An Evaluation of the Pilot Implementation of RTS,S/AS01 Through Routine Health Systems in Moderate to High Malaria Transmission Settings in Africa
Conditions: Malaria,Falciparum, Feasibility, Safety, Mortality
Sponsor: Rafiq OKINE

                                                                                                                   RTS,S MVIP v9.0 22Apr2020 
 
 
 
 
The Malaria Vaccine Pilot Evaluation 
 
An evaluation of the cluster-randomised 
pilot implementation of RTS,S/AS01 
through routine health systems in 
moderate to high malaria transmission 
settings in sub-Saharan Africa: a post-
authorization observational study  
 
 
M A S T E R   P R O T O C O L 

Pilot implementation of RTS,S/AS01 
 
2 
PASS information 
 
Title 
An evaluation of the cluster-randomised pilot 
implementation of RTS,S/AS01 through routine health 
systems in moderate to high malaria transmission 
settings in Sub-Saharan Africa: A Post-Authorization 
Observational Study 
Protocol version identifier 
RTSS_MVIP_v9 22 April 2020 
Date of last version of protocol 19 October 2018 
EU PAS register number 
Study not registered 
Active substance 
RTS,S antigen and AS01E Adjuvant 
Medicinal product 
 Mosquirix™ 
Product reference 
 EMEA/H/W/002300 
Procedure number 
 Not applicable 
Study sponsor  
World Health Organization 
Joint PASS 
 No 
Research question and 
objectives 
Primary impact objectives 
The primary objectives of the impact evaluation are to 
estimate the effect of the routine delivery of RTS,S/AS01 
on.:  
• all-cause mortality (excluding accidents); 
• the incidence of hospital admission with severe 
malaria;   
overall and each country. 
Primary safety objectives 
The primary objectives with regard to safety are to 
estimate the effect of RTS,S/AS01 introduction on: 
the incidence of hospital admission with: 
• meningitis  
• cerebral malaria 
(data pooled across the three countries).   
and on all-cause mortality in boys and girls,  to 
determine whether there is any evidence that 
RTS,S/AS01 increases mortality in girls, overall and in 
each country 
 

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Primary feasibility objectives 
The primary objectives with regard to feasibility are to 
estimate: 
• the proportion of children aged 12-23 months 
who received three doses of RTS,S/AS01 by 12 
months of age (in each country) 
• the proportion of children aged 27-38 months 
who received their fourth dose of RTS,S/AS01 by 
27 months of age (in each country) 
Country(-ies) of study 
Three moderate to high malaria endemicity countries 
of sub-Saharan Africa: Ghana, Kenya and Malawi 
Author 
David Schellenberg 
World Health Organization 
20 Avenue Appia, 1211 Geneve, Switzerland 
 
Revisions 
Date: April 22, 2020 
Revisions made by: 
David Schellenberg 
Mary J Hamel 
Paul Milligan 
 
Scientific opinion holder 
Scientific opinion holder 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
 
 

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1 Table of contents 
Primary impact objectives .................................................................................................... 2 
Primary safety objectives ..................................................................................................... 2 
Primary feasibility objectives ................................................................................................ 3 
1 
Table of contents .......................................................................................................................... 4 
2 
List of abbreviations ...................................................................................................................... 8 
3 
Responsible parties ..................................................................................................................... 11 
4 
Abstract ....................................................................................................................................... 12 
5 
Amendments and updates .......................................................................................................... 17 
6 
Milestones ................................................................................................................................... 19 
7 
Rationale and background .......................................................................................................... 20 
7.1 
Efficacy of RTS,S/AS01 ........................................................................................................ 20 
7.2 
Safety of RTS,S/AS01 .......................................................................................................... 21 
7.2.1 
SAEs in the phase 3 trial ...................................................................................... 21 
7.2.2 
Febrile convulsions .............................................................................................. 22 
7.2.3 
Meningitis............................................................................................................ 22 
7.2.4 
Cerebral malaria .................................................................................................. 23 
7.2.5 
Mortality and gender .......................................................................................... 23 
7.2.6 
Summary of Safety .............................................................................................. 24 
7.3 
International regulatory and policy review ........................................................................ 24 
7.4 
Alignment of the Malaria Vaccine Pilot Evaluation and the Phase 4 evaluation ............... 24 
7.5 
Selection of countries for the pilot programme ................................................................. 25 
7.6 
Overview of RTS,S/AS01 delivery and evaluation .............................................................. 25 
7.6.1 
Approach to delivery of RTS,S/AS01 ................................................................... 25 
7.6.2 
Evaluation Design ................................................................................................ 26 
7.6.3 
Study dates .......................................................................................................... 27 
7.6.4 
Vaccination Schedule .......................................................................................... 28 
7.6.5 
Evaluation of RTS,S/AS01 .................................................................................... 28 
7.6.6 
MVIP and decision-making for vaccine roll out .................................................. 30 
8 
Research questions and objectives ............................................................................................. 33 
8.1 
Key questions on impact, safety and feasibility ................................................................. 33 
8.2 
Objectives related to impact and community-based surveillance ..................................... 34 
8.2.1 
Primary impact objectives ................................................................................... 34 
8.2.2 
Secondary impact objectives .............................................................................. 34 
8.3 
Objectives related to safety and surveillance in sentinel hospitals ................................... 34 
8.3.1 
Primary safety objectives .................................................................................... 34 
8.3.2 
Secondary safety objectives ................................................................................ 35 
8.4 
Analysis populations ........................................................................................................... 35 
8.5 
Objectives related to feasibility .......................................................................................... 35 
8.5.1 
Primary feasibility objectives .............................................................................. 35 
8.5.2 
Secondary feasibility objectives .......................................................................... 35 
9 
Research Methods for Impact Evaluation .................................................................................. 37 
9.1 
Study design ....................................................................................................................... 37 

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9.2 
Setting ................................................................................................................................. 37 
9.2.1 
Surveillance population and surveillance period ................................................ 37 
9.2.2 
Community-based surveillance ........................................................................... 37 
9.2.3 
Community sensitisation ..................................................................................... 38 
9.2.4 
Identification and training of Village Reporters .................................................. 38 
9.2.5 
Identification and training of supervisors for Village Reporters ......................... 38 
9.2.6 
Identification of deaths ....................................................................................... 39 
9.2.7 
Expected numbers of events ............................................................................... 39 
9.2.8 
Case definitions ................................................................................................... 40 
9.3 
Variables ............................................................................................................................. 40 
9.4 
Data sources ....................................................................................................................... 41 
9.5 
Study size ............................................................................................................................ 42 
9.6 
Data management .............................................................................................................. 44 
9.7 
Data analysis ....................................................................................................................... 44 
9.8 
Quality control .................................................................................................................... 45 
9.9 
Limitation of the research methods ................................................................................... 45 
10 
Research Methods for Safety Evaluation .......................................................................... 47 
10.1 Study design and timing ..................................................................................................... 47 
10.2 Setting ................................................................................................................................. 47 
10.2.1 
Selection of Sentinel Hospitals ............................................................................ 47 
10.2.2 
Characteristics of Sentinel Hospitals ................................................................... 48 
10.2.3 
Enhanced Hospitalisation Surveillance ............................................................... 50 
10.2.4 
Detection of Adverse Events Following Immunization (AEFIs) ........................... 50 
10.3 Study procedures ................................................................................................................ 51 
10.3.1 
Data capture in sentinel hospitals....................................................................... 52 
10.3.2 
Informed consent for the collection of surveillance data ................................... 52 
10.3.3 
Data to be captured ............................................................................................ 52 
10.3.4 
Sample collection ................................................................................................ 54 
10.3.5 
Record review ..................................................................................................... 54 
10.4 Case definitions .................................................................................................................. 54 
10.4.1 
Meningitis............................................................................................................ 54 
10.4.2 
Malaria ................................................................................................................ 56 
10.4.3 
Anaemia .............................................................................................................. 58 
10.4.4 
Admissions .......................................................................................................... 58 
10.4.5 
Death ................................................................................................................... 58 
10.4.6 
Febrile convulsions .............................................................................................. 59 
10.4.7 
Adverse Event Following Immunisation (AEFI) ................................................... 59 
10.4.8 
Adverse Event of Special Interest (AESI) ............................................................. 59 
10.4.9 
Serious Adverse Event ......................................................................................... 59 
10.5 Biological sample handling and analysis............................................................................. 60 
10.5.1 
Biological samples ............................................................................................... 60 
10.5.2 
Laboratory assays ................................................................................................ 61 
10.6 Capacity building ................................................................................................................ 62 
10.7 Variables ............................................................................................................................. 62 
10.8 Data sources ....................................................................................................................... 64 
10.9 Case ascertainment ............................................................................................................ 64 
10.9.1 
Meningitis cases .................................................................................................. 64 
10.9.2 
Severe malaria cases, including cerebral malaria ............................................... 65 

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10.10 Study size ............................................................................................................................ 66 
10.11 Data management .............................................................................................................. 67 
10.12 Data analysis ....................................................................................................................... 67 
10.13 Quality control .................................................................................................................... 67 
10.14 Limitation of the research methods ................................................................................... 68 
10.15 Other aspects...................................................................................................................... 68 
11 
Research Methods for Feasibility Evaluation .................................................................... 70 
11.1 Study design ....................................................................................................................... 70 
11.1.1 
Approaches to estimating the coverage of RTS,S/AS01...................................... 70 
11.2 Setting ................................................................................................................................. 72 
11.2.1 
Timing of household surveys .............................................................................. 72 
11.2.2 
Survey population ............................................................................................... 73 
11.3 Variables ............................................................................................................................. 74 
11.4 Data sources ....................................................................................................................... 75 
11.5 Study size ............................................................................................................................ 76 
11.6 Data management .............................................................................................................. 76 
11.7 Data analysis ....................................................................................................................... 76 
11.8 Quality control .................................................................................................................... 76 
11.9 Limitation of the research methods ................................................................................... 76 
11.10 Other aspects...................................................................................................................... 76 
12 
Protection of human subjects ........................................................................................... 76 
12.1 Regulatory and ethical considerations, including the informed consent process ............. 76 
13 
Management and reporting of adverse events/adverse reactions .................................. 78 
13.1 Safety definitions ................................................................................................................ 78 
13.1.1 
Definition of an adverse event ............................................................................ 78 
13.1.2 
Definition of a serious adverse event ................................................................. 79 
13.2 Safety reporting .................................................................................................................. 79 
13.3 AEFI Detection .................................................................................................................... 80 
13.4 Evaluation of initial AEFI report .......................................................................................... 81 
13.5 Further investigation of an AEFI ......................................................................................... 82 
13.5.2 
Assessment of causality ...................................................................................... 83 
13.6 Follow up after causality assessment: ................................................................................ 86 
13.6.1 
Assessment of outcomes .................................................................................... 87 
13.7 Timeframes for reporting AEFI ........................................................................................... 88 
14 
Reporting to GSK ............................................................................................................... 88 
15 
Contact information for reporting serious adverse events ............................................... 88 
16 
Plans for disseminating and communicating study evaluation results ............................. 89 
17 
References ......................................................................................................................... 91 
Annex 1. List of stand-alone documents............................................................................................ 93 
Annex 2. ENCePP checklist for study protocols ................................................................................. 94 
Annex 3. List of investigators, including contact details .................................................................. 100 

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Annex 4. DRAFT Practical Operating Guide for the Malaria Vaccine Implementation Programme 101 
Annex 5: Governance and coordination structure for the RTS,S/AS01 Malaria Vaccine Pilot 
Evaluation ......................................................................................................................................... 113 
Annex 6. Community engagement in the MVIP .............................................................................. 116 
Annex 7. 2014 cause of death list for verbal autopsy with corresponding ICD-10 codes ............... 118 
Annex 8: Verbal Autopsy for children aged four weeks to 11 years, adapted for MVIP impact 
evaluation......................................................................................................................................... 123 
Annex 9. Village Reporter CRF ......................................................................................................... 161 
Annex 10. CRF for impact evaluation ............................................................................................... 163 
Annex 11. Vaccination Registry ........................................................................................................ 167 
Annex 12. Sentinel hospital CRF ...................................................................................................... 168 
Annex 13. Household Survey CRF .................................................................................................... 174 
Annex 14: Model informed consent statement for verbal autopsy ................................................ 183 
Annex 15: Model Informed consent form for Inpatient Surveillance ............................................. 184 
15.1 Model ICF for Inpatient Surveillance .................................................................................. 184 
15.2  Model ICF for Long term storage of samples ..................................................................... 187 
Annex 16: Model informed consent statement for household surveys .......................................... 190 
Annex 17: Standard AEFI reporting form ......................................................................................... 192 
Annex 18: AEFI investigation form ................................................................................................... 194 
Annex 19: AEFI Causality Assessment Worksheet ........................................................................... 199 
 
 
 

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2 List of abbreviations 
 
AE 
Adverse Event 
AEFI 
Adverse Event Following Immunization 
AESI 
Adverse Event of Special Interest 
ARC 
National AEFI Review Committee 
ATP 
According to Protocol  
AVPU 
Alert, Voice, Pain, Unresponsive 
BCG 
Bacillus Calmette–Guérin 
BCS 
Blantyre Coma Scale 
BH 
Birth History 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COPD 
Chronic Obstructive Pulmonary Disease  
CORP 
Community Own Resource Person 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSF 
Cerebro-Spinal Fluid  
DHS 
Demographic and Health Survey 
DIFP 
District Immunization Focal Person  
DSMB 
Data and Safety Monitoring Board 
DSS 
Demographic Surveillance System 
DTP 
Diphtheria, Tetanus, Pertussis 
DTP3 
Third Dose of DTP vaccine 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for Pharmacoepidemiology and     
 
  Pharmacovigilance 
EPI 
Expanded Programme on Immunization 
g/dL 
Grams per deciliter 
GACVS 
Global Advisory Committee on Vaccine Safety 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GIS 
Geographic Information System 
GSK 
GlaxoSmithKline 
GVAP 
Global Vaccine Action Plan 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HepB 
Hepatitis B 
Hib 
Haemophilus influenzae type b 
HIV 
Human Immunodeficiency Virus 
HMIS 
Health Management Information System 
HRP2 
Histidine-Rich Protein 2 
HSB 
Health-Seeking Behaviour  
ICD-10 
International Classification of Disease 10th revision 
ICF 
Informed Consent Form  

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ICH 
 International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICTRP 
International Clinical Trials Registry Platform 
ID 
Identification, Identifier 
IEC 
Independent Ethics Committee 
IHME 
Institute for Health Metrics and Evaluation 
IMR 
Infant Mortality Rate 
IRB 
Institutional Review Board 
IRS 
Indoor Residual Spraying 
ITN 
Insecticide-Treated Net 
JTEG 
Joint Technical Expert Group 
K 
Intra-Class Correlation Coefficient 
LAR 
Legally Acceptable Representative 
LLIN 
Long-Lasting Insecticidal Net 
LP 
Lumbar Puncture  
M 
Month 
MCV1 
First Dose of Measles-Containing Vaccine 
MCV2 
Second Dose of Measles-Containing Vaccine 
MenA 
Meningococcal group A vaccine 
MICS 
Multi-Indicator Cluster Survey 
MIS 
Malaria Indicator Survey 
MoH 
Ministry of Health 
MPAC 
Malaria Policy Advisory Committee 
MVIP 
Malaria Vaccine Implementation Programme 
MVPE 
Malaria Vaccine Pilot Evaluation 
NRA 
National Regulatory Agency 
OPV 
Oral Poliovirus Vaccine 
PAG 
Programme Advisory Group 
PCR  
Polymerase Chain Reaction 
PCV 
Pack-Cell Volume 
PI 
Principal Investigator 
PIE 
Post-Introduction Evaluation 
pIMD 
Potential Immune-Mediated Disease 
PIP 
Pilot Implementation Programme 
PSU 
Primary sampling units 
PV 
Pharmacovigilance 
QA 
Quality Assurance 
QC 
Quality Control 
RDT 
Rapid Diagnostic Test 
RMP 
Risk Management Plan 
RR 
Risk Ratio 
SAE 
Serious Adverse Event 
SAGE 
Strategic Advisory Group of Experts on immunization 
SAP 
Statistical Analysis Plan 
SE 
Study End 
SOP 
Standard Operating Procedures 
SPM 
Study Procedures Manual 

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SSA 
Sub-Saharan Africa 
TOR 
Terms of Reference 
UN 
United Nations 
UNFPA 
United Nations Population Fund 
VA 
Verbal Autopsy 
VE 
Vaccine Efficacy 
VR 
Village Reporters 
WHO 
World Health Organization 
 
 

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3 Responsible parties 
 
WHO takes overall responsibility for the conduct of this study. The main responsible parties for 
this protocol are as follows: 
 
Dr Mary Hamel, Senior Technical Officer (WHO/HQ/FWC/IVB/IVR) and Dr David Schellenberg, 
Scientific Adviser (WHO/HQ/HTM/GMP) are the designated contact people at WHO HQ, Geneva, 
for the study. 
 
Coordinating investigators for each country will be listed in country-specific protocols. 
 
A list of all investigators, including contact details, will be kept in a stand-alone document (Annex 
3). 
 
Contact person for the Scientific Opinion Holder: 
 
Pascale Vandoolaeghe 
 
GlaxoSmithKline Biologicals S.A. 
89, rue de l’Institut - 1330 Rixensart 
Belgium 
 
Telephone: +3210852896 
E-mail: gsk.malaria-vaccines@gsk.com 
 
 
 

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4 Abstract 
 
Title 
An evaluation of the cluster-randomised pilot implementation of 
RTS,S/AS01 through routine health systems in moderate to high 
malaria transmission settings in Africa 
 
Version and Date 
of the protocol 
V 9.0 22 April 2020 
Main Authors 
David Schellenberg, Mary Hamel and Paul Milligan  
 
Rationale and 
background 
RTS,S/AS01 has been developed as a vaccine to prevent disease 
caused by Plasmodium falciparum. A phase 3 trial in 15,459 infants 
and young children in 7 sub-Saharan African countries showed that in 
the 12 months following completion of the first three doses, the 
incidence of clinical malaria was reduced by 51% (95% confidence 
interval (CI) 47%, 55%) and the incidence of severe malaria was 
reduced by 44.5% (95% CI 24%,60%) in children aged 5-17 months at 
the time of dose 11. Estimated efficacy decreased over time: in 
successive 6 month periods, the efficacy of 3 doses against clinical 
malaria declined from 68% in the first 6-month interval to 39% in the 
second, and 28% in the third interval, resulting in an overall efficacy 
estimates of 46% (95% CI 42, 50) against clinical malaria and 38% 
(95% CI 18, 53) against severe malaria by 18 months after dose 3. A 
fourth dose, given 18 months after dose 3, increased efficacy against 
clinical malaria over the whole of the 4-year study period (a median 
of 48 months follow-up) from 26% (95% CI 21, 31) to 39% (95% CI 
34,43) and from -2 (95% CI -31,20) to 31.5% (95% CI 9,48) against 
severe malaria. Vaccine efficacy over the whole study period in those 
who received 4 doses of RTS,S/AS01 was also confirmed against 
malaria hospitalization (37%, ATP, 95%CI 27-48.5), all-cause 
hospitalization (15%, ATP, 95%CI 6-25) and severe anaemia (62%, 
ATP, 95%CI 26.5-81). Vaccine efficacy for all time periods and 
endpoints was substantially lower in children aged 6-12 weeks at the 
time of dose 1 than in the 5-17 month olds and thus further 
evaluation in the young infants was not recommended by WHO. This 
protocol therefore focusses on the evaluation of RTS,S/AS01 when 
administered to children age 5 months and above. 
 
The benefits of RTS,S/AS01 were demonstrated in the presence of 
                                                     
1 The efficacy estimates presented here are from according to protocol analyses of multiple episodes, considered the most relevant 
analytical approach to inform understanding of the potential public health impact of the intervention.  

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high ITN coverage and where the identification and treatment of 
clinical and severe malaria episodes was optimized. The enhanced 
access to good quality curative services likely limited disease 
progression and precluded the measurement of vaccine impact on 
mortality. However, modelling suggests 1 life may be saved per 200 
children vaccinated with 4 doses of RTS,S/AS01 outside trial settings 
in moderate to high transmission settings. 
 
No fatal adverse events were assessed as causally related to 
RTS,S/AS01 vaccination. The overall incidence of SAEs (both all SAEs 
and non-malaria SAEs) in the phase 3 study was lower in children 
receiving RTS, S/AS01 than in children in the comparison arm. Among 
children receiving the vaccine at 5-17 months of age, febrile 
convulsions were an identified risk in RTS,S/AS01 recipients in the 7 
days following vaccination. In the same age group, meningitis was 
identified as a potential risk, with more cases of meningitis in 
RTS,S/AS01 recipients, compared to the control group (relative risk 
(RR) 8.0 (95% Confidence Interval (CI) 1.1-60.3)). Unplanned, 
exploratory analyses in children in the 5-17 month age category 
revealed more cerebral malaria cases in the RTS,S/AS01 group and, 
for both age categories, more deaths from all causes combined in 
vaccinated girls compared to the control group.  
The European Medicines Agency provided a positive scientific 
opinion on the benefit/risk balance of RTS,S/AS01 in mid-2015, 
accepting a proposed Risk Management Plan which included a Phase 
4 study to investigate the observed safety signals. In late 2015, 
WHO’s expert vaccination and malaria advisory committees 
recommended pilot implementation studies to assess (1) the 
programmatic feasibility of delivering RTS,S/AS01 with three to four 
new immunization contacts, including the fourth dose in the second 
year of life; (2) the vaccine’s impact on mortality and (3) the 
vaccine’s safety in the context of a routine immunization 
programme. 1  
This Master Protocol describes the evaluation of the first-time use of 
the RTS,S/AS01 vaccine, implemented in a pilot programme by 
Ministries of Health using an expanded schedule of their routine EPI 
contacts, building on the national immunization programmes which 
routinely deliver vaccines to young children living in SSA countries. 
Delivery of RTS,S/AS01 will be the responsibility of the MOH and 
implementation is expected to continue beyond the period of the 
evaluation, assuming the benefit-risk assessment remains 
favourable. Using routine systems for vaccine introduction will 
facilitate ongoing vaccine delivery and expansion country-wide 
should WHO provide a positive policy recommendation.  Efforts to 
assure vaccine access beyond the period of the pilot implementation 

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started in late 2017. 
The RTS,S/AS01 Malaria Vaccine Implementation Programme (MVIP) 
comprises pilot implementation of the vaccine, with support for 
optimisation of the implementation, GSK’s Phase 4 studies and the 
WHO-led RTS,S/AS01 Malaria Vaccine Pilot Evaluation  (MVPE) 
described in this protocol. These evaluations will provide data to 
bridge the knowledge gaps currently inhibiting wider scale use of 
RTS,S/AS01. The programme has been designed to complement the 
GSK-sponsored Phase 4 study. Data from the pilots will inform policy-
making at global and national levels, allowing decisions to be made 
about larger-scale adoption of RTS,S/AS01.  
 
Study Design 
This will be an evaluation of the pilot implementation of RTS,S/AS01 
by Ministries of Health in three countries in sub-Saharan Africa. The 
first dose will be administered as soon as possible after children 
reach age 5 months, followed by doses two and three at 
approximately one month intervals, and a fourth dose 15-18 months 
after dose three. 
The pilot implementation will use a cluster-randomized design, with 
some areas Districts, Sub-counties or Clusters, referred herein as 
“clusters”) introducing RTS,S/AS01 at the beginning of the 
programme and other clusters, initially without RTS,S/AS01, acting as 
comparison areas. The division of areas into implementation or 
comparison areas will be randomized in order to generate the 
strongest possible evidence on the impact and safety of the vaccine. 
Identical monitoring systems will be established in both 
implementation and comparison areas to record impact and safety 
outcomes. Follow up of children aged up to 39 months will enable 
key outcomes to be evaluated up to 1 year following the fourth dose 
of RTS,S/AS01 in the majority of vaccinated children.  (see also 
‘Population’, below). in children 1-59 months of age.  
This master protocol assumes that a total of  approximately 60 
clusters areas will be identified per country, evenly split between 
implementation and comparison areas, with each cluster 
contributing approximately 4,000 children per year to the evaluation 
of RTS,S/AS01. All areas will contribute to the evaluation of the 
impact on mortality through surveillance at the village level where 
Village Reporters (VR) will document deaths. A sub-set of clusters, 
with access to care in up to 24 sentinel hospitals across the 
programme (up to 8 per country), approximately equally split 
between implementation and comparison areas, will contribute to 
the hospital-based surveillance of safety and cause-specific impact 
assessments. Feasibility will be evaluated by estimating vaccine 
coverage and other relevant data in a representative sample of 

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households in each cluster, by using the routine administrative data 
from vaccinating facilities across the whole pilot programme, and - 
where feasible - by using data from clinic-based vaccination 
registries.  
 
Population 
Children are eligible for the malaria vaccine starting at 5 months of 
age, with the 4th vaccination dose provided around 2 years of age, 
however surveillance will include all between the ages of 1 and 59 
months living in the areas designated for RTS,S/AS01 malaria vaccine 
implementation, and comparison areas. The household surveys to 
asses feasibility of reaching children with 4 vaccine doses will be 
carried out through community based household vaccine coverage 
surveys in children 5-48 months old.   
Evaluation of the pilot implementation will run for a total of about 46 
months in each country. 
 
Variables 
The primary objectives of the impact evaluation are to estimate the 
effect of the routine delivery of RTS,S/AS01 on all-cause mortality 
and on the incidence of hospital admission with severe malaria, 
overall and in each country.    
Secondary objectives include assessment of the effect of RTS,S/AS01 
on all-cause hospital admissions, on admissions for specific causes, 
and on the incidence of non-malaria hospital admissions.  
The  primary objectives of the safety evaluation are to estimate the 
effect of routine delivery of RTS,S/AS01 on a) the incidence of 
hospital admission with meningitis and b) the incidence of hospital 
admission with cerebral malaria,  pooled across the three countries, 
and c) on all-cause mortality in boys and girls and to determine 
whether there is any evidence that RTS,S/AS01 increases mortality in 
girls, overall and in each country; and pooled across three countries  
The safety evaluation will also use spontaneous reporting to detect 
adverse events following immunization (AEFI) with RTS,S/AS01.  
The primary objective of the feasibility evaluation will be to estimate 
the coverage of RTS,S/AS01 in the implementation areas, defined as 
the proportion of children aged 12-23 months who had received 3 
doses of RTS,S/AS01 by 12 months of age, and the proportion of 
children aged 27-38 months who had received their fourth dose of 
RTS,S/AS01 by 27 months of age.  
Secondary feasibility objectives are to measure, in implementation 
and comparison areas, the timely administration of RTS,S/AS01 
vaccination; the coverage of other recommended EPI vaccines; the 
coverage and utilization of ITN/LLIN and IRS; and the patterns of 

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health-seeking behaviour for febrile children. In addition, there will 
be study of the effect of strategies to achieve optimal coverage of 
the fourth dose; whether the introduction of additional contacts 
between 5-9 months of age influences drop-out rates for routine 
vaccinations and changes the number of fully vaccinated children; 
and whether the introduction of RTS,S/AS01 is associated with 
growth (measured by MUAC) or increased coverage of other key 
childhood interventions, including anti-helminth administration 
(deworming) and Vitamin A supplementation. 
 
