospitalisation or 
death, in children, prior to implementation of RTS,S/AS01E. 
• 
To estimate the incidence of aetiology-confirmed meningitis, in children, prior to 
implementation of RTS,S/AS01E. 
8.2. 
Secondary objectives 
In children living in the study area, prior to implementation of RTS,S/AS01E: 
• 
To estimate the incidence of aetiology-confirmed, and/or probable meningitis (final 
classification). 
• 
To estimate the incidence of probable meningitis (final classification). 
• 
To estimate the incidence of aetiology-confirmed, probable and/or clinically 
suspected meningitis (final classification). 
• 
To monitor trends over time of meningitis cases identified at site level (first line 
laboratory). 
• 
To describe risk factors for AESI, other AE leading to hospitalisation or death, 
meningitis and malaria. 
• 
To describe the causes of hospitalisation (including AESI, other AE, meningitis and 
malaria). 
• 
To describe the causes of death, overall and by gender. 
• 
To assess the risk of febrile convulsions during the 7-day period and 1-month period 
following administration of routine EPI vaccines. 
• 
To estimate the incidence of any malaria (including P. falciparum malaria) using 
rapid diagnostic test (RDT) and/or microscopy. 
• 
To estimate the incidence of severe malaria (including P. falciparum malaria) using 
RDT and/or microscopy. 
• 
To estimate the incidence of cerebral malaria (malaria diagnosed by RDT and/or 
microscopy). 
• 
To estimate the prevalence of anaemia among hospitalised children. 
                                                 
2 Acute disseminated encephalomyelitis, encephalitis, Guillain-Barre Syndrome, hypotonic hyporesponsive episode, 
generalised convulsive seizure. 
Intussusception, hepatic failure, renal insufficiency. 
Juvenile chronic arthritis, Stevens-Johnson syndrome/toxic epidermal necrolysis, Henoch-Schonlein purpura, Kawasaki 
disease. 
Diabetes mellitus type I, thrombocytopenia, anaphylaxis. 
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• 
To estimate the incidence of all-cause hospitalisations and hospitalisations attributed 
to malaria (including P. falciparum). 
• 
To estimate the mortality rate (all-cause mortality and deaths attributed to malaria 
[including P. falciparum]), overall and by gender. 
9. 
RESEARCH METHODS 
9.1. 
Study design 
The aim of this study is to estimate the incidence of protocol-defined AESI in a setting 
without existing surveillance systems designed to capture those rare events. The study 
also aims to estimate the incidence of other AE leading to hospitalisation or death, 
meningitis, severe malaria, including cerebral malaria, and malaria morbidity and 
mortality at the same time. The mortality rate, overall and by gender, will also be 
estimated. Therefore, the design of the study is defined as a disease surveillance study 
with prospective cohort event monitoring. The cohort is technically dynamic, as children 
will be entering and leaving the cohort throughout the study period. The design 
incorporates both active surveillance and enhanced hospitalisation surveillance. The 
study uses multiple data sources, to increase the opportunity to capture the events of 
interest.  
Active surveillance: 
Approximately 30,000 children will be recruited within the collaborating study sites, and 
enrolled into active surveillance, with about 20,000 children enrolled where the 
RTS,S/AS01E vaccine will be implemented. These children will be actively followed up 
through home visits and through continuous monitoring of outpatient visits and 
hospitalisations at all health care facilities. Among these children, approximately 15,000 
children will be enrolled in the 6-12 weeks group (with about 10,000 children in sites 
where the vaccine will be implemented) and approximately 15,000 children will be 
enrolled in the 5-17 months group (with about 10,000 children in sites where the vaccine 
will be implemented; see Section 9.2.1.1). For the purpose of this study, the 6-12 weeks 
group and the 5-17 months group are defined as follows: 
6-12 weeks group:  
• 
Children identified at first administration of DTP/HepB/Hib vaccine (usually given 
at 6, 10 and 14 weeks of age) and for whom the home visits will be conducted 
according to the EPI schedule. 
5-17 months group: 
• 
5-17 months group, enrolled at first DTP: Children identified at first administration 
of DTP/HepB/Hib vaccine (usually given at 6, 10 and 14 weeks of age), for whom 
the home visits will be scheduled from 6 months of age onwards (mimicking 
administration of RTS,S/AS01E in the 5-17 months group). In case a child is first 
seen during hospitalisation, before first administration of DTP/HepB/Hib vaccine, 
and meeting the inclusion criteria for active surveillance, the child can be enrolled in 
active surveillance (5-17 months group, enrolled at first DTP) during hospitalisation 
and home visits will be scheduled from 6 months of age onwards. 
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• 
5-17 months group, catch-up: Children aged 5 to <18 months, identified at first 
encounter with the study staff, for whom the home visits will be scheduled from the 
first encounter with the study staff onwards (mimicking administration of 
RTS,S/AS01E in the 5-17 months group). In case a child aged 5 to <18 months is 
first seen during hospitalisation and meeting the inclusion criteria for active 
surveillance, the child can be enrolled in active surveillance (5-17 months group, 
catch-up) during hospitalisation and home visits will be scheduled after being 
discharged from the hospital. 
Enrolled children will be followed up through home visits for a total period of 44 months 
(see Figure 1 and Section 9.2.7.1) except for subjects enrolled from Burkina Faso sites 
for whom their participation in the study has been early terminated. This follow-up period 
corresponds to the follow-up period of the children enrolled in EPI-MAL-003 (i.e. 24 
months after the 4th dose of RTS,S/AS01E). 
In addition to the home visits, in children enrolled in the active surveillance, all visits to 
health care facilities (primary health care and hospital level) for any diseases, signs and 
symptoms will be reported to the study staff up to the end of the active follow-up period 
for each individual child (see Section 9.4.2). Thereafter there will be continuous 
monitoring of hospitalisations only, up to study conclusion (i.e. study end or child 
reaches 5 years of age, whichever occurs first) (Figure 1). 
Note: There might be an overlap of studies EPI-MAL-002 and EPI-MAL-003. Therefore, 
children enrolled in active surveillance of EPI-MAL-002 and who meet the eligibility 
criteria for the EPI-MAL-003 study may have their study conclusion for the 
EPI-MAL-002 study before the end of the 44 months of active follow-up if enrolled in 
EPI-MAL-003 (see Section 9.2.7.1.12). 
Enhanced hospitalisation surveillance:  
All children under the age of 5 years of age, within the study areas, not already enrolled 
in the active surveillance (because parents/ LARs declined enrolment in active 
surveillance or because recruitment had been completed) or not eligible for active 
surveillance, are eligible for enrolment in enhanced hospitalisation surveillance during 
any hospitalisations throughout the whole study period, to allow data collection regarding 
those hospitalisations (see Figure 1 and Section 9.2.7.2). For the purpose of this study, 
hospitalisation is defined as spending at least one night at a health care facility. 
In this protocol, active surveillance will refer to children who are enrolled in active 
surveillance, and enhanced hospitalisation surveillance will refer to children who are 
enrolled in enhanced hospitalisation surveillance. Data collected regarding the 
hospitalisation will be uniformly collected whether the child is enrolled in active 
surveillance or in enhanced hospitalisation surveillance. 
Because of a possible overlap of studies EPI-MAL-002 and EPI-MAL-003, study 
conclusion of EPI-MAL-002 for children enrolled in enhanced hospitalisation 
surveillance will be done at start of study EPI-MAL-003 (as the RTS,S/AS01E vaccine 
becomes available in the sites that are exposed clusters).  
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Figure 1 
Study design overview 
 
 
* Hospitalisation is defined as spending at least one night at a health care facility 
V = visit; W = week(s); M = month(s); SC = study conclusion (i.e. study end or child reaches 5 years of age, whichever 
occurs first); Enrol = enrolment. 
For the children enrolled in active surveillance in the 6-12 weeks group, enrolment is at first administration of 
DTP/HepB/Hib vaccine. The home visits will take place approximately 1 week after administration of each dose of 
DTP/HepB/Hib vaccine (V1, V2, V3), and 6 weeks (V4) and 6 months (V5) after administration of the third dose. These 
visits will be followed by a visit (V6) approximately 18 months after administration of the third dose, and visits 
approximately 5 weeks (V7), 12 months (V8) and 24 months (V9) after V6. A last home visit (V10) will be conducted at 
study conclusion. 
The 5-17 months group of the active surveillance will include a group of selected children identified at first 
administration of DTP/HepB/Hib vaccine, or first seen during hospitalisation, before first administration of 
DTP/HepB/Hib vaccine, and meeting the inclusion criteria for active surveillance, and a group of children aged 5 to 
<18 months, corresponding to a catch-up. The first visit (V1) for selected children identified at first administration of 
DTP/HepB/Hib vaccine will be at 6 months of age, and for children aged 5 to <18 months, corresponding to a catch-up, 
at time of their first encounter with study staff or approximately 1 week later. The following visits will be scheduled in a 
similar way as for the 6-12 weeks group. 
Continuous monitoring of outpatient visits at health care facilities will be done up to the end of active follow-up (V9) for 
all children enrolled in the active surveillance. 
Continuous monitoring of hospitalisations will be done throughout the whole study period. 
Active Surveillance
1W
1W
Enrolled in:
V1
V2
M1
V3
M2
V4
M3.5
V5
M8
Enrol
V8
M32
V9
M44
V7
M21.5
V6
M20
V5
M8
6W
5W
M3.5
M0
18 M
12 M
12 M
6M
V2
V3
V4
V5
V5
V9
V10
SC
V1
M0
V2
M1
V3
M2
V4
M3.5
V5
M8
V8
M32
V9
M44
V7
M21.5
V6
M20
V5
M8
M0
V10
M0
6 months
of age
6M
1M
1M
5W
V4
V1
V8
V7
V6
5W
12 M
12 M
1W
V10
SC
18 M
6M
1M
1M
5W
18 M
5W
12 M
12 M
5-17 M group 
(catch-up)
Enh. hosp. 
Surv.
Continuous monitoring of hospitalisations*
Continuous monitoring of health care facility visits
Continuous monitoring of hospitalisations*
All enrolled
SC
5W
DTP/HepB/Hib vaccine
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9.1.1. 
Rationale for the study design 
The target population for this study is defined as infants and young children < 5 years of 
age. The active surveillance will include approximately 15,000 children in the 
6-12 weeks group (with about 10,000 children where the RTS,S/AS01E vaccine will be 
implemented; to collect background data in this age group) and approximately 15,000 
children in the 5-17 months group (with about 10,000 children where the RTS,S/AS01E 
vaccine will be implemented; to mimic administration of RTS,S/AS01E in the 
5-17 months age group). The active follow-up will be based on administration of a 
primary schedule of 3 doses of RTS,S/AS01E administered at 1-month intervals, with a 
4th dose 18 months after last primary dose, and 24 months of active follow-up after the 
last dose. Refer also to Section 9.9 for details about limitations. 
The safety, effectiveness and impact of RTS,S/AS01E vaccination is planned to be 
evaluated through EPI-MAL-003. To collect comparable baseline information, this study, 
EPI-MAL-002, must collect data as similarly as possible as described in the 
EPI-MAL-003 protocol. EPI-MAL-003 will recruit subjects from a population of 
children less than 5 years of age living within a study catchment area. EPI-MAL-002 
utilises a similar approach in similar if not identical settings for comparability of data.  
The main outcomes of the EPI-MAL-002 study are the incidence of AESI, other AE 
leading to hospitalisation or death, and meningitis. The AESI were selected because they 
have been historically associated with vaccines other than RTS,S/AS01E, or may be 
hypothetically associated with RTS,S/AS01E because this vaccine has components which 
are new compared to current widely used vaccines. Meningitis was identified in the Phase 
III efficacy trial, MALARIA-055, as a potential risk. Therefore, the estimation of the 
incidence of meningitis (classified as aetiology-confirmed, probable or clinically 
suspected meningitis - see case definitions in Section 9.2.5.3) has been added as specific 
safety objective in this protocol. The diseases under surveillance for safety will be 
monitored among children enrolled in active surveillance and in enhanced hospitalisation 
surveillance. 
All malaria events (morbidity, mortality and hospitalisation) will be monitored 
throughout the study. Background incidence rates of any malaria and severe malaria, 
including cerebral malaria, will be collected. This will enable the investigation of the 
impact (indirect, total and overall effect) of the RTS,S/AS01E vaccine by comparing all 
malaria events in EPI-MAL-002 to all malaria events in unvaccinated children in 
EPI-MAL-003 (indirect effect), in vaccinated children in EPI-MAL-003 (total effect), or 
in all children in EPI-MAL-003 (overall effect); for children enrolled in the active 
surveillance. The mortality rate, overall and by gender, will also be estimated. 
Since RTS,S/AS01E is only protecting against P. falciparum, all analyses done for any 
malaria cases and for severe malaria cases regardless of the plasmodium species will be 
repeated for episodes with evidence of the P. falciparum parasite only. Analyses will also 
be performed for cerebral malaria due to P. falciparum, which is a complication of severe 
P. falciparum malaria (see Section 9.2.5.5 for case definitions). 
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Active surveillance  
In order to detect the events of interest, active surveillance will be conducted among 
enrolled subjects through a series of home based visits and continuous monitoring of 
outpatient visits and hospitalisations at all health care facilities. For children in the 
6-12 weeks group (identified at the first administration of DTP/HepB/Hib vaccine) these 
home visits will take place approximately 1 week after administration of each dose of 
DTP/HepB/Hib vaccine (V1, V2, V3), and 6 weeks (V4), 6 months (V5) and 18 months 
(V6) after administration of the last dose of DTP/HepB/Hib vaccine, followed by visits 
approximately 5 weeks (V7), 12 months (V8) and 24 months (V9) after V6, to mimic the 
potential active follow-up in study EPI-MAL-003 (Figure 1).  
The 5-17 months group of the active surveillance will include a group of selected 
children identified at first administration of DTP/HepB/Hib vaccine, or first seen during 
hospitalisation, before first administration of DTP/HepB/Hib vaccine, and meeting the 
inclusion criteria for active surveillance, and a group of children aged 5 to <18 months, 
corresponding to a catch-up (see Section 9.2.1.1). The first visit (V1) for selected 
children identified at first administration of DTP/HepB/Hib vaccine will be at 6 months 
of age and for children aged 5 to <18 months, corresponding to a catch-up, at time of 
their first encounter with study staff or approximately 1 week later. The visits will be 
scheduled in a similar way as for the 6-12 weeks group (Figure 1). The intent for the 
5-17 months group is to mirror the home visits of infants of the 6-12 weeks group, to 
capture events in a uniform manner and, for the children in the 5-17 months group 
identified at first administration of DTP/HepB/Hib vaccine, to mimic the potential 
immunisation schedule in study EPI-MAL-003 in the 5-17 months age group. For all 
children enrolled in active surveillance, a last home visit will be conducted at study 
conclusion (V10). 
In addition to the home visits, any diseases, signs and symptoms in children enrolled in 
the active surveillance will also be reported to the study staff by all health care facilities 
(primary health care and hospital level) up to the end of the active follow-up period for 
each individual child, and will thereafter be continuously monitored up to study 
conclusion during hospitalisations only.  
An important additional function of the active surveillance component is to ensure 
referral of sick children to the health care facilities.  
Enhanced hospitalisation surveillance  
For the purpose of this study, and of EPI-MAL-003, enhanced hospitalisation 
surveillance corresponds to case detection during hospitalisation through monitoring of 
medical records and registries. Enhanced hospitalisation surveillance is included to 
supplement the active surveillance to capture events in children whose parents/ Legally 
Acceptable Representatives (LARs) declined enrolment in active surveillance, in children 
who were not enrolled in active surveillance as recruitment had been completed or in 
children not eligible for active surveillance. Throughout the whole study period, all 
children under the age of 5 years within the study areas who are hospitalised, not already 
enrolled in the active surveillance (because parents/ LARs declined enrolment in active 
surveillance or because recruitment had been completed) or not eligible for active 
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surveillance, are eligible for enrolment in enhanced hospitalisation surveillance, to allow 
for data collection regarding that hospital visit and any subsequent hospital visits until 
study conclusion (see also Section 9.2.1.1). Children already enrolled in active 
surveillance will have hospitalisations monitored as part of the procedures related to the 
active surveillance and will therefore not be enrolled in enhanced hospitalisation 
surveillance. 
To assess the operational conduct of both enhanced hospitalisation surveillance and 
active surveillance, two control outcomes have been included in the study protocol. 
Abscess at injection site (after routine vaccination) is included as a positive control and 
positional foot deformation is included as a negative control (see case definitions in 
Section 9.2.6). These conditions are relatively easy to diagnose and could be used to 
assess changes in the performance of health care systems to diagnose disease. 
Selected study sites are expected to have a health and demographic surveillance system 
(HDSS) or equivalent surveillance system in place. If a site does not have an equivalent 
surveillance system in place, the INDEPTH procedures for demographic census might be 
implemented to ensure consistency across study sites. In addition, being part of the 
International Network for the Demographic Evaluation of Populations and Their Health 
(INDEPTH) (or seeking membership to INDEPTH) is an asset to ensure standard health 
and demographic surveillance practices, thereby enabling standardised calculation of 
incidence rates. 
9.2. 
Setting 
The three studies EPI-MAL-002, EPI-MAL-003 and EPI-MAL-005 are planned to be 
anchored when possible on the INDEPTH HDSS platform (http://www.indepth-
network.org) or equivalent surveillance system to provide both population and health 
facility linkage [INDEPTH, 2015]. INDEPTH provides an international platform of 
sentinel HDSS centres in low and middle income countries designed to longitudinally 
follow populations and provide demographic and health information. For this study, the 
HDSS or equivalent surveillance system provides the population and its characteristics, 
from which a cohort may be identified. The cohort will be a subset of the total eligible 
population of children specified within the geographic catchment area of the study sites. 
The cohort is considered dynamic, as newborns and immigrants are included in the cohort 
and the birth or in-migration date is recorded. Similarly, deaths and out-migrations are 
recorded.  
The process begins with a census of the population and proceeds with regularly 
scheduled (at least once a year) monitoring of vital events (births, deaths), migration, 
selected health outcomes, and other demographic and lifestyle variables. The census 
serves as the source document for the initial screening for study population eligibility.  
Note: If a site is not part of the INDEPTH network, or does not have an equivalent 
surveillance system in place, the INDEPTH procedures for demographic census might be 
implemented to ensure consistency across study sites. 
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Initially, seven sites in five SSA countries were planned to participate in the EPI-MAL-
002 study. Following SAGE/MPAC recommendations of pilot implementations of 
RTS,S/AS01E in 3-5 distinct settings in SSA restricted to moderate-to-high transmission 
of malaria [WHO, 2015(a)], some of the initially chosen sites located in low endemicity 
settings had to be terminated. For this reason, other sites in SSA settings with moderate-
to-high transmission of malaria, pertaining to a region where the RTS,S/AS01E vaccine is 
planned to be implemented according to the MVIP, were added to the already defined 
study sites as described below.  
In April 2017, the WHO Regional Office for Africa announced that the RTS,S/AS01E 
vaccine will be first introduced in 3 countries (Ghana, Kenya and Malawi) through the 
MVIP. The 3 countries were selected to participate in the pilot programme based on the 
following criteria: high coverage of long-lasting insecticidal-treated nets, well-
functioning malaria and immunisation programmes, a high malaria burden even after 
scale-up of long-lasting insecticidal-treated nets, and participation in the Phase III 
RTS,S/AS01E malaria vaccine trial. Each of the 3 countries will decide on the districts 
and regions to be included in the MVIP. High malaria burden areas will be prioritized 
[WHO, 2017]. GSK baseline, Phase IV and ancillary studies (i.e. EPI-MAL-002, EPI-
MAL-003 and EPI-MAL-005, respectively) being fully embedded in the MVIP, selection 
of the clusters that are/will participate in those studies depends on the cluster 
identification process led by the Ministries of Health according to WHO guidance. They 
have been, or will be, selected as follows: 
• 
EPI-MAL-002 study sites: currently, a total of 5 sites (2 in Ghana [Kintampo, 
Navrongo], 1 in Kenya [Kombewa] and 2 in Burkina Faso [Sapone, Nouna]) have 
enrolled study participants in the EPI-MAL-002 study. 
– 
Since sites have been, or will be, selected from the 3 countries where the 
RTS,S/AS01E vaccine will be implemented, Burkina Faso sites that started EPI-
MAL-002 have early terminated the follow-up activities in active surveillance 
and enrolment in enhanced hospitalisation surveillance on 06 June 2018, with 
the exception of the follow-up check-ups at the hospital for children diagnosed 
with meningitis, cerebral malaria or with an AESI (see sections 9.2.7.4.1, 
9.2.7.4.2 and 9.2.7.4.5). All study activities are planned to be terminated by Q2 
2019. A description of data from these sites will be presented in the progress 
reports up to Q4 2019, but none of the data from these sites will be part of the 
statistical analyses for the interim and final reports (neither in the before/after 
comparison analyses of the EPI-MAL-002 and EPI-MAL-003 studies, nor in 
any other indicators planned to be generated by EPI-MAL-002 data to inform 
analyses of the EPI-MAL-003 study [e.g. background incidence of meningitis 
for study sample size and the exposure to other vaccines]). Burkina Faso sites 
will not be included in EPI-MAL-003 because the MVIP will not take place in 
the country. 
(Amended 5 May 2020) 
– 
Two sites in Malawi have fulfilled the criteria of the study feasibility assessment 
and were planned to initiate the EPI-MAL-002 study in Q1-Q2 2018. 
Considering the RTS,S/AS01E vaccine implementation date in Malawi, 
currently planned in October 2018, the baseline data that might be collected in 
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Malawi in the EPI-MAL-002 study would be too limited to be relevant for the 
before/after comparisons in this country. Therefore, GSK, in agreement with the 
WHO, decided to focus the conduct of the EPI-MAL-002 study in Ghana and 
Kenya, not initiating the study in Malawi, and partially compensating the 
expected sample size from Malawi sites by using the high recruitment observed 
from sites in Kenya (Kombewa) and Ghana (Kintampo) and extending 
recruitment in Ghana (Navrongo). 
• 
EPI-MAL-003 study sites: as currently planned in the MVIP and according to WHO 
guidance, 4 study sites (corresponding to 4 clusters of the MVIP) in each of the 3 
countries selected for the RTS,S/AS01E pilot implementation programme (12 study 
sites/clusters in total) are planned to be part of EPI-MAL-003: 2 of them should 
become exposed clusters and 2 of them should become unexposed clusters (see 
Annex 3 for definitions of exposed and unexposed clusters). In order to allow the 
before-after comparison of study endpoints and according to WHO guidance, study 
sites from Ghana and Kenya included in the EPI-MAL-002 should become study 
sites in EPI-MAL-003 which will be exposed clusters. 
• 
EPI-MAL-005 study sites: being an ancillary study to EPI-MAL-002 and EPI-MAL-
003 studies, EPI-MAL-005 is/will be conducted in study sites conducting EPI-MAL-
002 and/or EPI-MAL-003. 
• 
Of note, all study sites are submitted to a comprehensive scientific and operational 
study site assessment conducted by GSK, which will determine study feasibility in 
those sites. Exposed and unexposed clusters will be comparable in terms of malaria 
transmission, health facilities level, geographical region and population size. 
• 
A replacement strategy has also been elaborated in case one or more of the sites 
conducting EPI-MAL-002 cannot participate in EPI-MAL-003. It could consist in 
extending the recruitment period in the remaining sites (depending on vaccine 
implementation strategy). 
9.2.1. 
Study population 
The study population is defined as those children living in the study areas who are 
< 5 years old. 
Following SAGE/MPAC recommendations, sites with moderate-to-high transmission of 
malaria have started enrolment. In order to reach a birth cohort of about 17,250 children 
per year (with about 11,500 children per year where the RTS,S/AS01E vaccine will be 
implemented), other sites in SSA settings with moderate-to-high transmission of malaria, 
from the 3 countries where the RTS,S/AS01E vaccine will be implemented (see Section 
9.2), were added to the already defined study sites.  
The assumption of such a birth cohort was done to allow recruitment of about 
30,000 children in active surveillance in 16 months, with about 20,000 children enrolled 
where the RTS,S/AS01E vaccine will be implemented. 
Although participation rates are thought to be high in these study sites, taking into 
account the potential refusal of parents/LARs for their children to join the study, the 
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targeted number of 30,000 children to be enrolled into active surveillance is feasible. 
Among the 30,000 children recruited for active surveillance with about 20,000 children 
enrolled where the RTS,S/AS01E vaccine will be implemented, approximately 
15,000 will be part of the 6-12 weeks group (with about 10,000 children enrolled in sites 
where the vaccine will be implemented) and approximately 15,000 will be part of the 
5-17 months group (with about 10,000 children enrolled in sites where the vaccine will 
be implemented). 
In addition to the children enrolled for active surveillance, events of interest will also be 
collected through the enhanced hospitalisation surveillance. 
9.2.1.1. 
Participant recruitment 
Active surveillance 
All children will be identified through HDSS or equivalent surveillance system review. 
Parents/LARs of potentially eligible children will be invited to enrol their children into 
active surveillance and the informed consent form (ICF) for active surveillance will be 
signed or witnessed and thumb printed. 
Participant recruitment is expected to be done as follows, based on the birth cohort: 
• 
Parents/LARs of children presenting for the first administration of 
DTP/HepB/Hib vaccine (usually given at 6, 10 and 14 weeks of age) will be 
proposed to enrol their child in active surveillance. Among children whose 
parents/LARs accept to enrol their child into active surveillance, two out of three 
children will be included in the 6-12 weeks group and the remaining children (one 
out of three) will be included in the 5-17 months enrolled at first DTP group until the 
enrolment target of the 5-17 months (first DTP) group is reached. Thereafter, all 
children whose parents/LARs accept enrolment in active surveillance will be 
included in the 6-12 weeks group, until the expected number of children is reached. 
An expected number of 15,000* children will be enrolled in the 6-12 weeks group, 
and of 6,375* children in the 5-17 months enrolled at first DTP group. The first visit 
(V1) for the 6-12 weeks group will be approximately 1 week after the first 
administration of DTP/HepB/Hib vaccine. For the 5-17 months enrolled at first DTP 
group the first visit (V1) will be at the age of 6 months. 
• 
Parents/LARs of children aged 5 to <18 months will be contacted by the study staff 
and invited to enrol their child into active surveillance. Children whose 
parents/LARs accept to enrol their child into active surveillance will be included in 
the 5-17 months catch-up group. The first visit (V1) for the 5-17 months catch-up 
group will be at time of their first encounter with study staff or approximately 
1 week later, depending on site. Recruitment will be done until the expected number 
of children is reached (expected number of children in this group: 8,625*). 
* Based on a birth cohort of 17,250 children (see Section 9.2.1), which is a 
conservative estimate knowing that the birth cohort is increasing.  
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• 
In case a child is first seen during hospitalisation, before first administration of 
DTP/HepB/Hib vaccine (usually given at 6, 10 and 14 weeks of age), and meeting 
the inclusion criteria for active surveillance, within the recruitment period, the child 
can be enrolled in active surveillance in the 5-17 months enrolled at first DTP group. 
The first visit (V1) will be at the age of 6 months. In case a child aged 5 to <18 
months is first seen during hospitalisation and meeting the inclusion criteria for 
active surveillance, within the recruitment period, the child can be enrolled in active 
surveillance in the 5-17 months catch-up group. The first visit (V1) will be 1 week 
after being discharged from the hospital. The ICF for active surveillance will be 
signed or witnessed and thumb printed during hospitalisation. 
In case a subject enrolled in active surveillance is returning to the study area having 
previously been declared as an emigrant (migration being defined as spending more than 
3 months outside the study area) this subject will keep the same subject study number and 
continue the original follow-up. 
In each site, a proportion of approximately 50% children enrolled in the 6-12 weeks 
group and 50% children enrolled in the 5-17 months group is expected. 
Note: As part of routine EPI vaccination programmes, the standard DTP/HepB/Hib 
vaccinations usually given at 6, 10 and 14 weeks of age will be administered by the 
National EPI system in the study area (in some countries the EPI schedule may differ by 
a few weeks). Vaccination types and dates will be recorded, but no vaccination will be 
administered as part of this study. 
Parents/LARs should be prompted to attend EPI if their child is late in receiving their 
first dose of the EPI three dose vaccines usually given at 6, 10 and 14 weeks of age.  
Enhanced hospitalisation surveillance 
Parent(s)/LAR(s) from all children who are hospitalised, who are under the age of 5 and 
who can be linked to the HDSS or equivalent surveillance system census, will be 
approached to enrol their child into this study: 
• 
If a child, who is first identified during hospitalization by study staff, fulfills the 
eligibility criteria for enrolment in active surveillance (within the recruitment 
period), enrolment in active surveillance will be proposed. If the parents/LARs 
decline enrolment in active surveillance enrolment in enhanced hospitalisation 
surveillance will be proposed. 
• 
If a child, who is first identified during hospitalization by study staff, is not eligible 
for enrolment in active surveillance but fulfills the eligibility criteria for enrolment in 
enhanced hospitalisation surveillance, enrolment in enhanced hospitalisation 
surveillance will be proposed. 
Note: ‘first identified during hospitalization by study staff’ means ‘not already 
enrolled in the study’. 
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In case a subject enrolled in enhanced hospitalisation surveillance is returning to the 
study area having previously been declared as an emigrant (migration being defined as 
spending more than 3 months outside the study area) this subject will keep the same 
subject study number and continue the original follow-up. 
Enrolment into the study, as documented by signed or witnessed and thumb printed ICF, 
will allow for the collection of data that were generated during the hospitalisation under 
the local standards of care. In case a subject is hospitalised more than once during the 
study duration, the subject will be enrolled only once and followed for all hospitalisations 
occurring throughout the study duration or until he/she reaches 5 years of age. 
Hospitalisation is defined as spending at least one night at a health care facility, for a 
subject registered in the study area. 
Some primary health care facilities have beds available for overnight monitoring; these 
stays are considered to be “hospitalisations” for protocol purposes. There may be a 
difference in the degree of severity of cases admitted in the hospital and those 
hospitalised at primary health care facilities as the latter may include children with 
non-severe disease who live too far to be sent home on the same day. On the other hand, 
hospitalisations in primary health care facilities may also include cases that under 
European conditions would normally be referred to the hospital, such as: parental refusal 
to refer the child to a hospital, difficulties of transport or local standard practice. This 
issue will be addressed by identifying the type of health care facility (either hospital or 
primary health care facility) in case of hospitalisation. The type of health care facility will 
be included as covariate in the analyses, where appropriate. 
9.2.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects’ parent(s)/ LAR(s) who, in the opinion of the investigator, can and will 
comply with the requirements of the protocol. 
• 
Written informed consent provided from either the parent(s) or LAR of the subject. 
• 
Subject living in the HDSS or equivalent surveillance system area. 
• 
For enrolment in the active surveillance: children must be < 18 months of age 
OR 
For enrolment in the enhanced hospitalisation surveillance: children must be 
< 5 years of age and hospitalised at any time during the study. 
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Parents/LARs of children first identified during hospitalisation, before first 
administration of DTP/HepB/Hib vaccine or at the age of 5 to <18 months, must first be 
proposed enrolment in active surveillance (5-17 months group) within the recruitment 
period. 
Children already enrolled in active surveillance will have hospitalisation monitored as 
part of the procedures related to the active surveillance and can therefore not be enrolled 
in enhanced hospitalisation surveillance.  
9.2.3. 
Exclusion criteria for enrolment 
The following criterion should be checked at the time of study entry. If the exclusion 
criterion applies, the subject must not be included in the study: 
• 
Child in care. 
Please refer to Annex 3 for the definition of child in care. 
9.2.4. 
Study period 
Recruitment for active surveillance is expected to be done until the enrolment target is 
reached. Enrolment in enhanced hospitalisation surveillance has been early terminated for 
the sites where the RTS,S/AS01E vaccine will not be implemented. For the sites where 
the RTS,S/AS01E vaccine will be implemented, the enrolment in enhanced 
hospitalisation surveillance will end at start of study EPI-MAL-003.  
Active surveillance will last 44 months for each subject (mimicking 24 months of active 
follow-up after the 4th dose of RTS,S/AS01E in EPI-MAL-003) except for subjects 
enrolled from Burkina Faso sites for whom their participation in the study has been early 
terminated. The EPI-MAL-002 study will last for approximately 5 years (depending on 
recruitment timelines). 
Note: There might be an overlap of studies EPI-MAL-002 and EPI-MAL-003, some 
children enrolled in EPI-MAL-002 may have the possibility to be part of EPI-MAL-003 
(see Section 9.2.7.1.12 for more details). 
The study began enrolment during Q4 2015. 
9.2.5. 
Case definitions 
9.2.5.1. 
AESI 
Adverse events of special interest (AESI) are protocol-defined diseases corresponding to 
AEs that have historically been associated with vaccines other than RTS,S/AS01E, or 
may hypothetically be associated with RTS,S/AS01E due to the fact that this vaccine has 
components which are new compared to current widely used vaccines.  
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The list of AESI has been developed in collaboration with a group of paediatricians 
working in SSA. This group of paediatricians was consulted following an opportunity to 
receive a scientific advice with the EMA in 2011. Indeed, the Committee for Medicinal 
Products for Human Use (CHMP) suggested to seek advice from relevant paediatric 
clinicians on which additional AESI may be of most relevance for SSA countries. In 
addition, GSK had considered four diseases which have been identified as potential AE 
with other vaccines and has added these to this list (Intussusception, Kawasaki diseases, 
Henoch-Schonlein Purpura and Hypotonic Hyporesponsive Episode [HHE]). 
When available, the Brighton Collaboration Working Groups case definitions are used. 
These aim at defining levels of diagnostic certainty of reported events following 
vaccination. Their global use enhances data comparability within and across clinical trials 
and surveillance systems and allows for the adaption of the diagnosis based on the health 
facility’s settings. Each case definition is structured in a two or three level of diagnostic 
certainty format, each level being defined by a set of clinical and/or additional diagnostic 
criteria. 
• 
Level 1 of diagnostic certainty: most specific and least sensitive level 
• 
Level 2 of diagnostic certainty: intermediate level of specificity and sensitivity 
• 
Level 3 of diagnostic certainty: most sensitive but lower level of specificity. 
Job Aids are field guides that act as a reference tool for study staff. For this study, Job 
Aids have been developed to standardise the definition of each AESI during a 
collaborative initiative between GSK, Agence de Médecine Préventive (AMP) and 
Réseau en Afrique Francophone pour la Télémédecine (RAFT). RAFT physicians will 
provide support for case diagnosis through virtual consultation infrastructure.  
The predefined list of AESI and associated clinical information is provided in Table 3 
and case definitions are provided in Annex 5. 
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Table 3 
Summary of adverse events of special interest (AESI) by body 
system  
Body 
System/ 
AESI 
Expected incidence  
(per 100 000 person-years) 
Risk of AE 
Risk period 
identified 
(for other 
licensed 
vaccines) 
Brighton 
Case (BC) 
definition/ 
Protocol (P) 
definition 
Nerves and Central Nervous System 
ADEM 
0.6 to 0.8/100,000 PY [Karussis, 2014]; 
0.2/100,000 PY (in < 18 yr olds, 
Canada) [Banwell, 2009];  
0.40, 0.27 and 0.30/100,000 PY (10-14 
yr olds, 15-19 yr olds, 20-29 yr olds, 
respectively, China) [Xiong, 2014];  
0.03/100,000 PY (10-16 yr olds, 
Germany) [Pohl, 2007];  
0.2/100,000 PY (< 18 yr olds, The 
Netherlands) [Ketelslegers, 2012]; 
0.34/100,000 PY (1-15 yr olds, UK) 
[Absoud, 2012];  
0.3/100,000 PY (≤ 18 yr olds, US) 
[Langer-Gould, 2011];  
0.4/100,000 PY (< 20 yr olds, US) 
[VanLandingham, 2010] 
1-2 per million following 
vaccination against measles, 0.2 
per 100,000 following vaccination 
against Japanese encephalitis, 1 
per 300 to 1 per 7,000 following 
administration of neural vaccine 
against rabies [Tenembaum, 
2007] 
NA 
BC 
Encephalitis 11.1 (95% CI: 10.1, 12.1) and 4.7 
(95% CI: 4.3, 5.1) encephalitis-
associated hospitalisations /100,000 PY 
(in <1 yr and 1-4 yr olds, US, 
respectively) [Vora, 2014] 
1396 cases (mean age 23.4 yrs, 
range 0-89 yrs) in the US from 
1990 to 2010 [Al Qudah, 2012]  
Onset within 
6 wks and 2 
wks after 
vaccination: 
65.2% and 
50.7% of 
patients, 
respectively 
[Al Qudah, 
2012] 
BC 
Guillain Barré 
Syndrome 
0.7/100,000 PY (in 12-29 yr olds, 
Tanzania) [Howlett, 1996] 
0.38/100,000 PY (in 0-4 yr olds, China) 
[Chen, 2014] 
0.62/100,000 PY (95% CI: 0.52, 0.75) in 
0-9 yr olds in a meta-analysis from 
studies in North America and Europe 
[Sejvar, 2011] 
1 additional case per 106 doses 
with influenza vaccination in US, 
1992-1994 [Lasky, 1998] 
 