Data Sources 
The impact evaluation will capture data at the community level 
through resident Village Reporters (VR) specially trained to 
document and report deaths in the target age group. Trained VR 
supervisors will conduct Verbal Autopsies, using WHO-recommended 
methods. This will allow assessment of impact on all-cause mortality 
excluding deaths due to accidents and injuries, and will provide the 
opportunity to capture vaccination status and to confirm age at 
death. Sentinel hospital admission data will be used to measure the 
impact of RTS,S/AS01 introduction on incidence of admission with 
severe malaria. 
 
In addition to strengthened routine pharmacovigilance, involving 
training of health care workers and sensitisation of communities, 
safety data will be captured in up to 24 sentinel hospitals by means 
of systematic, prospective, monitoring of all paediatric admissions, 
paying particular attention to meningitis and cerebral malaria.  
 
The feasibility of routine RTS,S/AS01 deployment will be evaluated 
primarily through the assessment of vaccine coverage in two 
standardised household surveys conducted across the pilot 
implementation areas. These data will be complemented by routine 
(“administrative”) health facility data and, to the extent possible, by 
facility-based electronic vaccination registries. 
 
Study Size 
The implementation of the RTS,S/AS01 vaccine will use the EPI, 
building on routine systems. The evaluation period is the time 
needed to monitor a sufficient number of children for vaccine safety, 
impact and feasibility. The evaluation of mortality drives the overall 
scale of the Malaria Vaccine Pilot Evaluation. In order to detect in 
each country a 10% decrease in all-cause mortality in vaccine-eligible 
children, and assuming a minimum mortality risk of 25 per 1000 in 
the target age group, a total of 60 areas each contributing 
approximately 4,000 children per year to the evaluation, and evenly 
split between implementation and comparison areas, will be 
required. Country-specific protocols will include updated sample size 
estimates, based on cluster size and local mortality estimates, and 

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are expected to require a range of 46-60 areas per country. Each 
year this will generate a total of approximately 120,000 children in 
the implementation areas and 120,000 children in the comparison 
areas in each country.  
 
Hospital-based safety surveillance will be nested within parts of the 
MVPE area and include up to 8 hospitals per country, serving up to 
24 areas across the Programme. This is designed to enable detection, 
with 90% power, of a 2.6-fold increase in the risk of meningitis and 
an 1.7-fold increase in the risk of cerebral malaria in children living in 
areas where RTS,S/AS01 is introduced. In addition, all health care 
facilities in the study areas will be supported to identify and report 
AEFI and VRs will identify non-hospitalized deaths. All AEFI and 
deaths will have their relationship with immunisation status 
evaluated. 
A representative sample of 100 households per cluster (up to 6,000 
households per country) will be surveyed to estimate the coverage of 
vaccinations in both implementation and comparison areas with a 
precision of +/- 2% in each of the three countries. 
 
Data Analysis 
Impact on survival will be evaluated by comparing the rate of death 
among children living in implementation areas with the rate of death 
among children living in comparison areas, with analysis by gender. 
as a subgroup analysis, as described in section 9.4.   
 
The incidence rates of hospitalised probable meningitis and of 
cerebral malaria in vaccine-eligible age groups will be compared 
between implementation and comparison.  
The proportion of children who received RTS,S/AS01 doses 1, 2 and 3 
(children aged 12-23 months) and dose 4 (children aged 27-38 
months) will be estimated from household surveys, using 
documented evidence (using vaccination cards) and maternal recall.  
 
Milestones 
The milestones will be adapted based on the timing of vaccine 
introduction in the intended study sites in the target SSA countries. 
 
 
 
5 Amendments and updates 
 
Number 
Date 
Amendment or update 
Reason 

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18 
7.2  
09 Feb 2018 
Amendment  
Changes proposed by advisory 
committees on review  
8.1 
19 Oct 2018 
Ammendment  
Changes proposed by advisory 
committees on review  
9.0  
22 Apr 2020 
Ammendment  
Changes to include statistical analysis 
plan  
 
 
 

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19 
 
6 Milestones 
 
All timings are tentative and dependent on the timing of implementation of RTS,S/AS01 by 
Ministries of Health, following confirmation of adequate surveillance systems in each country. 
Please also refer to figure 2 in section 7.6.5.  
 
 
Milestone 
Planned date 
Country-specific protocol submitted to Independent Ethics Committee & 
Regulatory Authority in country 1 
Q3. 2018 
Country-specific protocol submitted to Independent Ethics Committee & 
Regulatory Authority in country 3 
Q3. 2018 
Start of dose 1 in country 1 = Start of evaluation data capture 
Q2. 2019 
Dose 4 provided to last of children who were first vaccinated in year 1 in country 1 Q1. 2023 
Start of dose 1 in country 3 
Q3. 2019 
Dose 4 provided to last of children who were first vaccinated in year 1 in country 3 Q4. 2023 
Surveillance complete in country 1 
Q1. 2023 
Surveillance complete in country 3 = End of evaluation data capture 
Q4. 2023 
Final report of study results 
Q4. 2023 
 
Milestones in italics are dependent on the timing of implementation of RTS,S/AS01 by Ministries 
of Health and will drive the timing of the beginning and end of evaluation data capture. 
 
 

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7 Rationale and background 
In 2015, WHO estimated that 214 million malaria episodes caused 438,000 deaths, the vast 
majority in young children in sub-Saharan Africa (SSA). Current control tools are only partially 
effective, and all are based on insecticides or drugs, both of which are increasingly threatened by 
resistance. Available tools are unable to control malaria everywhere, even with good coverage, 
and there is an urgent need for new interventions2  
7.1 Efficacy of RTS,S/AS01 
RTS,S/AS01, the world’s first malaria vaccine, was evaluated in a phase 3 trial in 15,459 infants (6-
12 weeks old at the time of dose 1) and young children (5-17 months old at the time of dose 1) in 
7 sub-Saharan African countries3–6. Three doses of RTS,S/AS01 generated protection against 
clinical malaria which, though moderate compared with the efficacy achieved by vaccines against 
common viral diseases, is substantial in the context of malaria where there is a very high burden 
of disease and available interventions cannot offer high levels of protection (table 1). In the 12 
months following completion of the primary vaccination course in children aged 5-17 months at 
the time of dose 1, the incidence of clinical malaria was reduced by 51% and the incidence of 
severe malaria was reduced by 44.5%. Protection appeared to wane over time: by 18 months after 
the primary vaccination course, efficacy was 46% against clinical malaria and 38% against severe 
malaria. Efficacy against clinical malaria of 3 doses alone declined in the successive 6-months 
periods from 68% in the first 6-month interval to 39% and 28% in the successive 6-month 
intervals. A fourth dose, given 18 months after dose 3, increased efficacy to 39% against clinical 
and 31.5% against severe malaria over the whole of the study (a median of 48 months follow-up) 
whereas, among the children randomised to receive only three doses of RTS,S/AS01, efficacy 
against clinical malaria fell to 26% and against severe malaria to -2.2%. The 4th dose of RTS,S/AS01 
therefore appears to be needed to maintain efficacy against severe malaria. 
 
Over the whole (median 4-year) follow-up of children in the phase 3 trial, vaccine efficacy was also 
confirmed against malaria hospitalization (37%, ATP, 95%CI 27-48.5), all-cause hospitalization 
(15%, ATP, 95%CI 6-25) and severe anaemia (62%, ATP, 95%CI 26.5-81). These benefits were 
demonstrated in the presence of high ITN coverage and where the identification and treatment of 
clinical and severe malaria episodes, as well as other medical care, was optimized. The enhanced 
access to good quality curative services likely limited disease progression and precluded the 
measurement of vaccine impact on mortality. However, modelling suggests a substantial potential 
survival impact of RTS,S/AS01 outside trial settings (1 life saved per 200 fully vaccinated children in 
moderate to high transmission settings)7. 
Vaccine efficacy was substantially lower in those whose first vaccine dose was at 6-12 weeks of 
age than in the 5-17 month olds and thus further evaluation in the younger age group of infants is 
not recommended by WHO. 
 
 
 

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Table 1: Summary of RTS,S/AS01 vaccine efficacy (95% Confidence Interval) in the 5-17 month 
age category for all episodes of clinical malaria and severe malaria from Month 2.5 to selected 
time points (primary case definitions, ATP population). Source: WHO JTEG 
 
7.2 Safety of RTS,S/AS01 
The safety of RTS,S/AS01 in the phase 3 trial was evaluated by comparing the rates of events, 
detected through both active and passive surveillance, in children receiving 4 doses of RTS,S/AS01 
and the rates in children receiving 3 doses of RTS,S/AS01 followed by meningococcal C conjugate 
vaccine at the time of the 4th dose, with the rates in children in the control group who received 
three doses of rabies vaccine followed by meningococcal C conjugate vaccine at the time of dose 
4.  
No fatal adverse events were causally related to RTS,S/AS01 vaccination. An increase in the risk of 
self-limiting febrile seizures, as seen previously with several other vaccines, was not associated 
with any long-lasting sequelae. Among children in the older age group, an increase in the number 
of cases of meningitis and of cerebral malaria was found in the group receiving the malaria vaccine 
compared to the control group. The significance of these findings in relation to RTS,S/AS01 
vaccination is unclear. An excess of meningitis and cerebral malaria was not seen in infants first 
vaccinated aged 6–12 weeks.6 
7.2.1 SAEs in the phase 3 trial 
Up to 20 months after dose 1, at least one SAE was reported in 18.6% (95% CI 17.6, 19.6) of 
RTS,S/AS01 recipients compared with 22.7% (95% CI: 21.1, 24.3) of the control children. SAEs 
related to vaccination were reported in 0.2% of RTS,S/AS01 and 0.0% of the rabies vaccine 
recipients. Over the entire study period (i.e. including follow up after dose 4 of RTS,S/AS01) at 
least one SAE was documented in 24.2% of the children vaccinated with four doses of RTS,S/AS01, 

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25.3% of the children vaccinated with three doses of RTS,S/AS01, and 28.4% of the children in the 
control arm. The equivalent figures for non-malaria SAEs (22.6%, 23.7% and 26.4%, respectively) 
followed a similar pattern.  
An SAE related to vaccination was reported in 8 children receiving a 4th dose of RTS,S/AS01 (1 
injection site cellulitis, 1 convulsion and 6 febrile convulsions); in 4 children vaccinated with three 
doses of RTS,S/AS01 and one dose of meningococcal C conjugate vaccine (1 injection site reaction,  
1 epilepsy, 1 febrile convulsion and 1 pyrexia); and in one child in the control group (febrile 
convulsion). Six cases of potential immune-mediated disease (pIMD) were reported: 3 cases 
among children vaccinated with four doses of RTS,S/AS01, 1 case among children receiving three 
doses of RTS,S/AS01, and 2 cases among children in the control group. 
7.2.2 
Febrile convulsions 
The rate of generalised convulsive seizures with fever within 7 days of primary vaccination in 
RTS,S/AS01 recipients was 1.04 cases/1000 doses compared with 0.57 cases/1000 doses of control 
vaccine. The incidence of febrile convulsions within 7 days of administration of the fourth dose of 
RTS,S/AS01 was 2.5 cases/1000 doses, compared with 1.2 case/1000 doses in children vaccinated 
with 3 doses of RTS,S/AS01 but receiving meningococcal C conjugate vaccine at the time of the 4th 
dose, and 0.4 cases/1000 doses in the control group. Febrile convulsions within 7 days of 
vaccination are therefore considered an identified risk in RTS,S/AS01 recipients, for which the 
cause is unknown. 
7.2.3 Meningitis  
More meningitis cases were documented in children aged 5-17 months who received RTS,S/AS01 
than among children in the control group. Table 2 summarises meningitis cases during the 20 
month period following Dose 1.  
Table 2: Meningitis cases in children aged 5-17 months at dose 1 in the phase 3 trial 
Analysis 
available 
Follow up (post 
dose 3) 
Number of cases in 
RTS,S/AS01 group 
(Number of 
RTS,S/AS01 study 
participants) 
Number of cases 
in control group 
(Number of 
control study 
participants) 
RR 
95% CI 
June 2014 
18 months 
16 (5949) 
1 (2974) 
8.0 
1.1-60.3 
 
The 16 cases comprised a mixture of aetiologies (4 meningococcal, 1 viral, 1 pneumococcal, 1 
Haemophilus influenza, 9 unknown).  
Five meningitis cases occurred in children between study month 20 and study end, including 2 
cases in a child who received a fourth dose of RTS,S/AS01, compared with 3 cases in the same time 
period among children randomised to receive three doses of RTS,S/AS01. There were no further 
cases in the control group.  
Hence 22 meningitis cases occurred in the 5-17 month age category throughout the complete 
study period (median 48 months follow-up from dose 1): 11 in children who received 4 doses of 
RTS,S/AS01, 10 in children who received 3 doses of RTS,S/AS01, and 1 in children in the control 
arm. Almost two thirds of cases were reported from just two of the 11 phase 3 trial sites (9 cases 
in Lilongwe, Malawi, and 5 in Kombewa, Kenya). There was no clear temporal clustering of cases, 

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with 12 cases (11/5949 in RTS,S/AS01 recipients and 1/2174 in children in the control arm) 
occurring in the 14 months following dose 1. 
Among infants aged 6-12 weeks when first receiving RTS,S/AS01, 9 meningitis cases occurred in 
the RTS,S/AS01 groups and 3 in the control group in the 20 month period following Dose 1 (RR = 
1.5 [95% CI: 0.4, 5.5]). The number of meningitis cases per group was similar by the end of the 
study (5 in children receiving 4 doses of RTS,S/AS01, 7 in children receiving 3 doses, and 6 in the 
control group).  
Despite the lack of a consistent aetiology, the absence of a temporal relationship with vaccination, 
the suggestion of clustering of cases in some sites and the lack of a plausible mechanism by which 
RTS,S/AS01 could lead to meningitis, the documented imbalance of meningitis cases warrants 
follow-up in the context of a pilot implementation study, as well as the Phase 4 study. Together 
these studies will provide evidence to help establish or exclude a causal association between 
meningitis and RTS,S/AS01 and further characterise and evaluate this safety signal.  
7.2.4 Cerebral malaria 
Exploratory analyses of the phase 3 trial data compared the distribution of severe malaria, as 
identified by a computer algorithm, in the study groups. An imbalance was observed amongst 
cerebral malaria cases (parasitaemia >5000 and Blantyre Coma Score <3) in the 5-17 month 
category: in the 20 months after Dose 1, 16 cerebral malaria cases occurred in the RTS,S/AS01 
group (5948 children), while 5 such cases occurred in the control group (2974 children). In 
addition, cerebral malaria and anaemia (parasitaemia >5000, Blantyre Coma Score <3 and 
haemoglobin <5 g/dL) was observed for 6 subjects in the RTS,S/AS01 group and 1 subject in the 
control vaccine group.  
Nine cerebral malaria cases (with or without anaemia) occurred among the 2719 children who 
received a 4th dose of RTS,S/AS01, 12 cases among the 2681 children vaccinated with RTS,S/AS01 
followed by meningococcal C vaccine, and 4 among the 2702 children in the control arm.  
There were 12 deaths among the cerebral malaria cases: 10 in the RTS,S/AS01 groups and 2 in the 
control group. 
The potential association between cerebral malaria and RTS,S/AS01 warrants further follow-up 
and evaluation in the context of the pilot implementation. 
7.2.5 Mortality and gender 
In girls, but not in boys, there was a higher mortality rate among those vaccinated with 
RTS,S/AS01 (with or without booster) than among controls, in both age categories . The all-cause 
mortality ratio, comparing vaccinated to controls, was 1.91 (95% CI: 1.30, 2.79) in girls and 0.84 
(95% CI: 0.61, 1.17) in boys. However, this finding was post-hoc, and hence difficult to interpret, 
mortality rates were low in the trial, and  particularly so in girls randomized to receive the 
comparator vaccine, and the absolute differences in the numbers of deaths by gender were small 
(35 of the 1467 girls and 26 of the 1509 boys randomised to receive 4 doses of RTS,S/AS01; 32 of 
the 1500 girls and 19 of the 1472 boys in the 3 dose group; and 17 of the 1503 girls and 29 of the 
1471 boys in the control group). Nevertheless, further follow-up of gender-specific mortality in 
children receiving RTS,S/AS01 is warranted. 

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7.2.6 Summary of Safety 
The overall incidence of SAEs – both all SAEs and non-malaria SAEs - in the phase 3 study was 
lower in children receiving RTS,S/AS01 than in children in the comparison arm. Febrile convulsions 
were an identified risk in RTS,S/AS01 recipients in the 7 days following vaccination, but the 
incidence rates equilibrated between the groups by 30 days post vaccination. Meningitis was 
identified as a potential risk. The imbalances observed for cerebral malaria and gender-specific 
mortality following post-hoc analyses of the phase 3 study data are also considered safety signals 
requiring further evaluation. 
 
7.3 International regulatory and policy review 
The vaccine received a positive scientific opinion from the EMA, reflecting the quality of the 
vaccine and favourable risk/benefit balance from a regulatory perspective8. In October 2015, the 
WHO advisory committees SAGE and MPAC recommended pilot implementation studies9 to 
assess, in the context of routine immunization programmes: 
• Programmatic feasibility of delivering RTS,S/AS01 with three to four new immunization 
contacts, including the fourth dose in the second year of life 
• Vaccine impact on all-cause mortality, including gender-specific mortality  
• Vaccine safety with specific attention to meningitis and cerebral malaria. 
The Malaria Vaccine Implementation Programme 10 will enable the first-time use of the vaccine in 
real-life settings and thereby bridge the knowledge gaps currently inhibiting wider scale use of a 
tool with considerable potential public health impact. Data from the pilots will inform policy-
making at global and national levels, allowing decisions to be made about larger-scale adoption, 
providing learnings on where and how to use the vaccine to optimize its impact and cost 
effectiveness in complementing other malaria interventions. The experience gained during the 
pilot implementations may also benefit future malaria vaccines facing similar questions (e.g. 
feasibility of a new dosing schedule, use alongside other malaria interventions).  
7.4 Alignment of the Malaria Vaccine Pilot Evaluation and the Phase 4 evaluation 
The Malaria Vaccine Implementation Programme has two main components: (1) vaccine 
implementation by the MoH, (2) evaluation of vaccine implementation including the WHO-led 
RTS,S/AS01 Malaria Vaccine Pilot Evaluation and the GSK-led Baseline and Phase 4 studies. 
As part of the Risk Management Plan agreed between GSK, the vaccine manufacturer, and the 
EMA, a set of Baseline and Phase 4 studies will evaluate vaccine safety in children receiving 
RTS,S/AS01 and estimate the vaccine’s impact and effectiveness. Cohort event monitoring will 
involve active surveillance (home visits and continuous monitoring of outpatient visits and 
hospitalisations) of approximately 65,000 children across the three countries of the RTS,S/AS01 
Malaria Vaccine Implementation Programme (20,000 unvaccinated prior to the Malaria Vaccine 
Implementation Programme, 22,500 vaccinated during the Pilot Implementation of the malaria 
vaccine, and 22,500 unvaccinated from the control areas of the Malaria Vaccine Implementation 
Programme). The Phase 4 study surveillance will be based in one or two hospitals per country in 
RTS,S/AS01 implementing areas (vaccinated clusters), with an equal number of hospitals from 
comparison areas (unvaccinated clusters) generating comparable data.  

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A high degree of coordination between the GSK-led studies and the WHO MVPE will ensure their 
complementarity. The two sets of evaluations will take place in different areas. However, 
resources developed for the GSK-led studies will assist the MVPE (see section 10.6, ‘Capacity 
building’) and enhance the comparability of the safety data generated by each evaluation 
programme. As far as possible, the approach to the collection and processing of samples, and data 
analysis, will be harmonised through the use of the same reference laboratory (section 10.5.2) and 
case definitions (10.4). At the global level, safety reports from the GSK and WHO-led studies will 
be reviewed on a 6--monthly basis for ongoing safety monitoring by the Data Safety Monitoring 
Board of the RTS,S/AS01 Malaria Vaccine Pilot Evaluation.   
7.5 Selection of countries for the pilot programme  
WHO launched a public call for expressions of interest in the MVIP from the MOHs in sub-Saharan 
Africa in December 2015. Ten countries, all classified as low or lower-middle income countries per 
World Bank definition, submitted written expressions. A country selection process from January to 
April 2016 included the following criteria: 
• Confirmation of engagement and interest from MOHs including discussions about the 
purpose of the pilots and cluster randomized vaccine introduction.  
• Functional immunization and malaria control programmes as evidenced by DTP3 and 
MCV1 coverage, and LLIN usage (using the most recent survey-based estimates). 
• High all-cause mortality in the planned regions of the pilots, with high malaria transmission 
indicating that a large proportion of childhood deaths are due to malaria in such settings. 
• Existence of at least one highly capable sentinel hospital per region to facilitate the 
collection of high quality data on meningitis and cerebral malaria. 
• National pharmacovigilance readiness.  
In addition, prior participation in the RTS,S/AS01 Phase 3 trial was considered favourably. 
Subnational settings in Kenya, Ghana and Malawi were identified based on these criteria, each 
with a track record of strengthening malaria and immunization programmes, as well as experience 
introducing new vaccines, and links with immunization and malaria research infrastructures for 
the evaluation components.  
7.6 Overview of RTS,S/AS01 delivery and evaluation  
7.6.1 Approach to delivery of RTS,S/AS01 
This protocol describes the evaluation of the routine delivery of RTS,S/AS01 by Ministries of Health 
using an expanded schedule of their routine EPI contacts, building on the national immunization 
programmes which routinely deliver vaccines to young children living in SSA countries. Delivery of 
RTS,S/AS01 will be the responsibility of the MOH, guided by good participatory practices and will 
include the development, testing and implementation of training materials and strategies for 
relevant staff; adaptation of relevant delivery and surveillance systems (e.g. involving child 
vaccination health cards, recording sheets, supply forms, ledgers and registers); and updates of 

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cold chain assessments for pilot implementation areas. A draft Practical Operating Guide for the 
Malaria Vaccine Implementation Programme is included in Annex 4. 
Given the importance of receiving all 4 doses to maximise benefit from the vaccine, the MoH will 
be encouraged to develop its routine services to identify and track children to maximise the 
coverage of the 4-dose regimen. Should routine data show inadequate coverage of RTS,S/AS01 
there is provision within the programme budget to explore supplementary activities to boost 
coverage. The emphasis will be on approaches which are potentially sustainable by routine 
immunisation services. 
If a decision is taken to terminate the RTS,S/AS01 vaccination programme in a country, specific 
efforts will be made to maximise the completeness of the vaccine regimen in children who have 
received one or more doses, assuming the reason for termination is not a vaccine safety concern.  
As part of the implementation process, pharmacovigilance systems will be evaluated and 
assistance provided, as necessary, to strengthen routine vaccine pharmacovigilance. The routine 
vaccine safety surveillance systems will be supported to generate information to support decision-
making about vaccine use and to maintain the public’s trust by providing data to counter fear and 
misinformation. The activities will be guided by the Global Vaccine Action Plan 11 and progress 
with system strengthening monitored using the standard indicator – the AEFI reporting rate per 
100,000 surviving infants per year – which is expected to be at least 10 cases per 100,000 surviving 
infants per year. Activities will include encouragement of AEFI reporting; strengthening of AEFI 
investigation, data analysis and causality assessment; and managing the communications response 
to vaccine safety events. As such, the RTS,S/AS01 MVIP is expected to help increase health 
workers’ awareness of safety issues, improve the sensitivity of adverse event case detection, allow 
identification and correction of any problems and enhance the interpretation of pre- and post- 
vaccine introduction safety data.  
7.6.2 Evaluation Design  
The evaluation will be conducted in the context of the early, limited deployment of the 
RTS,S/AS01 vaccine by routine health systems. Vaccine implementation is expected to continue 
beyond the evaluation period and with the progressive roll out beyond the pilot areas if there are 
no significant safety signals or concerns about the feasibility of deploying the vaccine. It will take 
until about month 30 of the programme for children receiving dose 1 in the first year to receive 
their fourth dose. Routine vaccinations with RTS,S/AS01 are therefore expected to continue at 
least until month 30 of the programme.  
The pilot implementation will use a cluster-randomized design, with some areas (Districts, Sub-
counties, Clusters, referred to herein as “clusters”) introducing RTS,S/AS01 at the beginning of the 
programme and other clusters, without RTS,S/AS01, acting as comparison areas. Randomization is 
a fair way to choose implementation areas during the initial period of implementation in which 
delivery of the new vaccine, which involves visits outside the existing EPI schedule, is being 
piloted. The division of areas into implementation or comparison areas will be randomized, by the 
respective country’s EPI team, to enable the MVPE pilot implementation programme to generate 
the strongest possible evidence on the impact and safety of the vaccine by limiting potential 
biases and providing a contemporaneous comparison group that allows for strong statistical 
inferences to be made. The approach to sensitisation of communities and in-country stakeholders 
at all levels will be described in country-specific protocols. In general, communities will be 
informed about the randomised introduction of the RTS,S vaccine through the EPI programme and 

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the corresponding social mobilization plan. This will include information on the potential risks and 
benefits of the vaccine, including the moderate level of protection it provides so that the use of 
other preventive measures is sustained by the communities. Through the same means, 
communities will learn whether they are living in an area that has been randomised to receive the 
vaccine, or not, at the beginning of the programme, and provided with updates as the programme 
progresses (see also section 14). 
Areas will be allocated to intervention or comparator, taking into account the capacity of hospitals 
and health facilities within the areas (three levels, described in section 10.2.2), malaria 
transmission (as reflected by the P falciparum prevalence in children aged 2-10 years modelled to 
the cluster level12, divided into tertiles), geographic location (such as county/region) and  
population size (divided in tertiles), using a constrained randomization  procedure to ensure that 
the vaccination and comparison areas are balanced for these characteristics, which could be 
associated with the incidence of the outcome measures13.  
Figure 1 illustrates the overall design with details presented in the following sections.  
Figure 1: Overview of the WHO-led RTS,S/AS01 Malaria Vaccine Pilot Evaluation 
 
    
7.6.3 Study dates 
• Surveillance systems to be developed/consolidated during 2018 - early 2019 in all 
countries. 
• Baseline household surveys planned to be conducted by March 2019. 
• Vaccinations planned to start February-May 2019 (e.g. Country 1, Q1 2019; Country 2, Q2 
2019; Country 3, Q2 2019). 