Calculated RR in different studies 
on influenza vaccination from 
1978 to 2005 produced RR values 
ranging from 0.4 to 1.7 [Sejvar, 
2011] 
Ranges from 
3-5 days to 
6-10 wks, 
and up to a 
few months 
and even 
years 
[Sejvar, 
2011] 
BC 
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Body 
System/ 
AESI 
Expected incidence  
(per 100 000 person-years) 
Risk of AE 
Risk period 
identified 
(for other 
licensed 
vaccines) 
Brighton 
Case (BC) 
definition/ 
Protocol (P) 
definition 
Generalised 
convulsive 
seizure 
Unknown 
1.04 per 1,000 (95% CI: 0.62, 
1.64) after primary vaccination 
with RTS,S/AS01 in children 5-17 
months at first dose [The RTS,S 
Clinical Trials Partnership, 2011]; 
2.5 per 1,000 and 2.2 per 1,000 
after 4th dose of RTS,S/AS01 in 
children 5-17 months at first dose, 
and in children aged 6-12 weeks 
at first dose, respectively 
[The RTS,S Clinical Trials 
Partnership, 2015] 
0-7 days 
after 
RTS,S/AS01 
BC 
Hypotonic 
Hypo-
responsive 
episode 
NA 
Reported rates following whole-
cell and acellular pertussis 
component combination vaccines 
range from 21 to 71 episodes and 
7 to 36 episodes per 100,000 
doses and 36 to 250 episodes 
and 4 to 140 episodes per 
100,000 children, respectively 
[Buettcher, 2007] 
3–4h but 
ranges from 
immediately 
to 48h post 
vaccination 
BC 
Hepato-Gastrointestinal and Renal System 
Intussuscep-
tion 
Average rate 1 case per 3,300; yearly 
variations 1:2,500 to 1:5,000 (<1 yr old, 
Panama) [Sáez-Llorens, 2004] 
<5/100,000 PY (<9 wks), 62/100,000 
PY (26-29 wks), 26/100,000 PY (52 
wks) (US) [Tate, 2008] 
8.1/100,000 PY (<1 yr Australia) 
[Justice, 2005] 
Overall estimate of risk of IS 
during the 7 days after 
vaccination with Rotarix 6.8 (95% 
CI: 2.4, 19.0) and with RotaTeq 
9.9 (95% CI: 3.7, 26.4) after dose 
1. Small increase after dose 2 for 
both vaccines [Carlin, 2013; 
Rosillon, 2015]  
1 to 7 days 
after 1st and 
2nd doses of 
Rotarix and 
RotaTeq 
vaccines  
BC 
Hepatic 
insufficiency 
Unknown 
NA 
1-10 days 
BC 
Renal 
insufficiency 
Unknown 
NA 
1-10 days 
BC 
Skin and Mucous Membrane & Bone and Joints 
Juvenile 
chronic 
arthritis 
18/100,000 PY (in ≤16 yr olds, Canada) 
[Feldman, 2009];  
7/100,000 PY (Germany); 24/100,000 
PY (Australia) [Begg, 2007] 
NA 
≤6 months 
P 
SJS and TEN SJS:1-6 per million PY [Roujeau, 1995]  
TEN: 0.4-1.2 per million PY [Roujeau, 
1995] 
NA 
1-3 weeks 
P 
Henoch 
Schonlein 
purpura 
Peak at 70/100,000 PY (in 4-6 yr olds, 
UK) [Gardner-Medwin, 2002] 
NA 
NA 
P 
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Body 
System/ 
AESI 
Expected incidence  
(per 100 000 person-years) 
Risk of AE 
Risk period 
identified 
(for other 
licensed 
vaccines) 
Brighton 
Case (BC) 
definition/ 
Protocol (P) 
definition 
Kawasaki 
disease 
About 215/100,000 PY (in <5 yr olds, 
Japan) [Nakamura, 2010] 
20/100,000 PY (in <5 yr olds, US); 
17/100,000 PY (in <5 yr olds, African 
Americans) [Holman, 2010];  
6.4/100,000 PY (in <5 yr olds, Israel) 
[Bar-Meir, 2011] 
Reporting to VAERS in the US, 
from 1990 through mid-October 
2007: Hib (31 cases of Kawasaki 
disease), PVC-7 (29 cases), MMR 
(22 cases), diphtheria and tetanus 
toxoids and acelluar pertussis (21 
cases), inactivated polio (17 
cases), rotavirus (16 cases), 
diphtheria and tetanus toxoids, 
acellular pertussis, hepatitis B, 
and inactivated polio combined 
(16 cases), hepatitis B (13 cases). 
0.65 and 0.37 reports /100,000 
PY for RotaTeq and Pediarix, 
respectively, before label revision 
of RotaTeq, and 2.78 and 
2.44/100,000 PY for RotaTeq and 
Pediarix , respectively, after label 
revision [Hua, 2009] 
 
PCV-7: 4.6 per 100,000 doses, 
PCV-13: 5.4 per 100,000 doses 
[Tseng, 2013] 
 
PCV-13: 1 case in 233 vaccinated 
children, considered not to be 
related to vaccination [Gutierrez 
Brito, 2013] 
 
Electronically captured health 
insurance claims in the US, from 
2006 to 2007: RotaTeq: 1 case 
within 30 days, 2 cases between 
31 and 60 days after vaccination 
in North Wales. DTaP: 1 case 
[Loughlin, 2012] 
1 month 
after 
vaccination 
P 
 
 
 
 
 
Systemic Disease and Haematology 
Diabetes 
mellitus  
type 1 
0.06/100,000 PY (0.0, 0.13) (in 0-4 yr 
olds, Tanzania) [Swai, 1993];  
0.9/100,000 PY (in 0-4 yr olds, Sudan) 
[Karvonen, 2000];  
2.3 to 6.3/100,000 PY (in 0-4 yr olds, 
Tunisia) [Karvonen, 2000];  
9.06/100,000 PY (0-4 yr olds, Cyprus), 
14.15/100,000 PY (5-9 yr olds, Cyprus) 
[Skordis, 2012];  
3.1/100,000 PY (in <18 yr olds, Egypt) 
[El-Ziny, 2014];  
NA 
≤6 months 
P 
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Body 
System/ 
AESI 
Expected incidence  
(per 100 000 person-years) 
Risk of AE 
Risk period 
identified 
(for other 
licensed 
vaccines) 
Brighton 
Case (BC) 
definition/ 
Protocol (P) 
definition 
12.9/100,000 PY (0-5 yr olds, 
Germany), 18.7/100,000 PY (5-10 yr 
olds, Germany) [Galler, 2010];  
8.59/100,000 PY (0-4 yr olds, Israel), 
13.29/100,000 PY (5-9 yr olds, Israel) 
[Sella, 2011];  
17.1/100,000 PY (0-4 yr olds, Saudi 
Arabia), 10.9/100,000 PY (5-9 yr olds, 
Saudi Arabia) [Habeb, 2011];  
4.3/100,000 PY (0-4 yr olds, Turkey), 
9.1/100,000 PY (5-9 yr olds, Turkey) 
[Demirbilek, 2013] 
Thrombo-
cytopenia 
2.2/100,000 PY (in <16 yr olds, 
Germany) [Sutor, 2001] 
NA 
12-25 days 
median 
(range 1-83 
days) 
BC 
Anaphylaxis 70/100,000 PY (in 0-19 yr olds, 
Minnesota, US) [Decker, 2008] 
Monovalent measles (12 per 
100,000 doses), MMR (1 per 
100,000 doses), HPV bivalent 
(1.4 per million doses) or HPV 
quadrivalent (from 2.6 per 
100,000 to 1.7 per million doses) 
[Vanlander, 2014] 
0.65 (95% CI: 0.21, 1.53) per 
million doses for the most 
common vaccines for children and 
adolescents [Bohlke, 2003] 
0-48 hours 
[Bohlke, 
2003] 
BC 
ADEM= Acute Disseminated Encephalo-Myelitis; AE = adverse event; AESI = adverse event of special interest; Hib = 
Haemophilus influenza type B; HPV = human papilloma virus; MMR = measles, mumps, rubella; PCV = pneumococcal 
conjugate vaccine; SJS= Stevens Johnson Syndrome; TEN = toxic epidermal necrolysis; NA = not available; PY = 
person years; RR = relative risk; VAERS = Vaccine Adverse Event Reporting System. 
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9.2.5.2. 
Hospitalisations for an AE other than an AESI, meningitis, any malaria 
or severe malaria (including cerebral malaria) 
These include all hospitalisations reported by the physician not due to an AESI (Section 
9.2.5.1), or to meningitis (Section 9.2.5.3), or to any malaria or to severe malaria 
(including cerebral malaria) (Section 9.2.5.5). 
9.2.5.3. 
Meningitis 
Of note, because meningitis was identified as a potential risk during RTS,S/AS01E 
clinical development (see Section 7.2), the disease is identified separately from the other 
AESI. 
• 
At the site level, a suspected meningitis case based on clinical symptoms and/or 
signs is defined as [adapted from WHO, 2003]: 
– 
A child with sudden onset of fever (> 38.0 °C rectal or 37.5 °C axillary) and one 
or more of the following signs: neck stiffness, altered consciousness with no 
other alternative diagnosis, or other meningeal sign such as bulging fontanelle in 
children under one year of age. 
Lumbar puncture will be performed according to routine medical practice for 
examination of cerebrospinal fluid (CSF). Children with symptoms and/or signs of 
meningitis will be classified as follows based on first line laboratory results (for 
monitoring trends over time): 
– 
If a CSF sample is available and a bacterial agent has been identified, as 
bacterial confirmed meningitis case; 
– 
If a CSF sample is available, no bacterial agent has been identified in the CSF, 
but some abnormalities in the CSF have been detected (such as turbid 
macroscopic aspect, positive Gram, positive antigen test, pleiocytosis, abnormal 
glucose or protein levels) or positive blood culture to a bacterial agent, as 
probable meningitis case; 
– 
If a CSF sample is available and all examinations are normal at first line 
laboratory level, or if no CSF sample is available and no alternative diagnosis, 
as clinically suspected meningitis case. 
• 
Based on second line laboratory results (see Section 9.2.7.3.1 and 9.2.7.3.2) and after 
external panel of experts review (see Section 9.2.7.4.1), final classification of 
meningitis cases will be as follows (for the statistical analyses): 
– 
If a CSF sample is available and any known aetiologic agent (bacterial or not) 
has been identified, as aetiology-confirmed meningitis case; 
– 
If a CSF sample is available, no aetiologic agent has been identified in the CSF, 
but some abnormalities in the CSF have been detected (such as turbid 
macroscopic aspect, positive Gram, positive antigen test, pleiocytosis, abnormal 
glucose or protein levels), or positive blood culture to a bacterial agent as 
probable meningitis case; 
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– 
If a CSF sample is available and all laboratory results are normal after second 
line laboratory results, or if no CSF sample is available and no alternative 
diagnosis, as clinically suspected meningitis case. 
If none of the criteria (no specific clinical symptoms and/or signs or laboratory 
results) are fulfilled, after review by the external panel of experts, the case will be 
classified as a no meningitis case. 
9.2.5.4. 
Febrile convulsions 
• 
Adapted from Brighton case definition for generalised seizures (see Annex 5): 
generalised seizures with measured fever ≥ 37.5 °C (axillary) or reported history of 
fever.  
9.2.5.5. 
Malaria 
Case definitions according to the WHO will be used [WHO, 2015(b)]. Any malaria will 
include uncomplicated and severe malaria cases, including cerebral malaria. 
• 
Uncomplicated malaria [WHO, 2015(b)]: 
Plasmodium parasitaemia > 0 detected by microscopy and/or RDT 
AND 
Presence of fever (temperature ≥ 37.5°C), as reported by the parent(s)/LAR(s) or 
recorded at the time of presentation 
OR 
Occurring in a child who is unwell and brought for treatment to a health care facility. 
AND 
Without signs of severity or evidence (clinical or laboratory) of vital organ 
dysfunction. 
• 
Severe falciparum malaria [adapted from WHO, 2015(b)]: 
P. falciparum parasitaemia > 0 detected by microscopy and/or RDT 
AND 
One or more of the following, occurring in the absence of an identified alternative 
cause:  
– 
Impaired consciousness: a Glasgow coma score < 11 in children ≥ 2 years of age 
or a Blantyre coma score < 3 in children < 2 years of age; 
– 
Prostration: generalised weakness so that the person is unable to sit, stand or 
walk without assistance; 
– 
Multiple convulsions: more than two episodes within 24 h; 
– 
Acidosis: a base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate 
level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis 
manifests clinically as respiratory distress (rapid, deep, laboured breathing). 
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– 
Hypoglycaemia: blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL); 
– 
Severe malarial anaemia: haemoglobin concentration ≤ 5 g/dL or a haematocrit 
of ≤ 15% in children < 12 years of age with a parasite count > 10,000/µL; 
– 
Renal impairment: plasma or serum creatinine > 265 μmol/L (3 mg/dL) or blood 
urea > 20 mmol/L; 
– 
Jaundice: plasma or serum bilirubin > 50 μmol/L (3 mg/dL) with a parasite 
count > 100,000/µL; 
– 
Pulmonary oedema: radiologically confirmed or oxygen saturation < 92% on 
room air with a respiratory rate > 30/min, often with chest indrawing and 
crepitations on auscultation; 
– 
Significant bleeding: including recurrent or prolonged bleeding from the nose, 
gums or venepuncture sites; haematemesis or melaena;  
– 
Shock: compensated shock is defined as capillary refill ≥ 3 s or temperature 
gradient on leg (mid to proximal limb), but no hypotension. Decompensated 
shock is defined as systolic blood pressure < 70 mm Hg in children, with 
evidence of impaired perfusion (cool peripheries or prolonged capillary refill); 
– 
Hyperparasitaemia: P. falciparum parasitaemia > 10% (i.e. percentage of 
infected red blood cells > 10%; corresponding to > 500,000/µL). 
• 
Severe vivax malaria is defined as for severe falciparum malaria but with no parasite 
density thresholds [WHO, 2015(b)]. 
• 
Cerebral malaria [adapted from WHO, 2015(b)]: 
Severe P. falciparum malaria with impaired consciousness (Glasgow coma score 
< 11 in children ≥ 2 years of age or Blantyre coma score < 3 in children < 2 years of 
age);  
AND 
If malaria with seizure: coma persisting for > 30 min after the seizure. 
Other treatable causes of coma should be excluded before diagnosing cerebral 
malaria (e.g. hypoglycaemia, bacterial meningitis). 
Note: Suspected malaria cases routinely tested using RDT will have a blood smear for 
reading by microscopy in parallel, in order to measure sensitivity and specificity. This 
will be done for all suspected cases presenting at primary health care facilities one day 
per month during the first year of the study. 
9.2.5.6. 
Anaemia 
• 
All anaemia: haemoglobin <11g/dL [Stoltzfus, 1993]. 
• 
Severe anaemia: haemoglobin <7g/dL [Stoltzfus, 1993]. 
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9.2.5.7. 
Hospitalisation 
• 
Hospitalisations (all causes) 
A subject requiring overnight stay in hospital/inpatient facility.  
• 
Hospitalisation for malaria (including P. falciparum malaria) 
A hospitalised subject with malaria (including P. falciparum malaria) and for whom 
malaria is the primary cause of hospitalisation.  
9.2.5.8. 
Deaths 
• 
Deaths – all cause 
A fatality (of any cause).  
• 
Malaria attributed deaths (including P. falciparum malaria) 
A fatality for which malaria (including P. falciparum malaria) is listed as a 
contributing cause of death. This is based on verbal autopsy using the INDEPTH 
Standard Verbal Autopsy Questionnaire* [INDEPTH, 2003] for children who died at 
home or medical judgment/medical records for children who died at a primary health 
care facility or hospital. 
• 
Deaths attributed to an AE  
A fatality for which an AE is listed as a contributing cause of death, based on either 
verbal autopsy using the INDEPTH Standard Verbal Autopsy Questionnaire* 
[INDEPTH, 2003] for children who died at home or medical judgment/medical 
records for children who died at a primary health care facility or hospital.  
* If a site is not part of the INDEPTH network, or does not have an equivalent 
surveillance system in place, the INDEPTH procedures for verbal autopsy might be 
implemented to ensure consistency across study sites. 
Deaths, including malaria attributed deaths with an uncertain diagnosis and outcome after 
review by the GSK safety physician will be reviewed by the expert panel to confirm the 
primary/secondary cause of death (see Section 9.2.7.4.4). 
9.2.6. 
Surveillance quality indicators 
To ensure the quality of the surveillance that will be performed in the study sites, two 
surveillance quality indicators have been added based on discussion with African 
paediatricians: abscess at injection site during the 7-day period (Days 0-6) after routine 
vaccination and foot positional deformations. 
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9.2.6.1. 
Case definition for abscess at injection site 
The diagnosis and monitoring of abscess at the injection site will be used as a positive 
control, as this is an AE that is relatively frequently observed after routine vaccination in 
Africa, and is defined as: 
• 
A localised collection of material in subcutaneous tissue, fat, fascia or muscle at the 
site of immunisation confirmed in spontaneous or surgical drainage of material from 
the mass or by presence of palpable fluctuance (defined as a wavelike motion on 
palpation due to liquid content). The abscess may be further classified as due to 
infectious aetiology, a sterile abscess or not-determined. Abscesses of infectious 
aetiology may be accompanied by fever/regional lymphadenopathy. Sterile abscesses 
are not accompanied by fever/regional lymphadenopathy. 
9.2.6.2. 
Case definition for foot positional deformations  
The diagnosis and monitoring of foot positional deformations as a birth defect will be 
used as a negative control (to assess changes in the performance of health care systems to 
diagnose disease) and is defined as: 
• 
Metatarsus adductus characterised by medial deviation (adduction) of the forefoot 
while the hindfoot remains in a normal position, thus forming a "C" shape, or 
concavity of the medial aspect of the foot  
OR 
• 
Positional calcaneovalgus feet characterised by hyperdorsiflexion of the foot with the 
abduction of the forefoot, which often results in the forefoot resting on the anterior 
surface of the lower leg 
OR 
• 
Clubfoot characterised by the foot being excessively plantar flexed, with the forefoot 
swung medially and the sole facing inward. 
9.2.7. 
Study procedures3 
9.2.7.1. 
Active surveillance 
For children enrolled in active surveillance (i.e. home visits and monitoring of outpatient 
visits and hospitalisations at all health care facilities), enrolment procedures may be 
conducted at the time of the first administration of DTP/HepB/Hib vaccine, at the time of 
first encounter with the study staff, or approximately 1 week later, or during 
hospitalisation (for children first identified and enrolled during hospitalisation: either 
before 1st DTP or children aged 5 to < 18 months) (see Section 9.2.1.1). 
                                                 
3 Supplementary study conduct information not mandated to be present in this protocol is provided in the 
accompanying Study Procedures Manual (SPM). The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the safety of the 
subjects. 
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The organisation of visits will be study site dependent and based on the listing obtained 
through the HDSS or equivalent surveillance system database. The schedule of subject 
recruitment and first visit should be established just prior to study start and updated using 
the data collected between and during study area rounds after study start (e.g. for 
newborns).  
In case a child in the 6-12 weeks group has received the first dose of DTP/HepB/Hib 
vaccine, but is delayed for dose 2 and/or dose 3, parents/LARs should be prompted to 
attend EPI for completing immunisations and the visits V2 and/or V3 will take place 
1 week post vaccination. 
If the child does not receive the complete primary schedule, V2 and/or V3 will not take 
place, but V4, V5 and V6 will be done 6 weeks, 6 months and 18 months after the 
recommended scheduled visit for the third dose of DTP/HepB/Hib vaccine. 
Two attempts should be made to visit the child at home within the month of the 
scheduled follow-up visit/study conclusion visit before it is abandoned. 
Table 4 and Table 5 detail study procedures to be conducted during the visit, both at 
home visits and during any hospitalisation. Data collected regarding the hospitalisation 
will be uniformly collected whether the child is enrolled in active surveillance or in 
enhanced hospitalisation surveillance.  
Data collected will be entered into the study database/ electronic case report form 
(eCRF). 
Note: As the study has been early terminated in Burkina Faso, subjects will no longer be 
followed up (i.e. no more home visits, outpatient visits or hospitalisations). However, the 
1, 6, and 12 months follow-up check-ups in case of an already diagnosed meningitis, 
cerebral malaria or AESI before the early termination should still be done. (See sections 
9.2.7.4.1, 9.2.7.4.2 and 9.2.7.4.5). 
9.2.7.1.1. Informed consent 
Freely given and written or witnessed and thumbprinted informed consent must be 
obtained from each subject’s parent(s)/LAR(s), as appropriate, prior to participation in 
the study. Refer to Section 10.1 for the requirements on how to obtain informed consent.  
Note: In special circumstances (Section 9.2.8), there could be certain restrictions that 
will make it not possible for parents/LARs to provide written consent. In these special 
circumstances parents/LARs of subjects enrolled and still under follow up will provide 
consent verbally. 
(Amended 5 May 2020) 
9.2.7.1.2. Check inclusion and exclusion criteria 
Check all applicable inclusion and exclusion criteria as described in Sections 9.2.2 and 
9.2.3 before enrolment.  
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9.2.7.1.3. Assign subject study number 
Assign subject study number and record in the eCRF. Provide study ID card and 
study-specific stickers. Study-specific stickers with the subject’s study number should be 
used at health care facilities to identify any visit of the subject in the facility register if no 
other system is in place. A holder will be provided for carrying the subject’s ID 
card/study stickers together with other records e.g. welfare card, child growth record, 
immunisation record to avoid double enrolment. 
9.2.7.1.4. Collect demographic data  
Record socio-demographic data (e.g. date of birth and gender, the number and age of 
persons in the household) and active participation in any trial with an investigational 
product in the subject’s eCRF. 
9.2.7.1.5. Health history  
Record brief medical history (e.g. chronic co-morbidities such as known HIV infection or 
congenital disease, such as known hemoglobinopathies) and perform physical 
examination at the first visit V1.  
9.2.7.1.6. Check and record vaccinations 
Record all standard vaccinations administered, including type and dates. Received 
vaccinations must be recorded during the first visit and updated if needed at all 
consecutive visits or at study conclusion. See also Section 9.3.3.1 for ascertainment of 
vaccine history. 
9.2.7.1.7. Record information about health care seeking behaviour, malaria 
control measures, drug use and exposure to environmental hazards 
Record data on access to care and health care seeking behaviour, neighbourhood of 
residence (urban/rural area), distance from health facilities, use of malaria control 
intervention at individual level (e.g. use of bednets, indoor residual spraying, seasonal 
malaria chemoprevention), information on medication intake (including curative 
antimalarial drugs) during the 14 days preceding onset of symptoms, whether recorded 
(evidence of prescription) or reported (prescribed without any evidence or 
self-medicated). Record also information on medication given as treatment of an AESI, 
meningitis or malaria, information on medication given for chronic therapy, information 
on medication administered in anticipation of a reaction to the vaccination, and exposure 
to environmental hazards such as chemicals (see Section 9.3.3).  
9.2.7.1.8. Record health care facility visits and hospitalisations 
Record any outpatient visits and hospitalisations at all health care facilities between 
enrolment and Visit 1, or since the last follow-up visit (for subsequent follow-up visits) in 
the eCRF. 
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9.2.7.1.9. Physical examination, record of signs and symptoms, record any 
serious delay in developmental milestones or physical disability 
Perform a basic examination of the subject e.g. change in food/milk intake, crying, 
identification of dehydration, bleeding, oedema, jaundice, neck stiffness to detect any 
potential signs and symptoms indicating that the child is sick. Record any signs and 
symptoms detected during examination or in the past 48 hours preceding the visit in the 
eCRF. At study visits 1, 3 and 10 (study conclusion), ask the parent/LAR for any noticed 
or previously diagnosed abnormalities while checking for developmental milestone 
delays and presence of physical disability using study specific guidance document (see 
Annex 6).  
Care of any abnormality observed during this examination should be provided according 
to local medical practice in the study site or by referral to an appropriate health care 
provider (see Section 9.2.7.5).  
Community health workers will use visual aids and other training materials to detect any 
potential signs and symptoms indicating that the child is sick. They will also be trained to 
recognise symptoms and signs of AESI, meningitis and will be instructed to measure 
body temperature systematically of all children. In case of fever, body temperature will 
be recorded in the eCRF. 
9.2.7.1.10. Refer sick children or children with disabilities to outpatient clinic or 
hospital 
Refer children who are sick, have an acute condition or with disabilities to health 
facilities for further assessment and care, that will be dispensed according to routine 
medical practice, including consultation, laboratory tests and treatment.  
Refer children with fever (≥ 37.5°C) and symptoms suggestive of malaria to the primary 
health care facility or hospital where diagnosis of malaria will be ensured using RDT 
and/or microscopy. 
Record referral in the eCRF. 
9.2.7.1.11. Record cases of death 
In the event of death occurring at home, the cause of death will be systematically 
obtained through verbal autopsy using the INDEPTH Standard Verbal Autopsy 
Questionnaire [INDEPTH, 2003] as is routinely done in the study area.  
If a site is not part of the INDEPTH network, or does not have an equivalent surveillance 
system in place, the INDEPTH procedures for verbal autopsy might be implemented to 
ensure consistency across study sites. 
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9.2.7.1.12. Study conclusion 
Subjects will exit the study when they reach 5 years of age or at study end (whichever 
occurs first), if not earlier due to migration or in the event of death.  
At the study conclusion (home visit, V10), a record will be taken of the subject’s health 
and vital status, any disabilities and all vaccinations received. 
The investigator will review collected data to ensure accuracy and completeness and will 
complete the Study Conclusion screen in the eCRF. 
Note: There might be an overlap of studies EPI-MAL-002 and EPI-MAL-003. Children 
enrolled in active surveillance of EPI-MAL-002, and not eligible for RTS,S/AS01E 
vaccination or declining vaccination will continue to be followed up to the study 
conclusion visit in EPI-MAL-002. Children enrolled in active surveillance of 
EPI-MAL-002, and becoming vaccinated with RTS,S/AS01E, will have their study 
conclusion of EPI-MAL-002. Thereafter, these children can be eligible and enrolled in 
EPI-MAL-003 according to the inclusion/ exclusion criteria and the EPI-MAL-003 
recruitment procedures. For children enrolled in enhanced hospitalisation surveillance of 
EPI-MAL-002, study conclusion of EPI-MAL-002 will be done at start of study EPI-
MAL-003 (as the vaccine becomes available in the study sites that are exposed clusters). 
Thereafter, these children can be eligible and enrolled in active surveillance or in 
enhanced hospitalisation surveillance of EPI-MAL-003 according to the inclusion/ 
exclusion criteria and the EPI-MAL-003 recruitment procedures. 
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9.2.7.1.13. Outline of study procedures 
Table 4 
List of study procedures to be conducted at each visit, and study visit schedule (active surveillance)  
Epoch 
1 
Type of contact 
Enrolment 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10  
Visit days: 6-12 weeks group 6 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
1 wk  
(±3 days) after 
1st DTP/ HepB/ 
Hib dose  
1 wk (±3 
days) after 
2nd DTP/ 
HepB/ Hib 
dose  
1 wk  
(±3 days) 
after 3rd 
DTP/ 
HepB/ Hib 
dose  
6 wks  
(±5 days) 
after 3rd 
DTP/ HepB/ 
Hib dose 
6 mths  
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
18 mths 
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks) 
 post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
At the age of 
6 mths (> 5 
mths to < 7 
mths) 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(catch-up, enrolled at 5 to <18 
mths of age) 
 
First contact 
with study staff 
or 1 wk later 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 
7(±2 wks)  
 
Time point (Month) 
 
M0 
M1 
M2 
M3.5 
M8 
M20 
M21.5 
M32 
M44 
 
Informed consent 
●1 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
●1 
 
 
 
 
 
 
 
 
 
 
Assign subject study number 
●1 
 
 
 
 
 
 
 
 
 
 
Provide study ID card and study-
specific stickers  
○1 
 
 
 
 
 
 
 
 
 
 
Record socio-demographic details 
and active participation in any trial 
with an investigational product 
●1 
 
 
 
 
 
 
 
 
 
 
Record brief medical history (e.g. 
chronic co-morbidities, such as 
known HIV infection, or congenital 
disease, such as known 
hemoglobinopathies) 
 
● 
 
 
 
 
 
 
 
 
 
Record vaccination 2 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
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Epoch 
1 
Type of contact 
Enrolment 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10  
Visit days: 6-12 weeks group 6 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
1 wk  
(±3 days) after 
1st DTP/ HepB/ 
Hib dose  
1 wk (±3 
days) after 
2nd DTP/ 
HepB/ Hib 
dose  
1 wk  
(±3 days) 
after 3rd 
DTP/ 
HepB/ Hib 
dose  
6 wks  
(±5 days) 
after 3rd 
DTP/ HepB/ 
Hib dose 
6 mths  
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
18 mths 
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks) 
 post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
At the age of 
6 mths (> 5 
mths to < 7 
mths) 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(catch-up, enrolled at 5 to <18 
mths of age) 
 
First contact 
with study staff 
or 1 wk later 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 
7(±2 wks)  
 
Time point (Month) 
 
M0 
M1 
M2 
M3.5 
M8 
M20 
M21.5 
M32 
M44 
 
Record information about malaria 
control measures, health care 
seeking behaviour, drug use and 
exposure to environmental 
hazards 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Record any outpatient visits and 
hospitalisations at all health care 
facilities 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Conduct physical examination, 
including systematic 
measurement of body 
temperature 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Record any detected signs and 
symptoms (including AESI, other 
AE leading to hospitalisation or 
death, meningitis, malaria, 
abscess at injection site, foot 
positional deformations) 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
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Epoch 
1 
Type of contact 
Enrolment 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10  
Visit days: 6-12 weeks group 6 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
1 wk  
(±3 days) after 
1st DTP/ HepB/ 
Hib dose  
1 wk (±3 
days) after 
2nd DTP/ 
HepB/ Hib 
dose  
1 wk  
(±3 days) 
after 3rd 
DTP/ 
HepB/ Hib 
dose  
6 wks  
(±5 days) 
after 3rd 
DTP/ HepB/ 
Hib dose 
6 mths  
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
18 mths 
(±2 wks) 
after 3rd 
DTP/ HepB/ 
Hib dose 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks) 
 post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(identified at first 
administration of DTP/HepB/Hib 
vaccine) 
 
At the age of 
6 mths (> 5 
mths to < 7 
mths) 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 7 
(±2 wks)  
Visit days: 5-17 mths group 
(catch-up, enrolled at 5 to <18 
mths of age) 
 
First contact 
with study staff 
or 1 wk later 
4 wks  
(±3 days)  
post V1 
4 wks  
(±3 days)  
post V2 
5 wks  
(±5 days)  
post V3 
6 mths  
(±2 wks)  
post V3 
18 mths  
(±2 wks)  
post V3 
5 wks  
(±5 days) 
post V6 
12 mths  
(±2 wks)  
post V6 
24 mths  
(±2 wks)  
post V6 
At 5 yrs of 
age or 
study end 
7(±2 wks)  
 
Time point (Month) 
 
M0 
M1 
M2 
M3.5 
M8 
M20 
M21.5 
M32 
M44 
 
Record any serious delay in 
developmental milestones or 
physical disability 3 
 
● 
 
● 
 
 
 
 
 
 
● 
Refer sick children or children with 
disabilities to outpatient clinic or 
hospital according to clinical 
diagnosis 4 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
If death, record verbal autopsy 
diagnosis 5 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study conclusion 
 
 
 
 
 
 
 
 
 
 
● 
Children in 6-12 weeks group: subjects identified at first administration of DTP/HepB/Hib vaccine 
Children in 5-17 months group: subjects identified at first administration of DTP/HepB/Hib vaccine or subjects 5 to <18 months (catch-up) 
V= Visit; Wks = weeks; mths = months; yrs = years 
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the eCRF 
1. Procedures at Enrolment visit may be conducted at Visit 1 for children in the 6-12 weeks group and children in the 5-17 months catch-up group. 
2. All immunisations will be recorded 
3. See Annex 6 
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4. See Annex 5 
5. 
Using the INDEPTH Standard Verbal Autopsy Questionnaire [INDEPTH, 2003] for children who died at home. If a site is not part of the INDEPTH, or does not have an equivalent 
surveillance system in place, the INDEPTH procedures for verbal autopsy might be implemented to ensure consistency across study sites. 
6. 
In case a child in the 6-12 weeks group has received the first dose of DTP/HepB/Hib vaccine, but is delayed for dose 2 and/or dose 3, parents/LARs should be prompted to 
attend EPI for completing immunisations and the visits V2 and/or V3 will take place 1 week post vaccination. If the child does not receive the complete primary schedule, V2 
and/or V3 will not take place, but V4, V5 and V6 will be done 6 weeks, 6 months and 18 months after the recommended scheduled visit for the third dose of DTP/HepB/Hib 
vaccine. 
7. 
Because of a possible overlap of studies EPI-MAL-002 and EPI-MAL-003, study conclusion of EPI-MAL-002 will be done for children enrolled in active surveillance and becoming 
vaccinated with RTS,S/AS01E 
(Amended 5 May 2020) 
 
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9.2.7.2. 
Enhanced hospitalisation surveillance 
Table 5 provides details on the procedures to be conducted for children enrolled in 
enhanced hospitalisation surveillance at or around the time of hospitalisation.  
Data collected regarding the hospitalisation will be uniformly collected whether the child 
is enrolled in active surveillance or in enhanced hospitalisation surveillance.  
9.2.7.2.1. Informed consent (for subjects not enrolled previously, i.e. for previous 
hospitalisation or for active surveillance) 
Freely given and written or witnessed and thumb printed informed consent must be 
obtained from each subject’s parent(s)/LAR(s), as appropriate, prior to participation in 
the study. Refer to Section 10.1 for the requirements on how to obtain informed consent. 
In case routine procedures are performed before the ICF signature, collection of those 
data for the study CRF will be done retrospectively once the ICF is signed or witnessed 
and thumb printed. No study specific procedures will be performed before the ICF is 
signed or witnessed and thumb printed.  
9.2.7.2.2. Check inclusion and exclusion criteria (for subjects not enrolled 
previously) 
Check all applicable inclusion and exclusion criteria as described in Sections 9.2.2 and 
9.2.3 before enrolment.  
9.2.7.2.3. Assign subject study number (for subjects not enrolled previously) 
Provide study ID cards and assign subject study number and record in the eCRF for all 
newly enrolled subjects (for subjects already enrolled - previous hospitalisation or for 
active surveillance - the same subject study number applies). A holder will be provided 
for carrying the subject’s ID card/study stickers together with other records e.g. child 
growth record, immunisation record to avoid double enrolment. 
In the event a child is first detected during hospitalisation (before 1st DTP or aged 5 to < 
18 months) before the active surveillance recruitment is terminated, parents/ LARs will 
be invited to enrol their child in active surveillance. If consenting, they will be provided 
with study-specific stickers and a follow-up visit will be scheduled for active surveillance 
(see Section 9.2.7.1). For all subjects enrolled into active surveillance, study-specific 
stickers with the subject’s study number should be used at health care facilities to identify 
any visit of the subject in the facility register if no other system is in place.  
9.2.7.2.4. Collect demographic data (for subjects not enrolled previously) 
Record socio-demographic data (e.g. date of birth and gender, the number and age of 
persons in the household) and active participation in any trial with an investigational 
product, in the subject’s eCRF. 
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9.2.7.2.5. Record type of health care facility 
Record type of health care facility. 
9.2.7.2.6. Record any serious delay in developmental milestones or physical 
disability (for subjects not enrolled previously and at study conclusion) 
Perform an assessment of developmental milestones and physical disabilities according to 
the study specific guidance document (see Annex 6). 
9.2.7.2.7. Health history 
Record medical history (e.g. chronic co-morbidities, such as known HIV infection, or 
congenital disease, such as known hemoglobinopathies), and perform a physical 
examination. Ask the parent/LAR for any noticed or previously diagnosed abnormalities. 
Record any pre-existing conditions present in a subject prior to the start of the study.  
9.2.7.2.8. Record information about health care seeking behaviour, malaria 
control measures, drug use and exposure to environmental hazards 
Record data on access to care and health care seeking behaviour, neighbourhood of 
residence (urban/rural area), distance from health facilities, use of malaria control 
intervention at individual level (e.g. use of bednets, indoor residual spraying, seasonal 
malaria chemoprevention), information on medication intake (including curative 
antimalarial drugs) during the 14 days preceding onset of symptoms, whether recorded 
(evidence of prescription) or reported (prescribed without any evidence or 
self-medicated). Record also information on medication given as treatment of an AESI, 
meningitis or malaria, information on medication given for chronic therapy, information 
on medication administered in anticipation of a reaction to the vaccination, and exposure 
to environmental hazards such as chemicals (see Section 9.3.3). 
9.2.7.2.9. Record standard vaccinations 
Record all immunisations received, including type and dates, in the eCRF. Update if 
needed with vaccinations received since the last visit. See also Section 9.3.3.1 for 
ascertainment of vaccine history. 
9.2.7.2.10. Record diagnosis  
Record main diagnosis and any secondary diagnoses made by the physicians in the eCRF.  
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9.2.7.2.11. Record haemoglobin measurement 
For all hospitalised subjects, measurement of haemoglobin concentration, if available, at 
hospital entry will be recorded in the eCRF. 
9.2.7.2.12. Record deaths 
In the event of death occurring at the hospital, the cause of death from the medical record 
or the death certificate will be recorded in the eCRF.  
9.2.7.2.13. Record cases of suspected AESI, other AE leading to hospitalisation or 
death, meningitis cases, malaria episodes diagnosed by RDT and/or 
microscopy, abscess at injection site and foot positional deformations 
For all suspected AESI or any meningitis case, details of risk factors, medication history 
and results of the clinical examination and diagnostic testing (see Annex 5) will be 
recorded in the eCRF. A blood sample will be taken for storage for all AESIs and 
meningitis (see Section 9.2.7.3.1). For all cases suspected of meningitis or neurological 
AESIs, a part of the CSF sample, collected according to routine practice, will be stored 
for further confirmatory testing (see Section 9.2.7.3.1). Final diagnosis will be recorded 
in the eCRF.  
Children diagnosed with meningitis, cerebral malaria or with an AESI will be followed 
up after hospital discharge up to study conclusion (i.e. study end or child reaches 5 years 
of age, whichever occurs first) in order to evaluate any sequelae. This will be done by a 
check-up at the hospital 1 month, 6 months and 1 year after hospital discharge.  
Note: Although the study has been early terminated for subjects from the sites in Burkina 
Faso, this follow-up check-up should still be done in case the diagnosis with meningitis, 
cerebral malaria or with an AESI occurred before the termination.  
For all hospitalisations, details of risk factors, medication history and results of the 
clinical examination as well as the final diagnosis will be recorded in the eCRF. 
For suspected malaria, malaria microscopy and/or RDT or other results, such as 
retinoscopy for cerebral malaria (refer to Section 9.2.7.3.1) will be recorded in the eCRF. 
For foot positional deformations and abscess at injection site after routine vaccination, 
record in the eCRF.  
9.2.7.2.14. Record serious adverse events related to a study procedure 
Record any SAE occurring as a result of the blood draw for a suspected AESI or 
meningitis (see Section 11.1.1).  
Refer to Section 11.2 for procedures for the investigator to record SAEs that are related to 
study participation and to Section 11.3 for guidelines on how to report these SAEs to 
GSK Biologicals. 
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9.2.7.2.15. Study conclusion 
Subjects will exit the study when they reach 5 years of age or at study end (whichever 
occurs first), if not earlier due to migration or in the event of death. 
At the study conclusion (home visit), a record will be taken of the subject’s health and 
vital status, any disabilities and all vaccinations received. The investigator will review 
collected data to ensure accuracy and completeness and will complete the Study 
Conclusion screen in the eCRF. 
Note: There might be an overlap of studies EPI-MAL-002 and EPI-MAL-003. For 
children enrolled in enhanced hospitalisation surveillance of EPI-MAL-002, study 
conclusion of EPI-MAL-002 will be done at start of study EPI-MAL-003 (as the vaccine 
becomes available in the study sites that are exposed clusters). Thereafter, these children 
can be eligible and enrolled in active surveillance or in enhanced hospitalisation 
surveillance of EPI-MAL-003 according to the inclusion/ exclusion criteria and the EPI-
MAL-003 recruitment procedures. 
9.2.7.2.16. Outline of study procedures 
Table 5 
List of study procedures to be conducted in the event of 
hospitalisation  
Epoch 
1 
Type of contact 
Hospitalisation 
Visit 
Study Conclusion 
Visit 
(At 5 years of age or 
study end, whichever 
occurs first)7(±2 wks)  
Informed consent (for subjects not enrolled previously in either active 
surveillance or enhanced hospitalisation surveillance) 
● 
 
Check inclusion/exclusion criteria (for subjects not enrolled 
previously) 
● 
 
Assign subject study number (for subjects not enrolled previously) 
● 
 
Provide study ID card (to all subjects not enrolled previously) and 
study-specific stickers (only to subjects identified before 1st DTP or 
aged 5 to <18 months not enrolled previously and enrolled before 
the active surveillance recruitment is terminated) 
○ 
 
Record socio-demographic details and active participation in any trial 
with an investigational product (for subjects not enrolled previously) 
● 
 
Record type of health care facility 
● 
 
Record medical history 
● 
 
Record information about malaria control measures, health care 
seeking behaviour, drug use and exposure to environmental hazards 
● 
 
Record any serious delay in developmental milestones or physical 
disability1 
●6 
● 
Record all vaccinations2 
● 
● 
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Epoch 
1 
Type of contact 
Hospitalisation 
Visit 
Study Conclusion 
Visit 
(At 5 years of age or 
study end, whichever 
occurs first)7(±2 wks)  
For all subjects 
Identify if specific signs and symptoms present (standard for AESI 
screening among all hospitalisations) 
● 
 
Record diagnosis with major symptoms and test results 
● 
 
Record measurement of haemoglobin concentration 
● 
 
Record any cases of death and cause of death 
● 
 
Record risk factors 
● 
 
Record medication history 
● 
 
Confirm diagnoses at discharge 
● 
 
Only for subjects with suspected AESI, cerebral malaria or meningitis 
Consult specialised health care professional, if required3 
● 
 
Record clinical examination and additional testing according to 
clinical diagnosis for suspected AESI4, cerebral malaria or meningitis 
● 
 
For each diagnosis of an AESI or meningitis, collect approx. 5 mL of 
whole blood and store serum 5 
● 
 
For each diagnosis of a neurological AESI or meningitis, where a 
CSF sample has been taken as part of routine practice, store part of 
the CSF sample (minimum 500 µL)5 
● 
 
Record any SAE occurring as a result of blood draw for a suspected 
AESI or meningitis 
● 
 
Follow-up children up to study conclusion, by a check-up at the 
hospital 1 month, 6 months and 1 year after hospital discharge  
● 
 
Only for subjects with suspected malaria 
For suspected malaria, record malaria microscopy and/or RDT or 
other result 
● 
 
Study conclusion  
 
● 
Hospitalisation visits: subjects aged < 5 years, to include subjects referred in between active surveillance visits. 
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the eCRF 
1. See Annex 6 
2. All immunisations will be recorded 
3. See Study Procedures Manual (SPM) 
4. See Annex 5 
5. See Section 9.2.7.3.1 
6. For subjects not enrolled previously  
7. Because of a possible overlap of studies EPI-MAL-002 and EPI-MAL-003, study conclusion of EPI-MAL-002 for 
children enrolled in enhanced hospitalisation surveillance will be done at start of study EPI-MAL-003 (as the 
RTS,S/AS01E vaccine becomes available in the sites that are exposed clusters). 
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9.2.7.3. 
Biological sample handling and analysis 
9.2.7.3.1. Biological samples 
All enrolled subjects admitted to the hospital are expected to have routine laboratory tests 
performed according to good medical practice and routine practice (see Section 9.2.7.5), 
including, but not limited, to: 
• 
All hospitalised children: haemoglobin concentration or full blood count  
• 
Malaria suspects: Access to diagnosis of malaria using RDT and/or microscopy 
according to routine practice will be ensured for all children clinically suspected of 
malaria during active surveillance and at all the health care facilities. 
• 
Meningitis suspects: CSF examination (and blood culture if feasible) according to 
routine practice (first line testing). 
• 
Neurological diseases such as seizures, encephalitis, Acute Disseminated 
Encephalo-Myelitis (ADEM), Guillain Barre syndrome suspected: require 
neurological investigations (e.g. magnetic resonance imaging if available), 
eventually CSF analysis and other laboratory testing according to routine practice.  
• 
Some AESI (such as diabetes mellitus, renal failure, hepatic failure, severe 
thrombocytopenia with bleeding) require laboratory testing for case management. 
For all hospitalised children suspected of having an AESI or meningitis, a sample of 
approximately 5 mL of whole blood will be collected; a sample of at least 500 µL of CSF 
would be ideally collected for all cases of a suspected neurological AESI (seizures, 
encephalitis, ADEM, Guillain Barre syndrome suspected) or meningitis, when a CSF 
sample is taken as part of routine practice. 
Full details for obtaining, storing and shipment of biological samples are provided in the 
Study Procedures Manual (SPM) accompanying this protocol.  
Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number).  
Collected samples will be used for protocol mandated research. In addition, these samples 
may be used to perform research related to the improvement, development and quality 
assurance of the laboratory tests described in this protocol. This may include the 
management of the quality of these tests, the maintenance or improvement of these tests, 
the development of new test methods, as well as making sure that new tests are 
comparable to previous methods and work reliably. 
It is also possible that future findings may make it desirable to use the samples acquired 
in this study for future research, not described in this protocol. Therefore, all subjects in 
countries where this is allowed will be invited to give another specific consent to allow 
GSK or a contracted partner to use the samples for future research including development 
of tests and their quality assurance. Future research will be subject to the laws and 
regulations in the respective countries and will only be performed once an independent 
Ethics Committee or Review Board has approved this research. 
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Information on further investigations and their rationale can be obtained from GSK 
Biologicals.  
Any sample testing, in the context of the study, will be done in line with the consent of 
the individual subject’s parent(s)/LAR(s). 
Refer also to the Investigator Agreement (Annex 9), that notes that the investigator 
cannot perform any other biological assays except those described in the protocol or its 
amendment(s).  
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit/contact), unless local rules, regulations or 
guidelines require different timeframes or different procedures, which will then be in line 
with the subject consent. These extra requirements need to be communicated formally to 
and discussed and agreed with GSK Biologicals. 
9.2.7.3.2. Laboratory assays 
Any biological sample evaluation will be limited to the scope of this study and only 
related to assessment of study endpoints; it could include, for example, serology or 
deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) for infectious diseases or 
confirmatory tests for autoimmune diseases.  
For all required biological sample evaluations, details of assay type, assay method, test 
kit/manufacturer and laboratory used, as applicable for the test conducted, will be 
recorded. 
GSK will ensure that all consumables and reagents are available to perform first line 
routine testing for all diseases under investigation, according to good medical practice 
and routine practice. In case second line confirmatory testing is required (for instance 
PCR for meningitis or antibody testing for auto-immune AESI), samples will be sent to a 
qualified referral second line laboratory in South Africa (Clinical Laboratory Services 
[CLS]). 
9.2.7.4. 
Management of AESI, other AE leading to hospitalisation or death, 
meningitis cases, malaria episodes, abscess at injection site and foot 
positional deformations 
Children showing defined signs and symptoms during a follow-up visit will be referred to 
a health care facility for further assessment if in need of investigation and care. 
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9.2.7.4.1. Case ascertainment for meningitis 
Meningitis case identification 
At the site level, a suspected meningitis case, based on clinical symptoms and/or signs is 
defined as [adapted from WHO, 2003]: 
A child with sudden onset of fever (> 38.0 °C rectal or 37.5 °C axillary) and one or more 
of the following signs: neck stiffness, altered consciousness with no other alternative 
diagnosis, or other meningeal sign such as bulging fontanelle in children under one year 
of age. 
Meningitis case characterisation 
Further characterisation of a suspected meningitis case will imply performing a lumbar 
puncture for examination of CSF (and blood culture if feasible) and etiological (bacterial, 
viral, protozoal or fungal) search with a two-step laboratory approach. 
Lumbar puncture will be performed according to routine medical practice. The diagnosis 
of bacterial meningitis will first be made on site, based on CSF macroscopic and 
microscopic examinations and blood culture if feasible (first line laboratory results). CSF 
tests will include selective culture for Neisseria meningitidis, Streptococcus pneumoniae 
and Haemophilus influenza type b; latex agglutination tests for detection of bacterial 
antigens (Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenza 
type b), Gram stain, white blood cell counts and cell differentiation and biochemistry 
testing (protein and glucose). Cryptococcal infection will be diagnosed using Indian ink, 
for HIV-positive children and those with unknown HIV-status, if feasible.  
In addition, an external laboratory based in South Africa (CLS) is contracted to 
harmonize laboratory procedures, to provide Quality Assessment and Quality Control and 
to train laboratory technicians in all sites. If needed, GSK will supplement reagents and 
consumables to ensure that all diagnostic procedures can be conducted according to 
protocol. 
Based on these first examinations, the diagnosis of bacterial meningitis will be made by 
the physicians in charge of the children, with support from RAFT upon request from the 
investigators. Job Aids for medical staff and training on standardized diagnosis are put in 
place in EPI-MAL-002 to improve the sensitivity and specificity of the case diagnosis for 
all meningitis. Decisions to start treatment of children with suspected meningitis will be 
based on the medical routine practice, and should not be delayed by the second line 
laboratory investigations. 
All collected CSF samples, regardless of first line testing outcome, will be shipped to a 
referral second line laboratory based in South Africa (CLS; unique for all sites) for 
identification of bacterial, viral, protozoal and fungal meningitis using molecular testing 
such as PCR. 
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Final meningitis case ascertainment 
For the purpose of this study, a panel of experts will be set up and a charter will be 
defined. As much as possible, the same experts will be involved in the case ascertainment 
process for studies EPI-MAL-002 and EPI-MAL-003, using the same rules and charter. 
A specific subgroup of two experts will perform case ascertainment following strictly the 
definitions for meningitis as described in Section 9.2.5.3. The two experts will 
independently review all meningitis cases. They will use all available medical 
information (including the first line and second line laboratory results) and classify the 
meningitis cases according to the case definitions. They will also be provided with all the 
data available in the eCRF (e.g. medical and family history, physical examination, 
clinical presentation/picture, laboratory results, concomitant medication/vaccination and 
any other relevant information identified in patient medical records). If the two experts 
cannot reach an agreement, then the different clinical opinions of the experts will be 
listed. This final classification (strictly following the case definitions) will be used for the 
statistical analyses. 
Additional follow-up of meningitis cases 
After hospital discharge, meningitis cases will be followed up to study conclusion (i.e. 
study end or child reaches 5 years of age, whichever occurs first) in order to evaluate any 
sequelae. This will be done by a check-up at the hospital 1 month, 6 months and 1 year 
after hospital discharge. 
9.2.7.4.2. Case ascertainment for AESI 
In the event of diagnosis of a disease specified as an AESI during routine care, case 
ascertainment will result in a diagnosis reaching the highest level of case definition at the 
hospital possible (see Table 3 and Annex 5). As part of good medical practice, study 
clinical staff will ensure appropriate diagnostic testing and adequate care to enrolled, 
hospitalised children diagnosed with a disease specified as an AESI as per National 
guidance (see Section 9.2.7.5). As diagnosis of these events may be challenging, the 
investigators and site physicians will be supported by specialized health care 
professionals, if required (see Section 9.2.7.6). 
In addition, a panel of experts in the different fields will perform ascertainment of AESI 
with an uncertain diagnosis and outcome after review by the GSK safety physician. These 
cases will be flagged in the eCRF during the manual cleaning by the GSK safety 
physician, for external expert review. Two selected experts will independently review the 
cases. They will be provided with all available medical information (e.g. medical and 
family history, physical examination, clinical presentation/picture, laboratory results, 
concomitant medication/vaccination and any other relevant information identified in 
patient medical records) and classify the cases according to the case definitions (Annex 
5). Anonymized copies of the medical records including laboratory results and technical 
examinations may be requested by the experts. If the two experts cannot reach an 
agreement, then the different clinical opinions of the experts will be listed. This final 
classification (strictly following the case definitions) will be used for the statistical 
analyses. 
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Children diagnosed with an AESI, will be followed up after hospital discharge up to 
study conclusion (i.e. study end or child reaches 5 years of age, whichever occurs first) in 
order to evaluate any sequelae. This will be done by a check-up at the hospital 1 month, 
6 months and 1 year after hospital discharge. 
9.2.7.4.3. Children suspected of having a serious adverse event (SAE) 
As part of good medical practice enrolled children presenting at health facilities 
(outpatient and inpatient) with signs and symptoms of SAEs (see Section 11), are 
expected to receive appropriate diagnostic testing and care by clinical staff following 
standard care in the country (see Section 9.2.7.5). 
9.2.7.4.4. Case ascertainment for other AE leading to hospitalisation or death 
Other AE leading to hospitalisation or death with an uncertain diagnosis and outcome 
after review by the GSK safety physician will be reviewed by the external panel of 
experts. These cases will be flagged in the eCRF during the manual cleaning by the GSK 
safety physician, for external expert review. Two selected experts will independently 
review the cases. They will be provided with all available medical information (e.g. 
medical and family history, physical examination, clinical presentation/picture, 
laboratory results, concomitant medication/vaccination and any other relevant 
information identified in patient medical records) and classify the cases. Anonymized 
copies of the medical records including laboratory results and technical examinations 
may be requested by the experts. If the two experts cannot reach an agreement, then the 
different clinical opinions of the experts will be listed. This final classification will be 
used for the statistical analyses. 
9.2.7.4.5. Case ascertainment for malaria 
Enrolled children presenting at health facilities (outpatient and inpatient) with signs and 
symptoms of malaria will receive malaria testing (RDT and/or microscopy) as part of 
standard care in the country (see Section 9.2.7.5). As part of good medical practice the 
clinical staff will ensure that all subjects diagnosed with malaria will receive adequate 
care following national guidelines. 
GSK will consider the following definition for cerebral malaria cases: severe 
P. falciparum malaria with impaired consciousness (Glasgow coma score < 11 in 
children ≥ 2 years of age or Blantyre coma score < 3 in children < 2 years of age), and, if 
malaria with seizure: coma persisting for > 30 min after the seizure (see Section 9.2.5.5 
[WHO, 2015(b)]). It should be noted that these coma scores are not specific for malaria 
and other treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis) should be 
excluded. Therefore each severe malaria case will be reviewed by GSK medical staff 
according to standard procedure for signal detection. In addition, a panel of experts will 
perform case ascertainment. The same procedures will be followed as for meningitis and 
AESI. Two selected experts will independently review all cerebral malaria cases and 
severe malaria cases with an uncertain diagnosis and outcome after review by the GSK 
safety physician. These last cases will be flagged in the eCRF during the manual cleaning 
by the GSK safety physician, for external expert review. They will be provided with all 
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available medical information (e.g. medical and family history, physical examination, 
clinical presentation/picture, laboratory results, concomitant medication/vaccination and 
any other relevant information identified in patient medical records) and classify the 
cases according to the case definitions (see Section 9.2.5.5). Anonymized copies of the 
medical records including laboratory results and technical examinations may be requested 
by the experts. If the two experts cannot reach an agreement, then the different clinical 
opinions of the experts will be listed. This final classification will be used for the 
statistical analyses. 
Children diagnosed with cerebral malaria will be followed up after hospital discharge up 
to study conclusion (i.e. study end or child reaches 5 years of age, whichever occurs first) 
in order to evaluate any sequelae. This will be done by a check-up at the hospital 1 
month, 6 months and 1 year after hospital discharge. 
9.2.7.4.6. Children with abscess at injection site  
Enrolled children presenting at health facilities (outpatient and inpatient) with abscess at 
the injection site following routine vaccination will receive appropriate care as part of 
good medical practice (see Section 9.2.7.5).  
9.2.7.4.7. Children with foot positional deformations 
As part of good medical practice it is expected that enrolled children presenting at health 
facilities (outpatient and inpatient) with foot positional deformations will be referred to 
hospital for medical diagnosis and provision of appropriate care following standard 
practice in the country (see Section 9.2.7.5).  
9.2.7.5. 
Package for standard of care 
Any child participating in active surveillance presenting at primary health care level 
should have access to basic care that can be dispensed at this level, including: 
• 
Consultation, Essential Medicines, RDT and any laboratory test available, if needed 
for diagnosis. 
• 
Treatment for common diseases including malaria. 
At the hospital level, any child enrolled in the study should have access to care and 
treatment as available, including: 
• 
Admission and emergency care, diagnostic testing including laboratory and 
radiological examinations, treatment and care until discharge. 
• 
For protocol-defined AESI and meningitis: diagnostic testing according to the 
algorithms (see medical Job Aid) and treatment required until the end of the study. 
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9.2.7.6. 
Capacity building 
• 
As diagnosis of AESI, or meningitis in the study sites may be challenging, training 
will be conducted and diagnosis will be supported by specialised health care 
professionals: 
– 
The Agence de Médecine Préventive (AMP, http://amp-vaccinology.org) will 
provide intensive training for the study staff, community health workers and 
health care professionals working at all health care facilities in the study area on 
diagnosis of AESI, meningitis, and on pharmacovigilance. Appropriate training 
packages and educational material will be developed. The community health 
workers involved in active surveillance will be trained to recognize clinical 
symptoms, using simplified visual aids (non-medical Job Aid). Health care 
professionals will be trained using medical Job Aid, developed to facilitate 
diagnosis using decision-making algorithms.  
– 
In addition, all sites will have access to online continued medical education, 
training packages (including training on AESI, meningitis, HIV and 
hemoglobinopathies) and a telemedicine system established by RAFT (Réseau 
en Afrique Francophone pour la Télémédecine, Geneva; 
http://raft.globalhealthforum.net). The latter will allow the investigators to 
discuss cases with their colleagues and with medical experts.  
In EPI-MAL-002, health care staff (including EPI staff) and study staff will be 
trained in pharmacovigilance procedures. This training will also be provided to any 
new health care and study staff hired during the course of that study or for study 
EPI-MAL-003 using the same materials.  
• 
Laboratory support 
GSK will ensure that all first line laboratory diagnostic procedures can be conducted 
according to routine practice by complementing reagents and consumables where 
needed. Specifically, if necessary, lumbar puncture kits and malaria RDT will be 
provided to the sites to facilitate adherence to the routine procedures required for 
diagnosis of meningitis and malaria. In addition, an external laboratory, CLS, is 
contracted to provide Quality Assessment & Control and training for laboratory 
technicians. 
CLS will perform PCR and serology testing on CSF and serum samples in order to 
complement the diagnosis done by the first line laboratory. 
(Amended 5 May 2020) 
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9.2.8. 
Study procedures during special circumstances  
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled participants:  
• 
Active safety follow-up through home visits may be made by a telephone call or 
other means of virtual contact. It is acknowledged that the systematic 
measurement of body temperature may not be performed. 
• 
For children diagnosed with AESI, meningitis or cerebral malaria, the check-up at 
the hospital at 1 month, 6 months and 1 year after hospital discharge may be 
replaced by a telephone call or other means of virtual contact. 
• 
A retrospective data collection of medical events may be implemented at any of the 
health care facilities. 
(Amended 5 May 2020) 
9.3. 
Variables 
Endpoints are aligned in EPI-MAL-002 and EPI-MAL-003. 
9.3.1. 
Co-primary endpoints 
In children living in the study area, prior to implementation of RTS,S/AS01E: 
• 
Occurrence of AESI (see Section 9.2.5.1 for definition). 
• 
Occurrence of other AE leading to hospitalisation or death (see Sections 9.2.5.2 and 
9.2.5.8 for definitions). 
• 
Occurrence of aetiology-confirmed meningitis (see Section 9.2.5.3 for case 
definition). 
9.3.2. 
Secondary endpoints 
In children living in the study area, prior to implementation of RTS,S/AS01E: 
• 
Occurrence of probable meningitis (final classification) (see Section 9.2.5.3 for case 
definition). 
• 
Occurrence of clinically suspected meningitis (final classification) (see Section 
9.2.5.3 for case definition). 
• 
Occurrence of meningitis cases identified at site level (first line laboratory) (see 
Section 9.2.5.3 for case definition). 
• 
Occurrence of hospitalisation (including those attributed to an AESI, other AE, 
meningitis, or malaria) or death. 
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• 
Occurrence of febrile convulsions during the 7-day period (Days 0-6) and 1-month 
period (Days 0-29) following administration of routine EPI vaccines (see Section 
9.2.5.4 for case definition). 
• 
Occurrence of two events used as surveillance quality indicators: abscess at injection 
site during the 7-day period (Days 0-6) following any routine vaccination and foot 
positional deformation (see Section 9.2.6 for case definitions). 
• 
Occurrence of episodes of malaria using RDT and/or microscopy 
− 
Any malaria (including P. falciparum malaria) (see Section 9.2.5.5 for case 
definition). 
− 
Severe malaria (including P. falciparum malaria) (see Section 9.2.5.5 for case 
definition). 
− 
Cerebral malaria (see Section 9.2.5.5 for case definition). 
• 
Occurrence of anaemia (see Section 9.2.5.6 for case definitions) at hospital entry 
among hospitalised children. 
• 
Occurrence of hospitalisation 
− 
All causes and hospitalisations for any malaria (including P. falciparum 
malaria), severe malaria (including P. falciparum malaria) and cerebral malaria 
(see Section 9.2.5.7 for case definitions). 
• 
Occurrence of death 
− 
All causes and malaria attributed deaths (including P. falciparum malaria 
attributed death) (see Section 9.2.5.8 for case definitions). 
− 
AE attributed deaths (see Section 9.2.5.8 for case definitions). 
9.3.3. 
Patient characteristics and potential confounding variables 
9.3.3.1. 
Recorded in EPI-MAL-002 and EPI-MAL-003 
For all enrolled subjects, socio-demographic characteristics, data on access to care and 
health care seeking behaviour, neighbourhood of residence (urban/rural area), distance 
from health facilities, use of malaria control intervention at individual level (e.g. use of 
bednets, indoor residual spraying, seasonal malaria chemoprevention), information on 
medication intake (including curative antimalarial drugs) during the 14 days preceding 
onset of symptoms, whether recorded (evidence of prescription) or reported (prescribed 
without any evidence or self-medicated) will be recorded in the eCRF. Information on 
medication given as treatment of an AESI, meningitis or malaria, information on 
medication given for chronic therapy, information on medication administered in 
anticipation of a reaction to the vaccination, and exposure to environmental hazards such 
as chemicals will also be recorded. Data on vaccination, more specifically, dates and 
doses of EPI vaccine administration, as well as data on medical history including co-
morbidities (e.g. chronic diseases, such as known HIV infection), or diagnosed congenital 
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diseases, such as known hemoglobinopathies, will also be collected. In case of 
hospitalisation, type of health care facility will be collected. 
For children enrolled in enhanced hospitalisation surveillance or hospitalised children in 
active surveillance, additional information on co-morbidities will be captured such as 
malnutrition, chronic diseases, known HIV infection status, known hemoglobinopathies. 
Of note, the vaccine history will be ascertained for all enrolled subjects through the 
following channels: individual vaccination cards, vaccination registers at the health care 
facilities and vaccination data collected during study area census rounds. If any of the 
sources described here above confirm vaccination, it will be assumed that vaccination has 
taken place for the analysis. 
9.3.3.2. 
Recorded in EPI-MAL-005 
Malaria transmission intensity (MTI) data will be collected through EPI-MAL-005 (see 
Section 9.4.3 for more detail). Rainfall and humidity, where available, will be collected at 
the study area level. Bednet use, seasonal malaria chemoprevention and other malaria 
control measures will also be collected at the HDSS or equivalent surveillance system 
(population) and individual level (which will be summarized at centre level). 
The P. falciparum parasite prevalence will be measured as a way to characterise the MTI. 
The P. falciparum parasite prevalence will be computed as the proportion of subjects 
infected with P. falciparum parasitaemia divided by the total number of subjects tested, 
and will be estimated through annual cross sectional surveys (study start, every 
12 months, and study end) during malaria peak transmission, in subjects at least 6 months 
and less than 10 years of age at the time of survey. These estimates will be calculated for 
each year and for each site separately. 
9.4. 
Data Sources 
9.4.1. 
Health Demographic Surveillance System (or equivalent 
surveillance system) 
Each HDSS or equivalent surveillance system site maintains a demographic database 
which is updated on a regular basis to include births, deaths, immigrations and 
emigrations. Data regarding vaccinations is also included in the study site database. This 
information is obtained through census rounds (at least once a year) and constantly 
updated in between the rounds with the help of key-informants living in the community. 
Cause of deaths is established by trained fieldworkers using the INDEPTH Standard 
Verbal Autopsy Questionnaire [INDEPTH, 2003] for children who died at home. From 
this database, the listing of children at the beginning of the study will provide the study 
site with a basis for recruitment of children <18 months old for active surveillance and 
for the total number of children < 5 years of age recorded at least once a year during the 
study duration. During the study, further newborns may be identified by one of several 
possible mechanisms (depending on the site): by subsequent HDSS or equivalent 
surveillance system updates, by existing community-based informers who report new 
births/deaths/other events to the study sites between censuses, at the time of first EPI 
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vaccination (e.g. BCG vaccination or first DTP/HepB/Hib vaccination), or at birth (if 
born at a health care facility).  
If a site is not part of the INDEPTH network, or does not have an equivalent surveillance 
system in place, the INDEPTH procedures for demographic census and for verbal 
autopsy might be implemented to ensure consistency across study sites. 
9.4.2. 
Active surveillance and enhanced hospitalisation surveillance of 
study EPI-MAL-002 
Subjects enrolled in active surveillance will have data collected during home visits, 
outpatient visits and hospitalisations at all health care facilities, while subjects enrolled in 
enhanced hospitalisation surveillance will have data collected during hospitalisation only 
(see also study procedures in Section 9.2.7). 
The surveillance system should be embedded into all health care facilities (including 
community health care services and potential mobile teams) of the study area. 
The first level of screening will be done at the community level during follow-up visits 
by study community health workers who will be trained to recognise signs and symptoms 
of AESI and meningitis. Any subject presenting with specific signs or symptoms, as 
described by the Job Aid tool, will be referred to the health care facility (usually primary 
care facility) where the public health care staff will perform clinical assessment according 
to routine practice (see Section 9.2.7.5). If a suspected AESI, meningitis or severe 
malaria, including cerebral malaria, case is detected at the primary health care facility 
level, the subject will be referred to a higher level health care facility (hospital) to 
confirm the diagnosis based on the highest level of diagnostic certainty available (see 
Annex 5). If another event is detected at the primary health care facility level, the study 
participant might be referred to a higher level health care facility according to the routine 
practice. In the case of a seriously sick child, this child will be referred directly to the 
hospital by the community health worker.  
Training on AESI and meningitis diagnosis, HIV and hemoglobinopathies will be 
provided and support will be available from specialised health care professionals to 
confirm diagnosis (see SPM for details) (see Section 9.2.7.6). 
The surveillance system will also be implemented in the study area at each health care 
level within the HDSS or equivalent surveillance system catchment area. Health care 
workers will record all outpatient visits (referral and non-referral) of subjects enrolled in 
the active surveillance up to the end of the active follow-up) on a register allowing for the 
collection of basic data (e.g. date of visit, clinical diagnoses and rapid testing 
confirmation, referral or treatment). In case appropriate registers are not available in the 
facilities, study registers should be developed. At enrolment, subjects participating in 
active surveillance will be given study specific stickers with the subject’s study number. 
The stickers can be used on the health care facility’s registers if no other system is in 
place to indicate a subject’s visit and facilitate identification of data from enrolled 
subjects from the facility’s register. The recorded data will be collected retrospectively on 
a regular basis and encoded in the eCRF. 
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Every day, study staff will perform a round at hospitals and other health care facilities 
(with hospitalisation facility) to see all newly hospitalised children that could be eligible 
for the study. Parents/LARs of eligible children not yet enrolled into the study should be 
asked if they would agree to their child’s participation and signed or witnessed and 
thumbprinted informed consent shall be obtained. 
The monthly total number of hospitalised children < 5 years of age will be recorded in the 
logbook monthly for the study duration, for the purpose of the aggregated data analysis. 
All enrolled hospitalised children will have their diagnosis recorded with main symptoms 
and results from routinely performed confirmatory tests. In the case of AESI and 
meningitis, additional information should be recorded according to clinical and 
laboratory standard of diagnosis (see Annex 5). Study staff will complete the eCRF 
containing all relevant information for each enrolled subject, to include an International 
Classification of Diseases (ICD) code allocated by a physician. All enrolled hospitalised 
subjects diagnosed with suspected AESI or meningitis will have a sample of 
approximately 5 mL of whole blood taken; in the case of neurological AESI or meningitis 
requiring a CSF sample according to routine practice, where possible, an additional 
aliquot will be reserved (for details refer to Section 9.2.7.3.1). Admitted subjects are 
expected to receive care by hospital staff following National guidance. As part of good 
medical practice, the clinical staff will ensure that sick subjects admitted to hospital will 
receive adequate care provided by health care facilities (see Section 9.2.7.5).  
AESI, other AE leading to hospitalisation or death, meningitis, or malaria will be 
recorded in the eCRF. Data entry is described in Section 9.6.  
The investigator will assess the maximum intensity (mild, moderate, severe) that 
occurred over the duration of the event for all AESI, other AE leading to hospitalisation 
or death, meningitis, or malaria reported during the study. The assessment will be based 
on the investigator’s clinical judgement. 
9.4.3. 
Study EPI-MAL-005 
The RTS,S/AS01E vaccine is expected to be introduced through national immunisation 
systems, and will lead to a reduction in the incidence of P. falciparum malaria in 
vaccinated subjects in EPI-MAL-003 when compared to baseline rates recorded in 
EPI-MAL-002. Annual fluctuations in malaria incidence occur as a result of changes in 
transmission intensity, which may be caused by changes in environmental factors such as 
rainfall or changes in usage of other malaria control interventions (use of bednets for 
example). Therefore, by taking into account these variations in MTI and malaria control 
intervention coverage, more accurate estimations of the vaccine impact on malaria 
disease using RDT and/or microscopy during EPI-MAL-003 will be possible.  
In EPI-MAL-005, the following parameters will be assessed: estimates of P. falciparum 
parasite prevalence and of the use of malaria control interventions at community level, 
changes in environmental factors such as rainfall, changes in health care seeking 
behaviour, within-site geographical heterogeneity in MTI and individual malaria 
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prevention measures and risk factors for clinical malaria. Compliance with DTP-based, 
measles and RTS,S/AS01E vaccines will also be collected. 
EPI-MAL-005 started in Q4 2014 and is planned to run in parallel with EPI-MAL-002 
and EPI-MAL-003, in similar if not identical settings. Its primary objectives are to 
estimate the annual parasite prevalence and record malaria control measures, providing 
information on potential confounding factors relevant to interpreting EPI-MAL-002/003 
outcome measures. 
It may happen that subjects enrolled in EPI-MAL-002 are also enrolled in EPI-MAL-005. 
Cases of malaria detected only during the annual home visits planned for EPI-MAL-005 
will not be included in the analysis of EPI-MAL-002. However, if the cases of malaria 
are detected during an EPI-MAL-005 home visit that coincides with a home visit 
scheduled in EPI-MAL-002, the events will be captured in EPI-MAL-002.  
9.5. 
Study size 
The study targets enrolling 15,000 children per group (i.e. 6-12 weeks group or 
5-17 months group; with about 10,000 children of 15,000 in each group enrolled where 
the RTS,S/AS01E vaccine will be implemented), for a total of 30,000 children with at 
about 20,000 children enrolled where the RTS,S/AS01E vaccine will be implemented. 
Burkina Faso sites are planned to early terminate any study activities by Q2 2019. As a 
consequence, the data from those sites will be presented in the progress reports up to Q4 
2019, but none of those data will be part of the statistical analyses for the interim and 
final reports. There will be a full follow-up of about 10000 and not 15,000 children. 
The co-primary objectives will estimate the incidence of AESI and meningitis. The 
precision of the estimate is related to the incidence and the period at-risk of these events 
following any dose (or equal point in time for 5-17 months group), with a censoring of 
the follow-up time when the subject receives the next dose. For some of the AESI the 
incidence could be very rare (around 1/100,000 person-years [PY]) and the period at-risk 
considered could be from 2 weeks till 6 months for AESI, and 12 months for meningitis.  
Table 6 provides an estimation of the 95% CIs based on:  
• 
A sample of 10,000 children per group (either 10,000 in the 6-12 weeks group, or 
10,000 in the 5-17 months group) where the RTS,S/AS01E vaccine will be 
implemented; 
• 
Different numbers of detected events (for the less frequent events): 1, 3 or 5 events; 
• 
Different risk periods following dose administration (with censoring to one month 
for the two first doses). 
• 
A follow-up corresponding to the risk period after the virtual dose 4. 
For example, the 95% CI around an observed incidence of 25.2 per 100,000 PY 
(corresponding to 1 event detected, in a risk period of 6 weeks following each dose 
[censored at the administration of the following dose], based on 10,000 subjects) will be 
[0.6, 140.2]. Other assumptions are displayed in Table 6. 
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Table 6 
Estimation of the lower (LL) and upper (UL) limits of observed 
incidences of events following dose administration based on 
10,000 subjects, different numbers of detected events, and different 
risk periods  
 