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• Dose 1 planned to be complete February-May 2020, for children contributing to the 
evaluation of feasibility, depending on timing of start of vaccinations and period required 
to vaccinate target number of children. 
• Dose 3 planned to be complete by June – September 2020. 
• Dose 4 planned to be complete by August 2021 – November 2021, dependent also on 
timeliness of doses 1 – 3 and dose 4. 
• Surveillance planned to be continued August 2022 – November 2022.  
Please also refer to figure 2 in section 7.6.5. Detailed timelines, including dependencies between 
activities, will be elaborated in country-specific protocols. 
7.6.4 Vaccination Schedule 
RTS,S/AS01 will be given as a four dose schedule with the first dose administered as soon after 5 
months of age as possible, followed by doses two and three at approximately one month intervals, 
and a fourth dose 15-18 months after dose three. The evaluation will continue for sufficiently long 
to ensure that children who receive RTS,S during the first year of the programme will have 
received the fourth dose at least 12 months before the pilot evaluations are completed. Children 
will be eligible for vaccination according to the manufacturer’s instructions, as approved by the 
national regulator. 
RTS,S/AS01 can be co-administered, as demonstrated in Phase 2 and 3 trials, with other vaccines 
in the national immunization programme (hepatitis B, diphtheria, tetanus, pertussis, polio, 
measles, yellow fever).14,15 Depending on the delivery schedule adopted by the national EPI 
programmes, it is possible that the first dose of  RTS,S/AS01 will be administered with the 3rd dose 
of DTP and dose 2 or, more likely, dose 3, delivered at  9 months of age, could be co-administered 
alongside existing vaccines, e.g. measles and yellow fever vaccinations. The specific schedules, and 
the potential for introduction of other new vaccines (e.g. Men A in Ghana in late 2016) into the 
routine schedule, will be described in country-specific protocols.  
Age-eligible children will be identified by health workers at health facilities and outreach clinics, in 
the course of routine child health and vaccination programmes in the pilot areas, and invited for 
doses of RTS,S/AS01, as they are for other vaccinations.  
7.6.5 Evaluation of RTS,S/AS01 
Identical monitoring systems will be established in both implementation and comparison areas to 
record impact and safety outcomes. Figure 2 presents an illustrative overview of study timings 
which will be updated, if necessary, in country-specific protocols. Surveillance will be maintained 
in children aged 1-59 months throughout the pilot. This will allow assessment of the effects of 
vaccine introduction  in the age groups of children eligible to receive RTS,S/AS01, while the data 
for children too young or old to be eligible for the vaccine, provide information about background 
rates of outcomes in the same cluster (see the statistical analysis plan (SAP).  

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Figure 2: Illustrative overview of study timings. 
 
This protocol describes the evaluation of a pilot implementation programme which has been 
designed on the basis of up to 60 areas per country, evenly split between implementation and 
comparison areas, with each cluster contributing approximately 4,000 study children per year. 
Country-specific protocols will present the number (expected to range from 46-60) and size of 
areas in the respective country. All areas will contribute to the evaluation of the impact on 
mortality. Mortality surveillance will be undertaken at the village level by Village Reporters (VR) 
documenting deaths in the area in which they live. A sub-set of clusters, with access to care in up 
to 8 sentinel hospitals per country (a maximum of 24 across the programme), equally split 
between implementation and comparison areas, will provide hospital-based surveillance data for 
safety and cause-specific impact assessments. Feasibility will be evaluated by generating vaccine 
coverage and other relevant data in a representative sample of households in each cluster, by 
using the routine administrative data from vaccinating facilities across the whole pilot programme, 
and, where feasible, by using data from clinic-based vaccination registries. Pooled analyses of 
safety and impact data will be conducted to the extent possible. 
Areas will be defined according to the size of the birth cohort, aiming for an annual birth cohort of 
4,000 children. Feasibility will be evaluated in the context of routine ongoing RTS,S/AS01 
vaccination. Figure 3 illustrates that a minimum of 30 months of routine vaccination will be 
required to provide sufficient observation time to assess the feasibility of providing the fourth 
dose to children receiving their first dose in the first year of the programme (dark green in figure 
3). All children receiving any doses of RTS,S/AS01 in the 30 month window (light green in figure 3) 
will contribute to the evaluation of safety and impact. 

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Figure 3: Overview of children contributing to feasibility, safety and impact evaluations 
 
* To be decided by authorities of pilot countries 
7.6.6 MVIP and decision-making for vaccine roll out 
The MVIP has been developed to support and evaluate the first phase of the RTS,S/AS01 malaria 
vaccine implementation. The positive scientific opinion of the European Medicine’s Agency 
confirms the vaccine is considered safe for public health use from a stringent regulatory 
perspective. The MVIP is designed to assess the feasibility of introducing the four-dose vaccine, 
consolidate the vaccine’s safety profile, and measure its impact. In so-doing the MVIP will set the 
scene for larger-scale implementation. 
7.6.6.1 Informing a decision to roll out the vaccine more widely 
The main safety signals identified in the Phase 3 trial, for which a causal relationship with the 
vaccine has not been established, were an 8-fold increase in the risk of meningitis, an approximate 
doubling in the risk of cerebral malaria and, in the context of very low overall mortality among trial 
participants, an imbalance by gender among those who died during the course of the trial, with 
more deaths among girls than boys vaccinated with RTS,S/AS01 (section 7.2). It is possible that 
new safety signals will be identified in the MVIP. Safety data will be evaluated by the safety 
monitoring systems described in the sections 10.15 and 13.2.  
 
Specific criteria and thresholds for decision-making have not been established. During the early 
stages of the MVIP a framework for policy decision-making for RTS,S will be developed. This will 
describe how data collected through the programme will be used to inform the policy 
recommendations of WHO’s Malaria Policy Advisory Committee (MPAC) and its Strategic Advisory 
Group of Experts (SAGE) on immunization.  

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The Joint Technical Expert Group (JTEG) was convened with representation from SAGE, MPAC and 
additional independent experts, to monitor the Phase 3 trial of RTS,S/AS01. JTEG recommended 
that WHO should monitor emerging findings from pilot implementation and, based on those 
findings, “it would be appropriate for WHO to recommend countrywide introduction if concerns 
about safety have been resolved, and if favourable implementation data become available, 
including high coverage of the fourth dose”1. The JTEG recommendation did not state how data 
should be used, for example defining what should be considered “high coverage of the fourth 
dose” or whether demonstration of impact on mortality would be required for a policy 
recommendation. 
 
The framework for policy decision-making is expected to enable SAGE and MPAC members to 
discuss and refine ideas on the relative contributions of the collected data (feasibility, safety, 
impact) to a future policy recommendation. The framework will provide clarity on the expected 
use of the data for the SAGE and MPAC recommendations, expected in 2020 and/or 2022, a 
period in which changes in SAGE and MPAC membership are likely. It is expected that Ministries of 
Health, funders, potential funders, and manufacturers will refer to the framework for planning 
purposes, reducing the likelihood of gaps in funding or vaccine availability should the vaccine be 
recommended for broader use. 
 
It is not anticipated that the framework would articulate binding “go” or “no go” criteria. 
Rather two sets of data-driven criteria would be agreed: (i) a set of high-bar thresholds 
above which it is very likely the vaccine would be recommended for broader use (e.g. very 
high coverage of doses 1 – 4, safety concerns resolved), and (ii) a set of low-bar thresholds 
beneath which it is very unlikely the vaccine would be recommended (e.g. very low coverage of 
doses 1-4, confirmation of an 8-fold increase in meningitis in vaccine recipients). Should neither 
set of thresholds be met, a more nuanced discussion would be required to consider the public 
health utility of the vaccine (i.e. consideration of the benefit/risk profile). 
 
The MVIP will use mathematical modelling to assist in identifying a rational basis for proposing 
vaccine coverage thresholds that predict significant impact on severe malaria or mortality. 
 
7.6.6.2 Garnering commitments for vaccine supply 
WHO, PATH and the vaccine manufacturer, GSK, have signed a legal agreement which includes a 
commitment by GSK to supply, without charge, sufficient quantities of the RTS,S vaccine to allow 
the sound implementation of the MVIP, up to a maximum of 10 million doses. These are expected 
to enable all three pilot countries to continue routine delivery of RTS,S in implementation areas 
and to implement the vaccine in comparator areas, if appropriate, until the end of 2022.  
The collaboration agreement also includes access provisions to ensure the availability and 
affordability of the malaria vaccine beyond the pilots, should success of the programme be 
confirmed and WHO recommend its broader use. The agreement provides some assurances about 
the cost of the vaccine but it is recognised that the vaccine may not be readily affordable to many 
low income countries. To ameliorate this risk and to facilitate longer-term access, the MVIP will 
bring together partners from funding agencies which have an interest in supporting large-scale 
introduction and use of the vaccine beyond the pilots, should this be recommended by WHO. The 

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intention is to ensure continuity of supply and availability of the vaccine through the use of public 
funds.  
The necessary national and international political commitment to ensure appropriate action based 
on the findings of the pilot implementation will be cultivated as the MVIP proceeds. 
 
 

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8 Research questions and objectives 
8.1 Key questions on impact, safety and feasibility  
(See SAP) 
The following key questions will be evaluated in groups of children, eligible to receive RTS,S/AS01 
vaccine, residing in the RTS,S/AS01 implementation and comparison areas. 
Impact: 
• Is there any reduction in all-cause mortality following the introduction of the \ routine 
delivery of RTS,S/AS01??  
• By how much does the routine delivery of RTS,S/AS01 vaccine reduce the incidence of 
hospital admission with  severe malaria? 
Safety:  
• Does the introduction of routine RTS,S/AS01 vaccination result in an increased rate of 
meningitis and/or cerebral malaria in communities where the vaccine is introduced?  
• Does the introduction of RTS,S/AS01 have a different effect on all-cause mortality for boys 
and girls? Does RTS,S/AS01 increase mortality in girls? 
• What is the frequency and profile of RTS,S/AS01 reported AEFI?  
Feasibility: 
• What coverage is achieved with RTS,S/AS01 (including the fourth dose in the second or 
third year of life) and how timely are the doses?  
• What is the coverage and timeliness of recommended EPI vaccines (including MCV2) and 
does it change with RTS,S/AS01 introduction?  
• What is the coverage and utilization of other recommended malaria prevention and 
control measures, including ITN and IRS, and does it change with RTS,S/AS01 introduction?  
• Do treatment seeking behaviours for febrile children, use of malaria prevention measures, 
and EPI vaccination coverage change with the introduction of RTS,S/AS01?  
• What strategies help to achieve optimal coverage of the fourth dose?  
• Does the introduction of additional contacts between 5-9 months of age influence vaccine 
programme drop-out rates and the number of fully vaccinated children? 
• Does the introduction of RTS,S/AS01 alter the coverage of other key childhood 
interventions, including Vitamin A supplementation? 
The overall impact of RTS,S/AS01 will be evaluated in the MVPE. As with other vaccines, any risks 
identified need to be weighed against the benefits to understand the overall impact of the 

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vaccine. The overall assessment will consider both feasibility and impact outcomes. The evaluation 
of risks and benefits will be made by the Data Safety Monitoring Board and presented to WHO’s 
Global Advisory Committee on Vaccine Safety (GACVS), SAGE and MPAC to develop the WHO 
policy recommendation on the large-scale deployment of the RTS,S/AS01 vaccine. 
 
8.2 Objectives related to impact and community-based surveillance  
[See also statistical analysis plan (SAP)] 
8.2.1 Primary impact objectives 
The primary objectives of the impact evaluation are: 
• To estimate the effect of the routine delivery of RTS,S/AS01 on all-cause mortality 
(excluding accidents) 2 
• To estimate the effect of routine delivery of RTS,S/AS01 on the incidence of hospital 
admission with severe malaria (severe malaria anaemia or cerebral malaria)  
in each country and overall. 
8.2.2 Secondary impact objectives 
The secondary objectives of the impact evaluation are to estimate the effect of routine delivery of 
RTS,S/AS01 on incidence hospital admission with cerebral malaria  
• the incidence of hospital admission with severe malaria anaemia  (patients admitted, who 
had severe malaria anaemia) 
• incidence of all-cause hospital admission  
• incidence of non-malaria hospital admission 
• incidence of cause-specific hospital admission 
• incidence of the requirement for or provision of blood transfusions  
• cause-specific mortality (from verbal autopsy or hospital diagnosis) 
• malaria-specific mortality in hospital 
• all-cause mortality, excluding deaths due to trauma or accidents 
• malaria-specific mortality in hospital in boys and in girls  
in children eligible to receive the vaccine, in each country and overall. 
8.3 Objectives related to safety and surveillance in sentinel hospitals 
8.3.1 Primary safety objectives 
• to estimate the effect of RTS,S introduction on the incidence of hospital admission with 
probable or confirmed meningitis (data pooled across the three countries)  
                                                     
2 Please refer to section 7.6.5 for an explanation of the age ranges targeted for different endpoints 

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• to estimate the effect on the incidence of hospital admission with cerebral malaria (data 
pooled across the three countries) 
• to estimate the effect of RTS,S introduction on all-cause mortality in boys and girls and to 
determine whether there is any evidence that RTS,S is increases mortality in girls, overall 
and in each country 
8.3.2 Secondary safety objectives 
Exploratory analyses will: 
• Explore the association between RTS,S/AS01 and AESI, as agreed with each country’s 
immunization program and regulatory authority, and with the Data Safety Monitoring 
Board (Annex 5). 
8.4 Analysis populations  
(See SAP) 
• For each death and each hospital patient, cluster of membership will be determined from 
the location of normal residence. Within each implementation and comparator area, the 
following groups will be defined: children who are age-eligible for the vaccine and children 
who are not age-eligible for the vaccine, based on date of birth and age at the time of the 
RTS,S/AS01 introduction. 
• All primary outcome measures will also be analysed, in an exploratory secondary analysis, 
in  children who received DTP3.  
8.5 Objectives related to feasibility 
 
The primary quantitative outcome assessment of feasibility will be based on RTS,S/AS01 coverage 
estimated in repeated household surveys. Coverage of the first 3 doses and of the fourth dose will 
be estimated through household surveys in the middle and towards the end of the programme, 
respectively. These surveys, and a pre-implementation baseline household survey, will also 
generate estimates of the coverage of routine EPI vaccines, recommended malaria control 
measures, vitamin A and antihelminth treatment coverage, may include nutritional status by 
MUAC, and will document patterns of health-seeking behaviour for febrile children. 
 
8.5.1 Primary feasibility objectives 
For the second household survey: 
• To estimate the proportion of children aged 12-23 months, who had received three doses 
of RTS,S/AS01 by 12 months of age (in each country).  
For the third household survey: 
• To estimate the proportion of children aged 27-38 months, who had received their fourth 
dose of RTS,S/AS01 by 27 months of age (in each country). 
8.5.2 Secondary feasibility objectives 
The first, second and third household surveys are designed: 

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• To estimate the coverage of recommended EPI vaccines in children from areas 
implementing RTS,S/AS01 and in children from areas not implementing RTS,S/AS01.  
• To estimate the proportions of children receiving each individual dose (the first, second, 
third, fourth, as appropriate) for each recommended vaccine 
• To estimate the coverage and utilization of ITN/LLIN, IRS and any other recommended 
malaria prevention and control measures, in children from areas implementing RTS,S/AS01 
and in children from areas not implementing RTS,S/AS01. 
• To document patterns of health-seeking behaviour for febrile children among children 
from areas implementing RTS,S/AS01 and in children from areas not implementing 
RTS,S/AS01. 
• To assess if the introduction of additional contacts between 5-9 months of age alters drop-
out rates for routine vaccinations and changes the number of fully vaccinated children. 
• To assess whether the introduction of RTS,S/AS01 is associated with a change in the 
coverage of other key childhood interventions, including anti-helminth administration 
(deworming) and Vitamin A supplementation. 
It will be important to investigate, as part of the second survey or preferably as a separate study 
before the second survey, the agreement between malaria vaccine status by caregiver recall, from 
the home-based record, and from immunization registers, in order to understand the validity of 
RTS,S/AS01 status from different sources.  
Exploratory analyses will assess changes in malnutrition as measured by MUAC score (but not 
necessarily in all countries) following the introduction of RTS,S/AS01. 
 
 
 

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9 Research Methods for Impact Evaluation 
9.1 Study design 
The EPI programme will randomize areas (districts, sub-counties, clusters) to either implement or 
not implement the vaccine at the beginning of the pilot programme. The areas not initially 
introducing the vaccine will act as comparison areas. This randomized approach will enable a 
rigorous assessment of safety and impact in the pilot area. The evaluation design is described in 
more detail in section 7.6.5. The assessment of impact will draw on data from all clusters. The 
evaluation has been designed on the basis of each cluster contributing approximately 4,000 
children to the evaluation per year, generating approximately 240,000 children per country per 
year, equally split between implementation and comparison areas. The geographic area covered 
will vary according to population density but is expected to include a total population (all ages) 
approaching 5 million people in each country. 
9.2 Setting 
9.2.1 Surveillance population and surveillance period 
The population contributing to the impact evaluation surveillance systems will include vaccinated 
and unvaccinated children living in areas of moderate to intense malaria transmission and aged 
from 1 month to 59 months. The surveillance period will be 46 months, to provide 12 months of 
surveillance activities after children vaccinated during the first year of the programme receive 
their fourth vaccine dose, assuming that the first dose of RTS,S/AS01 is given as soon as possible 
after 5 months of age, that the third dose is given by 9 months of age, and the fourth dose is given 
by age 27 months. A 12 month surveillance period after dose 4 brings children to 39 months of 
age. Data will be collected in children aged up to 59 months to enable documentation of delayed 
critical events in children vaccinated at the beginning of the programme (figure 2, section 7.6.5). 
Collecting information on children reported to have died between the ages of 1 and 59 months 
should facilitate operational activities and minimise the risk of excluding relevant events due to 
inaccuracies in initial reporting of age in young children in such settings, and the data for those too 
young or old for RTS,S/AS01 provides important information about underlying rates of outcomes 
in the same cluster. 
9.2.2 Community-based surveillance 
The majority of deaths in many sub-Saharan countries occur in the community, rather than in 
hospitals or health facilities. The evaluation of the impact of RTS,S/AS01 on survival will therefore 
require the development and consolidation of community-based systems to document and report 
deaths. Experience from the INDEPTH network of demographic surveillance systems (DSS) has 
confirmed the feasibility of recruiting and training a cadre of village-based reporters (VRs). Their 
role is to identify and document deaths occurring in their village and any surrounding area 
assigned to the VR. Deaths may be identified either through (i) door-to-door visits of each 
household in the VR’s assigned area, in which case there will be approximately 131 VRs per 
cluster, employed full time and each expected to visit around 150 households every 3 months, or 
(ii) by VRs being notified of any key events by a specially developed local network of informants, in 
which case there would be around 25 VRs per cluster, each VR capturing information from around 
800 households. The MVPE will build on relevant existing and developing capacities and systems 
to generate key vital event data for the evaluation and do so with the aim of strengthening 
sustainably the local capacity for vital event monitoring.  

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9.2.3 Community sensitisation 
Following approval of the protocol by the relevant ethical committees/IRBs, the country-based PIs 
will work with MoH staff involved in the implementation of the vaccination programme to 
sensitise and engage relevant local stakeholders (e.g. Regional and District Directors, Regional and 
District Medical Officers, etc) and communities (e.g. through village meetings – ‘Durbars’) and/or 
their representatives (e.g. Councillors). This will be done in a locally appropriate manner, guided 
by good participatory practices, and described in more detail in Annex 6 and fully in the country-
specific protocols.  
9.2.4 Identification and training of Village Reporters 
Where possible, existing cadres of village-based workers will be supported, as locally appropriate 
and necessary, to act as VRs for the documentation of deaths in children in the target age group. 
The potential for this cadre also to support reporting of AEFI will also be assessed. Where such a 
cadre does not exist criteria for selection of VRs will be agreed locally. These criteria will likely 
include a specified level of education and being resident in the area in which they will be 
responsible for reporting deaths. Recruitment will proceed according to a locally agreed 
competitive selection process. A surplus of VRs will be identified and trained from each cluster to 
create surplus capacity in the event of trainees unable to complete the course, unwilling or unable 
to take on the role, illness, migration of the VR, etc. 
 
The VR training programme will ensure an understanding of the: 
• Importance of mortality monitoring in general. 
• Need to understand the causes of death in order to prioritise action to intervene and to 
assess the impact of new measures to improve survival.   
• Content and rationale for standard operating procedures, including locally appropriate 
ways to inquire about deaths.  
• Use of local events calendars to help capture critical dates (especially dates of birth and 
death) accurately. 
Vaccine safety principles and AEFI surveillance will also be included in settings where the 
identified cadre is considered able to contribute to the strengthening of routine 
pharmacovigilance. 
 
Training will include small group work and evaluations, with the best trainees invited to participate 
in a piloting exercise. The VRs’ performance in the piloting will be reviewed before a final selection 
of VRs and reserves is made. We will seek to build on any relevant training materials and 
approaches that have previously been developed (e.g. for Demographic Surveillance Systems) in 
the area.  
 
9.2.5 Identification and training of supervisors for Village Reporters 
In some settings VRs may be supervised by members of the District Health Team, District Council 
or other established cadre. Where no such capacity exists, VR technical supervisors will be 
identified from amongst the trainees (see 9.2.4) and may include staff known to the evaluation 
partners.  
 
Each VR technical supervisor will cover one cluster and supervise the activities of the VRs in that 
cluster.   
 

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The VR Technical Supervisors will be trained in:  
• Quality Assurance, including the conduct of repeat and accompanied interviews 
• Verbal Autopsies (VA), using the WHO-recommended VA questionnaire and including the 
seeking of consent.  
• Reporting AEFI, where AEFI identification is included in the activities. 
 
In addition to the technical supervisor, a local supervisor will also be identified for each VR. The 
local supervisor will be a Community Own Resource Person (CORP) such as a village chief, local 
Councillor, headman etc., who will tend to hear about any deaths in the area and help to ensure 
that the VR has documented them.  
 
Each VR will meet approximately monthly with both his or her technical and local supervisors. 
Such a hybrid approach to supervision has been shown to be useful.16 
 
Where a death has been documented, a locally appropriate period of time will elapse before the 
technical supervisor seeks consent from the parent/carer to conduct the verbal autopsy.  
 
The senior technical member of the evaluation team will occasionally join the hybrid supervision 
meetings, and conduct partial repeat and accompanied VR Supervisors interviews. Care will be 
taken to interact sensitively with bereaved families and to keep the frequency of interactions to 
the minimum required to assure the quality of data. 
9.2.6 Identification of deaths 
Following appropriate local sensitisation (see section 9.2.3) the assistance of leaders and CORPS 
will be sought to notify the VR about any death in a child under 5 years of age. A wider age group 
than that for vaccine during the pilot period is included in surveillance. This minimises the risk of 
missing an event due to errors in the dates, and the data for children too young or too old to 
receive RTS,S/AS01 provide important information about background rate of mortality in the same 
cluster.   
When the VR is notified s/he should visit the family as soon as possible to confirm the event and 
complete the ‘Fact of Death’ notification. 
In the event of a death in a child 1 – 59 months of age, the technical supervisor will be notified by 
the VR e.g. by phone/SMS. After a locally acceptable period of time, the technical supervisor will 
visit the bereaved family and complete a VA, to generate the ‘Cause of death’ classification, for 
children confirmed to have died while aged 1-59 months.  
VAs will be carried out  on all deaths in the age range 1-59 months, either using the full VA 
questionnaire,  or alternatively (depending on local capacity) using a minimal set of questions that 
include  age at death, sex, vaccine status, location of normal residence, and whether the death 
was due to illness or accident/ trauma.  
9.2.7 Expected numbers of events 
Sample size planning used a mortality risk of 25.2 per 1000 children (based on rates for children 
aged 6 – 36 months from 2015 World Bank data – see section 9.5), which translates to 10 deaths 
per 1,000 per year in the target age group. A cluster with an annual birth cohort of 4,000 can thus 
expect 40 deaths per year, and hence the field supervisor(s) responsible for a cluster can expect to 

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complete 3 or 4 Verbal Autopsies (VA) per month. The Country evaluation co-ordinator will 
oversee field activities and ensure the flow of data documenting the cause of death across all 
clusters: a study with 60 areas is expected to document approximately 2,400 deaths in the target 
age range per year, equivalent to 200 per month. 
9.2.8 Case definitions 
Refer to section 10.4.  
 