Note: 95% confidence interval limits are computed using the Poisson exact method [Ulm, 1990]. 
In addition, these incidences will be estimated, using the data collected for both active 
and enhanced hospitalisation surveillances, for all children less than 5 years of age during 
the study. Table 7 provides an estimation of the 95% CIs for the surveillances for all 
children less than 5 years of age based on:  
• 
A birth cohort of 11,500 children; 
• 
A follow-up of 2 years (for the enhanced hospitalisation surveillance, before the start 
of the EPI-MAL-003 study); 
• 
Different numbers of detected events (for the less frequent events).  
No. of events
Period at risk
Total 
person-years
Incidence
(in 100,000 PY)
LL
(in 100,000 PY)
UL
(in 100,000 PY)
1
2 weeks
1538.46
65.0
1.6
362.2
1
6 weeks
3974.36
25.2
0.6
140.2
1
3 months
6666.67
15.0
0.4
83.6
1
6 months
11666.67
8.6
0.2
47.8
1
12 months
21666.67
4.6
0.1
25.7
3
2 weeks
1538.46
195.0
40.2
569.9
3
6 weeks
3974.36
75.5
15.6
220.6
3
3 months
6666.67
45.0
9.3
131.5
3
6 months
11666.67
25.7
5.3
75.1
3
12 months
21666.67
13.8
2.9
40.5
5
2 weeks
1538.46
325.0
105.5
758.4
5
6 weeks
3974.36
125.8
40.8
293.6
5
3 months
6666.67
75.0
24.4
175.0
5
6 months
11666.67
42.9
13.9
100.0
5
12 months
21666.67
23.1
7.5
53.9
Events in different at-risk periods following dose administration (per age group)
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For example, the 95% CI around the observed incidence of 21.7 per 100,000 PY 
(25 events detected) will be [14.1, 32.1]. Other assumptions are displayed in Table 7. 
Table 7 
Estimation of the lower (LL) and upper (UL) limits of observed 
incidences of events among all children less than 5 years of age 
based on 11,500 birth cohort, and different numbers of detected 
events  
 
Note: 95% confidence interval limits are computed using the Poisson exact method [Ulm, 1990]. 
9.6. 
Data management 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/ transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designate. In all cases, the 
investigator remains accountable for the study data.  
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the clinical study 
report is complete and approved by all parties. 
9.7. 
Data analysis 
All analyses will be specified in detail in the supporting document, the Statistical 
Analysis Plan (SAP). 
Analyses will be based on about 20,000 children enrolled where the RTS,S/AS01E 
vaccine will be implemented. Descriptive statistics will be computed by age group, study 
site and overall, as well as by type of surveillance. 
No. of events
Period at risk
Total 
person-years
Incidence
(in 100,000 PY)
LL
(in 100,000 PY)
UL
(in 100,000 PY)
1
2 years
115000
0.9
0.0
4.8
5
2 years
115000
4.3
1.4
10.1
25
2 years
115000
21.7
14.1
32.1
50
2 years
115000
43.5
32.3
57.3
Events in all children < 5 years during a follow-up of 2 years
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Moreover, descriptive analysis of safety endpoints will be computed for specific 
sub-populations such as children with hemoglobinopathy and HIV-positive children. 
Burkina Faso sites are planned to early terminate any study activities by Q2 2019. As a 
consequence, a description of data from those sites will be presented in the progress 
reports up to Q4 2019, but none of these data will be part of the statistical analyses for the 
interim and final reports. There will be a full follow-up of about 10000 and not 15,000 
children. 
9.7.1. 
Total cohort 
The Total cohort will include all subjects enrolled in the study. All the information for 
these subjects will be collected in the eCRF (after receiving signed or witnessed and 
thumb printed informed consent).  
9.7.2. 
According-to-protocol (ATP) cohort 
The ATP cohort will include all evaluable subjects (i.e. those meeting all eligibility 
criteria, complying with the procedures defined in the protocol, with no elimination 
criteria during the study). 
A detailed, comprehensive list of reasons for elimination from ATP analyses will be 
established at the time of data cleaning. 
All analyses will be conducted on the ATP cohort, unless otherwise detailed. The 
analyses will be done also on the Total cohort only if there are more than 5% of 
eliminated subjects; except for the demography where all the tables will be performed for 
both cohorts. 
9.7.3. 
Derived and transformed data 
Age at time of enrolment in the study will be computed as the difference between the date 
of enrolment (date of ICF) and the date of birth. The age will be expressed in months or 
in years.  
For each AESI, the Time-to-Onset will be defined as the difference between the AESI 
onset date and the immunisation date of the most recently administered vaccine (when 
applicable) or the date 1 week prior to the most recent visit between the 3 first study 
visits. This second possibility is applicable for the 5-17 months group of children as they 
do not follow study visits according the EPI DTP/HepB/Hib vaccine administration 
schedule, in order to mimic study procedures in the subsequent EPI-MAL-003 study. 
Time-to-Onset will be expressed in days. 
For all enrolled subjects, the vaccine history will be summarized. As detailed in Section 
9.3.3.1, vaccine history will be collected from different sources. If any of the sources 
confirm vaccination, it will be assumed that vaccination has taken place. 
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9.7.4. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
9.7.4.1. 
Sequence of analyses 
Progress reports including listings and statistical tables for description of AESI, other AE 
leading to hospitalisation or death, meningitis and malaria, including severe malaria and 
cerebral malaria, will be produced every 6 months. Of note, data from Burkina Faso sites 
were part of the previous progress reports and will also be part of the progress reports 
planned up to Q4 2019. 
An interim analysis will be performed when the RTS,S/AS01E vaccine will be 
implemented in most of the study sites. This interim analysis will be done with clean 
data* collected on a sub-group of subjects from sites where the vaccine will be 
implemented having 6 months of follow-up following the administration of dose 3 of 
DTP/HepB/Hib vaccine (6-12 weeks group), or 6 months after V3 (5-17 months group); 
corresponding to V5. 
Of note, further details will be provided in the SAP. 
* Some data may change after the interim analysis as access to the eCRF will still be 
granted to sites and investigators throughout the follow-up period, until study conclusion. 
Final analysis will be carried out on clean data collected on study conclusion. 
9.7.5. 
Analysis of co-primary objectives 
9.7.5.1. 
Analysis population 
The population will include the subjects from the active surveillance of the 
EPI-MAL-002 study. 
A secondary population will include the subjects from the active and enhanced 
hospitalisation surveillance of the EPI-MAL-002 study, computing incidence for all 
children < 5 years. 
9.7.5.2. 
Statistical approach 
9.7.5.2.1. Incidence of AESI, and other AE leading to hospitalisation or death 
The incidence rate of each AESI and other AE leading to hospitalisation or death will be 
calculated by dividing the number of subjects reporting at least one event over the 
follow-up period by the total person-time. A 95% CI will be computed using an exact 
method for a Poisson variable. The at-risk period will follow any dose, with a censoring 
of subjects when they receive the following dose. The minimum at-risk period for the 
analyses is 2 weeks. All AESI expected to occur between 0 day and 13 days following 
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dose administration (see Table 3) will be analysed with an at-risk period of 2 weeks. The 
at-risk period of 6 weeks will be used for AESI expecting to occur between 14 days and 6 
weeks. Finally, at-risk periods of 3 months, and 6 months will be for the AESI expected 
to occur between 6 weeks and 3 months, and between 3 months and 6 months, 
respectively. For other AE leading to hospitalisation or death the at-risk period for the 
analyses will be defined with the support of the GSK safety physicians and the panel of 
experts. In addition, the distribution of the Time-to-Onset of events after vaccination will 
be described, and additional at-risk periods will be considered based on the results as 
sensitivity analyses. 
The person-time for an event of interest (e.g. juvenile chronic arthritis) will be calculated 
as the time between the reference date (date of first administration of DTP/HepB/Hib 
vaccine or date of first virtual vaccination, corresponding to the week before first visit) 
and the end of the at-risk period or the earliest of the followings: 
• 
Date of first diagnosis of event of interest (e.g. first episode of juvenile chronic 
arthritis). 
• 
Date of end of study period. 
• 
Date of enrolment in EPI-MAL-003 (when applicable). 
• 
Date when child reaches 5 years. 
• 
Date of last contact (Lost-to follow-up). 
• 
Date of death. 
Each AESI will be grouped as follows after case ascertainment for both confirmed and 
non-confirmed cases (see Section 9.2.7.4.2): 
• 
Nerves and central nervous system: ADEM, encephalitis, Guillain-Barre Syndrome, 
HHE, generalised convulsive seizure. 
• 
Hepato-, gastrointestinal and renal system: intussusception, hepatic failure or renal 
insufficiency. 
• 
Skin and mucous membrane, bone and joints system: juvenile chronic arthritis, 
Stevens-Johnson syndrome/toxic epidermal necrolysis, Henoch-Schonlein purpura, 
Kawasaki disease. 
• 
Systemic diseases and haematology: diabetes mellitus type I, thrombocytopenia, 
anaphylaxis. 
The incidence following DTP/HepB/Hib vaccine or virtual vaccination using at-risk 
period described above will be estimated for the 6-12 weeks group and 5-17 months 
group. 
Meningitis will not be grouped with other AESI and will be considered as a single 
endpoint (see case definition in Section 9.2.5.3). 
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Incidence rates of these composite endpoints will be calculated as described for 
individual AE leading to hospitalisation or death /AESI; in case of multiple cases in a 
subject, only the first event will be considered in this analysis. 
All other AE leading to hospitalisation or death will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) Dictionary and presented by System Organ Class 
(SOC) and Preferred Term (PT). 
Incidence following DTP/HepB/Hib vaccine or virtual vaccination will be computed for 
active surveillance only. 
In addition, the incidence will be estimated for all children < 5 years. In such case, the 
person-time denominators for each rate will be reflective of the entire community 
population in the age group of interest. Each child will contribute person-time until the 
relevant age (at study end or at 5 years, whichever occurs first). 
9.7.5.2.2. Incidence rate of aetiology-confirmed meningitis 
Incidence rate (and 95% CI) of aetiology-confirmed meningitis (final classification based 
on second line laboratory results and after external panel of experts review) will be 
estimated with the same approach as for an AE. 
Of note, the at-risk period of 12 months will be used for meningitis. This assumption is 
based on meningitis cases reported in MALARIA-055. In addition, the distribution of the 
Time-to-Onset of events after vaccination will be described, and additional at-risk periods 
will be considered based on the results as sensitivity analyses. 
9.7.6. 
Analysis of secondary safety objectives 
9.7.6.1. 
Analysis population  
The same population as for the co-primary objectives (see Section 9.7.5.1) will be used. 
9.7.6.2. 
Statistical approach 
• 
The incidence rate (and 95% CI) of probable meningitis, the incidence rate (and 
95% CI) of aetiology-confirmed and/or probable meningitis and the incidence rate 
(and 95% CI) of aetiology-confirmed, probable and/or clinically suspected 
meningitis (final classification based on second line laboratory results and after 
external panel of experts review) will be estimated with the same approach as for 
aetiology-confirmed meningitis (described in Section 9.7.5.2.2). 
(Amended 5 May 2020) 
For all suspected meningitis at the site level (based on first line laboratory results), a 
monthly listing report will be checked by the monitoring and GSK safety teams and 
every 6 months the number of cases of meningitis as well as the cumulative number 
of cases will be tabulated in the Progress Report. 
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• 
The incidence rate (and 95% CI) of cerebral malaria will be estimated with the same 
approach as for an AE as described in Section 9.7.5.2. 
• 
Exposure determinants and potential risk factors for AESI and meningitis will be 
evaluated by means of univariate and multivariable Poisson regression models only 
for the incidence following DTP/HepB/Hib vaccine or virtual vaccination.  
Adjusted covariates are described in Section 9.3.3: 
– 
Study site. 
– 
Demographic parameters such as age at reference date. 
– 
Medical history and other risk factors such as chronic disease or diagnosed 
congenital disease, known HIV infection, malaria, malnutrition, drugs exposure, 
toxic agent exposure. 
– 
Comorbidity factors such as premature birth, history of trauma. 
– 
Health care seeking behaviour and distance to health care facilities. 
– 
Type of health care facility. 
– 
Neighbourhood of residence (urban/rural area). 
– 
Total number of outpatient visits per centre. 
The following strategy for covariate selection will be applied: 
Covariates occurring in less than 5% of the subjects (percentage will be computed 
over subjects both in 6-12 weeks and 5-17 months group) will not be included in the 
model.  
Of note, models will be run if a minimum number of cases of AESI or meningitis are 
observed (at least 10 cases in total). 
Some predefined clinical relevant covariates might be forced into the models and 
will be listed in the SAP with the rationale (e.g. prior knowledge from literature). 
Covariates selection will be done using statistical significance. Confounders will be 
included in the multivariable models if univariate p-value will be less than 20%. 
Co-linearity (i.e. correlation among predictor covariates) will be assessed on the full 
model including forced-in covariate and the other selected with the variance inflation 
factor (level of 10% [Hair, 1995]). If it is necessary to drop a variable due to co-
linearity, the decision will be made on order of clinical importance. 
Then the selected set of covariates will be entered in the final model without 
transformations. 
• 
Descriptive analysis of the causes of hospitalisation (including AESI, other AE 
classified by MedDRA SOC and PT level, as well as meningitis and malaria) in 
children < 5 years will consist in computing the number of cases, person-time and 
incidence (with 95% CI). In the same way, descriptive analysis of causes of death 
classified by MedDRA will be done overall and by gender. 
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• 
Incidence rate (and 95% CI) of febrile convulsions will be estimated with the same 
approach as for an AE. Of note, two at-risk periods will be considered: 0-6 and 
7-29 days.  
• 
Surveillance indicator analysis 
The analysis done on AESI and other AE leading to hospitalisation or death will also 
be conducted on the incidence of foot positional deformations as a birth defect 
(negative control) and abscess at the injection site following routine vaccination 
(positive control). 
The incidence rate of the negative control should not increase after the vaccination, 
while the increase of incidence rate of the positive control after vaccination is 
expected. 
9.7.7. 
Analysis for other secondary objectives 
These analyses will be performed only on children enrolled in the active surveillance for 
each group (6-12 weeks and 5-17 months). 
9.7.7.1. 
Analysis population 
The main analysis on the other endpoints (i.e. malaria, anaemia, hospitalisation and 
death) will be performed at one year post last dose in order to anticipate further 
comparisons to be done with the EPI-MAL-003 study (i.e. indirect, total and overall 
effects computation): 
• 
one year after the third dose (before 12 months of age) of DTP/HepB/Hib vaccine or 
virtual vaccination evaluated from third dose. 
Additional analyses will be performed on the other endpoints: 
• 
One year after the visit mimicking the 4th dose (i.e. Month 32) evaluated from the 
3rd dose (before 12 months of age) of DTP/HepB/Hib vaccine or virtual vaccination; 
• 
Two years after the 3rd dose of DTP/HepB/Hib vaccine or virtual vaccination 
evaluated from 3rd dose of DTP/HepB/Hib vaccine or virtual vaccination; 
• 
Two years after the visit mimicking the 4th dose (i.e. Month 44) evaluated from the 
1st dose of DTP/HepB/Hib vaccine or virtual vaccination; 
• 
Two years after the visit mimicking the 4th dose (i.e. Month 44) evaluated from the 
3rd dose of DTP/HepB/Hib vaccine or virtual vaccination. 
9.7.7.2. 
Statistical approach 
Incidence rates for each event will be calculated by dividing the number of cases by 
person-time as defined in Table 8. Of note, for cerebral malaria, incidence following 
DTP/HepB/Hib vaccine or virtual vaccination will be derived and Time-to-Onset will be 
computed (see Section 9.7.5.2.1). 
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For analyses using detailed information from the eCRF, children whose parents do not 
consent for them to take part in the active surveillance groups will not be included in the 
denominator.  
Table 8 
Incidence rate and prevalence calculations for other objectives 
(children enrolled in active surveillance) 
Endpoints 
Numerator 
Denominator  
Any malaria 
 
# cases of any malaria  
Source: Outpatient visits and hospitalisations at 
all health care facilities 
Person-years contribution of 
enrolled children  
Any P. falciparum 
malaria 
# cases of any malaria due to P. falciparum 
Source: Outpatient visits and hospitalisations at 
all health care facilities 
Person-years contribution of 
enrolled children  
Severe malaria  
 
# cases of severe malaria  
Source: Hospitalisations 
Person-years contribution of 
enrolled children 
Severe P. falciparum 
malaria 
# cases of severe malaria due to P. falciparum 
Source: Hospitalisations 
Person-years contribution of 
enrolled children 
Cerebral malaria 
# cases of cerebral malaria  
Source: Hospitalisations 
Person-years contribution of 
enrolled children 
Anaemia in 
hospitalised children 
# cases of anaemia  
Source: Hospitalisations  
Number of enrolled children 
Death – all cause  
 
# deaths (due to any cause)  
Source: Scheduled home visits; outpatient visits 
and hospitalisations at all health care facilities; 
completion visit; HDSS or equivalent 
surveillance system register 
Person-years contribution of 
enrolled children 
Malaria attributed 
deaths 
 