9.3 Variables 
The following variables, at a minimum, will be recorded for each identified death: date of birth, 
date of death, age at death, gender, place of normal residence, longitude and latitude of the place 
of normal residence, place of death if different, whether cause of death was illness, or due to 
accident or trauma , and dates of each dose of each vaccination (BCG, OPV, DTP (or 
DTP/HepB/Hib, as appropriate), measles and RTS,S/AS01), when available. The vaccination history 
will be captured from the child’s health card wherever possible. A photograph of the health card 
may be taken and stored with the child’s CRF to facilitate validation of vaccinations received and 
dates. Where no health card is available the information will be solicited from the caregiver via 
maternal  recall (no dates) and documented as such. When vaccination information is collected 
through maternal recall, the caregiver/mother be asked about each vaccine (per country-specific 
EPI guidelines) and the number of doses, with detailed prompts characterizing the vaccines to 
enhance the quality of the recall (e.g., describing oral polio vaccine as bitter drops; etc.). In a 
subset of cases, parents may be asked additional questions to validate maternal recall. A 
validation study should be conducted in each country to understand the reliability of malaria 
vaccination status from different sources for children who have died, by comparing vaccination 
status from the home-based record, and from caregiver recall, with records at the immunization 
clinic. The distance to the nearest health facility, and distance from the nearest hospital will be 
calculated. Verbal autopsy will be performed for all children aged 1 – 59 months at the time of 
death. Verbal autopsy will follow the recommended WHO protocol using the 2016 WHO verbal 
autopsy instruments17 but including data on vaccination history (record-based and/or recall). 
Cause of death will be assigned using the WHO-recommended approach, currently the analytical 
software InterVA18. Other methods (such as IHME’s tariff method using the SmartVA application)19 
can also be run on WHO VA 2016. Annex 7 presents the list of causes of death according to the VA 
procedure. Consent for the VA will be documented; if consent for the VA is not provided, the basic 
details of the death will be reported but cause of death and other details will not be available. If  
no information is available about the death that enables the VA classification, the cause of death 
will be classified as “CAUSE OF DEATH UNKNOWN”.   
The effect of RTS,S/AS01 introduction on all-cause  mortality excluding accidents (the primary 
outcome) will be estimated by comparing the number of deaths in vaccine-eligible age groups in 
intervention and comparator areas, adjusted for differences in the incidence of mortality in non-
eligible age groups in the same clusters. Effects will be measured using incidence rate ratios and 
rate differences. Denominators (person time at risk), required for estimating rate differences, will 
be estimated using estimates from the most recent national census.  
Secondary outcomes will be analysed in the same way.  
Alternative methods of estimating denominators may also be investigated using one of the 
following models: 

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➢ MODEL A: A list of children aged 1-59 months maintained by VRs for their respective areas, 
or  
➢ MODEL B: A population estimate modelled using all available data either to (i) allocate 
populations within census units to a finer spatial level 20,21 or (ii) use a combination of very 
high resolution satellite imagery and small area focussed micro-census surveys to estimate 
population size and distribution. 
➢ Model C: Any alternative approach able to generate robust estimates of the denominator 
population, as agreed between the in-country evaluation partners and WHO.  
In the first modelling approach, census estimates from the most recent national census will be 
distributed on the basis of typical per-land cover class population densities, which have been 
estimated for African countries for which very fine resolution population data are available, 
following approaches described elsewhere21. The typical population densities are then applied as 
weightings to redistribute census counts according to the land cover and to map human 
population distributions at a finer spatial resolution using asymetric modelling techniques22. This 
modelling method distinguishes urban and rural populations in the redistribution of populations. 
The population distribution datasets will be projected to the relevant year using United Nations 
(UN) national rural and urban growth rates and made to match the total national population 
estimates provided by the UN Population Division. 
In the second modelling approach, 'bottom-up' geospatial population enumeration is undertaken 
in the absence of national population census data. Recently acquired very high resolution satellite 
imagery (50cm or finer spatial resolution) will be processed to map individual buildings and small 
settlements across the pilot implementation area, as well as to provide information on 
neighbourhood housing densities and urban/rural metrics. Small area focussed micro-census 
surveys will be undertaken across the areas of interest to obtain data on how the satellite-derived 
metrics translate into population numbers and age/sex compositions. This will enable construction 
of statistical models to predict population numbers and compositions into unsampled locations 
across the study areas, and to include measures of uncertainty in the predictions. This approach 
has been applied in (i) Northern Nigeria, as part of polio vaccination planning and coverage work23 
and (ii) Afghanistan, in collaboration with the government’s statistics office and UNFPA. High 
predictive accuracies have been demonstrated in both instances.24  
These approaches will allow estimation of the number of children in the target age-range in each 
cluster, together with uncertainty parameters around the estimates, and generate estimates of 
the community mortality impact of RTS,S/AS01 deployment.  
The data from the VAs (Annex 8) will be captured electronically and processed using InterVA 
and/or equivalent software to generate cause of death classifications according to the 
International Classification of Disease (ICD) version 10 or 11.  
9.4 Data sources 
The analysis  will include all deaths in the target age group, recorded by VRs. Cause-specific 
mortality analyses will draw on the results of VAs performed by VR supervisors and processed by 
InterVA or other WHO-recommended VA-coding process.  

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The denominators will be estimated using one of the approaches described in section 9.3 for the 
whole of the pilot implementation area in each country. Time at risk will be based on the 
estimated denominator and may be adjusted for seasonal variation in births. 
The number of children receiving vaccines will be obtained from the MoH`s vaccination registries.  
9.5 Study size 
Planning was based on the assumption that 4,000 children would be born per cluster per year, 
with 30 months of vaccination and a total surveillance period of 46 months, each cluster 
contributing 23,750 person years at risk (pyar) if all children survive. If 1% of children die in their 
first month of life, and 0.08% die every month after the first month, infant mortality would be 18.7 
per 1000, mortality (based on estimates  of rates for the 5 to 36 months age group) would be 22.2 
per 1000, and the average time at risk per cluster would be 23,134 years. 
Table 3 shows how this generic approach compares with the expected mortality between 6 and 36 
months of age, based on infant and child mortality data in 2015 from the World Bank26,27. The 
expected mortality between 6 and 36 months of age was estimated as follows: mortality between 
age 6 to 11 months was assumed to be 50% higher than the mortality during age 1 year, and 
between age 1 and 4 years the mortality decreases with age as follows: 35% in year 1, 27% in year 
2, 20% in year 3 and 18% in year 4. It is assumed that mortality rates in areas with high malaria 
endemicity are 50% higher than the estimates from the World Bank data.  
 
Table 3: Infant and under five mortality estimates 2015 from World Bank Data, and expected mortality 6m 
to 36m in high endemic areas in selected countries. 
Country 
Infant 
Mortality 
(per 1000) 
Under Five 
Mortality 
(per 1000) 
Mortality  
6m to 36m 
In high malaria 
endemic areas 
(per 1000) 
Ghana 
43 
62 
25.2 
Kenya 
36 
49 
17.2 
Malawi 
43 
64 
27.8 
The mortality rate can be estimated from mortality risk as -loge(1-risk)/time, where risk is the 
probability of dying during the time of follow-up, assuming an exponential distribution. A mortality 
risk of 25 per 1,000 equates to a rate, over 2.5 years, of 10.12712 per 1,000 pyar. A mortality risk 
of 21 per 1,000 equates to a rate, over 2.5 years, of 8.489455 per 1,000 pyar. 
Based on a minimum mortality rate of 8.5 per 1000 pyar, 23 areas each in the evaluation and 
comparator areas, each with an annual birth cohort of approximately 4,000 subjects, would have 
80% power to detect, at the 5% significance level, a decrease of at least 10% in overall mortality in 
each country. This compares with the modelled estimate of an 18% (range 6-29%) reduction in 
malaria-specific mortality in children under 5 years, assuming 72% coverage of a 4 dose regimen 
delivered at 6, 7.5, 9 and 27 months of age7. The sample size was obtained after applying the 
formula from Hayes and Bennett25 with an intra-class correlation of (k) 0.1. The design effect is 

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3.01. The total number of areas per country is expected to range from 46-60 and will be presented 
as part of country-specific sample size calculations in country-specific protocols.  
Figure 4 presents a sensitivity analysis showing how the coefficient of variation influences the 
required number of clusters.  
Figure 4: Sensitivity analysis illustrating effect of changing mortality rate and inter-cluster 
coefficient of variation on number of areas required to detect a 10% reduction in mortality  
 
 
Table 4 shows the reduction in mortality that can be detected at a 5% significance level if the 
number of areas and the population remain constant but the parameters of baseline mortality and 
intra-class correlation (k) change. 

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Table 4: Sensitivity analysis of the sample size. Decrease in mortality that can be detected at the 5% 
significance level with a power of 80% by baseline mortality and coefficient of variation of the mortality 
between areas assuming 30 areas with an annual birth cohort of 4,000  
Mortality risk per 1000 
in 
non-implementing 
clusters 
Coefficient of 
variation (K) 
Detectable 
decrease in 
mortality 
25 
0.10 
10.0% 
25 
0.15 
12.6% 
25 
0.20 
15.5% 
25 
0.30 
21.3% 
20 
0.10 
10.6% 
15 
0.10 
11.5% 
10 
0.10 
13.2% 
5 
0.10 
17.3% 
 
Based on simulations, a trial with these characteristics is estimated to have approximately 80% 
power to detect an interaction between gender and treatment of 1.15 (i.e an increased risk of 
mortality in girls of 1.035). This compares favourably with the 1.9-fold increase in risk among girls 
receiving RTS,S/AS01 in the phase 3 trial Mal-055. 
The assumptions in the sample size calculations will be checked against empirical data once the 
programme is underway, in accordance with an analytical plan to be developed in the early phase 
of the programme. 
9.6 Data management 
Deaths will be identified by the network of VR as described above. VRs will capture information 
using a paper CRF. Annex 9 shows a sample of the VR CRF.  
Technical VR supervisors will capture data using a tablet computer or similar mobile computing 
device and synchronise with the national MVPE data system. The VAs will also be captured 
electronically using mobile devices (e-CRF). Annex 8 shows a sample of the VA form. Annex 10 
presents the CRF to compile the data needed for the evaluation of impact. Details of the system, 
including the steps to ensure adequate anonymisation and security of data, will be agreed with 
the research partners and detailed in country-specific protocols. Information from the different 
countries will be harmonized and compiled monthly. Information from the MoH`s vaccination 
registries will also be obtained, harmonized and compiled at least once every month. Annex 11 
shows a sample of the vaccination registry recording data at the individual level. 
9.7 Data analysis 
Detailed statistical analysis plans will be developed during the course of the programme and 
reviewed by the Programme Advisory Group and, if necessary, external statistical experts, before 

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analyses are performed. The overall approach will be to compare mortality rates in 
implementation and non-implementation areas ,in terms of the incidence rate ratio and rate 
difference in vaccine-eligible age groups.  Secondary analyses will explore limiting analysis of 
mortality rates to children reported to have received DTP3  to exclude children who are not 
brought for routine vaccinations and therefore would be unlikely to come for RTS,S .  
Comparisons will be made for all-cause mortality and for deaths where VAs enable the 
exclusion of deaths due to accidents.   Pooled analyses of impact data from across the MVIP 
countries will be conducted in addition to analyses within each country. The limited extent of 
baseline mortality data is not expected to be sufficiently robust to inform these analyses.  
9.8 Quality control 
An independent Clinical Research Organization (CRO) will be contracted by WHO to assure the 
quality and integrity of the data collected. The CRO will review a set proportion of source 
documents, including informed consent forms. In addition, quality assurance procedures will be 
implemented by the evaluation partners to ensure that the data are generated appropriately and 
captured accurately in the databases. Checks will include partial repeat interviews and 
accompanied interviews. Partial repeat interviews, done by supervisors (both of VRs and of VR 
supervisors) on a randomly selected proportion of consenting interviewees, will seek to verify that 
the original interview took place, and to double-check the responses to key questions in those 
interviews. Accompanied interviews involve supervisors witnessing standard interviews to ensure 
the approach of the interviewer is appropriate and that responses to questions are elicited in a 
sensitive, acceptable and comparable way across the programme. Performance data will be 
reviewed monthly within each country and quarterly across the programme. Those areas 
identified as outliers, either because of increased or decreased reporting rates, will be prioritised 
for followed-up. Where a vaccine record or maternal recall do not provide information on the 
vaccine status, the potential to seek information from the clinic registers for deaths, in vaccine-
eligible age groups in RTSS clusters will be considered where feasible. Monitoring of data quality 
and completeness is described in the SAP. 
9.9 Limitation of the research methods 
The absence of routine vital event registration systems complicates the evaluation of impact on 
survival. Especially in the most remote areas, it is possible that children who die will not be 
notified to either the authorities or the village-based reporting system.  
The following steps will be taken to assure the quality and completeness of data captured by the 
VRs: 
(i) 
Repeat and accompanied interviews by VR supervisors. Repeat interviews involve re-
visiting households to confirm the intended visit took place and check the response to 
key questions, especially those which would trigger further actions or which are vital 
for the evaluation. Accompanied interviews are intended to ensure appropriate 
conduct from social, ethical and technical perspectives.  
(ii) 
Performance data review. The frequency of key variables (e.g. number of households 
visited, number of deaths reported, etc.) will be reviewed monthly, VRs with outlying 
values identified and in-depth discussions held to identify the need for any corrective 
actions. If feasible, VRs will report weekly or monthly, regardless of whether  deaths 

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occurred in the reporting period (zero-reporting), as an indicator of active engagement 
by all reporting units.  
(iii) 
Data triangulation. There may be potential to compare data from VRs with data from 
other settings, including cross-referencing hospital-based deaths from the surveillance 
hospitals. For example, people attending routine vaccination clinics could be asked 
about the location, timing and approximate age of any deaths in their residential area, 
or data from any separate vital events registration system could be interrogated. Any 
deaths identified should feature in the VR reports and any data apparently missing 
from the evaluation database should prompt follow-up.  
The strength of these approaches is not so much the direct detection of missed deaths, but the 
incentivisation of VRs, who will be made aware of the QA procedures, to make serious efforts to 
identify all deaths in their assigned areas. Estimates of mortality rates will be compared with 
estimates from DHS surveys and from DSS data. 
The analysis approach used for estimating rate ratios  does not involve population denominators. 
However, for rate differences, estimates of  population at risk are required. The same absence of 
vital registration systems that affect the detection of deaths affect the definition of the children at 
risk. The values obtained from census data and from the models will be compared in selected 
areas with the estimated population at risk obtained from the number of households covered by 
the VR.   
It is possible that children living in comparison areas will be brought for vaccination in areas 
allocated to RTS,S. Such “contamination” of comparison areas could potentially lead to an under-
estimate the impact of the vaccine on all-cause mortality detected at the community level. The 
level of contamination will be reduced by selecting areas which are as geographically large as 
possible, making it more difficult for people to seek vaccinations outside their own cluster. It is 
inevitable that some degree of contamination will occur. Sensitivity analyses will be conducted to 
explore the potential effect on the estimates of impact, for example by comparing effect estimates 
using all the data with estimates obtained after excluding from analysis events occurring within  
given distance from cluster boundaries.  
 
 
 

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10 Research Methods for Safety Evaluation 
10.1 Study design and timing 
The safety of RTS,S/AS01 will be monitored through a strengthened routine pharmacovigilance 
system operating across the whole of the MVIP area, and by a specific surveillance system 
established in sentinel hospitals covering part of the MVPE area.  
Across all three countries, a series of up to 24 sentinel hospitals will be identified across the MVPE, 
serving  and/or  comparison areas . The catchment area of each hospital is expected to have an 
annual birth cohort of, and provide services for, approximately 4,000 children in each cluster in its 
catchment areas. Hence a total of at least 48,000 children in implementation areas and at least 
another 48,000 children in comparison areas will contribute to the hospital-based evaluation of 
safety across the programme. The data from these hospitals will complement that generated by 
the hospitals involved in GSK’s Phase 4 study (up to 6 in areas implementing and 6 in areas not 
implementing RTS,S/AS01, serving an area with a total annual birth cohort of approximately 
24,000 children). 
The safety evaluation will be based on outcomes recorded in age groups of children eligible to 
receive RTS,S/AS01. There will be 12 months of surveillance after the children vaccinated during 
the first year of vaccine introduction have received dose 4, assuming that the first dose of 
RTS,S/AS01 is given by around 5 months of age, the third dose is delivered by age 9 months and 
the fourth dose is given by age 27 months. A 12 month surveillance period after dose 4 brings 
children to 39 months of age (figure 2, section 7.6.5). However, admitted children aged 1 to 59 will 
be included in the evaluation,  for practical simplicity, to enable documentation of critical events 
in children who are vaccinated near the beginning of the programme, and because events in 
children too young or old to receive RTS,S/AS01 provide useful information about underlying rates 
in the same cluster.  
10.2 Setting 
10.2.1 Selection of Sentinel Hospitals 
Sentinel hospitals in the pilot study will be selected according to the following criteria: 
• Either: 
o Catchment area comprising areas which will all implement RTS,S/AS01 or will all act 
as comparator areas for the pilot study, OR 
o Sentinel hospitals serving catchment areas some of which implement RTS,S/AS01 
and others which act as comparator areas for the pilot study, OR  
o Availability of a Vaccine Registry which can be linked to inpatient data. 
• A catchment area which includes approximately 4,000 infants from the MVPE area.  
• A functional system of case note recording for patients on the paediatric ward. 
• A track record of regular reporting of routine data (inpatient and vaccination clinic data) to 
the district health team. 

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• Demonstrable experience of LPs on children with signs of neurological illness. 
Hospitals without prior experience of enhanced meningitis and cerebral malaria surveillance will 
be supported to improve these capacities such that they are fully operational before RTS,S/AS01 
vaccinations begin. 
10.2.2 Characteristics of Sentinel Hospitals  
Sentinel hospitals will include different types of admitting facilities (table 5), offering a range of 
levels of investigation and care to different numbers of children. The number of each type of 
hospital will be balanced in implementing and comparison areas such that a similar number of 
children are admitted in each area to each type of facility. In addition to the signs and 
investigations included in the table, some hospitals may have the capacity to detect additional 
signs of value in the diagnosis of severe malaria (ophthalmoscopy on children with suspected 
cerebral malaria); significant bleeding (recurrent or prolonged bleeding from the nose, gums or 
venepuncture sites; haematemesis or melaena); capillary refill; systolic blood pressure; pulse 
oximetry; acidosis (base deficit, plasma bicarbonate, venous plasma lactate); creatinine or blood 
urea; bilirubin; chest X-ray).  
Hospitalisation will be defined as spending at least one night at a sentinel health facility or 
admitted and dying within the first 24 hours of admission.  
 
 

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Table 5: Characteristics of sentinel hospital 
Hospital Level 
Level 1 
Level 2 
Level 3 
Patient notes system available 
X 
X 
X 
LPs performed 
X 
X 
X 
Electricity supply 
X 
X 
X 
-20oC storage facility  
X 
X 
X 
Recording of Clinical History 
Fever 
X 
X 
X 
Multiple convulsions 
X 
X 
X 
Altered consciousness 
X 
X 
X 
 
 
 
 
Recording of Clinical Signs 
Respiratory rate  
X 
X 
X 
Chest indrawing 
X 
X 
X 
Deep breathing 
X 
X 
X 
 
 
 
 
Neck stiffness 
X 
X 
X 
Bulging fontanelle in children under 
one year of age 
X 
X 
X 
Prostration 
X 
X 
X 
BCS / GCS 
X 
X 
X 
Ophthalmoscopy 
 
 
X 
Recording of Investigations 
Temperature (axillary/rectal) 
X 
X 
X 
Malaria RDT 
X 
X 
X 
Malaria microscopy for parasite count 
& species 
 
X 
X 
Blood glucose (dip-stick or lab-based) 
X 
X 
X 
Hb / Hct 
X 
X 
X 
LP and visual macroscopic 
examination 
X 
X 
X 
CSF protein 
 
X 
X 
CSF glucose 
 
X 
X 
Antigen detection tests 
 
X 
X 
Microscopy for cells & organisms 
 
X 
X 
Culture – blood 
 
 
X 
Culture – CSF 
 
 
X 
Molecular and/or serological tests 
 
 
(X) 

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10.2.3 Enhanced Hospitalisation Surveillance  
Hospital-based surveillance will systematically document all admissions to the paediatric ward in 
order to capture information on the safety profile of RTS,S/AS01. This will be characterised by 
measuring the extent to which programmatic delivery of RTS,S/AS01 is associated with changes in 
the hospital-based incidence rates of meningitis, cerebral malaria, febrile convulsions, other 
illnesses, all-cause and malaria-specific mortality. Data will be collected from sentinel hospitals 
both in implementation and comparison areas.  
Some pilot implementation countries may have a limited number of hospitals (1-3) with 
considerable experience in meningitis surveillance, or diagnosing meningitis or cerebral malaria in 
a research setting.  These “highly capable” hospitals will be balanced between implementation 
and comparison areas by the restricted randomisation procedure (section 7.6.2). Such hospitals 
will require minimal support to begin capturing data on meningitis or cerebral malaria cases, and 
will be able to evaluate and document patient findings using a wider range of diagnostics than 
would be available in most hospitals (e.g. blood and CSF cultures). If introduction of RTS,S/AS01 is 
staggered for operational reasons, RTS,S/AS01 will first be introduced into the areas with highly 
capable sentinel hospitals to enable any clinically significant safety signals to be assessed early and 
with a greater range of diagnostic tools than will be available in other sentinel hospitals.   
Training, including in routine pharmacovigilance (see section 13), inpatient management 
algorithms to assess case definitions in a standardised way, and shipping of CSF to reference 
laboratories will be established in all sentinel hospitals prior to the start of the pilots. 
Relevant demographic, vaccination and clinical data will be captured in a CRF on all children under 
5 years of age admitted to the paediatric wards of sentinel hospitals in the RTS,S/AS01 
implementation and comparison areas. As far as possible, the routine Health Management 
Information System will be supported to capture standard information and additional modules 
added, as necessary, to capture the specific data required for the RTS,S/AS01 evaluation. 
Consolidated, quality assured, inpatient surveillance systems will be supported by Evaluation 
Partners in each country. Although hospitals are likely to vary in the level of expertise available, 
and their experience in surveillance for meningitis and cerebral malaria, minimum standards will 
be assured to enable the systematic, standardised clinical and laboratory assessment and 
management of all admissions.  
10.2.4 Detection of Adverse Events Following Immunization (AEFIs)  
Although routine pharmacovigilance is not conducted as part of the research protocol, the routine 
pharmacovigilance system will be strengthened through a standardised set of activities to support 
staff at all health facilities located within the MVIP areas (section 7.6). This pharmacovigilance 
strengthening will be the responsibility of the health care system, as will routine reporting  on AEFI 
and AESI (see also section 13.2) with support from WHO. The strengthened pharmacovigilance 
system is designed to capture any spontaneously reported vaccine-related adverse events, 
including febrile convulsions and rare and unexpected AEFI, which might be experienced by some 
children following RTS,S/AS01 vaccination.  
Adverse Events of Special Interest (AESI) may be captured through country-specific protocols, as 
agreed with national authorities, as a complement to the detailed information generated by GSK’s 
Phase 4 study.  

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10.3 Study procedures 
Data from all children admitted to hospital should be captured in a routine health Management 
Information System (HMIS). This will typically include minimal demographic and clinical 
information such as name, age, gender, area of residence, diagnosis, treatment and outcome 
(dead, alive, referred). Some hospitals may have an electronic system but the majority are 
expected to be paper-based. The content and functioning of the HMIS will be reviewed before 
study start and arrangements made to augment data collection, as necessary, for children in the 
target age range (i.e. from 1 month - 4 years inclusive). Informed consent will be sought for 
capture of any data not routinely collected and according to local requirements.   
Demographic information, RTS,S/AS01 and other vaccination status, key clinical signs - including 
criteria for lumbar puncture - details of samples collected and the result of malaria and CSF testing 
will be captured in a CRF, as appropriate. An algorithm for investigations will be developed that is 
consistent with national guidelines, with agreed criteria in each country for sample collection. 
Relevant clinical staff will be provided with refresher training on the relevant national routine care 
guidelines to facilitate patient management according to the national guidelines. The MoH in each 
country will retain responsibility for assuring the availability of the treatments it recommends in 
its national guidelines. At the same time, the staff will also be trained in the pilot programme’s 
investigation algorithm (which is aligned with the WHO and national guidelines of the three pilot 
countries) to ensure that children are assessed in a standard way, with blood and CSF samples 
collected as necessary to enable assessment of study endpoints against standardised case 
definitions. The MVIP will work with the MoH and evaluation partners to assure, as far as possible, 
the availability of the supplies needed for essential investigations and treatment.  
Children will be managed according to national guidelines and the final clinical diagnosis and 
outcome will be recorded at the end of admission. All relevant clinical and laboratory data will be 
compiled in an electronic CRF to enable case ascertainment for the analysis of the evaluation’s 
endpoints.   
The enhanced hospital-based surveillance will be in place prior to the introduction of RTS,S/AS01, 
generating data for Programme Advisory Group review to confirm the integrity of the surveillance 
and allowing an assessment of the comparability of facilities in implementing and comparison 
areas in terms of completeness and quality of the data. Data from the enhanced HMIS will be 
monitored until the end of the evaluation, approximately 50 months after the start of vaccination 
(see section 9.2.1), using automated data routines to evaluate completeness and internal 
consistency of records. 
 Children with any sequelae following a diagnosis of meningitis or cerebral malaria will be invited 
to re-attend hospital for follow-up appointments after hospital discharge. These will be scheduled 
at intervals considered appropriate by the attending clinician.  
If, at any time, the attending clinician suspects the admission is related to RTS,S/AS01 the 
procedures to report an AEFI should be followed (see section 13) and the Evaluation Partner’s 
Clinical Surveillance Coordinator notified by phone or SMS text message. The fact that an event 
was reported as an AEFI will be captured in the CRF. 

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10.3.1 Data capture in sentinel hospitals 
Children will be admitted to hospital according to local procedures. At the time of admission the 
standard HMIS data will be documented according to standard practice. All children aged 1 to 59 
months will have a brief purpose-made questionnaire completed by the attending clinical staff in 
order to capture the demographic, vaccination and clinical information necessary to trigger 
specific investigations and eventually enable a final diagnosis to be made. Completeness of the 
hospital surveillance will be checked during the daily ward rounds, at which time every admission 
in the target age group should have had a hospital surveillance screening form completed, and at 
period visits by the clinical surveillance co-ordinator of the in-country evaluation partners. 
Completeness of data capture in the enhanced HMIS will be assessed through triangulation with 
hospital admission registers. Hospital staff will be encouraged to contact the clinical surveillance 
co-ordinator by phone in case of any concern or uncertainty regarding the assessment of patients 
contributing to the evaluation. 
10.3.2 Informed consent for the collection of surveillance data  
Where considered necessary by local IRBs, written, or witnessed and thumb-printed, informed 
consent will be obtained from each child’s carer before data are included in the evaluation 
dataset. The intention is to capture data that should in any case be documented as part of clinical 
care. Consent will be sought for any data capture, diagnostic procedure or test required by the 
study which would not otherwise be needed to satisfy the relevant national paediatric inpatient 
protocol. Country-specific protocols will address this point in detail and provide country-specific 
information. The seeking of consent and capture of any study-specific data should not impede the 
assessment or management of the child. Data may be captured retrospectively once the Informed 
Consent Form (ICF) is signed/ thumbprinted. No study-specific procedures, including any follow-up 
visits specially-scheduled for the purposes of the evaluation, will be performed before the ICF is 
signed/ thumbprinted.  
10.3.3 Data to be captured  
The following data will be collected into a CRF (paper or electronic, annex 12) from all children 
aged 1-59 months admitted to hospital: 
• From the standard, routine HMIS: age, date of admission, gender, normal place of 
residence (village or urban address), current place of residence if this is different, 
diagnosis, treatment and outcome of admission. Records will include identifiers of the 
sentinel hospital and the patient’s hospital number.  
Children from the programme area will have the following additional information collected:  
• Date of birth (if not included in the routine HMIS), active participation in any clinical trial. 
• Use of malaria control measures (ITN, IRS, anti-malaria drugs), other health care seeking 
for the current illness or drug use in the previous 14 days. This will include whether 
evidence of prescription was available or if drug use was reported, and capture 
information on antibiotic and anti-malarial use (which may affect detection of bacteria 
and/or P falciparum), and medication for chronic conditions (e.g. HIV). 

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• Vaccination history – types and dates of vaccinations received through the routine EPI. This 
will be captured from the child’s health card wherever possible. A photograph of the health 
card may be taken and stored with the child’s CRF to facilitate validation of vaccinations 
and dates. This will include dates of vaccination with OPV, BCG, DTP (or DTP/HepB/Hib, as 
appropriate), measles and RTS,S/AS01. Where no health card is available the information 
will be solicited from the caregiver through verbal recall (no dates) and documented as 
such. When vaccination information is collected through maternal recall, the 
caregiver/mother will be asked about each vaccine (per country-specific EPI guidelines) and 
the number of doses, with detailed prompts characterizing the vaccines to enhance the 
quality of the recall (e.g., describing oral polio vaccine as bitter drops; etc.). In a subset of 
cases, parents may be asked additional questions to validate maternal recall . Where a 
vaccine record or maternal recall do not provide information on the vaccine status, the 
potential to seek information from the clinic registers for meningitis and cerebral malaria 
cases in vaccine-eligible age groups in RTSS clusters will be considered where feasible. 
• Any known pre-existing medical conditions e.g. HIV infection, congenital disease (including 
haemoglobinopathies). 
• History of fever, difficulty breathing, convulsions, altered consciousness. 
• Findings from physical examination including body temperature, respiratory rate, presence 
of chest indrawing, deep breathing, the components of the Blantyre Coma Score, neck 
stiffness, bulging fontanelle. 
• Whether a blood sample was collected and, if so, the tests requested, results available 
during the admission and sample identification number for tests requested off the 
paediatric ward. All children will be expected to have a malaria test (RDT and microscopy) 
and a haemoglobin/PCV.  
In addition, children under 2 years of age with a BCS <3, or assessed as P or U on AVPU3 score, or 
aged 2 years and over and with a Glasgow Coma Score <11, will have the following data captured:  
• Blood glucose result 
• Whether a CSF sample was collected and, if so, the sample identification number and 
results available during admission. 
At the time of discharge a final main and any secondary diagnoses will be recorded by the 
attending clinician, taking into account the clinical assessments, available test results, evolution of 
the illness and response to treatment, and the final outcome (alive, dead, referred, absconded).  
All data will be recorded in a record form (CRF) and entered into the programme’s database. 
                                                     
3 AVPU: Alert, responding to Voice, responding to Pain, Unresponsive 

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10.3.4 Sample collection   
Details of suspected meningitis or cerebral malaria cases – including medication history, findings 
on clinical examination and results of diagnostic testing - will be recorded in the CRF. Part of the 
CSF sample, collected according to routine practice, will be stored for further testing at the 
reference laboratory. Standard Operating Procedures will be implemented to govern sample 
storage and the transfer of samples to the central laboratory.   
Local analyses of blood & CSF samples will be undertaken on site to the extent possible (table 5) 
and samples stored for additional processing in a reference laboratory. In some cases, anti-CS or 
anti-Hep B antibodies may be measured as supportive evidence of prior RTS,S/AS01 vaccination. 
Details of which examinations will be performed in which hospitals will be confirmed only once 
the hospitals have been selected but are expected to fall into the categories in table 5. At a 
minimum, CSF examination will include visual inspection before freezing and shipment to 
reference laboratories. Some hospitals may, in addition, perform microscopy, glucose and protein 
measurement, and run antigen detection tests, and a few will also culture CSF samples.  
10.3.5 Record review 
The clinical surveillance co-ordinator in each country will review clinical data as it accumulates to 
ensure its accuracy, completeness – including availability of sample information and local 
laboratory results - and internal consistency. Data monitoring at hospital, evaluation partner, 
country and programme levels will be supported by automated data review routines to enable 
targeted case review and follow-up action. 
10.4 Case definitions 
10.4.1 Meningitis 
Meningitis was identified as a potential risk during the RTS,S/AS01 phase 3 study and particular 
efforts will be made to identify meningitis cases, defined in line with WHO’s meningitis 
surveillance guidelines28. For all cases with a diagnosis of meningitis, and a sample of non-
meningitis diagnoses, an independent expert review, blinded to vaccine status, may be conducted 
on the patient’s record (this is dependent on the ability to conduct a record review beyond the 
CRF) before a final diagnosis is provided. This is required to manage, in a standardised way across 
the MVPE, the potential confusion between meningitis and other severe illnesses, such as cerebral 
malaria. 
Table 6 summarises the meningitis case definitions. “Suspected meningitis” is a diagnosis based 
on clinical symptoms and/or signs defined as: 
A child with one or more of the following present (with or without fever , neck stiffness, two or 
more seizures in the last 24 hours, bulging fontanelle, convulsions (partial, complex febrile or other 
atypical presentations), seizures if less than 6 months or greater than 6 years , altered 
consciousness, (Blantyre Coma Score less than 3 or, Glasgow Coma Score less than 11 or P or U on 
the AVPU scale [Alert Verbal Painful Unresponsiveness Scale]) or any other clinical symptoms 
indicative of meningitis or cerebral malaria by clinical judgement. Lumbar puncture will be 
encouraged in all such children, according to national diagnostic and treatment guidelines, for 
examination of cerebrospinal fluid (CSF).  

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Children will be considered to have “probable meningitis” if:  
In a suspected case, the macroscopic aspect of the CSF is turbid, cloudy or purulent; or the CSF 
leukocyte count is >10 cells/mm3. 
A child will be classified as a “confirmed meningitis” case if: 
A suspected or probable case is laboratory confirmed by culturing or identifying (i.e. by polymerase 
chain reaction) bacterial, viral or other aetiology in the CSF.  

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Table 6: Meningitis case definitions for the MVPE 
Clinical signs & laboratory results 
In-country 
meningitis 
category 
Results from 
Reference lab 
Final meningitis 
category for 
analysis 
[No neck stiffness AND 
(No altered consciousness OR 
alternative explanation for altered 
consciousness) AND  
No other meningeal sign*]  
Not a 
meningitis 
case 
Not needed for 
definition 
Not a meningitis 
case 
If one or more of the following 
is present (with or without fever): neck 
stiffness, two or more seizures in the 
last 24 hours or another meningeal sign 
including bulging fontanelle, or any 
seizures if less than 6 months, altered 
consciousness, (Blantyre Coma Score 
less than 3 or, 
Glasgow Coma Score less than 11 or P 
or U on the AVPU scale [ 
Alert Verbal Painful Unresponsiveness 
Scale]) or any other clinical symptoms 
indicative of meningitis or cerebral 
malaria by clinical judgement 
Suspected 
meningitis 
Not needed for 
definition 
Suspected 
meningitis 
Any suspected case with 
macroscopically turbid, cloudy or 
purulent CSF; or with a CSF leukocyte 
count >10 cells/mm3.  
 
Probable 
meningitis 
No aetiological 
agent found or 
no sample 
available 
Probable 
meningitis 
Any suspected or probable case that is 
laboratory confirmed by culturing or 
identifying (i.e. by polymerase chain 
reaction) of bacterial, viral or other 
aetiology in the CSF . 
Bacterial or 
viral 
meningitis 
 No aetiological 
agent found or 
no sample 
available 
Probable 
meningitis 
  
Aetiological 
agent identified 
Aetiology 
confirmed 
meningitis 
 
10.4.2 Malaria  
WHO’s case definitions for malaria will be used. For all cases of severe malaria, including cerebral 
malaria, an independent expert review, blinded to vaccine status, may be conducted on the 
patient’s record before a final diagnosis is provided (this is dependent on the ability to conduct a 
record review beyond the CRF).  This is required to manage, in a standardised way across the 
MVPE, the difficulties of making some diagnoses, particularly cerebral malaria, which are difficult 
to standardize a priori. 
Uncomplicated malaria 

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• Plasmodium parasitaemia > 0 detected by malaria RDT (or  microscopy in the absence 
of an RDT result) 
AND  
• Presence of fever (temperature ≥ 37.5°C), as recorded at the time of presentation  
OR 
• Occurring in a child with recent (24 hour) history of fever 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 malaria 
• Plasmodium parasitaemia (> 0 detected/ µL) detected by RDT (or microscopy in the 
absence of an RDT result)  
AND 
• One or more of the following;  
▪ Impaired consciousness: a Glasgow coma score < 11 in children  2 years of age, 
a Blantyre coma score < 3 in children < 2 years of age, or child responding only 
to pain or unresponsive; 
▪ Multiple or atypical convulsions: more than two episodes within 24 h; 
▪ or prolonged at >15 minutes, or focal; 
▪ Respiratory distress (manifesting as chest indrawing or deep breathing); 
▪ Severe malarial anaemia: haemoglobin concentration ≤ 5 g/dL or a haematocrit 
of ≤ 15% ; 
Cerebral malaria: 
• Plasmodium parasitaemia with impaired consciousness (Glasgow coma score < 11 in 
children  2 years of age or Blantyre coma score < 3 in children < 2 years of age or 
assessed as P or U on AVPU score);  
AND 
• Clinician diagnosis of cerebral malaria 
AND 
• CSF findings not consistent with  

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• probable meningitis (LP must be done - if LP not done, cerebral malaria diagnosis is 
cannot be made) 
10.4.3 Anaemia 
All anaemia:  
• haemoglobin <11g/dL. 
Severe anaemia:  
• haemoglobin <5g/dL (or a PCV<15%). 
Malaria-associated anaemia 
• haemoglobin ≤ 11g/dL (or a PCV ≤ 33%) in children < 12 years of age with a positive RDT 
(or bloodfilm) 
Severe malaria-associated anaemia 
• haemoglobin ≤ 5 g/dL (or a PCV ≤ 15%) in children < 12 years of age with a positive RDT 
(or blood film) 
10.4.4 Admissions 
All cause admission 
• An individual requiring overnight stay in hospital/inpatient facility or individuals who 
are admitted and die before an overnight stay has been completed. 
Malaria admission  
• Admissions of an individual with confirmed malaria (including P. falciparum malaria). 
Non-malaria hospital admission  
• Admission of an individual with any condition except malaria. Primary diagnosis is not 
malaria, and malaria test, if performed, is negative. 
10.4.5 Death 
Deaths – all cause 
• A fatality (of any cause).  
Malaria associated mortality  
• A fatality in an individual who has malaria (positive RDT or blood film if RDT not done) 
Malaria attributed mortality 

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• A fatality for which malaria (including P. falciparum malaria) is listed as a contributing 
cause of death, based on the medical judgment/medical records for children who died 
at a sentinel hospital. 
10.4.6 Febrile convulsions 
Adapted from Brighton case definition for generalised seizures: generalised seizures that occur in 
a febrile children (6–60 months old) who does not have intracranial infection, metabolic 
disturbance or history of afebrile seizures30. 
10.4.7 Adverse Event Following Immunisation (AEFI) 
Any untoward medical occurrence which follows immunization and which does not necessarily 
have a causal relationship with the usage of the vaccine. The adverse event may be any 
unfavourable or unintended sign, abnormal laboratory finding, symptom or disease31. 
 
10.4.8 Adverse Event of Special Interest (AESI) 
Adverse events of special interest (AESI) are protocol-defined diseases corresponding to AEs that 
are potentially associated with RTS,S/AS01E, 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. A list 
of AESI has been developed for evaluation in the Phase 4 study. The potential and value of 
including AESI in country-specific versions of this protocol will be determined on the basis of 
consultation with each country’s immunization program and regulatory authority. AESI such as 
anaphylaxis, acute flaccid paralysis or purpura could be subjected to active surveillance in all 
health care facilities from the pilot areas.  
10.4.9 Serious Adverse Event 
An AEFI will be considered serious if it: 
• Results in death. 
• Is life-threatening. 
NB: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
individual 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. 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation. 
In general, hospitalisation signifies that the individual 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 outpatient 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. 

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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. 
• Results in disability/incapacity, 
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 individual 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. 
10.5 Biological sample handling and analysis 
10.5.1 Biological samples 
All children admitted to sentinel hospitals are expected to have routine laboratory tests 
performed according to National or local guidelines, including, but not limited, to the following: 
For all hospitalised children:  
• Haemoglobin concentration, packed cell volume (PCV) or full blood count. 
For suspected malaria cases:  
• P falciparum infection using RDT or microscopy (RDT is preferred) . 
For suspected meningitis cases:  
• CSF examination according to routine practice (visual inspection; glucose, protein; 
microscopy, with culture & sensitivity if feasible) 
• Blood glucose  
• In addition, suspected meningitis cases will have a sample and at least 500 µL of CSF, when 
a CSF sample is taken as part of routine practice. These samples will be used for 
microbiological and molecular analyses at reference laboratories, if the guardian provides 
informed consent. 
Country-specific protocols will describe existing local guidelines and any proposed changes for the 
purpose of the current evaluation.  

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Full details for obtaining, storing and shipment of biological samples will be provided in a study 
procedures manual (SPM) of Standard Operating Procedures, and adherence to them monitored. 
In brief, immediately after collection and processing, to the extent possible, in the sentinel 
hospital, the samples will be placed at -20oC until transfer to the evaluation partner’s facilities and 
then on to the central reference laboratory.  
Samples will not be labelled with information that directly identifies the child but with an identifier 
which will also be recorded in the child’s hospital notes and the CRF. Collected samples will be 
used primarily to guide patient management and for protocol mandated analyses to enable 
classification for data analysis. In addition, 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, the child’s Legally Acceptable 
Representative (LAR) will be invited to give another specific consent to allow WHO or a contracted 
partner to use the samples for future research. 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. 
Any sample testing beyond that to inform the clinical management of the admitted child will be 
done in line with the consent of the individuals’ parent(s)/LAR(s). 
Collected samples will be stored for a maximum of 5 years (counting from the end date of the 
MVPE), unless local rules, regulations or guidelines require different timeframes or different 
procedures. Any such extra requirements will be communicated formally to and discussed and 
agreed with WHO. 
The country-specific protocols will specify the governance mechanisms for storage and use of 
samples.  
10.5.2 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 
polymerase chain reaction (PCR) for infectious diseases, or confirmatory tests for autoimmune 
diseases. The specific lab analysis on CSF samples is given in sections 10.9.1.1. and 10.9.1.2. 
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. 
WHO will assure the supply of the consumables and reagents needed to perform first line routine 
testing for the cerebral malaria and meningitis according to national guidelines. In case second-
line confirmatory testing is required (for instance PCR for meningitis), samples will be sent to a 
qualified referral second-line laboratory in the African region. 

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10.6 Capacity building 
The pilot implementation study will draw on the materials, training and experience of the GSK-
sponsored Phase 4 study, as well as previous experience in relevant undertakings, to strengthen 
the identification, investigation and management of the events of interest.  
The Phase 4 study and WHO-led evaluation will involve different hospitals but there may be 
overlap in the research institutions involved in both. Investigators in the Phase 4 study will be 
encouraged to serve as a resource for colleagues within and beyond their institutions who are 
involved with the MVPE. Potential areas of support include: 
Training:  
Appropriate training packages and materials (e.g. medical Job Aid) developed for clinicians 
in the phase 4 study may be useful for the MVPE to facilitate diagnosis using decision-
making algorithms.  
Phase 4 investigators will be supported by online medical education training packages and 
a telemedicine system and, as such, may be well-placed to offer advice to personnel 
involved in the MVPE.  
The pharmacovigilance strengthening plan may benefit from the training provided to 
health care and study staff participating in the phase 4 study. 
Laboratory:  
The laboratory-related systems developed by investigators for use in the Phase 4 study – 
such as sample-tracking and transfer - may also serve the needs of the MVPE. The pilot 
programme will benefit from the approaches to Quality Assessment, Quality Control and 
training for laboratory technicians resulting from the interactions with the reference 
laboratories contracted for the phase 4 and MVPE studies. 
Alert system for time-sensitive events: 
The MVIP will work to strengthen the routine pharmacovigilance system (see the 
Pharmacovigilance Strengthening Plan) and to use, to the extent possible, the routine 
system based on spontaneous reporting. The use of the national AEFI Review Committee to 
review and adjudicate endpoints will strengthen the national PV-related systems. 
The national Coordinating Group will work with colleagues within the MoH to assure the supply of 
key commodities, such as malaria RDTs, LP kits and laboratory reagents, to enable the conduct of 
diagnostic procedures according to National guidelines.  
The strengthening of capacities related to routine pharmacovigilance are described in section 13. 
10.7 Variables 
At sentinel hospitals the Case ID, Hospital ID, Date of admission, age at admission, gender, 
residence location, vaccination dates and doses, signs and symptoms at recruitment, samples of 
interest collected during admission and the code to identify the sample, and the final diagnosis 
(ICD 10 – or later - code) will be captured. Results from the external laboratory and the review of 

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the expert panel will allow the final classification of each hospital admission with the following key 
variables: 
• Admission Date 
• Age at admission 
• Date of birth 
• Date of death (when applicable) 
• Gender 
• Residence location (to permit calculation of distances e.g.  to hospital) 
• Cluster ID 
• RTS,S/AS01 vaccination status (number and dates of doses received); health card or recall 
(no dates for recall) 
• Other vaccination status (type of vaccine, number and dates of doses received); health 
card or recall (no dates for recall) 
• Results of malaria microscopy and RDT at admission  
• Severe Malaria 
• Cerebral Malaria 
• Anaemia 
• Meningitis suspected 
• Meningitis probable 
• Meningitis etiologically confirmed at hospital level 
• Meningitis etiological confirmed at reference laboratory level 
• Etiology agent confirmed at hospital level 
• Etiology agent confirmed at reference laboratory level 
• (Other outcomes). 
A Geographic Information System will be used to map the residence locations of inpatients in the 
sentinel hospitals and the population at risk in the catchment area will be obtained disaggregating 
the population count data to a finer spatial detail (see below). 
 

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10.8 Data sources 
Information for this analysis will be obtained from the sentinel hospitals and the local and central 
laboratories. Information from the population at risk, based on the population of the hospital 
catchment area, will be obtained from the model described in 9.4. 
10.9 Case ascertainment 
An algorithm will be developed to categorise the meningitis and cerebral malaria status of all age-
eligible admissions to sentinel hospitals, according to the case definitions presented in section 
10.4 . The in-country evaluation partners will run the algorithm on the data for which they are 
responsible and assess the consistency of the algorithm-based diagnosis with the clinical diagnosis 
made in the light of the clinical history, signs on examination, results of investigations and 
response to treatment. If the case is classified as an AEFI, these data and classifications will be 
submitted to the National AEFI Review Committee (ARC) for review and validation. No assessment 
of causality will be made at the individual level for meningitis or cerebral malaria. Rather, 
conclusions about the likelihood that RTS,S/AS01 is responsible for a change in meningitis or 
cerebral malaria rates will be based on the analysis of data on exposure to the vaccine in the 
implementation and comparison areas.  
The ARC will verify and classifiy all AEFI reported through the routine system before presentation 
to the cross-country Data Safety Monitoring Board (DSMB). During the DSMB meetings, the data 
will be presented from the three countries on the AEFI findings and on the MVPE safety analysis.   
The DSMB will be provided the ARC assessments of the initially unclassified cases and have access 
to experts in meningitis and severe malaria diagnosis to inform their final decision on the 
classification, for analytical purposes, of individual cases. The experts may be provided with all 
available medical information on individual cases but will initially be agnostic to vaccine exposure. 
Both the ARCs and DSMB will operate according to agreed terms of reference and adhere strictly 
to the protocol-defined case definitions. Each will make causality assessments for adverse events 
reported through routine pharmacovigilance; those of the DSMB will be considered definitive for 
the purposes of the analysis across the three countries of the MVIP.  
10.9.1 Meningitis cases 
Clinically-suspected meningitis cases will have a lumbar puncture performed according to the 
national treatment guidelines and the CSF examined with a view to identification of an aetiological 
agent. Where feasible, blood culture will also be performed to facilitate the classification of 
meningitis-like diseases (table 6).  
10.9.1.1 CSF testing at the sentinel hospitals 
The appearance of CSF will be documented (purulent, cloudy, gin clear, bloody) at the time of 
collection. In level 1 hospitals (table 5), samples will then be stored at -20oC for transfer to the 
reference laboratory.  
Level 2 hospitals will in addition perform microscopy and gram staining of CSF, documenting 
differential white blood cell counts, and measure protein and glucose in the CSF and blood 
glucose. Latex agglutination tests on CSF will identify Neisseria meningitidis, Streptococcus 

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pneumoniae and Haemophilus influenza type b. Cryptococcal infection will be diagnosed using 
Indian ink, for HIV-positive children and those with unknown HIV-status, if feasible. 
Level 3 hospitals will in addition perform blood and CSF culture for Neisseria meningitidis, 
Streptococcus pneumoniae and Haemophilus influenza type b.   
If necessary, WHO will assure the supply of reagents and consumables to ensure that diagnostic 
procedures can be conducted as intended. 
10.9.1.2 CSF testing at the reference laboratory 
All CSF samples from children aged 1 – 59months in sentinel hospitals will be transferred to a 
reference laboratory, regardless of the outcome of testing in the sentinel hospital. The same, 
WHO-appointed, Africa-based reference laboratory, either in The Gambia (WHO Collaborating 
Centre for New Vaccines Surveillance, Medical Research Council Unit, Fajara) or South Africa 
(Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, 
division of the National Health Laboratory Service, Johannesburg), will be used for all hospitals in 
the MVPE to maximize the comparability of the information generated. The reference laboratory 
will do molecular tests for bacterial, viral, protozoal and fungal causes of meningitis, provide 
Quality Assessment and Quality Control.  
The MVPE will draw on the Job Aids and trainings developed for medical staff by the GSK-
sponsored Phase 4 study in order to strengthen capacity and enhance comparability of the 
meningitis-related classifications generated by the two evaluations.   
The clinicians in charge of the children’s care will be responsible for initiating treatment according 
to standard practice and national guidelines. The treatment of individual patients should be based 
on the results of investigations available in the hospital to which the child is admitted and should 
not be delayed pending the results of investigations at the reference laboratory. 
10.9.1.3 Surveillance function 
The number of meningitis cases identified in sentinel hospitals will be monitored at regular 
intervals (at least quarterly) throughout the pilot programme. If the number of cases, either in 
vaccinated or unvaccinated children, is significantly above that seen in previous intervals, the 
relevant in-country authorities (to be specified in the country-specific protocols) will be informed 
and the need for additional investigation, for example using a case control study, agreed. The final 
decision for further investigation will take into account any additional surveillance data available 
in the countries. 
10.9.2 Severe malaria cases, including cerebral malaria 
Children admitted to sentinel hospitals with a measured fever or history of fever will be tested for 
malaria by RDT and/or (with RDT as a priority). Those with positive malaria tests will be managed 
according to national guidelines. 
Any child hospitalised with an acute febrile illness and confirmed to have P falciparum infection 
will be considered a hospitalized malaria case. 
Cerebral malaria will be defined as children with a positive malaria test result and impaired 
consciousness (Glasgow coma score <11 in children  2 years of age or a Blantyre coma score <3 in 

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children <2 years of age). If there is a history of seizure, the coma needs to persist for more than 
30 minutes after the seizure. Other causes of coma (e.g. hypoglycaemia, bacterial meningitis) 
should be excluded.  
10.10 Study size 
Assuming a meningitis rate of 0.040% cases per year, a study with 12 areas each in the evaluation 
and comparator areas, and an annual birth cohort of 4,000 children in each of the evaluation and 
comparator areas, would have 80% power, across the three countries, to detect a 2.6-fold 
increase in risk. This sample size was obtained using the formula from Hayes and Bennet25 with an 
intra-class correlation (K) of 0.4. This value of K means that the observed rate of meningitis may 
range from approximately 1/12,500 to 1/1,390 with a mean rate on of 1 /2500. In the Phase 3 trial 
there was 1 case from 2974 subjects (0.035%) in the control area and a relative risk of 8 to 10, 
depending on the follow-up.  
The same sample size would provide 80% power to detect a 1.7-fold increase in the risk of 
cerebral malaria, assuming a baseline rate of 0.20% and an intra-class correlation (K) of 0.3. 
Cerebral malaria is expected to be more common than meningitis. In the Phase 3 trial, there were 
6 cases from 2974 subjects (0.06%) in the control arm and a relative risk of about 2.  
For the evaluation described in this protocol, approximately 360,000 children per year will be 
eligible for vaccination with RTS,S/AS01 in the three countries, with a subset of 48,000 per year 
within the population catchment areas of the sentinel hospitals (Sentinel Hospital level). Table 7 
shows the empirical power to detect at least a given number of events according to the true risk 
and the population size and assuming 90% vaccine coverage. At the sentinel hospital level there 
would be more than 80% power to detect 1 or more occurrences of a rare event if the true risk is 1 
per 10,000 subjects. There is more than 80% power to detect one or more occurrences of rare 
events in the whole MVIP if the risk is 1/100,000. The power to detect rare events of 1/1,000,000 
is low even across the MVIP. The empirical power was estimated using Monte Carlo simulations of 
100,000 trials with the given sample size and true probability level. 
 
Table 7: Empirical power to detect rare events 
Risk 
Observed events 
≥1 
≥2 
≥3 
≥4 
≥5 
Sentinel Hospitals (Approximately 108,833 children vaccinated) 
1/10,000 
100% 
100% 
100% 
99% 
98% 
1/100,000 
66% 
29% 
10% 
2% 
1% 
1/1.000,000 
10% 
1% 
0% 
0% 
0% 
ALL MVPE areas (Approximately 816,000 children vaccinated) 
1/10,000 
100% 
100% 
100% 
100% 
100% 
1/100,000 
100% 
100% 
99% 
96% 
91% 
1/1,000,000 
56% 
20% 
5% 
1% 
0% 
 

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10.11 Data management 
Information from sentinel hospitals will be captured using electronic devices. Details of the system 
will be agreed with the research partners.  A common database will be set up and information 
from the different countries harmonized and compiled monthly. Further information on the flow 
of safety data is given in section 13.2. 
10.12 Data analysis  
(see SAP) 
Children will not be assigned individual identifiers at the time of vaccination and there will be no 
systematic linkage between records of children admitted to participating hospitals and records of 
children vaccinated with RTS,S/AS01 or any other vaccine. The effect of RTS,S/AS01 will therefore 
be assessed by comparing incidence in vaccine-eligible age groups, in populations where SMC was 
introduced and populations in comparator areas. Effects will be measured in terms of the 
incidence rate ratio (the relative increase or decrease in incidence of the outcome due to 
introduction of RTS,S vaccine, in the age group of children eligible to receive the vaccine) and the 
incidence rate difference (the number of cases averted (or added) as a result of RTSS vaccine being 
introduced into an area, in the age groups of children eligible for the vaccine, expressed per 1000 
child years or other suitable units).  
As a secondary analysis, rate ratios will also be estimated in children known to have received 
DTP3. 
For mortality and severe malaria, effects will be estimated separately in each country, and 
averaged over the three countries. For meningitis and for cerebral malaria, the main analysis will 
be pooled across the three countries. Final analysis will be done after month 46 has been reached 
in all three countries. However, during the study incidence rates of the main outcomes will be 
monitored, and an analysis of the main safety outcomes and mortality, will be done when 
sufficient events have accrued for the analysis to have adequate power. Based on predicted rates 
of mortality and meningitis this is anticipated to be at about 24 months after start of vaccination.  
As for other routinely administered vaccines, routine systems will record doses of RTS,S/AS01 on 
child-held health cards. Information on doses of RTS,S/AS01 received, and their timing, will be 
recorded for all admissions, along with the source of information (child health card, verbal report 
or other). When vaccination information is collected through verbal recall, the caregiver/mother 
will be asked about each vaccine (per country-specific EPI guidelines) and the number of doses, 
with detailed prompts characterizing the vaccines to enhance the quality of the recall (e.g., 
describing oral polio vaccine as bitter drops; etc.).   
Hospital staff in the sentinel hospitals will also participate in the enhanced pharmacovigilance 
supported by the pilot implementation activities and report any suspected AEFI. 
10.13 Quality control 
Compliance with the treatment algorithm (number of cases presenting, completeness of clinical 
data, number requiring lumbar puncture, number with CSF result, number with samples received 
by reference laboratory) will be monitored monthly for each hospital and for each of the 
evaluation and comparator areas throughout the preparation and evaluation period. 
 