# deaths with malaria listed as a contributing 
cause 
Source: Scheduled home visits; outpatient visits 
and hospitalisations at all health care facilities; 
completion visit; HDSS or equivalent 
surveillance system register 
Person-years contribution of 
enrolled children 
Hospitalisation - all 
cause 
# of children hospitalised during study period 
Source: Hospitalisations 
Person-years contribution of 
enrolled children  
Malaria attributed 
hospitalisations 
# of children hospitalised during study period 
where malaria is listed as the primary diagnosis 
Source: Hospitalisations 
Person-years contribution of 
enrolled children 
Incidence rates will be adjusted by means of Poisson regression models (the dependent 
variable will be the number of events). The details are given in Section 9.7.9. 
Univariate and multivariable models will be conducted. Those adjusted covariates are 
described in Section 9.3.3: 
• 
Study site. 
• 
Demographic parameters such as age at reference date. 
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• 
Medical history and other risk factors such as chronic disease or diagnosed 
congenital disease, known HIV infection, malaria, malnutrition, drugs exposure, 
toxic agent exposure. 
• 
Use of malaria control measures such as bednets, indoor residual spraying, seasonal 
malaria chemoprevention. 
• 
Comorbidity factors such as premature birth, history of trauma. 
• 
Health care seeking behaviour and distance to health care facilities. 
• 
Type of health care facility. 
• 
Neighbourhood of residence (urban/rural area). 
• 
Total number of outpatient visits per centre. 
• 
Seasonal MTI (i.e. parasite prevalence) estimated in study EPI-MAL-005 on the 
vaccine ineligible group (see Annex 3 for definition). 
• 
Other centre level covariates estimated in study EPI-MAL-005 per year: malaria 
control intervention use, bednet use and health care seeking behaviour. 
The same strategy as described in Section 9.7.6.2 will be used for covariates selection to 
be included in the multivariable model. 
9.7.8. 
Statistical considerations 
All the statistical calculations will be done in SAS 9.2 or higher. 
Unless specified otherwise, all the statistical tests will be two-sided at alpha level of 0.05. 
9.7.8.1. 
Handling of missing data 
A worst case allocation will be done for suspected events (i.e. suspected AESI, suspected 
malaria) for which confirmation of the outcome is not available. In such case a sensitivity 
analysis will be done considering these unresolved events as confirmed. 
For the determinants included in multivariable models, a complete cases analysis will be 
performed as primary analysis (i.e. missing data will not be substituted). 
As sensitivity analysis, for analysis of risk factors of the co-primary endpoint only, a 
precise diagnosis of missing pattern will be done to describe the kind of missing data (i.e. 
missing at random, missing completely at random and missing not at random). 
Considering the diagnosis an appropriate method of imputation will be conducted and 
will only concern the covariates forced in the models. The strategy will be the following: 
• 
For continuous covariates, a multiple imputation [Rubin, 1987] method will be 
applied to handle missing value if missing at random mechanism is confirmed. 
Indeed, as noted by Sterne et al [Sterne, 2009], multiple imputations may give 
misleading results in case data are missing not at random. 
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• 
For categorical covariates, missing indicator method will be done (i.e. a specific 
category of missing value will be created). 
Of note, if the “complete cases” analysis contains 90% of the subjects, no imputation will 
be done. In the case that for a single covariate more than 50% of values are missing, the 
covariate will not be included in the model. 
The method of imputation will be detailed in the SAP. 
9.7.8.2. 
Descriptive statistics 
Frequency tables including number of cases and percentages will be generated for 
categorical variables. 
Mean, standard error, median and range will be provided for continuous variables. 
9.7.9. 
Statistical models 
Poisson regression will be conducted using the SAS GENMOD procedure. The 
dependent variable is the number of events (Y). The model will include the study site as a 
fixed effect, the log-transformed total person-time (PY) as an offset and the risk factors. 
Main model: ln(Y)= β0 + β1 X1 +…+ βk Xk+ ln (PY) 
The coefficients 1 and i are the coefficients associated to study sites and the covariates, 
respectively. The risk ratio of covariates will be derived as the exponential of their 
associated coefficient and their 95% Wald CI. 
The SAS code is: 
PROC GENMOD data=<filename> ; 
 CLASS X1 Xk;  
 MODEL Y= X1 Xk / OFFSET=Ln_PY DIST=poisson LINK=log ; 
RUN; 
For each model, the following assumptions will be checked in order to interpret the 
results obtained from the Poisson regression: the outcome variable follows a Poisson 
distribution and does not have an excessive number of zeros. The deviance will measure 
the adequacy of the model. If the scaled deviance is closed to one, the regression model is 
adequate. Otherwise, the validity of the model is questionable. In particular, value greater 
than 1 indicates over dispersion. 
In case of over dispersion, corrective measures will include the introduction of a 
dispersion parameter with respect to the Poisson model. This will be done by adding the 
option DSCALE and examining the fit statistics. If over dispersion is still a problem, 
another alternative approach considering a negative binomial distribution model will be 
discussed considering scientific inputs.  
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This last method will be detailed further in the SAP. Of note, the same procedure PROC 
GENMOD will be adapted by specifying option DIST=negbin in the model statement: 
PROC GENMOD data=<filename> ; 
 CLASS X1 Xk;  
 MODEL Y= X1 Xk / OFFSET=Ln_PY DIST=negbin LINK=log ; 
RUN; 
9.7.10. 
Statistical analyses during special circumstances  
Special circumstances (see section 9.2.8) may have an impact on the proposed analysis 
plan. Any changes in the analysis plan will be further described in the SAP. 
(Amended 5 May 2020) 
9.8. 
Quality Control  
9.8.1. 
Monitoring by GSK Biologicals 
Monitoring visits by a GSK Site Monitor or delegate are for the purpose of confirming 
that GSK Biologicals’ sponsored studies are being conducted in accordance with the 
ethical principles that have their origins in the Declaration of Helsinki and that are 
consistent with GCP or other applicable guidelines and the applicable regulatory 
requirement(s) (verifying continuing compliance with the protocol, amendment(s), 
verifying that the site staff and facilities continue to be adequate to conduct the study).  
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV GSK understands verifying eCRF entries by comparing 
them with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
For eCRF, the monitor will freeze the screen after she/he estimates that data are 
authentic, accurate and complete. 
In accordance with applicable regulations, GCP or other applicable guidelines, and GSK 
procedures, GSK Site Monitors or delegates will contact the site prior to the start of the 
study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing 
data collection procedures, the discussion will also include identification, agreement and 
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documentation of data items for which the eCRF/CRF entries will serve as the source 
document. 
GSK Site Monitors or delegates will monitor the study to verify that, amongst others, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any 
amendments, any other study agreements, GCP or other applicable guidelines and all 
applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agree to allow 
the monitor direct access to all relevant documents. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP or other applicable guidelines, and GSK procedures. 
9.8.2. 
Archiving of data at study sites 
Following closure of the study, the investigator must maintain all site study records in a 
safe and secure location. The records must be maintained to allow easy and timely 
retrieval, when needed (e.g. audit or inspection), and, whenever feasible, to allow any 
subsequent review of data in conjunction with assessment of the facility, supporting 
systems, and staff. Where permitted by applicable laws/regulations or institutional policy, 
some or all of these records can be maintained in a validated format other than hard copy 
(e.g. microfiche, scanned, electronic for studies with an eCRF); however, caution needs 
to be exercised before such action is taken. The investigator must assure that all 
reproductions are legible and are a true and accurate copy of the original and meet 
accessibility and retrieval standards, including re-generating a hard copy, if required. 
Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by International Conference on 
Harmonisation (ICH) GCP or other applicable guidelines any institutional requirements 
or applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, the following: archival at an off-site facility, 
transfer of ownership of the records in the event the investigator leaves the site.  
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9.8.3. 
Audits 
To ensure compliance with GCP or other applicable guidelines and all applicable 
regulatory requirements, GSK may conduct a quality assurance audit. Regulatory 
agencies may also conduct a regulatory inspection of this study. Such audits/inspections 
can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access 
to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 
9.9. 
Limitations of the research methods 
The Protocol Amendment 4 was taking into account a follow-up of children up to the age 
of 5 years, with baseline events collected for each subject in the active surveillance over 
44 months (mimicking 24 months of active follow-up after the 4th dose of RTS,S/AS01E 
in EPI-MAL-003). The study will enrol children in the two age groups in which the 
Phase III study MALARIA-055 was conducted (6-12 weeks at first dose and 5-17 months 
at first dose) to collect background data in both age groups. However, in the 
post-implementation safety study EPI-MAL-003, only the 5-17 months age group will be 
kept.  
The Protocol Amendment 5 described the sample size reduction from 40,000 to 30,000 
with at least 20,000 children to be enrolled where the RTS,S/AS01E vaccine will be 
implemented. There was a resultant reduction in the size of the two study groups to 
15,000 subjects each (with at least 10,000 children in sites where the vaccine will be 
implemented). 
At the start of this study, some uncertainties remained regarding the recommendations for 
use of RTS,S/AS01E in SSA, and what will be the vaccine uptake at the start of the 
vaccine programme implementation. Therefore, one or several amendments were needed 
during the course of the study. Participating countries have been identified because they 
have active HDSS or equivalent surveillance system sites and are representing 
moderate/high transmission of malaria. Other sites in SSA settings with moderate-to-high 
transmission of malaria, from the 3 countries where the RTS,S/AS01E vaccine will be 
implemented (see Section 9.2), were added to the already defined study sites. The 
transition from EPI-MAL-002 (pre-implementation) to EPI-MAL-003 (post-
implementation) is expected to occur in the study sites from Kenya and Ghana. The 
possible switch from a subject enrolled to EPI-MAL-002 to EPI-MAL-003 (if eligible) 
will be detailed in the EPI-MAL-003 protocol. GSK acknowledges that, in addition, the 
study start of EPI-MAL-003 might vary according to vaccination schedule and timing of 
vaccine implementation in each country.  
In terms of study design, to better take into account the potential vaccine scenarios and to 
perform the study most close to routine medical practice, a cohort design allowing to 
prospectively collect standardized information seems to be the most suitable approach. 
Collecting data at a large population level (population size estimated at 30,000 subjects) 
is challenging from an operational perspective in SSA countries. To base the studies on 
existing HDSS or equivalent surveillance system offers the opportunity to benefit from 
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existing research and health care structures, in a population that is already part of a 
demographic and health indicators survey, and thus likely to be willing to participate in 
additional research. The selected study sites vary with regards to MTI (from moderate to 
high), which covers the same malaria disease spectrum than recommended by 
SAGE/MPAC. Pre-implementation of the active and enhanced hospitalisation 
surveillance efforts will allow collecting data in a well-characterised population and 
better understanding fluctuations over time in the community of AESI, other AE leading 
to hospitalisation or death, meningitis, any and severe malaria, including cerebral 
malaria.  
This pre-implementation study will target enrolling 30,000 children eligible for 
vaccination in an active surveillance with at least 20,000 children enrolled where the 
RTS,S/AS01E vaccine will be implemented: approximately 15,000 children in the 
6-12 weeks group (with at least 10,000 children enrolled in sites where the vaccine will 
be implemented; to collect background data in this age group) and approximately 15,000 
children in the 5-17 months group (with at least 10,000 children enrolled in sites where 
the vaccine will be implemented; to mimic administration of RTS,S/AS01E in the 
5-17 months age group). To ensure a study duration compatible with the anticipated 
implementation of the RTS,S/AS01E vaccine in 2018, the children in the 5-17 months 
group will be recruited either from a subgroup corresponding to a catch-up, 5 to <18 
months of age at time of their first encounter with study staff, or from a subgroup during 
the first visit for administration of DTP/HepB/Hib vaccine.  
GSK acknowledges that this sample size is not appropriate to detect an increase of some 
rare adverse events or very rare adverse events following vaccination with RTS,S/AS01E 
(i.e. with incidence of 1/100,000 PY). To address safety research with rare outcomes, 
most epidemiological studies are based on existing disease-specific registries or large 
healthcare databases such as insurance claim databases, which do not exist in SSA at the 
time being. Thus, the limitation in the ability to detect increases in very rare events is 
partly related to the fact that the vaccine will be implemented only in SSA.  
All efforts will be made to reinforce the detection and standardize diagnosis of AESI, 
meningitis and severe malaria (including cerebral malaria). The enhanced hospitalisation 
surveillance should help to identify additional cases of AESI, other AE leading to 
hospitalisation or death, meningitis and severe malaria (including cerebral malaria) 
occurring in children living in the study area but not enrolled in the active surveillance. 
The surveillance is planned such that cases (AESI, other AE leading to hospitalisation or 
death, meningitis, any and severe malaria, including cerebral malaria) are likely to be 
identified. Training of physicians and field staff will start before this study. All efforts 
will be made to ensure an optimal standardized way of collecting data across the different 
sites. Progress reports every 6 months will help in monitoring the participation rate and 
the trends in event detection. An interim analysis will be performed when the 
RTS,S/AS01E vaccine will be implemented in most of the study sites, in order to get first 
results of background incidence (before implementation of RTS,S/AS01E vaccine), and to 
get information about feasibility/ capability to acquire data for EPI-MAL-003 according 
to the planned timelines. This interim analysis will be done with clean data collected on a 
sub-group of subjects having 6 months of follow-up following the administration of 
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dose 3 of DTP/HepB/Hib vaccine (6-12 weeks group), or 6 months after 
V3 (5-17 months group); corresponding to V5. The interim analysis will concern primary 
safety endpoints and the main impact endpoints (at 6 months post last dose for the 
purpose of this interim). 
Detecting the occurrence of AESI, other AE leading to hospitalisation or death, and 
meningitis cases are the primary objectives of this study. AESI and meningitis cases 
require specific diagnostic methods and such data may not be routinely collected in the 
study settings, potentially leading to underreporting. Therefore, specific training and 
monitoring of the field teams (community health workers, health care facilities staff, 
physicians and hospital staff) will be provided. The reinforcement of the 
pharmacovigilance practices and clinical and laboratory data collection most close to 
routine medical practice is a key component of this study. All procedures will be 
performed in line with the current national guideline recommendations in each of the 
participating countries. Improvement in surveillance over time may increase sensitivity in 
detecting those events and this potential bias will be taken into account when analysing 
data collected over time. Surveillance quality indicators will be utilised to help detect 
trends in changes in surveillance capacity. 
Longitudinal detection of events such as meningitis might also be difficult to interpret 
because of the changing meningitis disease epidemiology. The study will take place in 
countries of the “meningitis belt”, which is affected yearly by bacterial meningitis 
epidemics (mostly meningococcal meningitis). This zone comprises 22 countries from 
Senegal in the West to Ethiopia in the East. During 1993-2012, nearly one million 
suspected meningitis cases were reported; 80% of epidemics were caused by Neisseria 
meningitidis serogroup A. Despite successful introduction of a meningococcal A 
conjugate vaccine in the African meningitis belt since 2010 [Novak, 2012], 
meningococcal meningitis outbreaks may occur in some study sites during the 
EPI-MAL-002 study period, due to other Neisseria meningitidis serogroups, or if the 
study site is in a region/country which has not yet introduced the vaccine. Therefore, the 
interpretation of meningitis incidence rates should take into account the epidemiological 
context of each site. As for AESI, all efforts will be made to standardize meningitis 
diagnosis and reach an optimal proportion of laboratory confirmed cases to establish the 
aetiology. The case ascertainment process to classify meningitis cases will be based on 
additional laboratory testing (mainly based on molecular detection methods such as PCR) 
and the review of individual data by external experts.  
Because surveillance will be conducted in study areas covering mainly rural areas, 
children severely ill might die before being transported to hospital. In the event of death, 
the cause of death will be systematically documented through verbal autopsy using the 
INDEPTH Standard Verbal Autopsy Questionnaire* for children who died at home or 
medical judgment/medical records for children who died at a primary health care facility 
or hospital. However, ascertaining the cause of death remains a concern considering the 
limitation of the verbal autopsy methods in the field, this is why all-cause mortality is an 
important endpoint to consider in this study. 
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* If a site is not part of the INDEPTH network, or does not have an equivalent 
surveillance system in place, the INDEPTH procedures for verbal autopsy might be 
implemented to ensure consistency across study sites. 
All efforts will be made to standardize data collection during EPI-MAL-002. However, 
due to the long duration of this study, changes in diagnostic procedures, implementation 
of malaria control measures such as seasonal malaria chemoprevention [WHO, 2012], 
and changes in treatment measures will have to be considered during the analyses of the 
safety and malaria data. Potential confounders will be collected at individual level during 
EPI-MAL-002, and at community level during EPI-MAL-005. Some subjects might also 
leave the study area during the study period but this is regularly documented through 
demographic census (scheduled at least once a year during the study periods). 
To assess the vaccine effectiveness, the follow-up of an unvaccinated group during the 
EPI-MAL-003 study (post-implementation) is planned. However, there is an uncertainty 
about the recruitment of a sufficiently large unvaccinated group after the vaccine 
implementation of the RTS,S/AS01E in those countries. The decision to collect 
information related to any malaria cases has been taken because the vaccine uptake may 
be very high and the number of unvaccinated children in EPI-MAL-003 may be too low 
to reliably estimate the direct vaccine effect. In this instance, the unvaccinated 
comparison group may have to be derived from EPI-MAL-002 only (estimations of the 
overall and total vaccine effects).  
In summary, the data collection and result interpretation of the EPI-MAL-002 are key 
components to the success of the EPI-MAL-003 post-implementation study. This 
protocol has been written knowing that one or several amendments may be needed when 
more details about WHO recommendations and national policies on vaccine use will be 
known. The interpretation of the results will take into account the limitations described 
above. 
(Amended 5 May 2020) 
10. 
PROTECTION OF HUMAN SUBJECTS 
10.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with the ICH Guideline for GCP, Guidelines 
for Good Pharmacoepidemiology Practices (GPP) [ISPE, 2015], other applicable 
guidelines, all applicable subject privacy requirements and the guiding principles of the 
Declaration of Helsinki.  
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines. 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
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initiating the study in that country or will document that neither a favourable opinion nor 
an approval to conduct the study is needed. 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject/ subject’s parent(s)/LAR(s) informed consent, as appropriate. 
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
Freely given and written or witnessed and thumb printed informed consent must be 
obtained from each subject’s parent(s)/LAR(s) or the impartial witness, as appropriate, 
prior to participation in the study. 
GSK Biologicals will prepare a model ICF which will embody the applicable ICH GCP 
and GSK Biologicals required elements. While it is strongly recommended that this 
model ICF be followed as closely as possible, the informed consent requirements given in 
this document are not intended to pre-empt any local regulations which require additional 
information to be disclosed for informed consent to be legally effective. Clinical 
judgement, local regulations and requirements should guide the final structure and 
content of the local version of the ICF.  
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 
11. 
MANAGEMENT AND REPORTING OF SERIOUS 
ADVERSE EVENTS RELATED TO STUDY PROCEDURE 
The present study is performed prior to the introduction of the RTS,S/AS01E vaccine in 
the population. Therefore, there will be no management of AESI or other AE related to 
the use of the RTS,S/AS01E vaccine, but only reports of SAE related to study procedure. 
In addition to standard medical case management procedures, blood sampling is expected 
to be performed in case of a suspected AESI or meningitis. Serious adverse events 
(SAEs) related to this study procedure will therefore be collected.  
Each subject’s parent(s)/LAR will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious/of concern or 
indicating a change in their health status. 
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Note: Any untoward medical occurrence, which in the view of the investigator is 
suspected to be related to a GSK licenced vaccine/product, is to be reported to GSK 
Biologicals spontaneously via the local GSK Biologicals Named Safety Contact (see 
contact details in the Prescribing Information sheet). 
Any AESI or other AE occurring after standard EPI vaccination and recognised as being 
related to vaccination should be reported to National Health authorities following 
national reporting systems for the reporting of AE as part of routine practice. 
11.1. 
Safety definition 
11.1.1. 
Definition of a serious adverse event 
For the purpose of this study, a serious adverse event (SAE) is defined as any untoward 
medical occurrence in a subject temporally associated with a study procedure that: 
a. 
Results in death. 
b. Is life-threatening. 
NB: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation. 
NB: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or out-patient setting. 
Complications that occur during hospitalisation are also considered AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalisation’ 
occurred or was necessary, the adverse event should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known/diagnosed 
prior to informed consent signature) that did not worsen from baseline is NOT 
considered an SAE. 
d. Results in disability/incapacity, or 
NB: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
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Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
11.2. 
Detecting and recording serious adverse events 
11.2.1. 
Time period for detecting and recording serious adverse events 
In order to fulfil international reporting obligations, SAEs that are related to study 
participation (i.e. blood sampling in case of a suspected AESI or meningitis) will be 
collected and recorded from the time the subject consents to participate in the study until 
she/he is discharged. 
11.2.2. 
Evaluation of serious adverse events 
11.2.2.1. 
Assessment of intensity 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all SAEs reported during the study. The assessment will be based on the 
investigator’s clinical judgement. 
The intensity of each SAE recorded in the SAE screens should be assigned to one of the 
following categories: 
1 (mild) 
= 
A SAE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
A SAE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
A SAE which prevents normal, everyday activities (in a young 
child, such a SAE would, for example, prevent attendance at 
school/kindergarten/a day-care centre and would cause the 
parent(s)/LAR(s) to seek medical advice.  
11.2.2.2. 
Assessment of outcomes 
Outcome of any SAE reported during the entire study will be assessed as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal. 
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11.3. 
Reporting of serious adverse events 
11.3.1. 
Prompt reporting of serious adverse events to GSK Biologicals  
SAEs that occur in the time period defined in Section 11.2.1 will be reported promptly to 
GSK within the timeframes described in Table 9 once the investigator determines that the 
event meets the protocol definition of a SAE. 
Table 9 
Timeframes for submitting SAEs related to blood sampling in case 
of a suspected AESI or meningitis to GSK Biologicals  
Type of Event 
Initial Reports 
Follow-up of Relevant Information 
on a Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs related to blood sampling 
in case of a suspected AESI or 
meningitis 
24 hours* 
SAE screen 
24 hours* 
SAE screen 
* Timeframe allowed after receipt or awareness of the information. 
Study related SAEs will also be reported to PATH Research Ethics Committee (PATH 
REC) in accordance with PATH REC policy.  
11.3.2. 
Contact information for reporting serious adverse events to GSK 
Biologicals  
Study Contact for Reporting SAEs 
See Sponsor Information Sheet for contact details 
Back-up Study Contact for Reporting SAEs  
24/24 hour and 7/7 day availability: 
Email: RIX.CT-Safety-Vac@gsk.com 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
11.3.3. 
Completion and transmission of SAE reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the SAE screens of the 
eCRF WITHIN 24 HOURS. The SAE screens will always be completed as thoroughly as 
possible with all available details of the event. Even if the investigator does not have all 
information regarding a SAE, the SAE screens should still be completed within 24 hours. 
Once additional information is received, the SAE screens in the eCRF should be updated 
WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
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11.3.3.1. 
Back-up system in case the electronic SAE reporting system does not 
work 
If the electronic SAE reporting system does not work, the investigator (or designate) must 
complete, then date and sign a SAE Report Form and fax it to the GSK Biologicals 
Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system 
is working again, the investigator (or designate) must complete the SAE screens in the 
eCRF within 24 hours. The final valid information for regulatory reporting will be the 
information reported through the electronic SAE reporting system.  
11.3.3.2. 
Updating of SAE information after removal of write access to the 
subject’s eCRF  
When additional SAE information is received after removal of the write access to the 
subject’s eCRF, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or 
to GSK Biologicals Clinical Safety and Pharmacovigilance department within the 
designated reporting time frames specified in Table 9.  
11.4. 
Follow-up of serious adverse events 
All events documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 
Clinically significant laboratory abnormalities will be followed up until they have 
returned to normal, or a satisfactory explanation has been provided. Additional 
information (including but not limited to laboratory results) relative to the subsequent 
course of such abnormalities noted for any subject must be made available to the Site 
Monitor. 
GSK Biologicals may request that the investigator performs or arranges for the conduct 
of additional clinical examinations/tests and/or evaluations to elucidate as fully as 
possible the nature and/or causality of the event. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with a copy of any available post-mortem findings, 
including histopathology. 
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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS  
To comply with Guidelines for GPP or other applicable guidelines administrative 
obligations relating to data collection, archiving data, audits, confidentiality and 
publications must be fulfilled.  
Study information from this protocol will be posted on public registers (e.g., GSK 
Clinical Study Register, clinicaltrials.gov, Pan African Clinical Trials Registry) and the 
European Union Post-Authorisation Studies (EU PAS) register before the start of the 
study, as applicable. 
Progress reports will be written and submitted every six months from study start. An 
interim report will be written with the data collected on all subjects after 6 months of 
follow-up following the administration of dose 3 of DTP/HepB/Hib vaccine (6-12 weeks 
group), or 6 months after V3 (5-17 months group); corresponding to V5. A final study 
report will be written and submitted.  
For the three studies a Safety Post Approval Program Partnership Committee has been 
created and will ensure preparation and review of manuscripts resulting from the studies. 
This Committee is composed of local Principal Investigators with GSK and PATH 
representation. This Committee acts as the main governance body for the studies. 
(Charter is available upon request.) 
A manuscript will be submitted to a peer reviewed journal for publication within the 
policy defined timelines. In addition, study information will be posted to the GSK 
Clinical Study Register. 
13. 
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Annex 1 
LIST OF STAND-ALONE DOCUMENTS 
No. 
Document Reference No 
Date 
Title 
1. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
List of stand-alone documents 
2. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
List of principal and 
coordinating investigators 
3. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Glossary of terms 
4. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Trademarks 
5. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Case definitions for protocol-
defined adverse events of 
special interest (AESI) and 
surveillance indicators 
6. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Study specific guidance 
document 
7. 
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Amendments to the protocol 
8. 
115055 
(EPI-MALARIA-002 VS AME) 
4 May2020 
Protocol amendment 5 sponsor 
signatory approval 
9.  
115055 
(EPI-MALARIA-002 VS AME) 
5 May 2020 
Protocol amendment 5 
investigator agreement 
(Amended 5 May 2020) 
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Annex 2 
LIST OF PRINCIPAL AND COORDINATING 
INVESTIGATORS 
Contact details and list of all investigators available upon request. 
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Annex 3 
GLOSSARY OF TERMS  
Active surveillance: 
Screening for AESI and other diseases during study 
follow-up visits at the community level. 
Adverse event of special 
interest (AESI): 
A predefined list of adverse events that have historically 
been associated with vaccines other than RTS,S/AS01E, 
or may hypothetically be associated with RTS,S/AS01E 
due to the fact that this vaccine has components which are 
new compared to current widely used vaccines. 
Child in care: 
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian. 
Cohort event monitoring: 
A prospective, observational study of events that occur 
during the use of medicines, for intensified follow-up of 
selected medicinal products phase. Patients are monitored 
from the time they begin treatment, and for a defined 
period of time [The Uppsala Monitoring Centre, 2011]. 
Cohort study: 
A form of epidemiology study where subjects in a study 
population are classified according to their exposure 
status/disease and followed over time (prospective / 
retrospective) to ascertain the outcome(s) (disease).  
DTP/HepB/Hib 
This refers to Diphtheria, Tetanus, and Pertussis (DTP), 
or DTP-Hepatitis B (DTP-HepB tetravalent) or 
DTP-HepB-Haemophilus influenza type b (Hib) 
(DTP-HepB-Hib pentavalent) vaccines. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enhanced hospitalisation 
surveillance: 
Case detection during hospitalisation through monitoring 
of medical records and registries. 
Epidemiology study: 
An observational study or an interventional study without 
administration of medicinal product(s) as described in a 
research protocol. 
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eTrack: 
GSK’s tracking tool for clinical/epidemiology studies. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Section 9.7.2 for details on criteria for evaluability). 
Exposed clusters 
Study sites where the RTS,S/AS01E vaccine will be 
implemented at the beginning of the pilot implementation 
programme by Ministries of Health using an expanded 
schedule of their routine EPI. 
Job Aids Tool: 
Tool to help health care professionals detect signs and 
symptoms of AESI and to provide guidelines for 
diagnosis based on case definition. 
Hospitalisation: 
Subjects requiring overnight stay in a health care facility. 
National EPI: 
Routine vaccination programmes, administered by the 
national EPI system in place, usually given at 6, 10 and 
14 weeks of age (e.g. DTP/HepB/Hib vaccines. NOTE: in 
some countries the EPI schedule may differ by a few 
weeks).  
Pharmacovigilance: 
Pharmacovigilance is defined as the science and activities 
concerned with the detection, assessment, understanding 
and prevention of adverse reactions to medicines (i.e. 
adverse drug reactions or ADRs) [WHO Definition, 
2012].  
Protocol amendment: 
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study. 
Research protocol: 
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation 
of a trial. The protocol usually also gives the background 
and rationale for the trial, but these could be provided in 
other protocol referenced documents. 
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Serious Adverse Event: 
For the purpose of this study, a SAE is defined as any 
untoward medical occurrence in a subject temporally 
associated with a study procedure that: 
a. 
results in death; 
b. is life-threatening; 
c. 
requires hospitalisation or prolongation of existing 
hospitalisation; 
d. results in disability/incapacity; 
Medical or scientific judgment should be exercised in 
deciding whether reporting is appropriate in other 
situations, such as important medical events that may not 
be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the subject or may 
require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation. 
A full definition of the events that constitute SAEs can be 
found in Section 11.1.  
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical/ epidemiology 
studies at one or more investigational sites. 
Study population: 
Sample of population of interest. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical/ epidemiology study, or a 
person about whom some medical information has been 
recorded in a database. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Surveillance: 
Surveillance is defined as the ongoing systematic 
collection, collation, analysis, and interpretation of 
descriptive epidemiological health data on a specific 
disease. Surveillance can monitor incidence and/or 
prevalence, and/or inform about when and where health 
problems are occurring and who is affected. 
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Unexposed clusters 
Study sites where the RTS,S/AS01E vaccine will not be 
implemented in the pilot implementation programme by 
Ministries of Health using an expanded schedule of their 
routine EPI. 
Vaccine ineligible 
Vaccine ineligible is defined as those subjects that on the 
basis of age would be ineligible for RTS,S/AS01E 
vaccination, regardless of vaccine availability at the time 
of assessment. The age will depend on the label for 
RTS,S/AS01E vaccination in the country.  
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Annex 4 
TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the protocol (including the synopsis), the names of the vaccines will 
be written without the superscript symbol ™ or ® and in italics. 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Generic description 
MosquirixTM 
 
Plasmodium falciparum and hepatitis B 
vaccine (recombinant, adjuvanted) 
Rotarix®  
 
Live attenuated human rotavirus vaccine 
Pediarix®  
 
Diphtheria and tetanus toxoids and acellular 
pertussis adsorbed, hepatitis B 
(recombinant) and inactivated poliovirus 
combined vaccine 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
Generic description 
RotaTeq® (Merck & CO., Inc.) 
 
Live, oral, pentavalent rotavirus vaccine 
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Annex 5 
CASE DEFINITIONS FOR PROTOCOL-DEFINED 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
AND SURVEILLANCE INDICATORS 
Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Nerves and Central Nervous System 
ACUTE DISSEMINATED 
ENCEPHALOMYELITIS (ADEM) 
 
LEVEL 1  
• 
Diffuse or multifocal demyelination 
revealed on histopathological sampling 
OR 
Focal or multifocal impairment of the central 
nervous system with ≥ 1 of the following signs: 
• 
Focal cortical impairment (particularly but 
not exclusively: aphasia, alexia, agraphia, 
cortical blindness) 
• 
Cranial nerve abnormality/abnormalities 
• 
Visual field defect/defects 
• 
Presence of primitive reflexes (Babinski’s 
sign, inexhaustible glabellar reflex, 
snout/sucking reflex) 
• 
Motor weakness (diffuse or focal, most 
often focal) 
• 
Sensory abnormalities 
• 
Alterations in deep tendon reflexes (hyper 
or hypo reflexia, asymmetry). 
• 
Cerebellar impairment such as ataxia, 
dysmetria, cerebellar nystagmus 
AND 
• 
On MRI: diffuse or multi- focal involvement 
of the white matter on T2, weighted 
diffusion and/or FLAIR sequences 
AND 
• 
Monophasic character of the illness 
(absence of relapse within a minimum of 3 
months of symptomatic nadir) 
LEVEL 2  
• 
Signs of encephalopathy (depressed level 
of consciousness, somnolence, acute 
personality change for more than 24 hours) 
AND 
Focal or multifocal impairment of the central 
nervous system with ≥ 1 of the following signs: 
• 
Focal cortical impairment (particularly but 
not exclusively: aphasia, alexia, agraphia, 
cortical blindness) 
Sejvar JJ, Kohl KS, 
Bilynsky R, et al; Brighton 
Collaboration Encephalitis 
Working Group. 
Encephalitis, myelitis, and 
acute disseminated 
encephalomyelitis 
(ADEM): case definitions 
and guidelines for 
collection, analysis, and 
presentation of 
immunization safety data. 
Vaccine 2007;25:5771-
92.  
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
• 
Cranial nerve abnormality/abnormalities 
• 
Visual field defect/defects 
• 
Presence of primitive reflexes (Babinski’s 
sign, inexhaustible glabellar reflex, 
snout/sucking reflex) 
• 
Motor weakness (diffuse or focal, most 
often focal) 
• 
Sensory abnormalities 
• 
Alterations in deep tendon reflexes (hyper 
or hypo reflexia, asymmetry) 
• 
Cerebellar impairment such as ataxia, 
dysmetria, cerebellar nystagmus 
AND 
• 
On MRI: Diffuse or multi- focal involvement 
of the white matter on T2, weighted 
diffusion and/or FLAIR sequences 
AND 
• 
Follow up insufficient to confirm a 
monophasic nature of the illness (absence 
of relapse within a minimum of three 
months after the clinical nadir). 
LEVEL 3  
• 
Signs of encephalopathy (depressed level 
of consciousness, somnolence, acute 
personality change for more than 24 hours) 
AND 
Focal or multifocal impairment of the central 
nervous system with ≥ 1 of the following signs: 
• 
Focal cortical impairment (particularly but 
not exclusively: aphasia, alexia, agraphia, 
cortical blindness) 
• 
Cranial nerve abnormality/abnormalities 
• 
Visual field defect/defects 
• 
Presence of primitive reflexes (Babinski’s 
sign, inexhaustible glabellar reflex, 
snout/sucking reflex) 
• 
Motor weakness (diffuse or focal, most 
often focal) 
• 
Sensory abnormalities 
• 
Alterations in deep tendon reflexes (hyper 
or hypo reflexia, asymmetry). 
• 
Cerebellar impairment such as ataxia, 
dysmetria, cerebellar nystagmus. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Exclusion criteria for all levels of diagnostic 
certitude 
• 
Authentication of an acute infection or of a 
differential diagnosis is compatible with the 
clinical picture 
• 
Relapse of the illness at any moment after 
a minimum period of three months of 
clinical improvement after the nadir of 
clinical symptoms. 
• 
MRI images or histopathology in the 
clinical diagnosis is compatible with the 
case definition with the diagnosis of ADEM. 
In Summary 
ADEM can be confirmed if: 
• 
The clinical diagnosis is compatible with 
the case definition. 
• 
All differentials diagnoses have been 
excluded 
• 
The CSF exam supports the diagnosis of 
ADEM. 
NB: Plan for diagnostic confirmation by a 
neurologist (and MRI if possible). Generally the 
illness completely resolves in a few months. The 
diagnosis must be confirmed by a clinical 
examination performed 3 months after the nadir 
of the clinical symptoms. 
ENCEPHALITIS 
LEVEL 1  
• 
Demonstration of acute inflammation of the 
central nervous system parenchyma (+/- 
the meninges) on histopathology 
LEVEL 2  
• 
Signs of encephalopathy (depressed level 
of consciousness, somnolence , acute 
personality change for more than 24 hours) 
AND 
One or more of the following signs: 
• 
Absent or diminished reflexes to external 
stimuli (such as a loud noise or painful 
stimuli) 
• 
Absent or markedly diminished eye contact 
• 
Inadequate or absent response to an 
external stimuli 
• 
Seizures with loss of consciousness 
OR 
Sejvar JJ, Kohl KS, 
Bilynsky R, et al; Brighton 
Collaboration Encephalitis 
Working Group. 
Encephalitis, myelitis, and 
acute disseminated 
encephalomyelitis 
(ADEM): case definitions 
and guidelines for 
collection, analysis, and 
presentation of 
immunization safety data. 
Vaccine 2007;25:5771-
92. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Focal or multifocal impairment of the central 
nervous system with ≥ 1 of the following signs: 
• 
Focal cortical impairment (particularly but 
not exclusively: aphasia, alexia, agraphia, 
cortical blindness) 
• 
Cranial nerve abnormality/abnormalities 
• 
Visual field defect/defects 
• 
Presence of primitive reflexes (Babinski’s 
sign, an inexhaustible glabellar reflex, 
snout/sucking reflex) 
• 
Motor weakness (diffuse or focal, more 
often focal) 
• 
Sensory abnormalities 
• 
Altered deep tendon reflexes (hypo or 
hyperreflexia, asymmetry) 
• 
Cerebellar dysfunction, such as ataxia, 
dysmetria, cerebellar nystagmus 
AND 
Two or more of the following signs: 
• 
Fever (≥ 37.5°C) 
• 
CSF: Pleocytosis 
– 
>15 leukocytes/ mm3 in a child 2 
months of age or younger 
– 
>5 leukocytes/ mm3 in a child 2 
months of age or older 
• 
EEG signs compatible with an encephalitis 
• 
Cerebral imagery compatible with an 
encephalitis. 
LEVEL 3  
• 
Signs of encephalopathy (depressed level 
of consciousness, somnolence, acute 
personality change for more than 24 hours) 
AND 
One or more of the following signs: 
• 
Absent or diminished response to external 
stimuli (such as a loud noise, painful 
stimuli) 
• 
Absent or markedly diminished eye contact 
• 
Inconsistent or absent response to an 
external stimuli 
• 
Seizures with associated loss of 
consciousness 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
OR 
Focal or multifocal impairment of the central 
nervous system with ≥ 1 of the following signs: 
• 
Focal cortical impairment (particularly but 
not exclusively: aphasia, alexia, agraphia, 
cortical blindness) 
• 
Cranial nerve abnormality/abnormalities 
• 
Visual field defect/defects 
• 
Presence of primitive reflexes (Babinski’s 
sign, an inexhaustible glabellar reflex, 
snout/sucking reflex) 
• 
Motor weakness (diffuse or focal, most 
often focal) 
• 
Sensory abnormalities 
• 
Altered deep tendon reflexes (hypo or 
hyperreflexia, asymmetry) 
• 
Cerebellar impairment, such as ataxia, 
dysmetria, cerebellar nystagmus 
AND 
One of the following signs: 
• 
Fever (≥ 37.5°C) 
• 
CSF: Pleocytosis 
– 
>15 leukocytes/ mm3 in a child 2 
months of age or younger 
– 
>5 leukocytes/ mm3 in a child 2 
months of age or older 
• 
EEG signs compatible with an encephalitis 
• 
Cerebral imagery compatible with an 
encephalitis 
Evaluation Criteria 
• 
Exclude the presence of all diseases 
(cancer, toxic-metabolic encephalopathy, 
vascular problems, trauma, meningitis etc.) 
In Summary 
The diagnosis of encephalitis is confirmed if: 
• 
The clinical diagnosis is is compatible with 
the case definition. 
AND 
• 
The CSF analysis is compatible with an 
encephalitis picture. 
AND 
• 
The differential diagnoses (especially 
meningitis) have been excluded. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
GUILLAIN BARRÉ SYNDROME 
 
LEVEL 1  
• 
Bilateral weakness (symmetric) with flaccid 
extremities (usually of all 4 limbs) 
AND 
• 
Decreased or absent deep tendon reflexes 
in the impaired (paralyzed) extremities 
AND 
• 
Monophasic nature of the illness AND the 
interval between the beginning of the signs 
and the nadir of weakness is between 12 
hours and 28 days AND the appearance of 
a subsequent clinical plateau phase 
AND 
• 
Electromyography: Electrophysiological 
signs the clinical diagnosis is compatible 
with the case definition with GBS 
AND 
• 
Albuminocytologic dissociation: 
hyperproteinorachia (elevation of CSF 
protein) and normal CSF white cell count [< 
50 cells/μl] 
AND 
• 
Absence of plausible differential diagnosis 
(to explain the motor weakness) 
LEVEL 2  
• 
Bilateral AND flaccid weakness of the 
extremities 
AND 
• 
Decreased or absent deep tendon reflexes 
in the impaired (paralyzed) extremities 
AND 
• 
Monophasic illness pattern AND interval 
between onset and nadir of weakness 
between 12 h and 28 days AND 
subsequent clinical plateau 
AND 
• 
CSF total white cell count <50 cells/μl (with 
or without CSF protein elevation above 
laboratory normal value) 
OR 
• 
If CSF not collected or results not 
available, electrophysiologic studies 
consistent with GBS 
AND 
• 
Absence of identified alternative diagnosis 
for weakness 
LEVEL 3  
• 
Bilateral AND flaccid weakness of the 
extremities 
Sejvar JJ, Kohl KS, 
Gidudu J, et al. The 
Brighton Collaboration 
Guillain-Barré Syndrome 
Working Group. Guillain-
Barré Syndrome and 
Fisher Syndrome: Case 
Definitions and Guidelines 
for Collection, Analysis, 
and Presentation of 
Immunization Safety 
Data. Vaccine. 2011; 
29(3): 599–612. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
AND 
• 
Decreased or absent deep tendon reflexes 
in the impaired (paralyzed) extremities 
AND 
• 
Monophasic nature of the illness AND the 
interval between the beginning of the signs 
and the nadir of weakness is between 12 
hours and 28 days AND the appearance of 
a subsequent clinical plateau phase 
AND 
• 
Absence of plausible differential diagnosis 
(to explain the motor weakness) 
In Summary 
The diagnosis of Guillain-Barre Syndrome can be 
confirmed if: 
• 
The clinical diagnosis is compatible with 
the case definition 
• 
The poliovirus is not isolated from the stool 
• 
The CSF examination is compatible with 
GBS: Hyperproteinorachia (elevation of 
CSF protein), absence of pleocytosis. 
• 
There is diagnostic confirmation by a 
neurologist. 
GENERALIZED CONVULSIVE 
SEIZURE 
 
LEVEL 1  
• 
Witnessed sudden loss of consciousness 
AND 
• 
Generalized tonic, clonic, tonic-clonic or 
atonic motor manifestations 
LEVEL 2  
• 
Reported sudden loss of consciousness 
AND 
• 
Generalized tonic, clonic, tonic-clonic or 
atonic motor manifestations 
LEVEL 3  
• 
Reported sudden loss of consciousness 
AND 
• 
Other generalized motor manifestations 
In Summary 
The diagnosis of generalized seizure can be 
confirmed if: 
• 
The clinical diagnosis is compatible with 
the case definition. 
• 
The history of present illness evokes 
seizure activity 
Bonhoeffer J, Menkes J, 
Gold MS, et al; The 
Brighton Collaboration 
Seizure Working Group. 
Generalized convulsive 
seizure as an adverse 
event following 
immunization: case 
definition and guidelines 
for data collection, 
analysis, and 
presentation. Vaccine 
2004; 22:557-562. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
• 
The etiological work up is negative: (i.e. 
febrile seizure that does not fit GCS 
definition, acute intoxication, trauma, 
severe malaria etc. have all been 
excluded) (Amended 5 May 2020) 
HYPOTONIC HYPORESPONSIVE 
EPISODE (HHE) 
 
LEVEL 1  
• 
Hypotonia (muscular weakness) 
AND 
• 
Reduction or absence of response to 
sensory or verbal stimuli 
AND 
• 
Pallor or cyanosis 
LEVEL 2  
• 
Indeterminate muscle tone 
AND 
• 
Reduction or absence of response to 
sensory or verbal stimuli 
AND 
• 
Pallor or cyanosis 
OR 
• 
Hypotonia (muscular weakness) 
AND 
• 
Reduction or absence of response to 
sensory or verbal stimuli 
OR 
• 
Indeterminate skin color 
LEVEL 3  
• 
Normal muscle tone 
AND 
• 
Reduction or absence of response to 
sensory or verbal stimuli 
AND 
• 
Pallor or cyanosis 
OR 
• 
Hypotonia (muscular weakness) 
AND 
• 
Indeterminate response to sensory or 
verbal stimuli 
AND 
• 
Palor or cyanosis. 
Bonhoeffer J, et al. 
Brighton Collaboration 
HHE Working Group. 
Hypotonic-
Hyporesponsive Episode 
(HHE) as an adverse 
event following 
immunization: case 
definition and guidelines 
for data collection, 
analysis, and 
presentation. Vaccine. 
2004; 22(5-6): 563–568. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Hepato-Gastrointestinal and Renal System 
HEPATIC FAILURE 
 