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Completeness of the hospital surveillance will be checked during the daily ward rounds, at which 
time every admission in the target age group should have had a hospital surveillance form 
completed, and at periodic visits by the clinical surveillance co-ordinator of the in-country 
evaluation partners. 
 
10.14 Limitation of the research methods 
Sentinel hospitals are likely to be a better-performing minority of the available hospitals and other 
health facilities, but they tend to serve a higher proportion of urban-dwelling, and possibly 
therefore less-poor, patients than are typical of the entire study population. Children presenting 
to hospitals are likely therefore to under-represent those with poor access to hospitals who may 
also be at greater risk of adverse outcomes. The hospital surveillance may therefore tend to 
under-estimate rates of severe disease. Rates also depend on distance from hospital and other 
factor affecting access to the hospitals, and the availability of alternative health facilities in the 
neighbourhood where patients can go. Estimates of rates and rate differences are therefore 
inevitably context-specific.  
 
Even well-functioning routine health information systems face challenges with the completeness 
of routine data. Automated data monitoring routines will be developed to provide feedback to the 
evaluation team, at all levels, and to front-line health staff, so that deficiencies can be identified 
and remedial action taken as necessary.  
 
The identification of vaccination status in admitted children will be a critical step. However, in the 
majority of sentinel hospitals it is likely that vaccination data will be available only on the child’s 
health and vaccination card. These will have been modified in implementation areas to document 
doses of RTS,S/AS01 (section 7.6.1). Carers will be encouraged to carry the card to all contacts 
with the health services, per routine practice. Where the card is not available at the time of 
admission, carer’s and their families will be encouraged to make the card available before the 
child’s discharge. In the absence of the health card, immunization information will be collected via 
verbal recall.  
 
Enumeration of the catchment population and the number of children who have been vaccinated 
is challenging given the scale of the MVIP, the absence of functional routine community-based 
data systems and availability of digitised catchment areas. The total populations will be estimated 
as described in section 9.3. 
 
Contamination is a risk to any cluster-randomised approach. Provided the normal residence 
location of hospital patients can be mapped, sensitivity analysis can be used to this to understand 
the potential effects of contamination, by comparing results after excluding events located near 
the cluster boundaries.  
 
10.15 Other aspects 
The MVIP will encourage and support adherence to national treatment (and investigation) 
guidelines. It is accepted that these may vary across the countries. Nevertheless, in addition to 
country-specific analyses, the potential to pool data for analysis across the countries will be 
evaluated.  
 

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At country level, safety data will be accrued from the systematic reporting from the sentinel 
hospitals and spontaneous reports from the Adverse Events Following Immunisation (AEFI) system 
from both the MVIP and the GSK-led Phase 4 study. These data will initially be reviewed by the 
country MVIP co-ordination group whose composition will include representation from the 
National AEFI Review Committee (ARC), EPI, NMCP, NRA and the local research groups running the 
evaluation, with support from the country’s WHO and PATH MVIP staff.  Safety data from across 
the three pilot countries as well as data from the GSK-led Phase 4 study will be reviewed by the 
Data and Safety Monitoring Board (DSMB). The DSMB will monitor the data quality indicators on a 
quarterly basis, with statistical analyses presented as described in the SAP. 
 
Safety concerns identified at country level will be reviewed by the DSMB and if confirmed will be 
escalated to the Programme Advisory Group (PAG). Country data reported to and reviewed by the 
DSMB will be available to the respective NRAs. The information will also be communicated to GSK 
so that identified safety signals can be evaluated in the context of all available safety information. 
GSK and WHO will communicate to the other party the result of their evaluations. The DSMB and 
PAG will agree a course of action to recommend to WHO’s Programme Leadership Team and this 
will be communicated to the national co-ordinating groups, including the NRAs, and others as 
appropriate. 
 
 

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11 Research Methods for Feasibility Evaluation 
11.1 Study design 
The feasibility of delivering RTS,S/AS01 according to the recommended schedule will be evaluated 
through a combination of approaches. Malaria vaccine coverage will serve as the primary 
quantitative outcome measure for both programmatic feasibility and the community’s acceptance 
of the vaccine and is described in this protocol. 
  
Secondly, a programmatic assessment tool, such as WHO’s Post Introduction Evaluation (PIE) tool, 
will examine the RTS,S/AS01 vaccination programme’s operations with a view to improving the 
delivery of RTS,S/AS01. The PIE (or equivalent, WHO-recommended) tool will be adapted for the 
malaria vaccine pilot implementation and used 6 to 12 months after introduction of the vaccine in 
each country. This will evaluate performance in relation to pre-introduction planning, vaccine 
storage and wastage, logistics of administering the vaccine, and community receptiveness 
(amongst others).  
 
Thirdly, a longitudinal, qualitative assessment, to be described in a separate protocol, will include 
exploration of any behaviour change, providing a contextual narrative and informing an 
understanding of the reasons that the quantitative estimates are what they are. The qualitative 
assessments will be implemented in all countries to provide insights as to whether and why 
behaviours, such as treatment seeking for febrile children, use of malaria prevention measures, 
EPI vaccination, etc., change with the introduction of RTS,S/AS01. The qualitative evaluation will 
complement the quantitative data gathered during representative household cluster surveys and 
will be described in a separate protocol.  
 
Finally, these feasibility studies will be complemented by work, under a separate study protocol, 
to cost the set up and maintenance of vaccine delivery. 
 
The primary assessment of feasibility will be based on repeated household surveys. Estimates of 
the coverage and timeliness of the first 3 doses and of the fourth dose of RTS,S/AS01 will be 
documented through two household surveys at the mid-line and end-line of the programme, 
respectively. These surveys, and a pre-implementation baseline household survey, will also 
generate estimates of the coverage of routine EPI vaccines, the coverage and utilization of 
recommended malaria control measures (e.g. ITN/LLIN, IRS), routine vitamin A and anti-helminth 
treatment, and document patterns of health-seeking behaviour for febrile children. Nutritional 
status through MUAC may also be measured.  This will allow assessment of secondary objectives 
relating to the effect of RTS,S/AS01 introduction on the coverage of important preventive health 
interventions and care-seeking behaviour. The surveys may enable examination of the effect of 
strategies to optimise coverage of the fourth dose, and whether RTS,S/AS01 introduction 
influences drop-out rates for routine vaccinations (and therefore the number of fully vaccinated 
children). Data on the effect of strategies to boost coverage of the 4th dose will also be generated 
by the routine administrative systems (section 11.1.1).   
 
11.1.1 Approaches to estimating the coverage of RTS,S/AS01 
 
The coverage of RTS,S/AS01 will be estimated using three, complementary approaches:  
 

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(i) 
Routine, facility-based administrative coverage data, reported monthly.  
 
(ii) 
A specially established or strengthened vaccination registry, potentially employing e-
health and other forward-looking approaches, tailored to country needs, and with a 
focus on sustainability beyond the pilots. Any such innovations in vaccine registries will 
be balanced between implementation and comparison areas. 
 
(iii) 
EPI cluster-sample household surveys, conducted thrice during the programme in order 
to provide representative community estimates of RTS,S/AS01 coverage (in the second 
and third surveys), along with coverage estimates for other EPI vaccines, for 
recommended malaria prevention and control measures, and for other childhood 
public health interventions of interest. Standard questions from the currently-
recommended Malaria Indicator Surveys (MIS), Multiple Indicator Cluster Surveys 
(MICS) or Demographic and Health Surveys (DHS) will be used. 
 
In this protocol we only briefly describe the routine administrative approach to estimating 
coverage, and the PIE surveys; these will be described in more detail in the country-specific 
RTS,S/AS01 Implementation Guidelines, to be developed by the MoH with support from WHO and 
partners. Separate protocols will be developed for work on vaccination registries and for the 
qualitative, behaviour change studies. This protocol focuses on the EPI cluster surveys.   
 
The three approaches to estimate coverage each have pros and cons. Routine facility data should 
be reported from all vaccinating health facilities, but reporting may be incomplete. As this is a 
standard component of EPI monitoring, and therefore entirely managed by the MoH, it may be 
beyond the control of the evaluation partners engaged in the MVPE. Estimating the denominator 
may also be problematic: each facility estimates the coverage of each dose by dividing the number 
of doses delivered by an estimate of the proportion of the facility’s catchment population eligible 
for that dose. Errors, especially in the estimation of the denominator, may lead to erroneous 
coverage estimates for individual facilities. For example, if children from outside the facility’s 
official catchment area tend to receive their vaccinations at the health facility the coverage 
estimate may exceed 100%. At district level, movement of children between facilities and 
estimation of an individual facility’s catchment population are less likely to result in biased 
coverage estimates as the number of children vaccinated with each dose of each antigen are 
compiled and the estimated population is that of the whole district.  
 
Many countries have a facility-based vaccination register. Each child from the catchment 
population who is eligible for vaccination has a row in the register, capturing key demographic 
data and recording the dates of at least some of the vaccinations administered. These manual 
registers should enable coverage estimation of routine vaccinations and facilitate follow-up of 
children late for expected doses, but are cumbersome to use and frequently unreliable. Electronic 
vaccination registers have the potential to enhance the utility of this approach but are 
complicated and costly to establish. 
 
 
 
 
Approach to estimating 
Pros 
Cons 

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coverage 
Routine ‘administrative’ data - Should be available from 
every vaccination clinic 
- Regular reporting (monthly) 
- Incomplete reporting 
- Technical problem of 
denominator estimation 
- Beyond the control of 
Evaluation partner 
Electronic vaccination 
register 
- Information captured on all 
children in a catchment area 
- Data easily retrieved and 
summarised 
- Complicated and costly to 
establish 
- Likely to be available only in 
limited areas 
Representative household 
surveys 
- Accepted methodology to 
generate standard, 
internationally-accepted 
indicators 
- Generates snapshot 
estimates of coverage at 
some point in the past 
- Captures data for only a 
sample of the population 
- Costly 
 
Several well-established nationally-representative household surveys use standardised 
approaches to generate estimates of key health-related parameters, including vaccination 
coverage. These have the benefit of generating standardised indicators (e.g. the proportion of 
children aged 12-23 months who have been vaccinated against measles by the age of 12 months) 
which can be compared from one setting to another or in the same setting over time. The surveys 
are costly to conduct and provide only a snapshot of coverage at some time in the past. In the 
context of the MVPE, they will be less useful than administrative coverage estimates to determine 
the need for timely campaigns or other efforts to raise coverage e.g. of the fourth dose, though 
can provide a means to evaluate the effects of such efforts.  
 
The pilot implementation will use a combination of approaches to document coverage and to 
identify, in a timely way, the need to intensify efforts to maximise coverage.  
 
11.2 Setting 
11.2.1 Timing of household surveys 
A baseline household survey will be conducted in each country before or soon after the start of 
vaccinations, to provide data on the prevalence of malaria infection and coverage of EPI vaccines, 
in both intervention and comparator areas , before RTS,S/AS01 introduction.  Follow-up surveys 
conducted approximately 18 and 30 months after the start of RTS,S/AS01 vaccination in 
intervention and comparator areas, will estimate the coverage of the standard EPI vaccines and, in 
intervention areas, the coverage of the primary series of RTS,S/AS01 (in the 18-month survey) and 
of the primary series and the fourth dose of RTS,S/AS01 (in the 30-month survey).  
 
Guidance on the conduct of household surveys is available as follows: 
 
DHS:  http://dhsprogram.com/What-We-Do/Survey-Types/DHS.cfm  
MIS:  www.malariasurveys.org/toolkit.cfm  
MICS:  http://mics.unicef.org/  
 

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Each is used to generate nationally or sub-nationally representative estimates of key indicators 
and powered to generate estimates with precision at the first subnational administrative level 
(e.g. regions).  
  
The choice of survey tool will be guided by any plans to conduct any of these surveys in the 
participating countries at the same time as the pilot implementation’s household surveys. Where 
possible, the programme will work with the national survey designers to oversample the areas in 
which the MVPE is operating in order to optimise efficiency, avoid repeated interviews of some 
households and to contribute to an improved understanding of the national indicators. Where key 
data (e.g. on vaccinations or use of non-vaccine preventive interventions) are not included in a 
scheduled survey (see table 8) the relevant module(s) from the DHS survey will be incorporated. 
 
It will be necessary to find out how well caregivers are able to recall whether their child has 
received the malaria vaccine and the number of doses. Surveys will rely on caregiver recall to 
establish vaccination history for children who do not have a card or home-based record. Sub-
studies should be planned, nested within the midline survey or separately before the survey, to 
compare vaccination histories from recall, home-based record and the vaccination register in the 
clinic. 
 
11.2.2 Survey population  
Surveys will be carried out in a sample of households from implementation and comparison areas. 
Four groups of ~25 households (survey “clusters” or primary sampling units, PSUs) will be selected 
from each implementation and comparison cluster, such that each household in a PSU has an 
equal probability of being included in the sample. New samples of households will be drawn for 
each of the surveys. The same sampling methods as used in standardised national surveys (DHS, 
MIS, MICS) will be used to enhance comparability of the findings and interpretation of the external 
validity of the evaluation of the RTS,S/AS01 pilot implementation.  
 
The surveys will include a representative sample of households.  A typical approach would be a 
two-stage cluster design as described below, but this may be varied or adapted, provided a 
probability sampling approach is used.  
 
In the first stage, enumeration areas (EAs) are selected with probability of selection proportional 
to the estimated population size of the EA. Shortly before the survey, a mapping team will visit the 
EA and identify all households in the EA. A household will be defined as a group of people who  eat 
meals together and/or who acknowledge the same individual as head of their household. This list 
of households will serve as the sampling frame for that EA.  Mapping teams may record whether 
any children <5 years of age live in each household, and the sampling frame could then draw only 
from those houses with the target population. In the second stage of the cluster design, a fixed 
number of households are systematically or randomly selected from the sampling frame ensuring 
that each household has an equal probability of selection. The selection of households will occur 
before the survey team visits the EA to ensure an unbiased sample. On the day of the survey, 
interviewers visit each of the selected households and questions the primary caretakers of all 
children under 5 years of age. All eligible children in a household should be included. If any 
primary caretakers of eligible children or the eligible children themselves are not present at the 
first visit, a revisit will be planned.  To minimize the introduction of bias, no substitute household 
will be included if the owner is repeatedly absent or does not wish to participate to ensure the 

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representativeness of the selected sample. The supervisor will visit all households where people 
are reportedly absent, as a quality control measure. Prior to the day of the survey, included 
villages may be visited and an invitation letter left in each of the selected households. Both village 
and sub-village leaders will be briefed about the surveys.  
 
All consenting primary caretakers/mothers of children aged 5-48 months will be interviewed and 
data collected on contextual factors (for example,  exclusive breast feeding, use of insecticide-
treated nets, socio-economic status, access to health facilities) as well as receipt of EPI vaccines 
and vitamin A. An interview will be conducted for each eligible child, thus some mothers may be 
asked interviewed more than once. The second household survey may be restricted to children 
aged 12-23 months, the target group for the assessment of coverage of RTS,S/AS01 doses 1-3, 
depending on the duration of implementation of dose 4 and any other local considerations.  
 
11.3 Variables 
The quantitative variables included in the analysis of feasibility will be taken from standard 
household survey questionnaires, summarised in table 8 and presented in annex 13. Data on 
vaccinations are not routinely collected in the MIS, and data on non-vaccine preventive 
interventions are only collected in the DHS. For these sections the DHS questions have been added 
to the MIS and MICS, as needed.  
 
Table 8: Summary of relevant questions in standardised surveys 
 
DHS4 
 MIS5 
MICS 20176 
Household Module 
Demographic data 
Region & District 
Cluster number & Interview Date 
Household number 
Household members (to identify children in target age range and their 
carers) & educational status 
Wealth quintile (socio-
economic) score 
Q142 (floor type), 
Q143 (roof type), Q144 
(wall type), 117, 119, 
123 (household assets) 
Q131 (floor), 132 
(roof), 133 (walls), 
108,110, 112-116 
(household assets) 
 
Questions HC4 (floor), 
HC5 (roof), HC6 
(walls), HC7 to 19 
(household assets) 
Malaria control  
Q125 & 126 (IRS) 
Q127-138 (ITNs) 
 
Q117-118 (IRS),  119 to 
-130 (ITN) 
 
IR1 IR2 (IRS) 
TN1 to TN16 (ITNs) 
Maternal Module 
Mother’s/carer’s age & 
education 
Q105, 107-111 
Q102, 104-106, 108 
Q111-112 (malaria 
messages) 
WB1-7 
Birth history questions 
(HHS2 & 3 only) 
Q201-223   
Q201-227 
BH1-BH11 
IPTp 
Q423-425 
Q301-306 
MN16MN18 
                                                     
4 See http://dhsprogram.com/publications/publication-dhsq7-dhs-questionnaires-and-manuals.cfm,  
5 See http://www.malariasurveys.org/toolkitfiles/02%20MIS%20Package_Household_Questionnaire.pdf,  
6 See www.malariasurveys.org/toolkit.cfm,  

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Child Health Module 
Vaccination dates 
Q501-524A 
From DHS 
questionnaire 
IM1-IM28 
Non-vaccine 
preventive 
interventions 
Q605-607 
From DHS questionnaire 
Health-seeking 
behaviour (HSB) 
Q608, 610 to 
614(diarrhoea) 
Q618 & Q619 (fever) 
Q526 (blood test for 
fever) 
Q620-621 (cough) 
: 624 625, 627, 628 
HSB for fever &/or 
cough  
Q404-405 (fever & 
blood test), 406 to 410 
(HSB) 
CA1, CA5, CA6 
(diarrhoea) CA14, 
CA15, (fever) CA 16, 
17 (cough), 20, 21 
(HSB)  
 
Treatment 
Q 629 to 645 
Q411-428 
CA22, 23, 25 -  29B 
(malaria treatment) 
 
 
A photograph of the health card may be taken and stored with the child’s CRF to facilitate 
validation of vaccinations received and dates. Where no health card is available the information 
will be solicited from the caregiver (no dates) and documented as such. When vaccination 
information is collected through maternal recall, the caregiver/mother will be asked about each 
vaccine (per country-specific EPI guidelines) and the number of doses, with detailed prompts 
characterizing the vaccines to enhance the quality of the recall (e.g., describing oral polio vaccine 
as bitter drops; etc.).  A sample of children with the health card available may be selected for the 
assessment of the verbal recall by the caregiver to enable the comparison between the written 
record and the recall and, therefore, allow for the validation of the verbal recall in this specific 
population. This information will be useful for estimating uncertainty of the vaccination coverage 
when the written records are supplemented by verbal recall. Additional information on the limited 
birth history (per DHS methodology) may be collected to estimate childhood mortality in the 
survey cluster, to serve as a source of validation for the impact objective.  
 
Additionally, finger prick blood samples and measurements of the middle upper arm 
circumference (MUAC) will be collected in the first household survey to enable detection of P. 
falciparum infection using Rapid Diagnostic and assess the baseline nutritional status. Where the 
results of the malaria RDT are positive, antimalarial treatment will be offered in accordance with 
the national guidelines and national IRB requirements. Where the results of the MUAC indication 
undernutrition, referral to the nearest health facility will be offered in accordance with the 
national guidelines and national IRB requirements. 
 
11.4 Data sources 
The information will come from the Household Surveys. 
 

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11.5 Study size 
A sample size of 100 houses per cluster will estimate the cluster-specific coverage of RTS,S/AS01 
to within 10%  (i.e. 95% CI from 40 to 60%) using a conservative estimate of 50% coverage and a 
high response rate above 95% in each cluster.  Assuming a design effect of 1.5 between clusters, 
the overall precision in RTS,S/AS01 and coverage estimates of other vaccines over the pilot 
programme’s implementation and comparison areas will be 2% (i.e. 95%CI  48% to 52%) in each 
country. The second household survey may be powered to generate coverage estimates in the 
evaluation vs. comparator areas, rather than in each cluster, to within ±2% of the true value.   
11.6 Data management 
Data will be captured electronically according to the standard approach in each country. Details of 
the system will be agreed with the research partners and presented in country-specific protocols. 
Information from the different countries will be harmonized and compiled into a single database.  
 
11.7 Data analysis 
The prevalence and corresponding 95% confidence intervals will be estimated for the different 
indicators, taking into account the clustered nature of the survey data. Descriptive statistics will 
describe the timeliness of vaccinations and breakdown key indicators (e.g., vaccine coverage) by 
gender. Comparison of the indicators between implementation and comparison areas will be 
based on the confidence intervals. 
11.8 Quality control 
Standard approaches to quality control will be implemented as is usually done by the DHS, MIS 
and/or MICS programmes in each country. Repeat and accompanied household interviews (as 
described in section 9.8), including in relation to the selection of households in the community, 
and in conjunction with internal consistency and logic checks of survey question responses, will 
assure the quality of household survey data. The CRO will review a 5% sample of informed consent 
forms. 
11.9 Limitation of the research methods 
Accepted approaches to selection of a representative sample of households will be used. 
Nevertheless, given the necessarily low household sampling fraction, it is possible that inaccurate 
estimates of the various parameters may be generated within individual clusters. This risk is 
ameliorated by the number of areas included in the pilot programme which should ensure overall 
robust parameter estimates in the evaluation and comparator areas.  
 
11.10 Other aspects 
None 
 
12 Protection of human subjects 
12.1 Regulatory and ethical considerations, including the informed consent process 
The evaluation will be conducted in accordance with all applicable study participant privacy 
requirements and the guiding principles of the Declaration of Helsinki. 
 

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WHO will obtain favourable opinion/approval to conduct the evaluation prior to a site initiating 
study-related activities in any country, according to local requirements, or will document that 
neither a favourable opinion nor an approval to conduct the study is needed. 
 
Implementation of the vaccine will be done by the Ministry of Health. Consent for administration 
of the vaccine will be implied by carers bringing their children to vaccination clinics and accepting 
the malaria vaccine. Individual written informed consent will not be sought for the administration 
of RTS,S/AS01 as (a) this is not standard practice when a new licensed vaccine is introduced; (b) 
the scale of the programme would make quality assurance of formal informed consent difficult to 
assure; and (c) the process of seeking consent would detract from the real-life nature of the 
programme and likely undermine the evaluation of feasibility and, as a result, impact. Signed 
consent will be sought from a parent or legal guardian of children who participate in household 
surveys, for verbal autopsies, and for the use of hospital data for research. 
 
This master protocol will be submitted to the EMA, WHO and relevant national and institutional 
review boards to seek approval of the overall design of the evaluation. The WHO review board is 
guided by the CIOMS guidelines. The national review boards adheres to the protocol and all 
applicable local regulations. 
 
Detailed country-specific protocols will be developed, including details of when and how informed 
consent will be sought, and submitted for review to the same ethics committees which review this 
master protocol. Informed consent forms will be modelled on standard forms for the conduct of 
verbal autopsies (Annex 14), the capture of non-routine data in hospitals and associated sample 
storage and processing (Annex 15), and for the household surveys (Annex 16).  
 
Following the joint ethical review, WHO will prepare model ICFs for the various consent-requiring 
activities. These will embody the applicable ICH GCP or other applicable guidelines. While it is 
strongly recommended that this model ICF be followed as closely as possible, the informed 
consent requirements in the model consent are not intended to prevent inclusion of any local 
requirements. Clinical judgement, local regulations and requirements will guide the final structure 
and content of the local version of the ICF. 
 
The in-country lead investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated and used by the 
investigators must be acceptable to WHO and approved (along with the protocol, and any other 
necessary documentation) by the relevant IRB/IECs. 
 
Standard approaches will be taken to ensure the confidentiality and security of the data collected 
as part of this evaluation.  
 
Where formal informed consent is required, freely given, written or witnessed/ thumbprinted 
informed consent will be obtained from each study participant’s parent(s)/LAR(s) or an impartial 
witness, as locally appropriate, prior to participation in the relevant evaluation component.  
 
During household surveys, written/thumb-printed and witnessed informed consent will be sought 
from the heads of households, with verbal consent sought from the carers of children in the target 
age range for the evaluation.  

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The development of village-based mortality surveillance will only proceed with the approval of the 
locally-relevant community and associated administrative organisations.  Before a verbal autopsy 
is attempted, written/thumb-printed and witnessed informed consent will be sought from 
parents/carers of children who have died in the eligible age range.  
 
Assessments of safety in sentinel hospitals will be based on recommended medical practise. As 
such, written informed consent will not be requested for the collection of blood or CSF samples for 
routine investigation. However written/thumb-printed and witnessed informed consent will be 
sought from parents/carers of children before their samples are subject to additional laboratory 
investigation or longer term storage.  
 
13 Management and reporting of adverse events/adverse reactions 
Serious adverse events related to the routine administration of the RTS,S vaccine will be detected 
through the health system’s national pharmacovigilance system, strengthened with support from 
the MVIP, and through the sentinel surveillance hospitals. Community-based mortality 
surveillance will capture fatal events and flag any which are considered possibly related to 
administration of RTS,S/AS01, or any other vaccine or medical intervention.  
 
Standard medical case management will be provided for patients presenting with suspected 
serious adverse events at health facilities. In addition, at sentinel hospitals, a clinical algorithm will 
guide the systematic investigation and data capture for admitted children and support their 
management according to national guidelines.  
 
Any child diagnosed with non-fatal meningitis or cerebral malaria will be invited to follow-up visits 
as described in section 10.3 to characterize the event further. 
 
The local Principal Investigator will be responsible during the study for the detection and 
documentation of SAEs associated with study procedures. As the evaluation is observational, SAE 
reporting associated with administration of vaccines is not the responsibility of the PI, but will be 
reported through the health system’s national pharmacovigilance system. No thresholds will be 
pre-specified for halting the programme on the grounds of safety concerns but data will be 
reviewed regularly at the local (monthly), national (quarterly) and international (6 monthly) level. 
Concerns at – or between - any of these reviews will be escalated and the Programme Advisory 
Group convened if the Data Safety and Monitoring Board recommends termination of the pilot 
programme. 
 
13.1 Safety definitions  
See also section 10.4. 
13.1.1 Definition of an adverse event 
An adverse event following immunization (AEFI) is any untoward medical occurrence which 
follows immunization and which does not necessarily have a causal relationship with the vaccine. 
The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, 
symptom or disease. If not rapidly and effectively dealt with, AEFIs can undermine confidence in a 
vaccine and have dramatic consequences for immunization coverage and disease incidence. 

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Adverse events will be routinely collected and reviewed during the MVPE through the health 
system’s strengthened AEFI surveillance (for all vaccines), in place prior to RTS,S/AS01 
administration.   
 
13.1.2 Definition of a serious adverse event 
Please refer to section 10.4.9. 
 
13.2 Safety reporting 
Safety reporting will comprise two main components: 
 
(i) 
Data on AEFI, identified by the strengthened routine pharmacovigilance in all health 
facilities in the pilot implementation area. Reporting will be the responsibility of the 
health care system, under national supervision from the immunization programme and 
regulatory authority. 
 
(ii) 
Information from the eight sentinel hospitals per country, focussed on meningitis and 
cerebral malaria. These data may flow through a specially augmented routine health 
information system or through a parallel, purpose-made reporting system. Details will 
be presented in country-specific protocols. In each case, an evaluation partner will be 
charged with assuring the completeness and accuracy of the relevant data. 
 
Further information on safety surveillance in sentinel hospitals is presented in Section 10. The 
approach to detecting and processing AEFI is described in the following sections (13.3-13.5).  The 
safety data flow is described in section 10.15 and illustrated in Figure 5.  
 
A national vaccine safety surveillance body will be designated by the MOH to review all serious 
AEFI and conduct causality assessments, according to procedures established by WHO (see section 
13.3.2). This group will ensure access to AEFI reports by the immunization program and regulatory 
authority, and will also review data originating from the sentinel hospitals. 
 
An information exchange mechanism will be established between the national vaccine safety 
surveillance body and GSK, with agreed, appropriate deadlines to communicate information 
according to the seriousness of the AEFI (see section 13.6). Details will be presented in country-
specific protocols.  
 
Following vaccine introduction, all AEFI, including cerebral malaria and meningitis cases, will be 
reported with other relevant information (e.g. numbers of vaccinations administered) on a 
monthly basis through the routine reporting systems. This information will be available to the pilot 
study’s nationally designated vaccine safety surveillance body, the national Co-ordination Group, 
and to the DSMB, via the Programme Coordination team (figure 5).  
 

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Figure 5: Overview of safety data flow 
 
 
 
All AEFI will be reported to the agreed national body and all serious AEFI (defined in section 
10.4.9) will be investigated within 24 hours (per routine systems). Investigation of non-serious 
AEFI will be decided on a case by case basis (see section 13.4) by the District Immunization Focal 
Person.  
 
13.3 AEFI Detection 
AEFI detection and reporting are the responsibility of the national pharmacovigilance system and 
MoH, and are described here and below 
(through section 13.9) for completeness. The 
parents/carers of immunized children, health 
care 
providers at immunization facilities and other 
staff 
in immunization facilities are most likely to 
recognize or detect AEFIs when they first occur. 
Any 
AEFI that is notified to or identified by a health 
care 
provider will be reported to the District 
Immunization Focal Person (DIFP), through the 
fastest means possible, using a standard 
reporting form (see, for an example, Annex 17).  
The 
DIFP should be informed of any Serious AEFI 
cases 
(see definition in section 10.4.9) by telephone as soon as possible, followed immediately by 
completion and submission of the standard AEFI reporting form (Annex 17). 

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Health workers, including vaccination staff, from all health facilities in the pilot implementation 
area, will be trained to recognize and report AEFIs, and to communicate appropriately about AEFI 
with parents. Health care providers will be responsible for the management, including referral of 
AEFI, as needed. 
 
13.4 Evaluation of initial AEFI report  
The DIFP should review all AEFI reports and determine if criteria for a detailed investigation are 
met. If necessary the DIFP should contact the primary reporter and visit the locality of the event to 
interview relevant stakeholders for additional information.  
 
AEFI reports case may be considered:  
1. 
Not warranting detailed investigation  
This applies to AEFI that are easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.  
 
The DIFP should indicate this on the reporting form and email/ fax this to the agreed 
authorities, including: 
a. the concerned supervisor 
b. the National Immunization Programme (e-mail address to be included in the 
country-specific protocol) and  
c. the NRA  (e-mail address to be included in the country-specific protocol). 
The representatives of the national Immunization Programme and NRA will thus ensure AEFI 
reports are available to the National Safety Committee. 
 
 
2. 
Warranting a detailed investigation. 
This criterion is met for:  
o Serious AEFI (see section 10.4.9)  
o AEFI forming part of a cluster (defined as two or more cases of the same event, or 
similar events, related in time, geography, and/or the vaccine administered30) 
http://www.who.int/vaccine_safety/publications/aefi_manual.pdf 
o AEFI forming part of a group of events above the expected rate/severity 
o AEFI which reflect a suspected safety signal. 
 
Other AEFI may be investigated in special cases, such as: 
o AEFI that may have been caused by immunization error (e.g. bacterial abscess, 
severe local reaction, high fever or sepsis, toxic shock syndrome); 
o Significant events of unexplained cause occurring up to 30 days after a vaccination 
(and that are not listed on the product label);  
o Events causing significant parental or community concern. 
 
The DIFP should discuss the initial AEFI report with any local experts and plan a detailed field 
investigation. Prior to initiating the investigation, the DIFP should e-mail the report (Annex 17) to 
the agreed authorities, as listed above. 
 

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13.5 Further investigation of an AEFI 
If the DIFP considers that the investigation can be handled adequately at the local level, they 
should contact the appropriate member(s) of the local health care team reporting the AEFI and 
visit the patient together to initiate the detailed investigation. If assistance from the regional (or 
equivalent) or national levels is required for the investigation, the relevant people/agency should 
be contacted and assistance solicited. National investigations are expected to be led by a team 
from the national AEFI committee, supported by the National Immunization Program and the 
National Regulatory Authority. During field investigations, the AEFI investigation form (Annex 18) 
should be used as a guide to collect the relevant information.  
 
Where an investigation is needed, more accurate information can be obtained by a single, 
coordinated and complete investigation than a series of partial investigations. 
 
Specific activities in an AEFI investigation will include the following: 
• Confirmation of the initial AEFI report. A unique report identifying number will be assigned, 
all details in the AEFI reporting form completed (in case any of them were missing when 
reporting) and the AEFI investigation initiated. 
 
• Convening any local experts to plan the investigation. 
 
• Visiting the patient, parents, immunisation clinic, reporting health worker, treating doctor, 
vaccine supply focal person, and others as needed. The visiting team should include local 
experts, the DIFP and the care provider(s) completing the initial report. 
 
• Completion of the AEFI investigation form (Annex 18). 
 
• Initiate collection of medical reports, a post-mortem report (if relevant), vaccine vials (if 
necessary, kept under cold chain conditions), logistic samples (e.g. syringes, needles, etc), 
and laboratory reports e.g. for CSF, serum or other biological products. 
 
During the course of investigations the investigators should be careful to document any 
deficiencies in a generic way and suggest corrective measures, and not single out any individuals 
to blame.  
 
Before the AEFI is attributed to any vaccine product, the investigator should rule out potential 
immunization errors, related to the storage, handling, reconstitution or administration of vaccines.  
 
Obvious coincidental events should be identified, for example by reviewing hospital admissions for 
similar conditions during the same period and verifying their vaccination status. A rapid review of 
the morbidity pattern of similar conditions in previous years may suggest that the event is part of 
a cyclical pattern. The medical literature may also help if the estimated background incidence of 
various conditions is available in the published domain. 
 
The completed AEFI investigation form (annex 18) along with the supporting documents (medical 
report, vaccine, logistic samples, laboratory reports, etc.) should be sent to the agreed authorities 
(as listed in section 13.4) within 7 days of the initial case notification. If this is not possible, at least 
a progress report should be made with details on when the completed report can be expected. 

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The District / State investigator should keep the National Immunization Program and the National 
Regulatory Authority, and thus the National Safety Committee, updated on the status and 
progress of the investigation. This is necessary as a national officer should be the spokesperson of 
the government to the media and the public about the investigation, if warranted.   
 
13.5.2 Assessment of causality 
All cases warranting an investigation (see section 13.3.1 above) should have a causality 
assessment. Causality will be assessed according to WHO standards32 and consider the following:  
 
• Temporal relationship: vaccine exposure must precede the occurrence of the event.  
• Availability of definitive proof that the vaccine caused the event (e.g. isolation of the BCG 
agent from a focus of osteomyelitis).  
• Population-based evidence for causality. If there is no clear answer to the question at the 
population level, this will often lead to an indeterminate conclusion at the individual level.  
• Biological plausibility. 
• Consideration of alternative explanations (pre-existing illness, newly acquired illness,  
spontaneous occurrence of an event without known risk factors, emergence of a genetic 
disease).  
• Other exposures to drugs or toxins prior to the event. 
• Surgical or other trauma that leads to a complication. 
• A manifestation of, or complication of, a coincidental infection that was present before or 
at the time of immunization, or was incubating, but was not apparent at the time of 
immunization.  
• Prior evidence that the vaccine in question could cause a similar event.  
 
An initial, preliminary, pre-investigation causality assessment will be made by the DIFP and relayed 
to the relevant national authorities.  
  
Data will then be gathered, as shown in the causality assessment checklist (Annex 19), to generate 
the definitive causality assessment using the algorithm in figure 6: 
 

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Figure 6: WHO-recommended algorithm for AEFI causality classification 
 
 
  
The WHO AEFI causality assessment software may be used to facilitate classification and reduce 
errors and is available at: http://www.who.int/vaccine_safety/causality-assessment-software-
EN/en/. 
 
13.5.2.1 Preparation for causality assessment 
Prior to causality assessment, the AEFI case investigation should have been completed. All details 
of the case should be available, including the case report form (annex 17), the case investigation 
form (annex 18), the completed clinical case record, lab reports, autopsy report, details of field 
investigations etc..  
 
There should be a “valid diagnosis” which is the extent to which the unfavourable or unintended 
sign, abnormal laboratory finding, symptom or disease is defined. 
 
Even with complete information the AEFI may be categorized as indeterminate due to the lack of 
clear evidence of a causal link, or conflicting evidence or other inconsistencies. Nevertheless, 
these assessments will be recorded because the reporting of more cases may lead to a stronger 
signal and a plausible hypothesis, or stronger refutation of any link.  
 
13.5.2.2 AEFI Causality Assessment team 
Causality assessment should be done by a national review team that: 
• is independent of real or perceived conflicts of interest 
• has broad expertise in the areas of infectious diseases, epidemiology, microbiology, 
pathology, immunology, neurology, vaccine program. 
The committee will have written terms of reference (ToR).  

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13.5.2.3 Final Classification of AEFI Causality  
The final classification will be based on the availability of adequate information (figure 7). 
13.5.2.3.1 Case with adequate information for causality conclusion 
A case with adequate information for causality conclusion can be classified as follows: 
 
A.  Consistent causal association with immunization  
A1. Vaccine product-related reaction; or 
A2. Vaccine quality defect-related reaction; or 
A3. Immunization error-related reaction; or 
A4. Immunization anxiety-related reaction. 
 
B.  Indeterminate  
B1. The temporal relationship is consistent but there is insufficient definitive evidence that 
the vaccine caused the event (it may be a new vaccine-linked event). This is a potential 
signal and further investigation will be considered. 
 
B2. Review of factors results in conflicting trends of consistency and inconsistency with a 
causal association with immunization (i.e. it may be vaccine-associated as well as 
coincidental and it is not possible clearly to favour one or the other). 
 
C.  Inconsistent causal association with immunization (coincidental): This could be due to 
underlying or emerging condition(s) or conditions caused by exposure to something other than 
vaccine. 
13.5.2.3.2 Case without adequate information for causality conclusion  
This case is categorized as “unclassifiable” and requires additional information for further review 
of causality. The available information on unclassifiable cases will be placed in a database and 
reviewed periodically to check if additional information is available for classification and to 
perform analyses for signal identification. 
 
The worksheet used for the causality assessment of an individual AEFI case is presented in Annex 
19. 
 

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Figure 7: Summary of final causality classifications 
 
 
13.6 Follow up after causality assessment: 
Responding to AEFI may involve immediate short-term activities or/and long-term follow-up. 
Follow-up should be based on findings of investigations, causality assessments and 
recommendations by the investigation/expert committees. 
 
Proper and early treatment should be provided to patients regardless of the diagnosis. Case 
management and referral will vary depending on the seriousness. Mild symptoms such as mild 
fever and pain are likely to be of short duration and can be managed by assuring and educating 
parents during immunization. If parents return to seek medical attention, these cases should be 
documented and reported in the standard form. In case patients need hospitalization, a clear 
system for referral should be in place. 
 
Table 9 summarises actions to be taken by the MoH upon completion of the investigation and 
causality assessment. 
 
 

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Table 9: Actions upon completion of the AEFI investigation 
Type of AEFI 
Follow-up action 
Vaccine-related 
reactions 
These will be reviewed monthly by the national safety committee and, 
along with data from other pilot countries, the multi-country Data 
Safety Monitoring Board(DSMB). The DSMB will recommend necessary 
actions for individual countries.   
Immunization 
error related 
Correct the cause of the error. This may mean one or more of the 
following: 
• Changing logistics for supply of the vaccine 
• Changing procedures at the health facility 
• Training of health workers 
• Intensifying supervision 
 
Whatever action is taken, it is important to review at a later date to 
check that the immunization error related events have been corrected.  
 
Coincidental 
The potential for coincidental events to harm the immunization 
programme through false attribution is immense.  
 
Present the evidence showing that there is no indication that the AEFI is 
a vaccine-related reaction or immunization-related error and that the 
most likely explanation is a temporal association between the event and 
vaccine/vaccination. Depending on the situation, for example if there is 
widespread belief that the event was caused by immunization, it may 
be useful to seek specialist communication advice, available through the 
Programme Coordination Team in Geneva. Further expert opinion (e.g 
from the DSMB) may be enlisted to reassure that the event was truly 
coincidental.  
 
 
Depending on the nature of the event(s), the number of people affected, and community 
perceptions, a further investigation may be conducted.  
 
13.6.1 Assessment of outcomes 
The outcome of any SAE reported during the entire study will be assessed as one of the following: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal. 
• 
Otherwise explained. 
• 
Lost to follow-up.  
 

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13.7 Timeframes for reporting AEFI 
Prompt notification of AEFI is essential so that the ethical responsibilities towards the safety of 
other potential RTS,S/AS01 recipients are met. These timelines are the responsibility of the MoH. 
WHO will support the MoH in the strengthening of pharmacovigilance to facilitate timely 
reporting. 
 
When a DIFP has been informed of an AEFI, even where minimal information is available initially, it 
will still be important that an initial, preliminary causality assessment is made prior to submission 
of the SAE. The DIFP may change his/her opinion of causality in light of follow-up information and 
update the AEFI information accordingly. The initial causality assessment is important as this is 
one of the criteria used when determining regulatory reporting requirements. 
 
Initial reports of possibly related AEFI will be submitted to the agreed authorities (as listed in 
section 13.4) within 247 hours of receipt/awareness of the relevant information by the DIFP.  
 
Completed AEFI Investigation Forms should be submitted to the agreed authorities (as listed in 
section 13.4) within 77 days of the original notification to the DIFP. 
 
A definitive assessment of causality should be made within 107 days of the original notification to 
the DIFP.  
 
14 Reporting to GSK 
Information exchange with GSK Biologicals will be defined as part of the risk management plan 
established at the time of registration in country. 
 
15 Contact information for reporting serious adverse events  
 
Name 
Organisation 
Role 
e-mail 
Telephone 
 
TBC 
National 
Regulatory 
Authority 
Coordination 
Group 
member 
 
TBC 
 
TBC 
 
TBC 
National 
Immunization 
Program 
Coordination 
Group 
member 
 
TBC 
 
TBC 
 
 
 
 
 
Additional rows to be added as necessary 
 
                                                     
7 To be reviewed in country-specific protocols in light of national standards 

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16 Plans for disseminating and communicating study evaluation results 
A communication strategy will be developed and maintained during the MVIP to ensure that all 
relevant stakeholders are provided with relevant information. Within the participating countries 
we will include specific efforts to reach the following groups: 
 
• The national population and local communities of pilot implementation areas will be 
informed through appropriate means (e.g. mass media, meetings of district councillors, 
village meetings, posters at health facilities, etc.) that RTS,S/AS01 is being introduced and 
evaluated. This will help ensure acceptance of the results of the evaluation. 
 
• National policy makers, malaria and vaccination programme implementers will be directly 
engaged within the national co-ordination group, which is expected to meet at monthly 
intervals throughout the programme. 
 
• National regulatory authorities will also be directly engaged through the national co-
ordination group. In addition, they will be furnished with mutually agreed reports 
documenting progress and summarising safety data on a 6-monthly basis.  
 
• National and local ethical review committees will be updated according to a mutually 
agreed schedule and format. 
 
In addition, the communication strategy will include efforts to inform key stakeholders beyond the 
countries involved in the pilot programme about the plans, progress and results of the pilot 
programme: 
 
• MoH, EPI, NMCP and other key stakeholders in other malaria endemic countries.  
 
• Regional and global policy makers will be provided with updates by the programme’s 
central co-ordination team at meetings of WHO’s MPAC and SAGE. 
 
• Funders of the MVIP will be kept updated on progress through a specially-convened 
funders forum. 
 
• Public health funders, especially vaccine and malaria programme funders, will be updated 
though participation in the Funders Forum, the MPAC and SAGE meetings and / or specific 
efforts by the programme to provide relevant information to them.  
 
• The research community will be informed of the MVIP through presentations at national 
and international meetings and publications in peer-reviewed journals. 
 
 
Following good research practice guidelines , the evaluation was registered on clinicaltrials.gov, as 
an observational study, NCT 03806465.  
 
Analysis of safety, impact and feasibility endpoints will be performed at the end of the evaluation 
as described in the Analysis Plan, at earlier time points if sufficient data have accrued to inform 
decision making.   

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A final report will be written and submitted drawing together the overall results of the MVPE but 
not precluding publication of country-specific reports. The publication strategy will be agreed by 
in-country stakeholders and the Programme’s Advisory Committee.  
 
 
 

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2. 
World Health Organization, Global Malaria Programme & World Health Organization. 
World Malaria Report 2015. (2015). 
3. 
Agnandji, S. T. et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African 
children. N. Engl. J. Med. 365, 1863–1875 (2011). 
4. 
RTS,S Clinical Trials Partnership et al. A phase 3 trial of RTS,S/AS01 malaria vaccine in 
African infants. N. Engl. J. Med. 367, 2284–2295 (2012). 
5. 
The RTS,S Clinical Trials Partnership (2014) The RTS. Efficacy and Safety of the RTS,S/AS01 
Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in 
Children and Young Infants at 11 African Sites. PLoS Med 11, e1001685 (2014). 
6. 
The RTS,S Clinical Trials Partnertship. Efficacy and safety of RTS,S/AS01 malaria vaccine 
with or without a booster dose in infants and children in Africa: final results of a phase 3, 
individually randomised, controlled trial. The Lancet (2015). doi:10.1016/S0140-6736(15)60721-8 
7. 
Penny, M. A. et al. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria 
vaccine: a systematic comparison of predictions from four mathematical models. Lancet Lond. 
Engl. 387, 367–375 (2016). 
8. 
Committe for Medicinal Products for Huma Use (CHMP), European Medicines Agency. 
Assessment Report. Mosquirix (TM). (2015). 
9. 
World Health Organization. Meeting of Strategic Advisory Group of Experts on 
Immunization (SAGE), 20-22 October 2015. (2015). 
10. 
Malaria vaccine: WHO position paper-January 2016. Relevé Épidémiologique Hebd. Sect. 
Hygiène Secrétariat Société Nations Wkly. Epidemiol. Rec. Health Sect. Secr. Leag. Nations 91, 33–
51 (2016). 
11. 
Decade of Vaccines Collaboration. Global Vaccine Action Plan 2011-2020. Global Vaccine 
Action Plan 2011-2020 Available at: 
http://www.who.int/immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/en/. 
(Accessed: 15th November 2016) 
12. 
Snow, R. W. et al. Assembling a geo-coded repository of malaria infection prevalence 
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13. 
Ivers, N. M. et al. Allocation techniques for balance at baseline in cluster randomized trials: 
a methodological review. Trials 13, 120 (2012). 
14. 
Agnandji, S. T. et al. Evaluation of the Safety and Immunogenicity of the RTS,S/AS01E 
Malaria Candidate Vaccine When Integrated in the Expanded Program of Immunization. J. Infect. 
Dis. 202, 1076–1087 (2010). 
15. 
Asante, K. P. et al. Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given 
with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, 
open-label, phase 2 trial. Lancet Infect. Dis. 11, 741–749 (2011). 
16. 
Mkumbo, E., Hanson, C., Penfold, S., Manzi, F. & Schellenberg, J. Innovation in supervision 
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17. 
World Health Organization. Verbal autopsy standards: The 2016 WHO verbal autopsy 
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InterVA. InterVA-4. (2016). Available at: http://www.interva.net/.  
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http://www.healthdata.org/verbal-autopsy/tools.  
20. 
Linard, C., Gilbert, M. & Tatem, A. J. Assessing the use of global land cover data for guiding 
large area population distribution modelling. Geojournal 76, 525–538 (2011). 
21. 
Linard, C., Gilbert, M., Snow, R. W., Noor, A. M. & Tatem, A. J. Population Distribution, 
Settlement Patterns and Accessibility across Africa in 2010. PLOS ONE 7, e31743 (2012). 
22. 
Mennis, J. Dasymetric Mapping for Estimating Population in Small Areas. Geogr. Compass 
3, 727–745 (2009). 
23. 
VTS. The vaccination Tracking System (VTS) - Supporting polio erradication in Nigeria. 
(2016). Available at: http://vts.eocng.org/.  
24. 
Tatem, A. J. Mapping the denominator: spatial demography in the measurement of 
progress. Int. Health 6, 153–155 (2014). 
25. 
Hayes, R. J. & Bennett, S. Simple sample size calculation for cluster-randomized trials. Int. J. 
Epidemiol. 28, 319–326 (1999). 
26. 
The World Bank. Mortality Rate, infant. Available at: 
http://data.worldbank.org/indicator/SP.DYN.IMRT.IN?view=chart. (Accessed: 24th October 2016) 
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The World Bank. Mortality rate, under-5. Available at: 
http://data.worldbank.org/indicator/SH.DYN.MORT?view=chart. (Accessed: 24th October 2016) 
28. 
World Health Organization. Managing meningitis epidemics in Africa. A quick reference 
guide for health authorities and health-care workers. (2015). 
29. 
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recommended surveillance standards. (WHO Press, 1999). 
30. 
Steering Committee on Quality Improvement and Management, Subcommittee on Febrile 
Seizures American Academy of Pediatrics. Febrile seizures: clinical practice guideline for the long-
term management of the child with simple febrile seizures. Pediatrics 121, 1281–1286 (2008).. 
31. 
Amarasinghe, A., World Health Organization & Global Advisory Committee on Vaccine 
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Annex 1. List of stand-alone documents 
 
Annex 
Number 
Document 
reference 
number 
Date 
Title 
1 
 
18jul18 
List of standalone documents 
2 
 
04mar17 ENCePP checklist for study protocols 
3 
 
28feb17 
List of investigators, including contact details 
4 
 
14jul17 
DRAFT Practical Operating Guide for the Malaria Vaccine 
Implementation Programme  
5 
 
10jul18 
Governance and coordination structure for the RTS,S/AS01 
Malaria Vaccine Pilot Evaluation 
6 
 
14jul17 
Community engagement in the MVIP 
7 
ICD-
10:v2016 
2014 
2014 cause of death list for verbal autopsy with 
corresponding ICD-10 codes 
8 
V1.4 
2016 
Verbal Autopsy for children aged four weeks to 11 years 
9 
 
28feb17 
Village Reporter CRF 
10 
 
18jul18 
CRF for impact evaluation 
11 
 
28feb17 
Vaccination Registry 
12 
 
18jul18 
Sentinel hospital CRF 
13 
 
18jul18 
Household survey CRF 
14 
 
14jul17 
Model informed consent for verbal autopsy 
15 
 
18jul18 
Model informed consent for inpatient surveillance and long-
term storage of samples 
16 
 
18jul18 
Model informed consent for household survey 
17 
 
28feb17 
Standard AEFI reporting form 
18 
 
28feb17 
AEFI investigation form 
19 
 
28feb17 
AEFI causality assessment worksheet 
20 
 
14jul17 
CVs of Dr Mary Hamel and Dr David Schellenberg 
21 
 
14jul17 
Preliminary budget estimate 
 
 
 

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Annex 2. ENCePP checklist for study protocols 
 
Study title: 
An evaluation of the randomised pilot implementation of RTS,S/AS01 through routine health 
systems in moderate to high malaria transmission settings in sub-Saharan Africa 
 
Study reference number: RTSS_PIP_28.02.2017 
 
 
Section 1: Milestones 
Yes 
No 
N/A 
Section 
Number 
1.1 
Does the protocol specify timelines for  
 
 
 
 
1.1.1 Start of data collection8 
 
 
 
6 
1.1.2 End of data collection9 
 
 
 
6 
1.1.3 Study progress report(s) 
 
 
 
6 
1.1.4 Interim progress report(s) 
 
 
 
 
1.1.5 Registration in the EU PAS register 
 
 
 
 
1.1.6 Final report of study results. 
 
 
 
6 
Comments: 
No interim analyses are planned. 
 
Section 2: Research question 
Yes 
No 
N/A 
Section 
Number 
2.1 
Does the formulation of the research question and 
objectives clearly explain:  
 
 
 
 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
management plan, an emerging safety issue) 
 
 
 
7 
2.1.2 The objective(s) of the study? 
 