Major criteria 
• 
Total serum bilirubin ≥1.5 times the upper 
limit of normal (ULN) 
OR 
• 
Elevation of the serum transaminases (ALT 
or AST ≥ 3 times the upper limit of normal 
(ULN)) 
(Amended 5 May 2020) 
AND 
• 
Coagulopathy unresponsive to vitamin K 
(prothrombin time (PT) ≥ 15 seconds or 
INR ≥1.5). 
In Summary 
The diagnosis of hepatic insufficiency can be 
confirmed if: 
• 
The diagnosis can be considered if the 
major criteria are present and confirmed on 
at least two blood draws. 
• 
The etiologies of the most frequent causes 
of jaundice and alterations of liver function 
tests and the non-hepatic 
encephalopathies are excluded: viral 
hepatitis, malaria, sickle cell anemia, 
exposure to toxins and medicines. 
NB: In case of fortuitous discovery of a 
perturbation in the hepatic panel without clinical 
manifestations, it is recommended to do a follow 
up hepatic panel. 
Gershman M., et al, 
Brighton Collaboration 
Viscerotropic Disease 
Working Group. 
Viscerotropic disease: 
Case definition and 
guidelines for collection, 
analysis, and presentation 
of immunization safety 
data. Vaccine. 
2012;30(33): 5038–5058. 
INTUSSUSCEPTION 
 
I) Definition of criteria 
DIAGNOSTIC CRITERIA 
• 
Surgical criteria 
– 
Demonstration of intussusception 
during exploratory surgery 
• 
Imaging criteria 
– 
Demonstration of intussusception via 
non-barium or aircontrast enema; 
– 
Demonstration via ultrasound of an 
intra-abdominal mass with specific 
characteristics – target (or doughnut) 
sign on transverse images and 
pseudokidney or sandwich sign on 
longitudinal images – the reduction of 
these signs by hydrostatic enema is 
also confirmed by ultrasound. 
Major criteria 
• 
Symptoms and signs of intestinal 
obstruction: 
– 
History of vomiting bile 
Bines JE, Kohl K, Forster 
J, et al and the Brighton 
Collaboration 
Intussusception Working 
Group. Acute 
intussusception in infants 
and children as an 
adverse event following 
immunization: case 
definition and guidelines 
of data collection, 
analysis, and 
presentation. Vaccine 
2004; 22:569–574. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
AND 
– 
Clinical examination shows acute 
abdominal distention and abnormal or 
absent bowel sounds 
OR 
– 
Radiological examination (plain 
abdominal X-ray) shows air-fluid levels 
and loops of distended small bowel. 
• 
Signs of intussusception, ≥ 1 following 
signs: 
– 
Abdominal mass 
– 
Rectal mass 
– 
Rectal prolapse 
– 
Plain abdominal X-ray shows a soft 
tissue mass 
– 
Abdominal ultrasound shows a soft 
tissue mass 
– 
Abdominal CT shows a soft tissue 
mass 
• 
Evidence of vascular compromise or 
venous congestion: 
– 
Anal bleeding 
OR 
– 
Currant jelly stools” 
OR 
– 
Blood detected during rectal 
examination 
Minor criteria 
• 
Predisposing factors: aged < 1 year, male 
• 
Abdominal pain 
• 
Lethargy 
• 
Pallor 
• 
Hypovolemic shock 
• 
Plain abdominal X-ray showing an 
abnormal and unspecific distribution of air 
in the intestines. 
II) Diagnostic certainty levels 
LEVEL 1  
• 
Surgical criteria: 
The demonstration of invagination of the intestine 
at surgery; 
AND/OR 
• 
Radiologic criteria: 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
The demonstration of invagination of the intestine 
by either air or liquid contrast enema; 
OR 
The demonstration of an intra-abdominal mass by 
abdominal ultrasound with specific characteristic 
features that is proven to be reduced by 
hydrostatic enema on postreduction ultrasound; 
AND/OR 
• 
Autopsy criteria: 
The demonstration of invagination of the 
intestine. 
LEVEL 2  
• 
Clinical criteria: 
Two major criteria or One major criterion and 
three minor criteria. 
LEVEL 3  
• 
Clinical criteria: 
Four or more minor criteria. 
RENAL INSUFFICIENCY 
 
Major criteria 
Creatinine ≥ 1.5 times the upper limit of normal 
(ULN) or 1.5 times the patient’s initial value. 
Minor criteria 
Urine production <0.5 ml/kg/hour 
In Summary 
Renal insufficiency can be confirmed if: 
• 
The major criteria is present and confirmed 
(at least two blood draws) 
• 
The etiological diagnosis has been carried 
out. 
Gershman M., et al, 
Brighton Collaboration 
Viscerotropic Disease 
Working Group. 
Viscerotropic disease: 
Case definition and 
guidelines for collection, 
analysis, and presentation 
of immunization safety 
data. Vaccine. 2012; 
30(33): 5038–5058. 
Skin and Mucous Membranes & Bones and Joints 
HENOCH SCHÖNLEIN PURPURA 
 
I) Definition of criteria 
MAJOR CRITERIA 
• 
Purpura (mandatory criterion) 
Purpura (commonly palpable and in crops) or 
petechiae, with lower limb predominance, not 
related to thrombocytopenia 
• 
Abdominal pain 
Diffuse abdominal colicky pain with acute 
onset assessed by history and physical 
examination. May include intussusception 
and gastrointestinal bleeding 
• 
Histopathology 
Typically leucocytoclastic vasculitis with 
predominant IgA deposit or proliferative 
glomerulonephritis with predominant IgA 
deposit 
• 
Arthritis or arthralgias 
 
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References 
Arthritis of acute onset defined as joint 
swelling or joint pain with limitation on 
motion. 
Arthralgia of acute onset defined as joint 
pain without joint swelling or limitation on 
motion. 
• 
Renal involvement 
Proteinuria >0.3 g/24 h or >30 mmol/mg of 
urine albumin/creatinine ratio on a spot 
morning sample. Haematuria or red blood 
cell casts: >5 red blood cells/high power 
field or red blood cells casts in the urinary 
sediment or ≥2+ on dipstick. 
MINOR CRITERIA 
• 
Other diagnoses unlikely (exclude 
meningitis) 
II) Diagnostic certainty levels 
LEVEL 1  
• 
Purpura or petechiae (mandatory) with 
lower limb predominance 
AND ≥ 1 following criteria 
• 
Abdominal pain 
• 
Histopathology 
• 
Arthritis or arthralgias 
• 
Renal involvement 
AND 
• 
Absence of thrombocytopenia 
LEVEL 2  
• 
Purpura or petechiae (mandatory) with 
lower limb predominance 
AND 
• 
Absence of thrombocytopenia. 
JUVENILE CHRONIC ARTHRITIS 
 
Juvenile Chronic Arthritis is defined by an 
evolution of symptoms of at least three months. 
The clinical examination often reveals a child with 
growth retardation. The different clinical forms are 
the following: 
1) Pauciarticular form (the most common form 
between 1 and 3 years of age). 
Clinically this presents with: 
• 
Involvement of four or less joints 
• 
Symmetric involvement of the small joints 
• 
Tenosynovitis of the flexor tendons and 
erosive nodules (frequent) 
• 
Rheumatoid factor seronegativity 
Medical websites 
resources: e.g. 
http://www.arthritis.co.za/j
ra.htm; 
http://emedicine.medscap
e.com/article/1007276-
overview; 
http://www.med.univ-
rennes1.fr/etud/pediatrie/
arthrite_cique.hthronm 
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References 
These signs can be associated with: 
• 
A positive anti-nuclear antibody (among 40 
to 75% of children) 
• 
Uveitis 
2) Polyarticular form 
• 
Affects 5 or more joints 
• 
Rheumatoid factor IgM can be positive or 
negative 
• 
Hips, cervical spine, hands and feet are the 
joints the most often affected, followed by 
the knees, wrists and ankles. 
• 
Among the patients seronegative for the 
rheumatoid factor, an association of fever, 
hepatosplenomegaly and symmetrical 
arthritis has been described. 
3) Systemic form 
• 
Accompanied by a fever up to 39.5°C 
during at least two weeks 
• 
A typical rash on the trunk and thighs can 
be seen 
• 
Frequent involvement of the wrists, knees, 
ankles as well as the temporomandibular 
joint, and the hands. 
• 
The illness typically lasts between 2 and 5 
years before complete resolution 
In Summary 
The diagnosis of Juvenile Chronic Arthritis (JCA) 
can be confirmed if: 
• 
The clinical diagnosis responds to the case 
definition 
• 
The biological panel shows signs of 
chronic inflammation 
• 
The most frequent differential diagnoses 
are excluded 
If necessary, the diagnosis should be 
confirmed by a specialist. The symptoms 
must last at least 3 months before 
concluding JCA. A confirmation of the 
diagnosis requires a follow up visit 3 
months after the beginning of the illness. 
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References 
STEVENS JOHNSON 
SYNDROME (SJS) AND TOXIC 
EPIDERMAL NECROLYSIS (TEN) 
 
Symptoms start by a feeling of malaise, fever, 
headache, cough and conjunctivitis. Then the 
macular eruption appears, rapidly transforming 
into confluent bullae over one to three days. Nails 
and eyebrows can be lost due to epidermal 
involvement. 
The diagnosis of Stevens-Johnson syndrome 
becomes evident with the appearance of 
cutaneous lesions, the rapid and expansive 
progression of symptoms, which include two 
mucosal sites. 
Bastuji-Garin S, Rzany B, 
Stern RS, et al. Clinical 
classification of cases of 
toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, and 
erythema multiforme. 
Arch Dermatol 1993; 
129:92-6. 
Diagnosis 
Lesion 
morphology 
Body surface 
area 
detachment 
SJS 
Maculae, bullae, 
atypical target 
lesions 
≤10% 
SJS-TEN 
overlap 
Maculae, bullae, 
atypical target 
lesions 
10-30% 
TEN with 
spots 
Maculae, bullae, 
atypical target 
lesions 
≥30% 
In Summary 
The diagnosis of STEVENS-JOHNSON 
SYNDROME (SJS) can be confirmed if: 
• 
The clinical diagnosis responds to the case 
definition 
• 
The etiological research indicates 
exposure to a triggering element 
(medication, immunization, toxin, febrile 
state, virus) 
• 
In case of doubt, consultation of a 
specialist is necessary. 
KAWASAKI DISEASE 
 
I) DEFINITION OF CRITERIA 
Major criteria 
• 
Fever ≥ 5 days 
• 
Clinical criteria: 
Signs of mucocutaneous inflammation: 
– 
Polymorphic exanthem 
– 
Non-exudative bilateral conjunctivitis 
– 
Involvement of the lips and oral cavity: 
erythema, cracked lips, “strawberry 
red” tongue, diffuse inflammation of 
the oral and pharyngeal mucosa 
– 
Involvement of the hands and feet: 
erythema of the palms and/or soles, 
oedema of the hands and/or the feet. 
Hand and/or foot periungual peeling 
skin (week 2-3 of disease course) 
Newburger JW, 
Takahashi M, Gerber MA, 
et al. Diagnosis, 
treatment, and long-term 
management of Kawasaki 
disease: a statement for 
health professionals from 
the Committee on 
Rheumatic Fever, 
Endocarditis and 
Kawasaki Disease, 
Council on 
Cardiovascular Disease in 
the Young, American 
Heart Association. 
Circulation 
2004;110(17):2747-71. 
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References 
– 
Usually unilateral neck 
lymphadenopathy (≥ 1.5 cm) 
Minor criteria 
• 
Erythrocyte sedimentation rate ≥ 40 mm/h 
or CRP ≥ 3 mg/dL 
• 
Echocardiogram showing coronary artery 
or heart involvement 
II) Diagnostic certainty levels 
LEVEL 1  
• 
Fever ≥ 5 days 
AND 
• 
≥ 4 clinical criteria: 
AND 
• 
Other diagnoses unlikely after clinical 
examination and laboratory tests 
LEVEL 2  
• 
Fever ≥ 5 days 
AND 
• 
< 4 clinical criteria: 
AND 
• 
Erythrocyte sedimentation rate ≥ 40 mm/h 
OR CRP ≥ 3 mg/dL 
AND 
• 
Other diagnoses unlikely after clinical 
examination and laboratory tests 
LEVEL 3  
• 
Fever ≥ 5 days 
AND 
• 
< 4 clinical criteria: 
AND 
• 
Normal erythrocyte sedimentation rate OR 
normal CRP 
AND 
• 
Coronary artery or heart involvement 
AND 
• 
Other diagnoses unlikely after clinical 
examination and laboratory tests. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Cardiovascular system and blood disorders 
ANAPHYLAXIS 
 
For all levels of diagnostic certainty 
• 
Sudden onset AND 
• 
Rapid progression of signs and symptoms 
AND 
• 
Involving multiple (≥ 2) organ systems, as 
follows: 
LEVEL 1  
• 
≥1 major dermatological criterion 
AND 
• 
≥1 major cardiovascular AND/OR ≥1 major 
respiratory criterion 
LEVEL 2  
• 
≥1 major cardiovascular AND ≥1 major 
respiratory criterion 
OR 
• 
≥1 major cardiovascular OR respiratory 
criterion 
AND 
• 
≥1 minor criterion involving ≥1 different 
system (other than cardiovascular or 
respiratory systems) 
OR 
• 
≥1 major dermatologic AND ≥1 minor 
cardiovascular AND/OR minor respiratory 
criterion 
LEVEL 3  
• 
≥1 minor cardiovascular OR respiratory 
criterion 
AND 
• 
≥1 minor criterion from each of ≥2 different 
systems/categories 
In Summary 
The diagnosis can be confirmed if: 
• 
The clinical diagnosis is compatible with 
the case definition (at least 2 major 
signs/criteria) 
• 
Symptom onset occurred after a short 
period of time (a few minutes to hours) 
after exposure to a food item, an insect 
sting, a vaccination, or contact with a 
product allergen (such as peanuts) 
• 
If the child reports a known allergy, one 
major sign/criteria following exposure to a 
known allergen is sufficient for a diagnosis 
of anaphylaxis. 
Rüggeberg JU, Gold MS, 
Bayas JM et al. Brighton 
Collaboration Anaphylaxis 
Working Group. 
Anaphylaxis: Case 
definition and guidelines 
for data collection, 
analysis, and presentation 
of immunization safety 
data. Vaccine 
2007;25:5675-5684. 
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Diagnosis/Level of Diagnostic Certainty 
References 
DIABETES MELLITUS TYPE 1 
 
• 
Serum fasting glucose ≥ 7 mmol/L (> 126 
mg/dL) 
OR 
• 
Postprandial serum glucose ≥11.1 mmol/L 
(≥ 200 mg/dL) 2 hours after ingesting 1.75 
g/kg (max.75g) of glucose (oral glucose 
tolerance test) 
OR 
• 
A1C Hemoglobin ≥ 6.5% AND 
Hyperglycemia 
AND 
• 
No other cause of hyperglycemia 
In Summary 
The diagnosis of type 1 diabetes mellitus can be 
confirmed when a confirmed hyperglycemia 
responds to the case definition. 
WHO Definition and 
Diagnosis of diabetes 
mellitus and intermediate 
hyperglycaemia, 2006 
and 
http://www.nlm.nih.gov/m
edlineplus/encyclopedia.h
tml 
THROMBOCYTOPENIA  
 
LEVEL 1  
• 
Platelet concentration < to 150 x 106/mL 
AND 
– 
Confirmation par blood smear 
OR 
– 
Clinical signs of spontaneous bleeding 
(i.e. non traumatic)* 
LEVEL 2  
• 
Platelet concentration < to 150 x 106/mL. 
*Spontaneous bleeding (i.e. non traumatic), 
includes purpura (i.e. petechiae, purpura sensu 
stricto, ecchymoses) exudative hemmorhage, 
hematomas, hematemesis, occult bleeding par 
rectum, epistaxis, hemoptysis, hematuria, vaginal 
bleeding, conjunctival bleeding, intracranial 
bleeding. 
In Summary 
The diagnosis of thrombocytopenia can be 
confirmed if: 
• 
It corresponds to the level 1 of diagnostic 
certainty case definition 
• 
An etiological investigation was carried out. 
Wise RP, Bonhoeffer J, 
Beeler J, et al. Brighton 
Collaboration 
Thrombocytopenia 
Working Group. 
Thrombocytopenia: Case 
definition and guidelines 
for collection, analysis, 
and presentation of 
immunization safety data. 
Vaccine 
2007;25:5717-5724. 
Surveillance indicators 
Injection Site Abscess 
Abscess of infectious aetiology 
LEVEL 1  
• 
Spontaneous or surgical drainage of the 
mass contents 
AND 
• 
Microbiologic confirmation (Gram stain, 
culture or other exam) of the presence of 
bacteria with or without altered polynuclear 
neutrophils in the aspirated/drained fluid. 
Kohl K, et al. The 
Brighton Collaboration 
Local Reactions Working 
Group for Abscess at 
Injection Site. Abscess at 
injection site: Case 
definition and guidelines 
for collection, analysis, 
and presentation of 
immunization safety data. 
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References 
LEVEL 2  
In situations where microbiologic confirmation 
(Gram stain, culture or other examination) was 
not performed, or was performed after the start of 
antibiotic therapy, or was not ordered at all. 
• 
Spontaneous or surgical drainage of the 
purulent fluid from the mass contents 
OR 
• 
Mass collection diagnosed by an imaging 
technique or the mass is fluctuant. 
AND 
• 
Signs of localized inflammation including at 
least one of the following aspects: 
erythema, pain on light palpation, and 
warmth to the touch at the injection site. 
AND 
• 
Resolution of symptoms after antibiotic 
therapy 
Vaccine. 2007; 25(31): 
5821–5838. 
Injection Site Abscess 
Sterile abscess 
LEVEL 1  
• 
 Spontaneous or surgical drainage of the 
mass contents 
AND 
• 
 Drainage liquid obtained before the 
beginning of antibiotic therapy and no 
infectious pathogen found on examination 
(Gram stain, culture or other examination) 
LEVEL 2 
In situations where microbiologic confirmation 
(Gram stain, culture or other examination) 
was not performed, or was performed after the 
start of antibiotic therapy, or was not ordered at 
all. 
• 
Non purulent fluid is spontaneous or 
surgically drained from the mass 
OR 
• 
A collection of material, such as fluid, is 
diagnosed by imagery or there is 
fluctuance on palpation. 
AND 
• 
Absence of signs of local inflammation: 
erythema, pain on light palpation, warmth 
to the touch at the injection site 
OR 
• 
No improvement following a course of an 
antibiotic treatment. 
In Summary 
An injection site abscess is confirmed by a 
clinical diagnosis responding to the case 
definition. 
Kohl K, et al. The 
Brighton Collaboration 
Local Reactions Working 
Group for Abscess at 
Injection Site. Abscess at 
injection site: Case 
definition and guidelines 
for collection, analysis, 
and presentation of 
immunization safety data. 
Vaccine. 2007; 25(31): 
5821–5838. 
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Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
Foot positional deformations 
• 
Metatarsus adductus characterised by 
medial deviation (adduction) of the forefoot 
while the hindfoot remains in a normal 
position, thus forming a "C" shape, or 
concavity of the medial aspect of the foot  
OR 
• 
Positional calcaneovalgus feet 
characterised by hyperdorsiflexion of the 
foot with the abduction of the forefoot, 
which often results in the forefoot resting 
on the anterior surface of the lower leg 
OR 
• 
Clubfoot characterised by the foot being 
excessively plantar flexed, with the forefoot 
swung medially and the sole facing inward. 
 
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Annex 6 
STUDY SPECIFIC GUIDANCE DOCUMENT 
Screening tool for assessing serious delays in developmental 
milestones and/or physical disabilities in children from 3 months 
to 36 months of age 
If the caregiver responds negatively to 2 or more questions, the child should be referred 
to a medical consultation for further investigations according to routine medical practice. 
All questions are to be responded by YES or NO. 
A. Screening questions for caregiver of children aged 3-4 months 
A1 
Does your baby smile to familiar people? 
A2 
Has your baby begun to make sounds? 
A3 
Does your baby follow moving people or objects with eyes? 
A4 
Does your baby hold his head unsupported? 
A5 
Does your baby bring his hands to his mouth? 
B. Screening questions for caregiver of children aged 5-9 months 
B1 
Does your baby grasp objects with both hands? 
B2 
Can your baby sit with support? 
B3 
Does your baby respond to sounds by making sounds? 
B4 
Does your baby know familiar faces and know if someone is a stranger? 
C. Screening questions for caregiver of children aged 10-15 months 
C1 
Does your baby sit without support? 
C2 
Does your baby crawl on hands and knees? 
C3 
Does your baby take steps holding on to furniture, walls, etc? 
C4 
Does your baby try to imitate words and sounds and respond to simple requests? 
C5 
Does your baby show fear in some situations? 
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D. Screening questions for caregiver of children aged 16-21 months  
D1 
Does your child point to things? 
D2 
Does your child say several single words? 
D3 
Does your child walk without any help? 
D4 
Does your child use 4-10 different words? 
E. Screening questions for caregiver of children aged 22-28 months 
E1 
Does your child copy others, especially adults and older children? 
E2 
Does your child say short sentences? 
E3 
Does your child follow simple instructions? 
E4 
Does your child run? 
E5 
Does your child scribble or draw? 
E6 
Does your child enjoy simple stories or songs? 
F. Screening questions for caregiver of children aged 29-36 months 
F1 
Does your child walk, run, climb, and kick a ball easily? 
F2 
Does your child talk using 2 to 3 short sentences? 
F3 
Can your child say his name or age? 
F4 
Does your child understand what “two” means? 
F5 
Does your child feed himself? 
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Annex 7 
AMENDMENTS TO THE PROTOCOL 
GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 1 
eTrack study number and 
Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
Amendment 1 
Amendment date: 
22 October 2013 
Co-ordinating author: 
 (Contract Scientific Writer for GSK 
Biologicals) 
Rationale/background for changes:  
• 
In order to improve pharmacovigilance across projects in Africa, a cross-project 
review of Periodic Safety Update Reports (PSUR) was conducted and four 
diseases were identified: Intussusception, Kawasaki diseases, Henoch-Schonlein 
Purpura and Hypotonic Hyporesponsive Episode (HHE). This amendment serves 
to classify them as adverse events of specific interest (AESI) thereby ensuring 
diagnosis according to well defined case definitions. 
• 
Meningitis of any etiology has been identified as a potential risk for RTS,S/AS01 
in the Phase III trial Malaria-055. Therefore meningitis of any etiology has 
become an AESI for RTS,S/AS01 and will be closely monitored in clinical and 
epidemiological studies. Bacterial meningitis has been added as an AESI in 
addition to aseptic meningitis currently included as an AESI in this study.  
• 
When a lumbar puncture is to be performed for evaluation of a neurological AESI 
an additional cerebrospinal fluid (CSF) sample will be taken for storage for 
potential further evaluation. 
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections: 
1. List of Abbreviations: AEFI, CSF, DNA, HHE, PCR, PSUR added; 
2. Trademarks: Rotarix® trademark added; 
3. Section 5.3.1. Protocol-defined diseases specified as adverse events of specific 
interest (AESI): addition of text on Bacterial Meningitis, Intussusception, Kawasaki 
diseases, Henoch-Schonlein Purpura and Hypotonic Hyporesponsive Episode 
[HHE]; 
4. Section 5.3.3 Case definition for malaria disease: more detailed definition for severe 
malaria disease added; 
5. Section 5.4.2 Surveillance of adverse events: text added on collection of 
cerebrospinal fluid sample when neurological AESI are observed; 
6. Section 5.4.3 Package for standard of care: small edits; 
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7. Section 5.7.1.11 Recording of cases of NC/NT-SAE, suspected AESI, malaria 
disease, abscess at injection site and foot positional deformations: new text on 
collection of cerebrospinal fluid sample when neurological AESI are observed; 
8. Section 5.8.1 Biological samples: new text on collection of cerebrospinal fluid 
sample when neurological AESI are observed; 
9. Section 5.8.2 Laboratory assays: small edits; 
10. Section 10 References: Agnandji, Bines, Buettcher, Gardner-Medwin, Holman, 
Nakamura, Newburger and WHO 2013 references added; 
11. Appendix A - CASE DEFINITIONS FOR PROTOCOL-DEFINED ADVERSE 
EVENTS OF SPECIFIC INTEREST (AESI): new text added to table particularly for 
aseptic meningitis, bacterial meningitis, Henoch Schönlein purpura, intussusception, 
hypotonic hyporesponsive episode, and Kawasaki disease; 
12. Appendix D - STUDY ACTIVITIES FLOWCHART DURING 
HOSPITALISATION: HOSPITALISED GROUP: small edits; 
13. Appendix F - POTENTIAL FUTURE TESTING OF STORED SAMPLES: small 
edit. 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 2 
eTrack study number 
and Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
Amendment 2 
Amendment date: 
03 June 2014 
Co-ordinating author: 
 (Keyrus Biopharma consultant for GSK 
Biologicals) 
Rationale/background for changes:  
• 
The EPI-MAL-002 protocol will serve to collect baseline information necessary to 
prepare the PASS study EPI-MAL-003 that will start with the implementation of 
the RTS,S/AS01E vaccine in Sub-Saharan Africa. 
• 
Although EPI-MAL-002 is not a targeted safety study the protocol has been 
formatted as a “PASS protocol”, proposed by the new EMA pharmacovigilance 
guidance [European Medicines Agency, 2012], and is therefore in alignment with 
EPI-MAL-003.  
• 
The EPI-MAL-003 protocol has been extensively reviewed within GSK 
Biologicals and with external regulatory agencies. For clarity, consistency and 
comparability in the objectives, endpoints and methodologies, text has been 
aligned in EPI-MAL-002 with the EPI-MAL-003 protocol. 
The following table summarises significant changes made in Protocol amendment 2 
(using the EMA “PASS protocol” template) compared to Protocol Amendment 1 
(that used GSK protocol template INS-BIO-EPI-1000 v13.2), by Section number. 
Amended text has been included in bold italics and deleted text in strikethrough for 
study Title, Objectives and Endpoints. 
Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
1. PROTOCOL 
INFORMATION 
Title page 
Revised 
2. OPINION HOLDER 
Title page 
No change 
3. RESPONSIBLE 
PARTIES 
- 
New section 
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Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
4. ABSTRACT 
SYNOPSIS 
 
Title 
Detailed Title 
An interventional epidemiology, cohort event monitoring 
study to define the incidence rates of diseases specified as 
protocol-defined potential adverse events of specific 
interest (AESI) and any other non-communicable and non-
traumatic serious adverse events (NC/NT-SAE) in infants 
and children in Africa prior to implementation of the 
RTS,S/AS01E candidate vaccine. 
Rationale and 
background 
Rationale for the 
study 
Reworded to provide clarity in background and rationale in 
relation to the primary aims of the study.  
Research question and 
objectives 
Objectives 
Co-primary objectives: 
• 
To estimate the incidence of protocol-defined 
diseases specified as adverse events of specific 
interest (AESI) among children <3 years of age, prior 
to implementation of the RTS,S/AS01 candidate 
vaccine, overall, by body system and by each AESI. 
• 
To estimate the incidence of any other non-
communicable and non-traumatic serious adverse 
event (NC/NT-SAE), with the exception of 
malnutrition, that requires hospitalisation among 
children <3 years of age. 
• 
To estimate the incidence of protocol-defined 
potential adverse events of special interest 
(AESI), and other serious adverse events (SAE) 
leading to hospitalisation or death, in children <3 
years of age, prior to implementation of 
RTS,S/AS01E. 
• 
To estimate the incidence of confirmed meningitis 
(any aetiology), in children <3 years of age, prior 
to implementation of RTS,S/AS01E. 
 
 
Secondary objectives: 
• 
To estimate the incidence of protocol-defined 
diseases specified as adverse events of specific 
interest (AESI) among children <3 years of age 
following immunisation, prior to implementation of the 
RTS,S/AS01 candidate vaccine, overall, by body 
system and by each AESI. 
• 
To assess if risk factors or health conditions can be 
associated with protocol-defined diseases specified 
as AESI, or any other NC/NT-SAE, among children 
<3 years of age. 
• 
To monitor serious morbidity, defined as requiring 
hospital admission, among children <3 years of age. 
• 
To estimate the prevalence of anaemia among 
hospitalised children <3 years of age prior to 
RTS,S/AS01 implementation. 
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Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
 
 
• 
To monitor mortality by cause of death among 
children <3 years. 
• 
To estimate the incidence of confirmed malaria 
disease as diagnosed in health facilities among 
children <3 years of age, prior to implementation of 
the RTS,S/AS01 candidate vaccine. 
• 
To estimate the prevalence of serious disabilities 
(developmental retardation or chronic physical 
impairment) among children <3 years of age. 
 
 
In children <3 years of age living in a geographically 
limited area with a health and demographic surveillance 
system (HDSS) in place, prior to implementation of 
RTS,S/AS01E: 
• 
To monitor trends over time of meningitis 
(confirmed and suspected)  
• 
To estimate the incidence of meningitis 
(confirmed and suspected) 
• 
To estimate the incidence of febrile convulsion 
• 
To explore the association between determinants 
and the incidence of protocol-defined potential 
AESIs 
• 
To estimate the incidence of anaemia among 
hospitalised children 
• 
To estimate the incidence of episodes of malaria 
(including P. falciparum malaria) clinically 
diagnosed in health care facilities (uncomplicated 
and severe disease) 
• 
To describe the causes of hospitalisation 
(including protocol-defined potential AESI and 
malaria) and death  
• 
To monitor mortality by cause of death. 
Study design 
Study design 
Reworded 
Population, including the 
setting and study 
population 
- 
Summary of information provided in Section 9.2 of protocol 
amendment 2. 
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Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
Variables 
Endpoints 
Co-primary endpoints 
In children <3 years old, prior to implementation of 
RTS,S/AS01E: 
• 
Occurrence of protocol-defined adverse event of 
specific interest (AESI): 
− 
Acute Disseminated Encephalo-Myelitis 
(ADEM), encephalitis, Guillain Barre 
Syndrome, Henoch-Schonlein purpura, 
juvenile chronic arthritis, diabetes mellitus 
Type I, thrombocytopenia, Kawasaki disease, 
intussusception 
− 
Anaphylaxis, Stephen-Johnson 
syndrome/toxic epidermal necrolysis 
− 
Hepatic or renal insufficiency 
− 
General convulsive seizure or hypotonic-
hyporesponsive episode. 
• 
Occurrence of any other non-communicable and non-
traumatic serious adverse event (NC/NT-SAE) that 
requires hospitalisation 
• 
Occurrence of serious adverse events leading to 
hospitalisation and death  
• 
Occurrence of confirmed meningitis (any 
aetiology). 
Secondary endpoints 
In children <3 years old, prior to implementation of 
RTS,S/AS01E: 
• 
Occurrence of confirmed and suspected 
meningitis 
• 
Occurrence of febrile convulsions  
• 
Demographic (age, gender, etc) and standard 
immunisations type and date administered.  
• 
Occurrence of risk factors in cases diagnosed with 
protocol-defined diseases specified as AESI, or any 
other NC/NT-SAE, that requires hospitalisation. 
• 
Occurrence of any serious adverse event that 
requires hospitalisation. 
• 
Occurrence of anaemia (see case definition section 
5.3.3) among hospitalised children; 
• 
Occurrence of confirmed clinical episodes of 
malaria diseases as diagnosed in primary health 
facilities (subjects enrolled in EPI and Non-EPI 
schedule groups) and hospital (any enrolled subject). 
− 
Uncomplicated and severe malaria (including 
P. falciparum malaria). 
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Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
 
 
• 
Occurrence of developmental retardation or chronic 
physical impairment. 
• 
Occurrence of hospitalisations 
− 
All causes and hospitalisations for malaria 
(including P. falciparum malaria). 
• 
Occurrence and cause of deaths as defined by 
hospital diagnosis or verbal autopsy 
− 
All causes and malaria attributed deaths 
(including P. falciparum malaria attributed 
death). 
• 
Occurrence of two events used as surveillance 
quality indicators: abscess at injection site and 
foot positional deformation. 
Data sources 
- 
Summary of information provided in Section 9.4 of protocol 
amendment 2. 
Study size 
Number of subjects 
Reworded 
Data analysis 
- 
Summary of information provided in Section 9.7 of protocol 
amendment 2. 
Milestones 
- 
Summary of Section 6 of protocol amendment 2. 
5. AMENDMENTS AND 
UPDATES 
- 
New section 
6. MILESTONES 
- 
New section 
7. BACKGROUND AND 
RATIONALE 
1. INTRODUCTION 
1.1 Background 
1.2 Rationale for the 
study 
Reworded and information/references updated. 
8. RESEARCH 
QUESTION AND 
OBJECTIVES 
2. OBJECTIVES 
See Section 4. ABSTRACT/ Research question and 
objectives 
9. RESEARCH 
METHODS 
3. Study design 
overview 
4. Study population 
5. Conduct of the 
study 
7. Data Evaluation: 
Criteria for Evaluation 
of Objectives 
8. Administrative 
matters 
Restructured and reworded sections. 
10. PROTECTION OF 
HUMAN SUBJECTS 
5.1 Regulatory and 
ethical 
considerations, 
including the informed 
consent process 
Reworded. 
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Protocol Amendment 
2: PASS Protocol 
Section 
Amendment 1 
Protocol Section  
(GSK template V13.2) 
Summary of Changes 
11. MANAGEMENT 
AND REPORTING OF 
ADVERSE 
EVENTS/ADVERSE 
REACTIONS 
6. SERIOUS ADVERSE 
EVENTS 
Reworded. 
12. PLANS FOR 
DISSEMINATING AND 
COMMUNICATING 
STUDY RESULTS 
8.6.4. Provision of 
study results to 
investigators, posting 
to the clinical trials 
registers and 
publication 
Reworded. 
13. REFERENCES 
10. REFERENCES 
Updated. 
ANNEX 1  
LIST OF STAND-
ALONE DOCUMENTS 
- 
New Annex. 
ANNEX 2  
LIST OF PRINCIPAL 
AND COORDINATING 
INVESTIGATORS 
- 
New Annex. 
ANNEX 3 
GLOSSARY OF TERMS 
GLOSSARY OF 
TERMS 
Updated. 
ANNEX 4 
TRADEMARKS 
TRADEMARKS 
No change. 
ANNEX 5 
CASE DEFINITIONS 
FOR MENINGITIS 
- 
Meningitis case definitions separated from ANNEX 6. 
Case definitions revised. 
ANNEX 6 
CASE DEFINITIONS 
FOR PROTOCOL-
DEFINED ADVERSE 
EVENTS OF SPECIFIC 
INTEREST (AESI) 
Appendix A 
Case definitions revised. 
ANNEX 7 DIAGNOSTIC 
TESTS FOR AESI 
- 
New ANNEX. 
ANNEX 8 STUDY 
ACTIVITY 
FLOWCHART – 
PASSIVE 
SURVEILLANCE IN 
HEALTH CARE 
FACILITIES 
Appendix C 
No change. 
ANNEX 9 STUDY 
SPECIFIC GUIDANCE 
DOCUMENT 
Appendix E 
No change. 
ANNEX 10 POTENTIAL 
FUTURE TESTING OF 
STORED SAMPLES 
Appendix F 
No change. 
ANNEX 11 
AMENDMENTS TO THE 
PROTOCOL 
Appendix G 
Updated. 
 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 3 & 4 
eTrack study number 
and Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
Amendment 3 & Amendment 4, Final  
Amendment date: 
19 March 2015 & 11 December 2015 
Co-ordinating author: 
 (Keyrus Biopharma consultant for GSK 
Biologicals) 
Rationale/background for changes:  
Protocol Amendment 3 was published for inclusion in the RTS,S/AS01E Risk 
Management Plan (July 2015) knowing that the SAGE/MPAC recommendations 
were not yet issued. 
This Protocol Amendment 4 describes changes to the protocol provided in 
Amendment 3 and includes the SAGE/MPAC recommendations. It will be submitted 
by the study investigators for review and approval by their local ECs before 
implementation. 
Amendment 4 has been prepared for the following reasons: 
• 
The background section has been updated with data about cerebral malaria from a 
post-hoc analysis of the Phase III study MALARIA-055. 
• 
Additional secondary objectives have been added for estimation of probable 
meningitis and for estimation of the incidence of cerebral malaria using RDT 
and/or microscopy. 
• 
The design and the analysis have been modified to take into account 
implementation of a 4th dose of RTS,S/AS01E. In addition, the follow-up period 
after the last dose has been extended to correspond to the follow-up period of the 
children enrolled in EPI-MAL-003 (i.e. 24 months after the 4th dose of 
RTS,S/AS01E). Indeed, home visits at 12 months and 24 months after the last 
RTS,S/AS01E dose will help to capture protocol-defined diseases that may have 
long risk window periods and that may not have been identified if the subject did 
not visit a health care facility, and to monitor the occurrence of malaria episodes 
for evaluation of vaccine effect. The age of the study population has been adapted 
accordingly (< 5 years). 
• 
The section about sites participating to the study was updated following 
SAGE/MPAC recommendations of pilot implementations of RTS,S/AS01E in 3–5 
distinct settings in SSA restricted to moderate-to-high transmission of malaria. 
• 
The activities related to home visits to detect malaria cases, including training of 
community health workers for systematic measurement of body temperature of all 
children, and availability of malaria tests have been clarified for alignment with 
the EPI-MAL-003 protocol.  
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• 
It has been clarified that cases of malaria only detected during the annual visits 
planned for EPI-MAL-005 will not be included in the analysis of EPI-MAL-002. 
However, if the cases of malaria are detected during an EPI-MAL-005 home visit 
that coincides with a home visit scheduled in EPI-MAL-002, the events will be 
captured in EPI-MAL-002. 
• 
The case definitions for malaria have been revised, according to the 3rd edition of 
the WHO guidelines for the treatment of malaria (2015). In addition, a case 
definition for cerebral malaria has been added. 
• 
Case ascertainment by the external panel of experts has been clarified. 
• 
It has been clarified that severe/cerebral malaria cases and other AE leading to 
hospitalisation or death will be reviewed by the external panel of experts. 
• 
The incidence of other AE leading to hospitalisation or death, meningitis and 
malaria morbidity and mortality will be monitored in sub-populations of children 
with hemoglobinopathies and HIV-positive children. 
• 
The section about analysis of co-primary objectives has been revised to mention 
that additional at risk periods will be considered based on results as sensitivity 
analyses. 
• 
The section about analysis of secondary objectives has been revised for 
clarification of potential variables that may be considered for models, in line with 
information collected in eCRF, and for estimation of the incidence of cerebral 
malaria. 
• 
It has been clarified that an interim analysis will be performed with the data 
collected on all subjects after 6 months of follow-up following the administration 
of dose 3 of DTP/HepB/Hib vaccine (6-12 weeks group), or 6 months after V3 (5-
17 months group). 
• 
The section about handling of missing data has been revised. 
• 
It has been clarified that data about seasonal malaria chemoprevention will be 
collected. 
Other changes were made for simplification, clarification or consistency. 
Amended text has been included in bold italics and deleted text in strikethrough.  
Booster dose of RTS,S/AS01E has been replaced by 4th dose of RTS,S/AS01E throughout 
the document. 
The age of 3 years has been replaced by the age of 5 years throughout the document. 
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Section 1 Title page 
Research question and objectives: 
• 
To estimate the incidence of adverse events of special interest, and of other adverse 
events leading to hospitalisation or death, in children < 3 years of age, prior to 
implementation of RTS,S/AS01E. 
• 
To estimate the incidence of aetiology-confirmed meningitis, in children <3 years of 
age, prior to implementation of RTS,S/AS01E. 
Countries of study: Reworded text – three countries selected (Burkina Faso, Ghana, and 
Kenya) and other countries in Sub-Saharan Africa might be added. 
Authors: 
 added, Path representative is now 
, 
 
 (Clinical Laboratory Services) added and authors who did not work on amendment 
removed. 
List of abbreviations: Added QS-21 Stimulon plus clarified meaning of abbreviation, 
Haemoglobin, MPAC, and SAGE  
Section 4 Abstract: Rationale and background: Reworded following positive opinion 
for the RTS,S/AS01E vaccine from European Medicines Agency and recommendations 
from WHO’s SAGE and the MPAC. 
Section 4 Abstract and Section 8: Research question and objectives  
Co-primary objectives 
• 
To estimate the incidence of AESI4, and of other AE leading to hospitalisation or 
death, in children <3 years of age, prior to implementation of RTS,S/AS01E. 
• 
To estimate the incidence of aetiology-confirmed meningitis, in children <3 years of 
age, prior to implementation of RTS,S/AS01E. 
Secondary objectives 
In children <3 years of age living in a geographically limited area with a health and 
demographic surveillance system (HDSS) in place, prior to implementation of 
RTS,S/AS01E: 
• 
To estimate the incidence of probable meningitis (final classification). 
• 
To estimate the incidence of any malaria and severe malaria (including P. falciparum 
malaria) diagnosed by using rapid diagnostic test (RDT) and/or microscopy. 
                                                 
4 Acute disseminated encephalomyelitis, encephalitis, Guillain-Barre Syndrome, hypotonic hyporesponsive episode, 
general generalised convulsive seizure. 
Intussusception, hepatic failure, renal insufficiency. 
Juvenile chronic arthritis, Stevens-Johnson syndrome/toxic epidermal necrolysis, Henoch-Schonlein purpura, Kawasaki 
disease. 
Diabetes mellitus type I, thrombocytopenia, anaphylaxis. 
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• 
To estimate the incidence of severe malaria (including P. falciparum malaria) 
using RDT and/or microscopy. 
• 
To estimate the incidence of cerebral malaria using RDT and/or microscopy. 
Section 4 Abstract: Study design: Reworded with information on active surveillance. 
Section 4 Abstract: Population, including the setting and study population: Age of 
children and number of sites in different countries clarified. 
Section 4 Abstract: Variables, Section 9.3.1 Co-primary endpoints, and Section 9.3.2 
Secondary endpoints 
Co-primary endpoints 
In children <3 years old, included in active or enhanced hospitalisation surveillance, prior 
to implementation of RTS,S/AS01E: 
• 
Occurrence of AESI. 
Secondary endpoints 
In children <3 years old, included in active or enhanced hospitalisation surveillance, prior 
to implementation of RTS,S/AS01E: 
• 
Occurrence of probable meningitis (final classification). 
In children <3 years old, included in active surveillance, prior to implementation of 
RTS,S/AS01E: 
• 
Occurrence of episodes of malaria diagnosed by using RDT and/or microscopy 
– 
Any malaria and severe malaria (including P. falciparum malaria). 
– 
Severe malaria (including P. falciparum malaria). 
– 
Cerebral malaria. 
• 
Occurrence of hospitalisation 
– 
All causes and hospitalisations for severe malaria (including P. falciparum 
malaria). 
Section 4 Abstract: Data sources: new wording on subjects actively participating in 
other trials. 
Section 4 Abstract: Study size: Reworded. 
Section 4 Abstract: Milestones: Updated with current dates / planned dates. 
Section 7.1 Background: Updated after EMA positive opinion for the RTS,S/AS01E 
vaccine, and recommendations about RTS,S/AS01E issued by WHO’s SAGE and MPAC. 
The study protocol has been adapted to take into account implementation of a 4th dose of 
RTS,S/AS01E 18 months after the 3rd dose. 
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Section 7.2. Safety results of the clinical development of RTS,S/AS01E : Updated with 
details of 4th vaccine dose and new text describing key safety e.g. cerebral malaria results 
from the Phase III MALARIA-055 study. 
Section 7.3 Efficacy results of the clinical development of RTS,S/AS01E :Updated 
with details of 4th vaccine dose. 
Section 7.4. Rationale for the study: EPI-MAL-002 was re-classified as a 
pre-implementation study rather than pre-authorisation study; EPI-MAL-003 was 
re-classified as a post-implementation study rather than post-authorisation study. 
Section 8.2 Secondary Objectives: Same edits are shown above for Section 1 Abstract: 
Secondary objectives. 
Section 9.1. Study design: New text describes usual dosing schedule for DTP/HepB/Hib 
vaccine, further details of the follow-up period and potential early study conclusion visit 
for EPI-MAL-002 subjects who meet eligibility criteria for EPI-MAL-003 study. Updates 
to the footnotes for Figure 1, for children in the 6-12 weeks age group and 5-17 months 
age group. 
Section 9.1.1 Rationale for the study design: Edits to the 1st paragraph on target 
population and new text on analyses for any malaria, severe malaria and cerebral malaria 
by plasmodium species. In active surveillance sub-section: more details on home based 
visits in relation to vaccine doses. 
Section 9.2. Setting: New details on use of INDEPTH procedures for demographic 
census and SAGE/MPAC pilot implementations of RTS,S/AS01E in 3-5 distinct settings 
in SSA restricted to moderate-to-high transmission of malaria. 
Section 9.2.1. Study population: Updates specifying a Safety Post Approval Program 
Partnership Committee meeting involving study site investigators in main text and Table 
2 footnote. Table 2 updated with latest estimates. Low malaria transmissions sites not 
pursued. Potential addition of moderate-to-high malaria transmission sites, or increased 
enrolment at current sites. 
Section 9.2.1.1. Participant recruitment: Details of dosing schedule for DTP/HepB/Hib 
vaccine. 
Section 9.2.4 Elimination criteria during the study: Text deleted. 
Section 9.2.4 Study period: Details of active surveillance for each subject and the 
potential early study conclusion for subjects enrolled in EPI-MAL-002 if they meet the 
eligibility criteria for EPI-MAL-003 study enrolment. 
Section 9.2.5.1 Case definition: AESI: In Table 3, per 100,000/year, and /100,000 per 
year has been replaced by /100,000 PY. 
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Section 9.2.5.2 Case definition: Hospitalisations for an AE other than an AESI, 
meningitis or severe malaria (including cerebral malaria): Added text on meningitis 
and severe malaria. 
Section 9.2.5.5 Case definition: Malaria: Updated text for severe falciparum malaria, 
and new text for severe vivax malaria and cerebral malaria. 
Section 9.2.5.7 Hospitalisation case definition: Small update. 
Section 9.2.5.8 Deaths: INDEPTH procedures for verbal autopsy will be implemented to 
ensure consistency across study sites. 
Section 9.2.6.2 Case definition for foot positional deformations: Small update. 
Section 9.2.7.1 Study procedures for active surveillance: Updates concerning study 
visits. 
Section 9.2.7.1 .4 Collect demographic data: Small update. 
Section 9.2.7.1.5 Health history: Record brief medical history and physical exam at 
Visit 1. 
Section 9.2.7.1.6 Check and record vaccinations: Small update. 
Section 9.2.7.1.7 Record information about health care seeking behaviour, malaria 
control measures, drug use and exposure to environmental hazards: Rewritten. 
Section 9.2.7.1.9 Physical examination, record of signs and symptoms, record any 
serious delay in developmental milestones or physical disability: New text describing 
role of community workers. 
Section 9.2.7.1.10 Refer sick children or children with disabilities to outpatient clinic 
or hospital: Reworded. 
Section 9.2.7.1.11 Record cases of death: INDEPTH procedures for verbal autopsy will 
be implemented. 
Section 9.2.7.1.12 Study conclusion: Small update. 
Section 9.2.7.1.13 Outline of study procedures: Table and footnotes 1, 5 and 6 updated. 
Section 9.2.7.2.1 Informed consent (for subjects not enrolled previously, i.e. for 
previous hospitalisation or for active surveillance): Small update. 
Section 9.2.7.2.3 Assign subject study number (for subjects not enrolled previously): 
Reworded. 
Section 9.2.7.2.7 Health history: Reworded. 
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Section 9.2.7.2.8 Record information about health care seeking behaviour, malaria 
control measures, drug use and exposure to environmental hazards: Rewritten. 
Section 9.2.7.2.9 Record standard vaccinations: Small update. 
Section 9.2.7.2.11 Record haemoglobin measurement: Small update. 
Section 9.2.7.2.13 Record cases of suspected AESI, other AE leading to 
hospitalisation or death, meningitis cases, malaria episodes diagnosed by RDT 
and/or microscopy, abscess at injection site and foot positional deformations: New 
wording on children diagnosed with meningitis, cerebral malaria or with an AESI. 
Section 9.2.7.2.15 Study conclusion: Small update. 
Section 9.2.7.2.16 Outline of study procedures: Table 5 updates. 
Section 9.2.7.3.1 Biological samples: Small updates. 
Section 9.2.7.3.2 Laboratory assays: New paragraph on consumables and reagents 
being provided to perform first line routine testing for all diseases under investigation. 
Section 9.2.7.4.1 Case ascertainment for meningitis: Meningitis case 
characterization: Small update. 
Final meningitis case ascertainment: Details on panel of experts. 
Additional follow-up of meningitis cases: Small update. 
Section 9.2.7.4.2 Case ascertainment for AESI: Doubtful diagnosis and outcome 
changed to uncertain diagnosis and outcome, and other updates concerning GSK safety 
physician review and external expert review. 
Section 9.2.7.4.4 Case ascertainment for other AE leading to hospitalisation or 
death: Doubtful diagnosis and outcome changed to uncertain diagnosis and outcome, and 
other updates concerning GSK safety physician review and external expert review. 
Section 9.2.7.4.5 Case ascertainment for malaria: Definition for cerebral malaria cases 
added together with details of GSK safety physician review and review by two selected 
experts. 
Section 9.2.7.6 Capacity building: Details of training packages for site staff. 
Section 9.3.3.1 Recorded in EPI-MAL-002 and EPI-MAL-003: Reworded. 
Section 9.3.3.2 Recorded in EPI-MAL-005: Reworded. 
Section 9.4.1 Health Demographic Surveillance System: Small updates. 
Section 9.4.2 Active surveillance and enhanced hospitalisation surveillance of study 
EPI-MAL-002: New first paragraph plus other updates. 
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Section 9.4.3 Malaria Transmission Intensity Study EPI-MAL-005: Details of 
enrolling subjects in EPI-MAL-002 and EPI-MAL-005 studies plus other small updates. 
Section 9.5 Study size: Updated text. 
Section 9.7 Data analysis: Text on descriptive analysis of safety endpoints. 
Section 9.7.4.1 Sequence of analyses: Details of interim analysis added. 
Section 9.7.5.1 Analysis population: Small update. 
Section 9.7.5.2.1 Incidence of AESI, and other AE leading to hospitalisation or 
death: Small updates. 
Section 9.7.5.2.2 Incidence rate of aetiology-confirmed meningitis: Small updates. 
Section 9.7.6.2 Statistical approach: Updates to text. 
Section 9.7.7 Analysis for other secondary objectives: Small updates. 
Section 9.7.7.1 Analysis population: New text on Main and Complementary analyses. 
Section 9.7.7.2 Statistical approach: Updates including updates to Table 8. 
Section 9.7.8.1 Handling of missing data: Details of a sensitivity analysis added. 
Section 9.8.2 Archiving of data at study sites: Small update. 
Section 9.9 Limitations of the research methods: Updates included length of 
follow-up, malaria transmission intensity for sites and the interim analysis. 
Section 10.1 Regulatory and ethical considerations, including the informed consent 
process: Small update. 
Section 12 Plans for disseminating and communicating study results: Details on the 
interim report added. 
Section 13 References: Added both European Medicines Agency references plus, Rubin, 
Sterne, The RTS,S Clinical Trials Partnership, WHO - Global malaria programme, WHO 
- Management of severe malaria, and WHO - Background brief: malaria vaccine 
RTS,S/AS01 references, removed the GlaxoSmithKline study report reference, and made 
updates to other references e.g. updating date last accessed. 
Annex 4 TRADEMARKS 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
Generic description 
Stimulon® (Licensed by GSK from Antigenics Inc, 
a wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation) 
 
Triterpene glycoside immune enhancer 
 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 5 
eTrack study number 
and Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
Amendment 5 
Amendment date: 
11 October 2017 
Co-ordinating authors: 
 (GSK Biologicals) 
, Lead Scientific Writer (GSK 
Biologicals) 
Rationale/background for changes:  
Protocol Amendment 5 describes the sample size reduction from 40,000 to 30,000 
with a resultant reduction in the size of the two study groups to 15,000 subjects each.  
Amendment 5 has been prepared for the following reasons: 
• 
In order to have a synergy with the WHO pilot implementation, the study size was 
reduced from 40,000 to 30,000 children in active surveillance with at least 20,000 
children enrolled where the RTS,S/AS01E vaccine will be implemented. Among 
the 30,000 children, approximately 15,000 children (with at least 10,000 children 
in sites where the vaccine will be implemented) will be enrolled in the 6-12 weeks 
group (to collect background data in this age group) and approximately 
15,000 children (with at least 10,000 children in sites where the vaccine will be 
implemented) will be enrolled in the 5-17 months group (to mimic administration 
of RTS,S/AS01E in the 5-17 months age group). Study size updates involved 
multiple sections, e.g. Section 9.1 Study Design and Section 9.5 Study size. 
• 
For multiple sections: the number of countries and number of study sites has been 
updated following the WHO announcement that the RTS,S/AS01E vaccine will be 
first introduced in 3 countries (Ghana, Kenya and Malawi) through the MVIP. 
• 
For multiple sections: estimation of the mortality rate, overall and by gender, has 
been added. 
• 
For multiple sections: the informed consent process has been clarified “signed or 
witnessed and thumbprinted ICF”. 
• 
For multiple sections: “or equivalent surveillance system” has been added after 
HDSS; and the term “study site(s)” or “study area” has been added. 
• 
For multiple sections: the replacement strategy has been updated. 
• 
For multiple sections: the duration of the recruitment period has been removed, as 
it could/can not be respected in all sites due to logistical constraints. 
• 
For multiple sections: it was clarified that census rounds are scheduled at least 
once a year during the study periods instead of twice a year. 
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• 
The milestones in Section 6 have been updated. 
• 
New sub-sections on “Severe malaria including cerebral malaria” and “Overall 
mortality by gender” have been added to Section 7.2 Safety results of the clinical 
development of RTS,S/AS01E. 
• 
The wording of “secondary objectives” on “describe the causes of hospitalisation” 
and “estimate the incidence of cerebral malaria” has been changed, and the 
secondary objective “To describe the causes of death, overall and by gender” has 
been added in Section 8.2 and in the corresponding part of Section 4 Abstract. 
• 
The opening paragraph of Section 8.2 Secondary Objectives and of the 
corresponding part of Section 4 Abstract has been updated. 
• 
The wording of the last two “study variables” / “study endpoints” on “Occurrence 
of hospitalisations” and “Occurrence of death” has been modified in Section 9.3.2 
and in the corresponding part of Section 4 Abstract.  
• 
In Section 9.2.1 Study population: the text on “Estimated annual birth cohorts by 
study site” (Table 2) has been removed, with removal of planned number of sites 
in selected countries. 
• 
Section 9.2.5.3 Meningitis has been edited, including addition of a new opening 
paragraph, addition of “turbid macroscopic aspect” as a sign of CSF abnormality, 
and clarification that clinically suspected meningitis cases included subjects with 
no CSF sample available and no alternative diagnosis. 
• 
For consistency between the way the objectives and the endpoints are presented, 
and to avoid repeating several endpoints, the two sub-sections in Section 9.3.2 
Secondary endpoints: "In children included in active or enhanced hospitalisation 
surveillance, prior to implementation of RTS,S/AS01E" and “In children included 
in active surveillance, prior to implementation of RTS,S/AS01E” have been 
replaced by one sub-section: “In children living in the study area, prior to 
implementation of RTS,S/AS01E”, followed by all the secondary endpoints. 
• 
In Section 9.4.3 Study EPI-MAL-005 “changes in environmental factors such as 
rainfall” has been added to the parameters assessed in EPI-MAL-005. 
• 
Section 9.5 Study size has been updated as shown in bullet 1 above with greater 
detail on the estimates of observed incidence of events following dose 
administration based on either: 15,000 subjects, 10,000 subjects, the estimated 
birth cohort of 11,500 subjects and an estimated birth cohort of 17,250 children in 
Tables 6-9. 
• 
Section 9.7.6 Analysis of secondary safety objectives has been updated, including 
analysis of cerebral malaria of the causes of death, overall and by gender. 
• 
Finally, changes in study personnel have been included on the protocol cover 
page. 
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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections. 
1. Cover page - Countries of study: The number of countries and number of study 
sites has been updated following the WHO announcement that the RTS,S/AS01E 
vaccine will be first introduced in 3 countries (Ghana, Kenya and Malawi) through 
WHO-coordinated pilot implementation programme the MVIP. 
2. Cover page - Authors: 
 has been added as coordinating 
author. 
, 
, 
, 
 and 
 have been added as main authors. 
, 
 
, and 
 have been added as 
other GSK contributing authors. Names of chair and co-chairs of the Safety Post 
Approval Program Partnership Committee have been removed as they change every 
year. Other non-GSK Biologicals partners have been updated as follows: PATH 
(represented by 
, Seattle, United States of America) and Quintiles 
(represented by 
, Project Manager). Training activities have been 
transferred from AMP Services to AMP Regional Office for Africa due to 
bankruptcy of AMP Services. Therefore Agence de Médecine Préventive (AMP) 
(represented by 
, Paris, France) has been replaced by Agence de 
Médecine Préventive (AMP) Regional Office for Africa (represented by Dr. 
, Abidjan, Ivory Coast). Considering EpiConcept did not update their 
IT standard as required per IT audit and conditional to the contract signature, was 
not performant and didn’t solve technical issues in due time, GSK study team has 
decided to early terminate the collaboration with EpiConcept. Parexel has been 
selected to provide similar services. Therefore EpiConcept (represented by 
 
 Paris, France) has been replaced by Parexel (represented by 
, 
Senior Project Manager). 
3. Section 2 Opinion Holder: Copyright © 2012-2017 GSK group of companies or 
its licensor. of the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
4. List of Abbreviations: CLS, DTP, DTP-HepB, MTI, MVIP, PT, RMP and SOC 
abbreviations have been added. Hb and NRA abbreviations have been removed. 
5. Section 3 Responsible Parties: Names and titles of 
, Senior 
Epidemiology Lead – Malaria and 
, Epidemiology Lead – 
Malaria have been added. Name of 
 has been removed. 
6. Section 4 Abstract: Names and titles of 
, Senior Epidemiology Lead – 
Malaria and 
, Epidemiology Lead – Malaria have been added. 
Name of 
 has been removed. 
Section 4 Abstract (continued): Edits for the “Rationale and background” section. 
Addition of the WHO announcement that the RTS,S/AS01E vaccine will be first 
introduced in 3 countries (Ghana, Kenya and Malawi) through a WHO-coordinated 
pilot implementation programme the MVIP. Estimation of the mortality rate, overall 
and by gender, has been added. 
Section 4 Abstract (continued): Edits to opening paragraph of “Secondary 
objectives” and to bullet points: 
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In children living in a geographically limited area with a health and demographic 
surveillance system (HDSS) in place the study area, prior to implementation of 
RTS,S/AS01E: 
• 
To describe the causes of hospitalisation (including AESI, other AE, meningitis and 
malaria) and death. 
• 
To describe the causes of death, overall and by gender. 
• 
To estimate the incidence of cerebral malaria (malaria diagnosed by using RDT 
and/or microscopy). 
• 
To estimate the mortality rate (all-cause mortality and deaths attributed to malaria 
[including P. falciparum]), overall and by gender.  
Section 4 Abstract (continued): For the “Study design” section, new wording for 
bullet point 3 and edits for bullet point 5 which are provided below 
– 
The study targets enrolling 40,00030,000 children in active surveillance, with at 
least 20,000 children enrolled where the RTS,S/AS01E vaccine will be 
implemented. Among the 40,00030,000 children, approximately 20,00015,000 
children (with at least 10,000 children in sites where the vaccine will be 
implemented) will be enrolled in the 6-12 weeks group (to collect background 
data in this age group) and approximately 20,00015,000 children (with at least 
10,000 children in sites where the vaccine will be implemented) will be 
enrolled in the 5-17 months group (to mimic administration of RTS,S/AS01E in 
the 5-17 months age group). 
– 
The diseases under surveillance for safety include AESI, other AE leading to 
hospitalisation or death, and meningitis, and will be monitored among children 
enrolled in active surveillance and in enhanced hospitalisation surveillance. To 
estimate vaccine For impact, several measures of malaria burden will be 
monitored among children in the active surveillance. The mortality rate, overall 
and by gender, will also be estimated. 
Section 4 Abstract (continued): For the section on “Population, including the 
setting and study population”, inclusion of “or equivalent surveillance system” after 
HDSS and removal of text on specific sites in specific countries. In addition, the 
number of countries and number of study sites have been updated following the 
WHO announcement that the RTS,S/AS01E vaccine will be first introduced in 3 
countries (Ghana, Kenya and Malawi) through a WHO-coordinated pilot 
implementation programme the MVIP. 
Section 4 Abstract (continued): For the “Variables” section, edits to opening 
paragraphs and to the bullet points as shown below: 
Co-primary endpoints 
In children included in active or enhanced hospitalisation surveillance living in the 
study area, prior to implementation of RTS,S/AS01E: 
Secondary endpoints 
In children included in active or enhanced hospitalisation surveillance living in the 
study area, prior to implementation of RTS,S/AS01E: 
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In children included in active surveillance, prior to implementation of RTS,S/AS01E: 
• 
Occurrence of hospitalisation 
– 
All causes and hospitalisations for any malaria (including P. falciparum 
malaria), severe malaria (including P. falciparum malaria) and cerebral 
malaria. 
• 
Occurrence of death 
– 
All causes and malaria attributed deaths (including P. falciparum malaria 
attributed death). 
– AE attributed deaths. 
Section 4 Abstract (continued): Small edits for the “Data Sources” section. 
Section 4 Abstract (continued): The “Study size” section was updated as shown 
below: 
The enrolment is fixed to study targets enrolling 20,00015,000 children per group 
(i.e. 6-12 weeks group and 5-17 months group; with at least 10,000 children of 
15,000 in each group enrolled where the RTS,S/AS01E vaccine will be 
implemented), for a total of 40,00030,000 children (at least 20,000 children enrolled 
where the vaccine will be implemented). For some of the AESI the incidence could 
be very rare (around 1/100,000 person years [PY]) and the period at-risk considered 
could be from 2 weeks till 6 months for AESI, and 12 months for meningitis. The 
95% confidence interval (CI) around an observed incidence of 17.725.2 per 100,000 
PY (corresponding to 1 event detected, in a risk period of 6 weeks following each 
dose [censored at the administration of the following dose], based on 20,000 10,000 
subjects) will be [0.40.6, 98.8140.2]. 
Section 4 Abstract (continued): Small edits for the “Data analysis” section as 
shown below: 
The incidence rate of aetiology-confirmed meningitis and of cerebral malaria will 
be computed with 95% CI using the same approach as described above. 
Section 4 Abstract (continued): Small edits for the “Milestones” section as shown 
below: 
The study started in Q4 2015, and is planned to end in Q2 2022 Q4 2020 (tentative 
date, depending on recruitment timelines). 
7. Section 5 Amendments and Updates: Details for Protocol Amendment 4 added. 
8. Section 6 Milestones: Planned dates for end of data collection and final report of 
study results have been updated. 
End of data collection 
Q2 2022 Q4 2020** 
Final report of study results 
Q4 2022 Q2 2021** 
9. Section 7.1 Background: Small edits. Addition of the WHO announcement that the 
RTS,S/AS01E vaccine will be first introduced in 3 countries (Ghana, Kenya and 
Malawi) through a WHO-coordinated pilot implementation programme the MVIP. 
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10. Section 7.2 Safety results of the clinical development of RTS,S/AS01E: General 
text on SAEs reports moved up to the start of the section; new sub-section titles 
added; new sections on “Severe malaria including cerebral malaria” including Table 
2 and “Overall mortality by gender” added; concluding summary updated; and other 
updates made to the text including updates to Table 1. 
11. Section 8.2 Secondary objectives: Updates to text for opening paragraph and to 
bullet points as in the abstract. 
12. Section 9.1 Study design: Updates to text on number of subjects recruited as for the 
abstract; modified paragraph on possible overlap between EPI-MAL-002 and 
EPI-MAL-003. Addition of sentence about estimation of mortality rate, overall and 
by gender. 
13. Section 9.1.1 Rationale for the study design: Updates to text on number of subjects 
recruited as for the abstract; and other edits e.g. adding “or equivalent surveillance 
system” after HDSS. Addition of sentence about estimation of mortality rate, overall 
and by gender. Clarification of participant recruitment for enhanced hospitalisation 
surveillance. 
14. Section 9.2 Setting: Edits including adding “or equivalent surveillance system” after 
HDSS or adding the term “study sites”. Clarification that census rounds are 
scheduled at least twice once a year during the study periods. Addition of new 
information about countries and sites that have started, or will start, enrolment, 
following the WHO announcement in April 2017 that the RTS,S/AS01E vaccine will 
be first introduced in 3 countries (Ghana, Kenya and Malawi) through a WHO-
coordinated pilot implementation programme the MVIP. Replacement strategy 
updated. 
15. Section 9.2.1 Study population: Updates to text on number of subjects recruited as 
for the abstract. Removal of text on “Estimated annual birth cohorts by study site” 
(Table 2) with removal of planned number of sites in selected countries. 
16. Section 9.2.1.1 Participant recruitment: Edits including adding “or equivalent 
surveillance system” after HDSS or adding the term “study area”. Figures for 
expected number of children recruited updated. Clarification that written or 
witnessed and thumbprinted informed consent must be obtained. Duration of the 
recruitment period removed, as it could/can not be respected in all sites due to 
logistical constraints. Clarification of participant recruitment for enhanced 
hospitalisation surveillance. 
17. Section 9.2.2 Inclusion criteria for enrolment: Inclusion criteria of enrolment: 
Edits including adding “or equivalent surveillance system” after HDSS. 
18. Section 9.2.4 Study period: First paragraph about enrolment period and last 
paragraph about overlap of study EPI-MAL-002 and study EPI-MAL-003 edited. 
Duration of the recruitment period removed, as it could/can not be respected in all 
sites due to logistical constraints. 
19. Section 9.2.5.1 AESI: Minor edits. 
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20. Section 9.2.5.2 Hospitalisations for an AE other an AESI, meningitis, any 
malaria or severe malaria (including cerebral malaria): Addition of “any 
malaria” to the sentence. 
21. Section 9.2.5.3 Meningitis: Edits including adding new opening paragraph, adding 
“turbid macroscopic aspect” as a sign of CSF abnormality, and clarifying that 
clinically suspected meningitis cases included subjects with no CSF sample available 
and no alternative diagnosis. 
22. Section 9.2.5.8 Deaths: Edits including new paragraph at end of section explaining 
that malaria-attributed deaths with an uncertain diagnosis and outcome after review 
by the GSK safety physician would be reviewed by an expert panel, to confirm 
primary/secondary cause of death. 
23. Section 9.2.7.1 Active surveillance: Edits including adding “or equivalent 
surveillance system” after HDSS, including the term “study area”, and text to clarify 
exactly which children would be recruited. 
24. Section 9.2.7.1.1 Informed consent: Clarification that written or witnessed and 
thumbprinted informed consent must be obtained. 
25. Section 9.2.7.1.9 Physical examination, record of signs and symptoms, record 
any serious delay in developmental milestones or physical disability: Minor edits. 
26. Section 9.2.7.1.11 Record cases of death: Minor edits. 
27. Section 9.2.7.1.12. Study conclusion: Last paragraph about overlap of study EPI-
MAL-002 and study EPI-MAL-003 edited. 
28. Section 9.2.7.1.13 Outline of study procedures: Minor edit. 
29. Section 9.2.7.2 Enhanced hospitalisation surveillance: Minor edit. 
30. Section 9.2.7.2.1 Informed consent: Clarification that written or witnessed and 
thumbprinted informed consent must be obtained. 
31. Section 9.2.7.2.3 Assign subject study number (for subjects not enrolled 
previously): Second paragraph edited. 
32. Section 9.2.7.2.11 Record haemoglobin measurement: Minor edit. 
33. Section 9.2.7.2.16 Outline of study procedures: Edits to several rows of Table: 
Provide study ID card (to all subjects not enrolled previously) and study-specific 
stickers (only to subjects identified before 1st DTP or aged 5 to <18 months 
not enrolled previously and enrolled before the active surveillance recruitment is 
terminated) 
○ 
 
For each diagnosis of an AESI, cerebral malaria or meningitis, collect approx. 5 
mL of whole blood and store serum 5 
● 
 
For each diagnosis of a neurological AESI, cerebral malaria or meningitis, 
where a CSF sample has been taken as part of routine practice, store part of the 
CSF sample (minimum 500 µL)5 
● 
 
34. Section 9.2.7.3.1. Biological samples: Small edits. 
35. Section 9.2.7.3.2. Laboratory assays: Small edits including adding CLS 
abbreviation for Clinical Laboratory Services. 
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36. Section 9.2.7.4.1. Case ascertainment for meningitis: Edits for Meningitis case 
characterisation subsection. 
37. Section 9.2.7.4.3. Children suspected of having a serious adverse event (SAE): 
New cross-reference to Section 11 added. 
38. Section 9.2.7.4.5. Case ascertainment for malaria: Addition of the following 
paragraph: Children diagnosed with cerebral malaria will be followed up after 
hospital discharge up to study conclusion (i.e. study end or child reaches 5 years of 
age, whichever occurs first) in order to evaluate any sequelae. This will be done by 
a check-up at the hospital 1 month, 6 months and 1 year after hospital discharge. 
39. Section 9.2.7.6. Capacity building: Edits including using terms “study area”, study 
team staff, community health worker, and “routine practice” and adding new 
paragraph on laboratory tests performed by CLS.  
40. Section 9.3.1 Primary endpoints: Edits to opening paragraph as shown below: 
In children included in active or enhanced hospitalisation surveillance living in the 
study area, prior to implementation of RTS,S/AS01E: 
41. Section 9.3.2 Secondary endpoints: Edits to opening paragraphs and to the bullet 
points as shown below: 
In children included in active or enhanced hospitalisation surveillance living in the 
study area, prior to implementation of RTS,S/AS01E: 
In children included in active surveillance, prior to implementation of RTS,S/AS01E: 
• 
Occurrence of hospitalisation 
− 
All causes and hospitalisations for any malaria (including P. falciparum 
malaria) severe malaria (including P. falciparum malaria) and cerebral 
malaria (see and cerebral malaria (see Section 9.2.5.7 for case 
definitions). 
• 
Occurrence of death 
− 
AE attributed deaths (see Section 9.2.5.8 for case definitions). 
42. Section 9.3.3.1. Recorded in EPI-MAL-002 and EPI-MAL-003: Added “study 
area”. Clarification that if any of the sources described here above confirm 
vaccination, it will be assumed that vaccination has taken place for the analysis. 
43. Section 9.3.3.2. Recorded in EPI-MAL-005: Added “or equivalent surveillance 
system” after HDSS and the terms “study area” and “malaria transmission intensity” 
(MTI). 
44. Section 9.4.1. Health Demographic Surveillance System (or equivalent 
surveillance system): Clarification that census rounds are scheduled at least twice 
once a year during the study periods. Edits including adding “or equivalent 
surveillance system” after HDSS and the terms “study site / study sites”. Last 
paragraph updated. 
45. Section 9.4.2. Active surveillance and enhanced hospitalisation surveillance of 
study EPI-MAL-002: Added “or equivalent surveillance system” after HDSS. 
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Clarification that signed or witnessed and thumbprinted informed consent shall be 
obtained. Last paragraph updated. 
46. Section 9.4.3 Study EPI-MAL-005: Addition of “changes in environmental factors 
such as rainfall” to the parameters assessed in EPI-MAL-005. 
47. Section 9.5 Study size: Updates to this section as shown for Section 4 Abstract with 
greater detail on the estimates of observed incidence of events following dose 
administration based on either: 15,000 subjects, 10,000 subjects, the estimated birth 
cohort of 11,500 subjects and an estimated birth cohort of 17,250 children in Tables 
6-9. 
48. Section 9.7 Data analysis: Text updated with new sample size numbers. 
49. 9.7.1 Total cohort: Clarification that written or witnessed and thumbprinted 
informed consent must be obtained. 
50. Section 9.7.5.2.1 Incidence of AESI, and other AE leading to hospitalisation or 
death: Two edits related to vaccination. 
51. Section 9.7.6.2 Statistical approach: New bullet point added (bullet point 3 about 
incidence of cerebral malaria), new text added to bullet points 4 and 5, and one short 
paragraph on the categorisation of covariates removed. 
52. Section 9.7.7.1 Analysis population: New text added to the first paragraph and 
further edits to put the emphasis on the main analysis and additional analyses rather 
than main and complementary analyses. 
53. Section 9.7.7.2 Statistical approach: New wording for first paragraph and in 
Table 10 - new text for rows 8 and 9. 
54. Section 9.7.8.1 Handling of missing data: New text for paragraph 3. 
55. Section 9.9 Limitations of the research methods: Edits including new paragraph 
on the content of protocol amendment 5, updated paragraph about countries/sites and 
number of children to be enrolled, adding “or equivalent surveillance system” after 
HDSS, providing new figures for the number of subjects recruited, and including the 
term “study area(s)”. Clarification that demographic census is scheduled at least 
twice once a year during the study periods. Duration of the recruitment period 
removed, as it could/can not be respected in all sites due to logistical constraints. 
56. Section 10.1 Regulatory and ethical considerations, including the informed 
consent process: Clarification that written or witnessed and thumbprinted informed 
consent must be obtained. 
57. Section 11 Management and reporting of serious adverse events related to study 
procedures: Minor edit. 
58. Section 11.3.3. Completion and transmission of SAE reports to GSK Biologicals: 
New second paragraph added. 
59. Section 13 References: Hair 1995, Rosillon 2015, Ulm 1990, United Nations 2011, 
WHO 2016(a), WHO 2016(b), WHO 2017 references added. WHO, 2015(a), ISPE 
2015 and The Uppsala Monitoring Centre, 2011 references updated. Bines 2004 
and Newburger 2004 references removed. 
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60. Annex 3 Glossary of Terms: Added DTP/HepB/Hib. 
61. Annex 4 Trademarks: Removed Stimulon® (Licensed by GSK from Antigenics Inc, 
a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation) 
 
Triterpene glycoside immune enhancer 
Added: Mosquirix TM: Plasmodium falciparum and hepatitis B vaccine 
(recombinant, adjuvanted) 
62. Annex 6 Recruitment scheme ratio 1-1 (6-12 weeks group - 5-17 months group): 
Figure removed, as the duration of the recruitment period could/can not be respected 
in all sites due to logistical constraints. 
63. Annex 7 Study specific guidance document: Title updated: Screening tool for 
assessing serious delays in developmental milestones and/or physical disabilities in 
children less than 3 years of age from 3 months to 36 months of age. Sentence 
updated: If the caregiver responds negatively to 2 or more questions, the child should 
be referred to a medical consultation for further investigations according to routine 
medical practice. 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 6 
eTrack study number 
and Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
Amendment 6 
Amendment date: 
06 July 2018 
Co-ordinating authors: 
, Lead Scientific Writer (GSK 
Biologicals) 
Rationale/background for changes:  
Protocol Amendment 6 has been put in place to document that the EPI-MAL-002 study 
sites in Burkina Faso will early terminate the study and that sites in Malawi, one of the 
country where RTS,S/AS01E will be introduced through the MVIP will not take part in 
the study. 
GSK, in agreement with WHO, decided to terminate the study EPI-MAL-002 in the 
two sites located in Burkina Faso, i.e. Nouna and Sapone. Briefly, it was previously 
decided that Burkina Faso sites would continue participating in EPI-MAL-002 until 
study end. However, given that the MVIP will not be conducted in this country, there is 
no scientific value to collect additional data (the EPI-MAL-002 data collected in 
Burkina Faso will neither be used for the before-after analyses, nor for the generation 
of EPI-MAL-002 indicators that inform any other analyses of the EPI-MAL-003 
study). Therefore, the study EPI-MAL-002 in Burkina Faso sites has been early 
terminated and data collected and recorded to date in those sites will be reported in a 
descriptive way. 
In order to align with the MVIP, the study sites for the GSK Phase IV studies have 
been selected from the 3 countries where the RTS,S/AS01E vaccine will be 
implemented (Ghana, Kenya and Malawi). Considering the RTS,S/AS01E vaccine 
implementation date in Malawi currently planned in October 2018, the baseline data 
that might be collected in Malawi in the EPI-MAL-002 study would be too limited to 
be relevant for the before/after comparisons in this country. Therefore, GSK, in 
agreement with the WHO, decided to focus the conduct of the EPI-MAL-002 study in 
Ghana and Kenya, not initiating the study in Malawi, and partially compensating the 
expected sample size from Malawi sites by using the high recruitment observed from 
sites in Kenya (Kombewa) and Ghana (Kintampo) and extending recruitment in Ghana 
(Navrongo), hence limiting the impact on the before/after comparison study power. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections. 
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1. Cover page - Countries of study: Sites in sub-Saharan Africa (SSA) countries have 
been or will be selected for EPI-MAL-002 based on      
In order to align with the MVIP, the study sites for the GSK Phase IV studies have 
been, or will be, selected from the 3 countries where the RTS,S/AS01E vaccine will 
be implemented (i.e. two sites in Malawi are planned to be included in EPI-MAL-
002 in addition to the already defined sites). As a consequence, The only exception 
is for Burkina Faso sites, that as they have had already started EPI-MAL-002, early 
terminated the follow-up activities in active surveillance and enrolment in 
enhanced hospitalisation surveillance since 06 June 2018, with the exception of 
the follow-up check-ups at the hospital for children diagnosed with meningitis, 
cerebral malaria or with an AESI. All study activities are planned to be terminated 
by Q2 2019. A description of data from these sites will be presented in the progress 
reports up to Q4 2019, but none of these data will be part of the statistical analyses 
for the interim and final reports. They will continue participating in EPI-MAL-002 
until study end. 
2. Cover page - Authors: 
, Clinical and Epidemiology Scientist (Keyrus 
Biopharma for GSK Biological, 
, GVCL CLS Clinical Read-out 
Manager Leader (GSK Biologicals), 
, Local Delivery Lead (GSK 
Biologicals), 
, Senior Local Delivery Lead Clinical Operations 
Head, Africa and Middle East (GSK Biologicals). Other non GSK Biologicals 
partners: Quintiles IQVIA (represented by 
 
 Project Manager) 
3. Section 2 Opinion Holder: © 2012- 20172018 GSK group of companies or its 
licensor. 
4. Section 4 Abstract-Study design: The study targets enrolling 30,000 children in 
active surveillance, with at least about 20,000 children enrolled where the 
RTS,S/AS01E vaccine will be implemented. Among the 30,000 children, 
approximately 15,000 children (with at least about 10,000 children in sites where the 
vaccine will be implemented) will be enrolled in the 6-12 weeks group (to collect 
background data in this age group) and approximately 15,000 children (with at least 
about 10,000 children in sites where the vaccine will be implemented)         
5. Active surveillance will last 44 months for each subject (mimicking 24 months of 
active follow-up after the 4th dose of RTS,S/AS01E in EPI-MAL-003), except for 
subjects enrolled from Burkina Faso sites for whom their participation in the study 
has been early terminated. 
6. Section 4 – Abstract: Population, including the setting and study population: 
Sites in SSA countries have been or will be selected for EPI-MAL-002 based on the 
existence of a HDSS      
7. In order to align with the MVIP, the study sites for the GSK Phase IV studies have 
been, or will be, selected from the 3 countries where the RTS,S/AS01E vaccine will 
be implemented (i.e. two sites in Malawi are planned to be included in EPI-MAL-
002 in addition to the already defined sites). The only exception As a consequence, 
Burkina Faso sites, that had already started EPI-MAL-002, stopped the follow-up 
activities in active surveillance and enrolment in enhanced hospitalisation 
surveillance on 06 June 2018, with the exception of the follow-up check-ups at the 
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hospital for children diagnosed with meningitis, cerebral malaria or with an AESI. 
All study activities are planned to be terminated by Q2 2019. A description of data 
from these sites will be presented in the progress reports up to Q4 2019, but none 
of these data will be part of the statistical analyses for the interim and final 
reports. is for as they have .They will continue participating in EPI-MAL-002 until 
study end. 
8. Section 4 Abstract - Study size: The study targets enrolling 15,000 children per 
group (i.e. 6-12 weeks group and 5-17 months group; with at least about 
10,000 children of 15,000 in each group enrolled where the RTS,S/AS01E vaccine 
will be implemented), for a total of 30,000 children (at least about 20,000 children 
enrolled where the vaccine will be implemented) 
9. Section 4 Abstract – Milestones: The study started in Q4 2015, and is planned to 
end in Q2 Q1 2022 (tentative date, depending on recruitment timelines). Progress 
reports will be generated every 6 months. An interim report is planned to be written 
by Q4 2018 Q3 2019(tentative date, depending on vaccine implementation 
timelines). 
10. Section 5 Amendments and Updates: Final: 31 May 2012, Amendment 5 Final: 
11 October 2017. The rationale for the protocol amendments 1, 2, 3, 4, 5 and 6, and 
the summary of changes are provided in Annex 7 
11. Section 6 Milestones: 
Milestone 
Planned date 
Start of data collection 
Q4 2015*  
End of data collection 
Q2 Q1 2022** 
Study progress report  
1 progress report every 6 months  
Interim report 
Q3 2019*** 
Final report of study results 
Q4 2022** 
*Actual date 
**Tentative date, depending on recruitment timelines 
***Tentative date, depending on vaccine implementation timelines 
12. Section 9.1 Study design - Active surveillance: Approximately 30,000 children 
will be recruited within the collaborating study sites, and enrolled into active 
surveillance, with at least about 20,000 children enrolled where the RTS,S/AS01E 
vaccine will be implemented. Among these children, approximately 15,000 children 
will be enrolled in the 6-12 weeks group (with at least about 10,000 children in sites 
where the vaccine will be implemented) and approximately 15,000 children will be 
enrolled in the 5-17 months group (with at least about 10,000 children in sites where 
the vaccine will be implemented; see Section 9.2.1.1).  
Enrolled children will be followed up through home visits for a total period of 44 months 
(see Figure 1 and Section 9.2.7.1) except for subjects enrolled from Burkina Faso sites 
for whom their participation in the study has been early terminated. 
13. Section 9.1.1 Rationale for study design: The active surveillance will include 
approximately 15,000 children in the 6-12 weeks group (with at least about 
10,000 children where the RTS,S/AS01E vaccine will be implemented; to collect 
background data in this age group) and approximately 15,000 children in the 5-17 
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months group (with at least about 10,000 children where the RTS,S/AS01E vaccine 
will be implemented; to mimic administration of RTS,S/AS01E in the 5-17 months 
age group). 
14. Section 9.2 Setting: For this reason, other sites in SSA settings with moderate-to-
high transmission of malaria, pertaining to a region where the RTS,S/AS01E vaccine 
is planned to be implemented according to the MVIP, were/will be added to the 
already defined study sites as described below.  
High malaria burden areas will be prioritized [WHO, 2017]. In order to align with 
the MVIP, study sites that are participating or will participate in the GSK baseline, 
Phase IV and ancillary studies (i.e. EPI-MAL-002, EPI-MAL-003 and EPI-MAL-
005, respectively). GSK baseline, Phase IV and ancillary studies (i.e. EPI-MAL-
002, EPI-MAL-003 and EPI-MAL-005, respectively) being fully embedded in the 
MVIP, selection of the clusters that are/will participate in those studies depends on 
the cluster identification process led by the Ministries of Health according to WHO 
guidance. They have been, or will be, selected as follows: 
• 
EPI-MAL-002 study sites: In summary: currently, a total of 5 sites (2 in Ghana 
[Kintampo, Navrongo], 1 in Kenya [Kombewa] and 2 in Burkina Faso [Sapone, 
Nouna]) are enrolling have enrolled study participants in the EPI-MAL-002 study. 
– 
Since sites have been, or will be, selected from the 3 countries where the 
RTS,S/AS01E vaccine will be implemented. The only exception is for Burkina 
Faso sites that as they have already started EPI-MAL-002 have early 
terminated the follow-up activities in active surveillance and enrolment in 
enhanced hospitalisation surveillance on 06 June 2016, with the exception of 
the follow-up check-ups at the hospital for children diagnosed with 
meningitis, cerebral malaria or with an AESI (see sections 9.2.7.4.1, 9.2.7.4.2 
and 9.2.7.4.5). All study activities are planned to be terminated by Q2 2019. A 
description of data from these sites will be presented in the progress reports up 
to Q4 2019, but none of the data from these sites will be part of the statistical 
analyses for the interim and final reports. They will continue participating in 
EPI-MAL-002 until study end. Their data will therefore not be included (neither 
in the before/after comparison analyses of the EPI-MAL-002 and EPI-MAL-003 
studies, nor in any other indicators planned to be generated by EPI-MAL-002 
data to inform analyses of the EPI-MAL-003 study [e.g. background incidence 
of meningitis for study sample size and the exposure to other vaccines]). 
Burkina Faso sites will not be included in EPI-MAL-003 because the MVIP 
will not take place in the country. Two new sites located in Malawi are planned 
to be included in EPI-MAL-002. 
• 
Two sites in Malawi have fulfilled the criteria of the study feasibility assessment and 
are were planned to initiate the EPI-MAL-002 study in Q1-Q2 2018. Considering 
the RTS,S/AS01E vaccine implementation date in Malawi, currently planned in 
October 2018, the baseline data that might be collected in Malawi in the EPI-
MAL-002 study would be too limited to be relevant for the before/after 
comparisons in this country. Therefore, GSK, in agreement with the WHO, 
decided to focus the conduct of the EPI-MAL-002 study in Ghana and Kenya, not 
initiating the study in Malawi, and partially compensating the expected sample size 
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from Malawi sites by using the high recruitment observed from sites in Kenya 
(Kombewa) and Ghana (Kintampo) and extending recruitment in Ghana 
(Navrongo). With the exception of the Burkina Faso sites and according to WHO 
guidance, all EPI-MAL-002 should become exposed study sites/clusters in EPI-
MAL-003. Selection of the unexposed study sites/clusters that will be included in the 
EPI-MAL-003 study is ongoing and is fully embedded in the MVIP. Study feasibility 
in all sites/clusters is assessed through a comprehensive scientific and operational 
study site assessment. 
• 
EPI-MAL-003 study sites: as currently planned in the Currently, as per MVIP and 
according to WHO guidance, 4 study sites (corresponding to 4 clusters of the MVIP) 
in each of the 3 countries selected for the RTS,S/AS01E pilot implementation 
programme (12 study sites/clusters in total) are planned to be part of EPI-MAL-003: 
2 of them should become exposed clusters and 2 of them should become unexposed 
clusters (see Annex 3 for definitions of exposed and unexposed clusters). Phase IV 
vaccine evaluation being fully embedded in the MVIP, selection of the clusters that 
will be included in study EPI-MAL-002 and EPI-MAL-003 depends on the cluster 
identification process led by the Ministries of Health in collaboration with the WHO. 
As per In order to allow the before-after comparison of study endpoints and 
according to WHO guidance, study sites from Ghana and Kenya and Malawi 
included in the EPI-MAL-002 should become study sites in EPI-MAL-003 which 
will be exposed clusters. Selection of the unexposed study sites/clusters that will be 
included in the EPI-MAL-003 study is ongoing and is fully embedded in the MVIP. 
• 
EPI-MAL-005 study sites: being an ancillary study to EPI-MAL-002 and EPI-
MAL-003 studies, EPI-MAL-005 is/will be conducted in study sites conducting 
EPI-MAL-002 and/or EPI-MAL-003. 
• 
Of note, all study sites the clusters, once pre-identified by the Ministries of Health 
are submitted to a comprehensive scientific and operational study site assessment 
conducted by GSK, which will determine study feasibility in those sites.  
15. Section 9.2.1 Study Population: “at least” in the number of subjects replaced by 
“about” 
16. Section 9.2.4 Study period: Recruitment for active surveillance is expected to be 
done until the enrolment target is reached. Enrolment in enhanced hospitalisation 
surveillance has been early terminated will continue throughout the whole study 
period for the sites where the RTS,S/AS01E vaccine will not be implemented. 
Active surveillance will last 44 months for each subject (mimicking 24 months of active 
follow-up after the 4th dose of RTS,S/AS01E in EPI-MAL-003) except for subjects 
enrolled from Burkina Faso sites for whom their participation in the study was early 
terminated. 
17. Section 9.2.7 Study procedures: Notes added to clarify that although the study has 
been early terminated at the Burkina Faso sites, the 1, 6, and 12 months follow-up 
check-ups in case of an already diagnosed meningitis, cerebral malaria or AESI 
before the early termination should still be done. 
18. Section 9.5 Study size: “at least” replaced with “about” and the following added and 
deleted respectively; Burkina Faso sites are planned to early terminate any study 
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activities by Q2 2019. As a consequence, the data from those sites will be presented 
in the progress reports up to Q4 2019, but none of those data will be part of the 
statistical analyses for the interim and final reports. There will be a full follow-up 
of about 10000 and not 15,000 children. 
Table 6 provides an estimation of the 95% CIs based on:  
• 
A sample of 15,000 children per group (either 15,000 in the 6-12 weeks group, or 
15,000 in the 5-17 months group); 
• 
Different numbers of detected events (for the less frequent events): 1, 3 or 5 events; 
• 
Different risk periods following dose administration (with censoring to one month 
for the two first doses). 
• 
A follow-up corresponding to the risk period after the virtual dose 4. 
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Table 6 
Estimation of the lower (LL) and upper (UL) limits of observed 
incidences of events following dose administration based on 15,000 subjects, 
different numbers of detected events, and different risk periods 
 
Note: 95% confidence interval limits are computed using the Poisson exact method [Ulm 1990]. 
Table 9 provides an estimation of the 95% CIs for the surveillances for all children less 
than 5 years of age based on: 
• 
A birth cohort of 17,250 children; 
• 
A follow-up of 2 years (for the enhanced hospitalisation surveillance, before the start 
of the EPI-MAL-003 study); 
• 
Different numbers of detected events (for the less frequent events). 
• 
Table 9 
Estimation of the lower (LL) and upper (UL) limits of observed incidences 
of events among all children less than 5 years of age based on 17,250 birth cohort, 
and different numbers of detected events 
 
Note: 95% confidence interval limits are computed using the Poisson exact method [Ulm, 1990]. 
19. Section 9.7 Data analysis: Analyses will be based on about 20,000 children 
enrolled where the RTS,S/AS01E vaccine will be implemented. Descriptive statistics 
will be computed by age group, study site and overall, as well as by type of 
No. of events
Period at risk
Total 
person-years
Incidence
(in 100,000 PY)
LL
(in 100,000 PY)
UL
(in 100,000 PY)
1
2 weeks
2307.69
43.3
1.1
241.4
1
6 weeks
5961.54
16.8
0.4
93.5
1
3 months
10000.00
10.0
0.3
55.7
1
6 months
17500.00
5.7
0.1
31.8
1
12 months
32500.00
3.1
0.1
17.1
3
2 weeks
2307.69
130.0
26.8
379.9
3
6 weeks
5961.54
50.3
10.4
147.1
3
3 months
10000.00
30.0
6.2
87.7
3
6 months
17500.00
17.1
3.5
50.1
3
12 months
32500.00
9.2
1.9
27.0
5
2 weeks
2307.69
216.7
70.4
505.6
5
6 weeks
5961.54
83.9
27.2
195.7
5
3 months
10000.00
50.0
16.2
116.7
5
6 months
17500.00
28.6
9.3
66.7
5
12 months
32500.00
15.4
5.0
35.9
Events in different at-risk periods following dose administration (per age group)
No. of events
Period at risk
Total 
person-years
Incidence
(in 100,000 PY)
LL
(in 100,000 PY)
UL
(in 100,000 PY)
1
2 years
172500
0.6
0.0
3.2
5
2 years
172500
2.9
0.9
6.8
25
2 years
172500
14.5
9.4
21.4
50
2 years
172500
29.0
21.5
38.2
Events in all children < 5 years during a follow-up of 2 years
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surveillance. Moreover, descriptive analysis of safety endpoints will be computed for 
specific sub populations such as children with hemoglobinopathy and HIV-positive 
children. Burkina Faso sites are planned to early terminate any study activities by 
Q2 2019. As a consequence, a description of data from those sites will be presented 
in the progress reports up to Q4 2019, but none of these data will be part of the 
statistical analyses for the interim and final reports. There will be a full follow-up 
of about 10000 and not 15,000 children. 
20. Section 9.7.4.1 Sequence of analyses: Of note, data from Burkina Faso sites were 
part of the previous progress reports and will also be part of the progress reports 
planned up to Q4 2019. 
This interim analysis will be done with clean data* collected on a sub-group of 
subjects from sites where the vaccine will be implemented 
21. Section 9.9 Limitations of the study: This The Protocol Amendment 5 described s 
the sample size reduction from 40,000 to 30,000 with at least 20,000 children to be 
enrolled where the RTS,S/AS01E vaccine will be implemented. There is was a 
resultant reduction in the size of the two study groups to 15,000 subjects each (with 
at least 10,000 children in sites where the vaccine will be implemented). 
Other sites in SSA settings with moderate-to-high transmission of malaria, from the 
3 countries where the RTS,S/AS01E vaccine will be implemented (see Section 9.2), 
were/will be added to the already defined study sites. The transition from 
EPI-MAL-002 (pre-implementation) to EPI-MAL-003 (post-implementation) is 
expected to occur in the study sites from Kenya and Ghana and Malawi. 
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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 7 
eTrack study number 
and Abbreviated Title 
115055 (EPI-MALARIA 002 VS AME) 
Amendment number: 
7 
Amendment date: 
5 May 2020 
Co-ordinating authors: 
, Lead Scientific Writer (GSK 
Biologicals) 
Rationale/background for changes:  
This protocol amendment 7 outlines measures that may be applicable during special 
circumstances (e.g., COVID-19 pandemic). The purpose of the amendment is to 
protect participant’s welfare and safety, and as far as possible ensure the potential 
benefit to the participant and promote data integrity.  
The use of the alert system has been early terminated in Q4 2019 due to its complexity 
and alternatives have been put in place by the study sites. 
1. Amended text has been included in bold italics and deleted text in strikethrough 
in the following sections. 
2. Cover page - Authors: 
, Oversight Data 
Management Manager (GSK Biologicals), 
, Epidemiology lead 
Clinical and Epidemiology Scientist (GSK Biologicals) 
, Safety 
Physician (GSK Biologicals), 
 /Study Delivery Lead (GSK 
Biologicals), Mobile Phone Alert System: Parexel (represented by 
, 
Senior Project Manager)  
3. Section 2 Opinion Holder: © 2012- 2018 
4. Section 5 Amendments and Updates: Amendment 6 Final: 06 July 2018. The 
rationale for the protocol amendments 1, 2, 3, 4, 5, 6 and 7, and the summary of 
changes are provided in Annex 7 
5. Section 7 Rationale for the study: The EPI-MAL-002 study started in Q4 2015 and 
will last for approximately 5 years (depending on recruitment timelines). EPI-MAL-
003 will start started in Q1 2019 when the vaccine became becomes available in the 
study sites that are exposed clusters after its implementation according to WHO 
guidelines in the framework of the MVIP (first vaccine introduction was foreseen in 
2018, see section 9.2). 
6. Section 9.2 Setting: – 
Since sites have been, or will be, selected from the 3 
countries where the RTS,S/AS01E vaccine will be implemented, Burkina Faso sites 
that started EPI-MAL-002 have early terminated the follow-up activities in active 
surveillance and enrolment in enhanced hospitalisation surveillance on 06 June 
20162018, with the exception of the follow-up check-ups at the hospital for children 
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PPD
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PPD
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diagnosed with meningitis, cerebral malaria or with an AESI (see sections 9.2.7.4.1, 
9.2.7.4.2 and 9.2.7.4.5). 
7. Section 9.2.7.6 Capacity building: Use of time sensitive event device 
An alert system using mobile phones will be developed in EPI-MAL-002. Health 
care staff and first line clinicians will use this system to communicate time-sensitive 
events to study staff. The alert system will be implemented in order to closely 
monitor AESI, meningitis cases, and severe malaria, and to ensure that all the 
procedures and tests specified in the protocol are done for a proper diagnosis of the 
diseases while maintaining the safety of the patients. Mobile phone reporting logs 
will be cross-checked with hospital discharge logs and primary health care facility 
registries for process improvement.  
In addition, GSK and Quintiles will also be made aware of the AESI, meningitis 
cases, and severe malaria cases, including cerebral malaria cases (they will not 
receive any patient’s personally identifiable information via that system). The system 
should act as an alert system between the health care facilities and the principal 
investigator, but is not intended to replace the reporting through eCRF (as defined in 
Section 11). 
8. Section 9.2.7.1.13 Outline of study procedures  
Table 4 
List of study procedures to be conducted at each visit, and study 
visit schedule (active surveillance)  
Epoch 
1 
Type of contact 
Enrolment 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10  
Visit days: 6-12 
weeks group 6 
(identified at first 
administration of 
DTP/HepB/Hib 
vaccine) 
 
1 wk  
(±3 days) 
after 1st 
DTP/ 
HepB/ 
Hib dose 
1 wk 
(±3 
days) 
after 
2nd 
DTP/ 
HepB/ 
Hib 
dose  
1 wk  
(±3 
days) 
after 
3rd 
DTP/ 
HepB/ 
Hib 
dose  
6 wks  
(±5 
days) 
after 
3rd 
DTP/ 
HepB/ 
Hib 
dose 
6 mths 
(±2 
wks) 
after 
3rd 
DTP/ 
HepB/ 
Hib 
dose 
18 
mths 
(±2 
wks) 
after 
3rd 
DTP/ 
HepB/ 
Hib 
dose 
5 wks 
(±5 
days) 
post 
V6 
12 
mths  
(±2 
wks) 
 post 
V6 
24 
mths  
(±2 
wks)  
post 
V6 
At 5 
yrs of 
age or 
study 
end 7 
(±2 
wks)  
Visit days: 5-17 
mths group 
(identified at first 
administration of 
DTP/HepB/Hib 
vaccine) 
 
At the 
age of 
6 mths (> 
5 mths to 
< 7 mths) 
4 wks  
(±3 
days)  
post 
V1 
4 wks 
(±3 
days) 
post 
V2 
5 wks  
(±5 
days)  
post 
V3 
6 mths 
(±2 
wks)  
post 
V3 
18 
mths  
(±2 
wks)  
post 
V3 
5 wks 
(±5 
days) 
post 
V6 
12 
mths  
(±2 
wks)  
post 
V6 
24 
mths  
(±2 
wks)  
post 
V6 
At 5 
yrs of 
age or 
study 
end 7 
(±2 
wks)  
Visit days: 5-17 
mths group (catch-
up, enrolled at 5 to 
<18 mths of age) 
 
First 
contact 
with 
study 
staff or 1 
wk later 
4 wks  
(±3 
days)  
post 
V1 
4 wks 
(±3 
days) 
post 
V2 
5 wks  
(±5 
days)  
post 
V3 
6 mths 
(±2 
wks)  
post 
V3 
18 
mths  
(±2 
wks)  
post 
V3 
5 wks 
(±5 
days) 
post 
V6 
12 
mths  
(±2 
wks)  
post 
V6 
24 
mths  
(±2 
wks)  
post 
V6 
At 5 
yrs of 
age or 
study 
end 
7(±2 
wks)  
 
 
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9. Section 9.2.7.2.16 Outline of study procedures 
Table 5 
List of study procedures to be conducted in the event of 
hospitalisation 
Epoch 
1 
Type of contact 
Hospitalisation 
Visit 
Study Conclusion 
Visit 
(At 5 years of age or 
study end, whichever 
occurs first)7(±2 wks)  
 
10. Section 9.2.8 Study procedures during special circumstances:  
During special circumstances (e.g., COVID-19 pandemic), the specific guidance 
from local public health and other competent authorities regarding the protection 
of individuals’ welfare must be applied. For the duration of such special 
circumstances, the following measures may be implemented for enrolled 
participants:  
– 
Active safety follow-up through home visits may be made by a telephone call 
or other means of virtual contact. It is acknowledged that the systematic 
measurement of body temperature may not be performed. 
– 
For children diagnosed with AESI, meningitis or cerebral malaria, the check-
up at the hospital at 1 month, 6 months and 1 year after hospital discharge 
may be replaced by a telephone call or other means of virtual contact. 
– 
A retrospective data collection of medical events may be implemented at any of 
the health care facilities. 
11. Section 9.7.6.2 Statistical approach: An alert system (see Section 9.4.2) will be 
implemented in order to closely monitor the meningitis cases 
12. Section 9.7.10 Statistical analyses during special circumstances: Special 
circumstances (see section 9.2.8) may have an impact on the proposed analysis 
plan. Any changes in the analysis plan will be further described in the SAP. 
13. Section 9.9 Limitations of the research methods: The introduction of an alert 
system using mobile phones to ease communications between the health care staff 
and the study staff will allow facilitating the adherence to national recommendations 
for diagnosis during the study. However, meningitis cases based on clinical 
symptoms only, or suspected cases, can be expected 
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14. Annex 5 Case definitions for protocol-defined adverse events of special interest 
(AESI) and surveillance indicators 
Body system/ AESI 
Diagnosis/Level of Diagnostic Certainty 
References 
GENERALIZED CONVULSIVE 
SEIZURE 
The etiological work up is negative: (i.e. febrile 
seizure that does not fit GCS definition, acute 
intoxication, trauma, severe malaria etc. have all 
been excluded)  
 
HEPATIC FAILURE 
 
Major criteria 
OR 
• 
Elevation of the serum transaminases 
(ALT or AST ≥ 3 times the upper limit of 
normal (ULN)) 
. 
 
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Annex 8 
PROTOCOL AMENDMENT 7 SPONSOR SIGNATORY 
APPROVAL 
eTrack study number and 
Abbreviated Title 
115055 (EPI-MALARIA-002 VS AME) 
Date of protocol amendment 
Amendment 7: 5 May 2020 
Detailed Title  
A prospective study to estimate the incidence of 
diseases specified as adverse events of special 
interest, of other adverse events leading to 
hospitalisation or death, and of meningitis in infants 
and young children in sub-Saharan Africa prior to 
implementation of the RTS,S/AS01E candidate 
vaccine. 
Sponsor signatory 
François Roman, Clinical and Epidemiological 
Project Lead, DDW Vaccines 
 
 
Signature 
 
 
 
Date 
 
 
 
 
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Annex 9 
PROTOCOL AMENDMENT 7 INVESTIGATOR 
AGREEMENT 
I agree: 
• 
To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site.  
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about 
study-related duties and functions as described in the protocol. 
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.  
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor, and more generally about his/her financial ties with the sponsor. GSK 
Biologicals will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.  
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 
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eTrack study number and 
Abbreviated Title 
115055 (EPI-MALARIA-002 VS AME) 
Date of protocol amendment  
Amendment 7: 5 May 2020 
Title 
A prospective study to estimate the incidence of 
diseases specified as adverse events of special 
interest, of other adverse events leading to 
hospitalisation or death, and of meningitis in infants 
and young children in sub-Saharan Africa prior to 
implementation of the RTS,S/AS01E candidate 
vaccine. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
115055 | Protocol Amendment 7 13 May 2020 | TMF-1767569 | 1.0