 
 
8 
2.1.3 The target population? (i.e. population or subgroup 
to whom the study results are intended to be generalised) 
 
 
 
7.6.5 
2.1.4 Which hypothesis(-es) is (are) to be tested? 
 
 
 
8.1 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
 
Comments: 
 
 
Section 3: Study design 
Yes 
No 
N/A 
Section 
Number 
3.1 
Is the study design described? (e.g. cohort, case-control, 
cross-sectional, new or alternative design)  
 
 
 
7.6.2 
                                                     
8 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use 
of data, the date from which data extraction starts. 
9 Date from which the analytical dataset is completely available. 

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Section 3: Study design 
Yes 
No 
N/A 
Section 
Number 
3.2 
Does the protocol specify whether the study is based 
on primary, secondary or combined data collection? 
 
 
 
7.6.5 
3.3 
Does the protocol specify measures of occurrence? 
(e.g. incidence rate, absolute risk) 
 
 
 
9.7  
10.12  
11.7 
3.4 
Does the protocol specify measure(s) of association? 
(e.g. relative risk, odds ratio, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year) 
 
 
 
9.7  
10.12 
3.5 
Does the protocol describe the approach for the 
collection and reporting of adverse events/adverse 
reactions? (e.g. adverse events that will not be collected in 
case of primary data collection) 
 
 
 
13.2 
Comments: 
 
 
Section 4: Source and study populations 
Yes 
No 
N/A 
Section 
Number 
4.1 
Is the source population described? 
 
 
 
7.6.5 
9.2.1 
10.1 
11.2.2 
4.2 
Is the planned study population defined in terms of: 
 
 
 
 
4.2.1 Study time period? 
 
 
 
7.6.3 
4.2.2 Age and sex? 
 
 
 
7.6.5 
4.2.3 Country of origin? 
 
 
 
7.5 
4.2.4 Disease/indication? 
 
 
 
 
4.2.5 Duration of follow-up? 
 
 
 
7.6.5 
4.3 
Does the protocol define how the study population 
will be sampled from the source population? 
(e.g. event or inclusion/exclusion criteria) 
 
 
 
7.5 
7.6.5 
Comments: 
Evaluation of the malaria vaccine will involve monitoring of all-cause and cause-specific 
mortality and cause-specific admission to sentinel hospitals. 
 
Section 5: Exposure definition and measurement 
Yes 
No 
N/A 
Section 
Number 
5.1 
Does the protocol describe how the study exposure 
is defined and measured? (e.g. operational details for 
defining and categorising exposure, measurement of dose and 
duration of drug exposure) 
 
 
 
11.1.1 
5.2 
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use of 
validation sub-study) 
 
 
 
11.1.1 
5.3 
Is exposure classified according to time windows? 
(e.g. current user, former user, non-use) 
 
 
 
8.4.1 

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Section 5: Exposure definition and measurement 
Yes 
No 
N/A 
Section 
Number 
5.4 
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug? 
 
 
 
7 
Comments: 
 
 
Section 6: Outcome definition and measurement 
Yes 
No 
N/A 
Section 
Number 
6.1 
Does the protocol specify the primary and secondary 
(if applicable) outcome(s) to be investigated? 
 
 
 
8.2 & 9.7 
8.3 & 10.12 
8.4 & 11.7 
 
6.2 
Does the protocol describe how the outcomes are 
defined and measured?  
 
 
 
6.3 
Does the protocol address the validity of outcome 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or retrospective 
ascertainment, use of validation sub-study) 
 
 
 
9.9 
10.14 
11.9 
6.4 
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management) 
 
 
 
9.3 
 
Comments: 
Separate protocols will be developed to evaluate cost-effectiveness and potential effects on 
health care utilisation 
 
Section 7: Bias 
Yes 
No 
N/A 
Section 
Number 
7.1 
Does the protocol describe how confounding will be 
addressed in the study? 
 
 
 
9.3 
9.7 
10.14 
7.1.1. Does the protocol address confounding by 
indication if applicable? 
 
 
 
 
7.2 
Does the protocol address: 
 
 
 
 
7.2.1. Selection biases (e.g. healthy user bias) 
 
 
 
10.14 
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias) 
 
 
 
9.10 
10.14 
7.3 
Does the protocol address the validity of the study 
covariates? 
 
 
 
 
Comments: 
Detailed analytical plans, in which issues of potential confounding, biases and covariates will 
be addressed, will be developed during the course of the evaluation.  
 
 
Section 8: Effect modification 
Yes 
No 
N/A 
Section 
Number 

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Section 8: Effect modification 
Yes 
No 
N/A 
Section 
Number 
8.1 
Does the protocol address effect modifiers? 
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect)  
 
 
 
8.2.2 
Comments: 
The first secondary objective of the impact analysis will analyse gender/specific mortality 
effects. Detailed analytical plans will include additional potential effect modifiers. 
 
Section 9: Data sources 
Yes 
No 
N/A 
Section 
Number 
9.1 
Does the protocol describe the data source(s) used 
in the study for the ascertainment of: 
 
 
 
 
9.1.1 Exposure? (e.g. pharmacy dispensing, general practice 
prescribing, claims data, self-report, face-to-face interview) 
 
 
 
11.1.1 
9.1.2 Outcomes? (e.g. clinical records, laboratory markers or 
values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics) 
 
 
 
9.4 
10.7 
11.3 
9.1.3 Covariates? 
 
 
 
9.4 
10.7 
11.3 
9.2 
Does the protocol describe the information available 
from the data source(s) on: 
 
 
 
 
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose,  
number of days of supply prescription, daily dosage,  
prescriber) 
 
 
 
11.1.1 
9.2.2 Outcomes? (e.g. date of occurrence, multiple event, 
severity measures related to event) 
 
 
 
9.4 
10.7 
11.3 
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle) 
 
 
 
9.4 
10.7 
11.3 
9.3 
Is a coding system described for:  
 
 
 
 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System) 
 
 
 
 
9.3.2 Outcomes? (e.g. International Classification of Diseases 
(ICD)-10, Medical Dictionary for Regulatory Activities 
(MedDRA)) 
 
 
 
9.3 
Annex 5 
9.3.3 Covariates? 
 
 
 
 
9.4 
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
10.3 10.12 
10.14 
Comments: 
Linkage of endpoints to vaccination status will use documented vaccination status on children’s 
health cards.  
 

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Section 10: Analysis plan 
Yes 
No 
N/A 
Section 
Number 
10.1 Is the choice of statistical techniques described?  
 
 
 
9.7 
10.12 
11.7 
10.2 Are descriptive analyses included? 
 
 
 
10.12 
11.7 
10.3 Are stratified analyses included? 
 
 
 
9.7 
10.4 Does the plan describe methods for adjusting for 
confounding? 
 
 
 
9.7 
10.5 Does the plan describe methods for handling missing 
data? 
 
 
 
 
10.6 Is sample size and/or statistical power estimated? 
 
 
 
9.5 
10.10 
11.5 
Comments: 
It is not expected to have missing data at the cluster level, e.g data on deaths and population 
will be available from every cluster in the evaluation. 
 
Section 11: Data management and quality control 
Yes 
No 
N/A 
Section 
Number 
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving) 
 
 
 
 
11.2 Are methods of quality assurance described? 
 
 
 
9.8 
10.13 
11.8 
11.3 Is there a system in place for independent review of 
study results?  
 
 
 
9.8, 11.8 
13.2 
Annex 4 
Comments: 
Details of data management will vary between countries and will be presented in country-
specific protocols.  
 
Section 12: Limitations 
Yes 
No 
N/A 
Section  
Number 
12.1 Does the protocol discuss the impact on the study 
results of: 
 
 
 
 
12.1.1 Selection bias? 
 
 
 
10.4 
12.1.2 Information bias? 
 
 
 
9.9, 10.14  
12.1.3 Residual/unmeasured confounding? 
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods) 
 
 
 
 
12.2 Does the protocol discuss study feasibility? (e.g. study 
size, anticipated exposure, duration of follow-up in a cohort 
study, patient recruitment) 
 
 
 
9.9 
10.14 

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Comments: 
 
 
Section 13: Ethical issues 
Yes 
No 
N/A 
Section  
Number 
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described? 
 
 
 
9.2.3 
10.5 
12.1 
13.2 Has any outcome of an ethical review procedure 
been addressed? 
 
 
 
 
13.3 Have data protection requirements been described? 
 
 
 
12.1 
Comments: 
Section 12.1 describes the approach to ensure the necessary and appropriate EC/IRB reviews 
are conducted and provides reassurance that data protection will be ensured. 
 
Section 14: Amendments and deviations 
Yes 
No 
N/A 
Section 
Number 
14.1 Does the protocol include a section to document 
amendments and deviations?  
 
 
 
5 
Comments: 
Amendments will be captured in section 5 and any deviations documented as the study 
proceeds. 
 
Section 15: Plans for communication of study 
results 
Yes 
No 
N/A 
Section 
Number 
15.1 Are plans described for communicating study results 
(e.g. to regulatory authorities)?  
 
 
 
14 
15.2 Are plans described for disseminating study results 
externally, including publication? 
 
 
 
14 
Comments: 
 
 
Name of the main author of the protocol: 
David Schellenberg 
Date: 4th March 2017 
 
 
 
 
 
Signature:  
 
 
 
 
 
 

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Annex 3. List of investigators, including contact details  
 
Investigators: Ghana  
Kintampo Health Research Centre (KHRC) is the lead organisation. 
 
Coordinating Investigator : Dr. Kwaku Poku Asante, Kintampo Health Research Centre, Research 
and Development Division, Ghana Health Service.  Email address: kwakupoku.asante@kintampo-
hrc.org  Contact telephone number: +233 20 8956598 
Lead for Impact module: Dr Abraham Oduro, Navrongo Health Research Centre, Research and 
Development Division, Ghana Health Service 
Lead for Feasibility module: Prof. Col. Edwin Andrews Afari (rtd.), School of Public Health, 
University of Ghana 
Lead for Safety module: Prof. Daniel Ansong, Malaria Research Centre/Presbyterian Hospital, 
Agogo 
 
Investigators: Kenya  
Centers for Disease Control and Prevention (CDC) is the lead organisation. 
 
Coordinating Investigator : Aaron Samuels,  CDC-Kenya Malaria Research Program                                
P.O. Box 1578, Kisumu 40100. Mobile: +254.724.255.633; Email: iyp2@cdc.gov   
Lead for Impact module: Meghna Desai, Centers for Disease Control and Prevention (CDC)                  
Lead for Feasibility module: Dr. Nelli Westercamp, Centers for Disease Control and Prevention 
(CDC) 
Lead for Safety module: Dr. Samuel Akech KEMRI-Wellcome Trust Research Program (KWTRP) 
 
Investigators: Malawi  
College of Medicine, School of Public Health, University of Malawi (COM) is the lead organisation. 
 
Coordinating Investigator : Dr. Don Pascal Mathanga , College of Medicine, P/Bag 360, Chichiri, BT 
3, Malawi. Contact telephone number: (+265) 1 870 145/878  Email: dmathang@mac.medcol.mw 
Lead for Impact module: Dr Victor Mwapasa, College of Medicine, School of Public Health, 
University of Malawi 
Lead for Feasibility module: Dr Atupele Kapito-Tembo, College of Medicine, School of Public 
Health, University of Malawi 
Lead for Safety module: Dr. Tisungane Knox Titus Mvalo, University of North Carolina Project 
(UNCP) – Malawi. 
  
 
The country-specific protocols include the extended investigator lists by country and collaborating 
institutions. 
 

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Annex 4. DRAFT Practical Operating Guide for the Malaria Vaccine 
Implementation Programme  
 
Pilot Introduction of the RTS,S/AS01 Malaria Vaccine into the Routine Childhood  Immunization 
Programmes in Ghana, Kenya and Malawi 
 
Preliminary Version 14 July, 2017 
 
Contents 
 
1. 
Preface 
 
2. 
Introduction 
 
3. 
Malaria Vaccine Implementation Programme (MVIP) 
 
4. 
The RTS,S/AS01 Malaria Vaccine 
 
 
5. 
Sub-national pilot introduction of the RTS,S/AS01 malaria vaccine through the national EPI 
Programmes in MVIP Pilot Countries 
 
 
6. 
Vaccine Characteristic and Cold Chain 
 
7. 
Vaccine safety 
 
8. 
Co-administration and multiple injections at one visit 
 
 
9. 
WHO recommendations for RTS,S/AS01vaccine in routine vaccination in MVIP Pilot  
Areas  
 
10. 
Planning 
 
11. 
Microplanning 
 
12. 
Communication and Social Mobilization 
 
 
13. 
Training 
 
14. 
Service Delivery 
 
15. 
Adverse events following immunization (AEFI) monitoring  
 
16. 
Supportive supervision 
 
 
17. 
Administrative method to calculate vaccine coverage 
 

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Preface 
This guide is intended for use by national expanded programme on immunization (EPI) managers 
and stakeholders involved in the programme. 
 
The specific objectives of this guide are: 
• To inform operational aspects for the sub-national pilot introduction of the RTS,S/AS01 
malaria vaccine through the national routine EPI programme as a component of the WHO-
coordinated Malaria Vaccine Implementation Programme (MVIP). 
• To provide up-to-date references on the technical and strategic issues related to the 
introduction of the RTS,S/AS01 malaria vaccine through the EPI  programme as part of the 
MVIP.  
The guide draws from Principles and Considerations for adding a vaccine to a national 
immunization programme. From decision to implementation and monitoring 10, the experiences 
of many countries that have introduced new vaccines, and other training materials for health 
workers and mid-level managers.11,12  
 
Introduction 
Malaria Disease 
Malaria, a parasitic disease transmitted by the anopheles mosquito, continues to be a major cause 
of childhood morbidity and death, especially in sub-Saharan Africa. Children are most vulnerable, 
and if not treated promptly, malaria can rapidly progress from fever to death. In high transmission 
areas, the most common manifestation of severe malaria is severe anaemia.  Effective treatment 
and a reliable safe blood supply are required to treat severe malaria anaemia, but too frequently 
these interventions are inaccessible to children living in poor or rural communities.  In 2015, WHO 
estimated that 214 million malaria episodes caused 438,000 deaths, the vast majority in young 
children in sub-Saharan Africa (SSA).  
Malaria Control Strategies 
WHO recommends a number of tools to reduce malaria transmission, morbidity and death.  
Insecticide treated nets, indoor residual spray, seasonal malaria chemoprophylaxis, intermittent 
treatment of malaria in pregnancy or for infants, and prompt effective treatment with artemisinin 
containing antimalarial treatment are all effective malaria control interventions. During the prior 
15 years, considerable advances have been made with these malaria control tools, resulting in 
marked reduction in malaria illness and death across much of Africa.  However, some areas 
continue to have high malaria burden despite good coverage with current tools. A vaccine could 
be an important addition to complement the tools we have, and reduce malaria further in areas 
with persistently high transmission.  
                                                     
10 Principles and considerations for adding a vaccine to a national immunization programme. From decision to implementation and 
monitoring. 
http://www.who.int/immunization/programmes_systems/policies_strategies/vaccine_intro_resources/nvi_guidelines/en/ 
11 WHO Vaccine Position Papers. http://www.who.int/immunization/documents/positionpapers/en/ 
12 Controlled temperature chain (CTC) publications and guidance. 
http://www.who.int/immunization/programmes_systems/supply_chain/ctc/en/index1.html  

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Malaria Vaccine Implementation Programme (MVIP) 
The MVIP is a collaborative effort, coordinated by WHO, and designed to address outstanding 
questions on the public health use of the RTS,S/AS01 malaria vaccine. The goal of the MVIP is to 
provide key information to inform and update the WHO policy recommendation on the use of the 
RTS,S/AS01 malaria vaccine in young children in sub Saharan Africa. The MVIP encompasses all 
aspects of the pilot implementation of the malaria vaccine, including:  
• Vaccine implementation led by the MOH and National Immunization Programme,  
• The evaluations of feasibility, impact, and safety, including the main WHO-led evaluations 
and the PATH-led health utilisation study and economic analyses; and  
• GSK-led Phase IV studies.  
The RTS,S/AS01 Malaria Vaccine 
The RTS,S/AS01 malaria vaccine, also known as Mosquirix™, is currently the only candidate malaria 
vaccine to have received a positive regulatory scientific opinion, which was issued by the European 
Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP).13 The vaccine 
development spanned a 30-year process, initiated in 1987 by scientists working at 
GlaxoSmithKline’s (GSK) laboratories. At present, no regulatory authority in the African region has 
licensed RTS,S/AS01 for use as a malaria vaccine.14 
 
Sub-national pilot introduction of the RTS,S/AS01 malaria vaccine through 
the national EPI Programmes in MVIP Pilot Countries 
The RTS,S/AS01 vaccine will be authorized by the respective National Regulatory Agencies (NRA) 
for use in the MVIP pilot areas of the three pilot countries. Vaccine introduction will be through 
the national EPI programmes, using the routine system for new vaccine introduction.  
Administrative areas, referred to as clusters, typically sub-counties or districts, will be randomized.  
Half of the areas will serve as vaccination and half as comparator clusters.  Initially, the RTS,S/AS01 
vaccine will be deployed only in the vaccination areas (see blue areas in figure below). 
Introduction in half of the clusters, while allowing the other half to serve as comparator areas 
allows a robust evaluation of feasibility, safety and impact.  Cluster allocation (randomisation) will 
be led by the respective Ministries of Health. To facilitate this exercise, WHO will provide technical 
assistance using data provided by the country on agreed upon criteria to generate the list of 
options from which one option will be drawn at random.    The selected option will be presented 
to the members at the country selection meeting (this will include membership from government 
and community leaders present as locally relevant) and messaging developed to share with 
stakeholders on how to best communicate the selection process and answer any questions. 
Following the cluster allocation process (randomization), the introduction and ongoing vaccine 
                                                     
13 The RTS,S/AS01 vaccine has received a positive Scientific Opinion by EMA in accordance with Article 58 of 
Regulation (EC) No 726/2004 which allows the Agency’s Committee for Medicinal Products for Human Use (CHMP) to 
give opinions, in co-operation with WHO, on medicinal products for human use that are intended exclusively for markets 
outside of the European Union (EU). For more information: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_ listing/document_listing_000157.jsp, 
accessed January 2016. 
14 WHO Questions and Answers on Malaria Vaccines: 
http://www.who.int/immunization/research/development/malaria_vaccine_qa/en/ 

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delivery in the vaccination areas is the responsibility of the National Immunization Programme.  
After approximately 30 months of routine delivery in the vaccination clusters, the countries may 
begin delivery of the RTS,S/AS01 vaccine in the comparator clusters. The decision to expand will 
be that of the respective Ministries of Health, and will depend, among other things, on findings of 
feasibility and safety in the vaccination clusters.  At the end of the MVIP evaluation, should the 
vaccine be recommended by WHO for broader use, every effort will be made to offer early 
introduction of the RTS,S/AS01 vaccine into the comparator areas. 
   
 
 
Vaccine Characteristic and Cold Chain  
The RTS,S/AS01 vaccine is a lyophilized vaccine that is reconstituted with a liquid adjuvant, AS01.  
RTS,S/AS01 is packaged as a two-dose vaccine, presented in two clipped vials.  A Vaccine Vial 
Monitor (VVM) is adhered to the AS01 vial, and not to the AS01 adjuvant vial. After reconstitution, 
residual vaccine should be discarded after 6 hours.  Storage of the vaccine is at +2°C to +8 °C for at 
least 3 years.  Cold chain capacity assessment will occur as part of vaccine introduction planning, 
and the MVIP will provide support to ensure sufficient cold chain capacity to support the addition 
of RTS,S/AS01 to the EPI. A summary of product characteristics can be found at: 
 
https://www.ema.europa.eu/en/documents/medicine-outside-eu/mosquirix-public-assessment-
report_en.pdf 
 

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Vaccine safety 
RTS,S/AS01 is associated with an increased risk of febrile seizures 
 
In the large multi-country phase 3 trial, an additional safety signal of meningitis was observed 
rarely in children in the 5-17 month age-category who received the RTS,S/AS01vaccine. A causal 
relationship has not been established, and this may have been a chance finding. 
 
A post hoc analysis of the same trial indicated an imbalance and potential increased risk of 
cerebral malaria and female mortality.  These potential signals were on a background of reduced 
severe malaria overall and very low mortality. No deaths were associated with RTS,S/AS01 
vaccination.  
 
Post marketing surveillance is needed to assess the safety profile of the vaccine. Strengthening of 
routine pharmacovigilance and the establishment of sentinel hospitals to monitor for safety 
signals, with particular attention to those listed above, will be an important component of the 
pilot introduction of the vaccine.  
 
Co-administration and multiple injections at one visit 
RTS,S/AS01 can be given concomitantly with any of the following monovalent or combination 
vaccines: diphtheria (D), tetanus (T), whole cell pertussis (Pw), acellular pertussis (Pa), hepatitis B 
(HepB), Haemophilus influenzae type b (Hib), oral polio (OPV), measles, yellow fever, rotavirus and 
pneumococcal conjugate vaccines (PCV). The co-administration of RTS,S/AS01 with PCV increases 
the risk of fever within 7 days post-vaccination.  
 
Product Characteristics: RTS,S/AS01 Malaria Vaccine 
• 
Duration of protection: Wanes with no substantial protection after 
approximately 18 months after the 3rd dose of the vaccine, but efficacy is 
enhanced with the 4th dose and persists in the following 12 months 
• 
Vaccine Efficacy: 39% (95% CI 34.3, 43.3) against clinical malaria after 4 doses 
given to children 5-17 months of age 
• 
Herd effect: None or minimal 
• 
Formulation: Lyophilized (freeze dried powder) 
• 
Preservative: No preservative 
• 
Vaccination schedule: 4 doses (starting from 5 months of age, 3 dose primary 
series with a minimum interval between doses of 4 weeks, followed by a later 
fourth dose 15-18 months after the last dose) 
• 
Storage temperature: 2-8˚C 
• 
Effect of freezing: Freeze sensitive; Must not be frozen 
• 
VVM type: To be confirmed (but will have VVM) 
• 
How vials and diluents are packaged: Vaccine and diluent vials clipped together 
• 
Packed volume per dose: 9.7 cc 

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Concomitant administration of rotavirus and pneumococcal conjugate vaccines with RTS,S/AS01 
may reduce the antibody response to the circumsporozoite (CS) antigen of RTS,S/AS01. The impact 
of this observation on the level of protection induced by RTS,S/AS01 is currently unknown. 
 
Multiple injections at one visit can be given as indicated in WHO recommendations, in particular if 
one cannot administer in separate limbs then WHO recommends separating the injections by at 
least 2.5 centimeters (an inch).15  
 
It is important to avoid confusion of the RTS,S/AS01 diluent with that of other vaccines during the 
co-administration. The clipped vial presentation should mitigate this possibility.  
 
WHO recommendations for RTS,S/AS01 vaccine in routine vaccination in 
MVIP Pilot Areas 
A 4-dose schedule with routine vaccine administration beginning at 5 or 6 months of age 
administered in monthly doses for 3 doses, with a fourth dose provided 15-18 months after the 
third dose. 
 
RTS,S/AS01 can be co-administered with other childhood vaccinations. Catch-up campaigns are 
not recommended as part of pilot implementation. Additional vaccination visits for the receipt of 
RTS,S/AS01 should be fully utilized as opportunities to provide other vaccines, vitamin A, 
antihelminth therapy or other nationally recommended childhood interventions that were 
previously missed.  
 
Planning 
A detailed planning process is underway in the three MVIP pilot countries. The target population, 
delivery strategy, vaccination schedule, and logistics are being carefully considered and a detailed 
introduction plan is under development. The introduction plan will outline all activities and steps 
required for the successful introduction of RTS,S/AS01 by programme component, identify 
government departments, institutions or external partners that are responsible for each activity, 
and will include a timeline and detailed budget.  
 
Given the unique considerations for the RTS,S/AS01 vaccine pilot introduction and evaluation, it is 
critical that countries allow enough time for planning and implementation of all the specified 
introduction activities and that the introduction is not rushed. Sequencing activities in a detailed 
chronogram will highlight critical milestones necessary for the RTS,S/AS01 vaccine introduction to 
proceed smoothly. 
 
Pilot countries are encouraged to refer to the checklist and tools contained in the WHO guide 
“Principles and considerations for adding a new vaccine to a national immunization programme: 
From decision to implementation and monitoring”16, particularly the template for a new vaccine 
introduction plan and the new vaccine introduction checklist, activity list, and timeline. 
                                                     
15 (SAGE meeting of April 2015 report. Session: administration of multiple injectable vaccines in a single visit, 
http://www.who.int/wer/2015/wer9022.pdf?ua=1) 
16 http://apps.who.int/iris/bitstream/10665/111548/1/9789241506892_eng.pdf  

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Microplanning 
Micro-planning at the district level prior to introduction is essential.  The randomized introduction 
of the RTS,S/AS01 vaccine presents unique challenges that will need to be anticipated and 
addressed.  Engagement of stakeholders at all levels will be important, and clear communication 
and transparency about the MVIP will be needed to foster trust in the programme and the 
process.   
 
Estimates of the target population will be done by the Ministries of Health with support from 
WHO.  Naturally occurring events, such as agriculture migration or natural disasters, could 
influence population estimates. Seasonality could also be a factor if populations move when 
vaccinations are scheduled in local areas. Planning for these known seasonal migration patterns 
can help ensure more accurate projections. Conflict, famine, and political stability may also be 
localized events impacting the movement of people. Understanding if this situation is present can 
help inform the estimates of the target population as well. 
 
Management of RTS,S/AS01 vaccine in local health centres should follow the same procedures as 
is done for any vaccine requiring continuous cold chain. A quality and recent effective vaccine 
management (EVM) assessment will inform if any health facilities require cold chain expansion, 
maintenance or strengthening in advance of RTS,S/AS01 vaccine pilot introduction.  
 
Communication and Social Mobilization 
Increasing awareness of communities through timely, complete and appropriate education and 
communication is the key to successful RTS,S/AS01 vaccine introduction.  
 
The introduction of RTS,S/AS01 vaccine will require a very well prepared IEC strategy and 
materials, and will need to actively engage local opinion leaders for success. 
 
There are a number of information needs that are novel and specific to RTS,S, including: 
• partial protection and need to link to other malaria control interventions 
• subnational and/or seasonal deployment (if adopted) 
• new age group for vaccination 
• importance of primary schedule and fourth dose 
• risk-benefit, safety and AEFI arrangements; and  
• rationale for campaign approach (if adopted). 
 It will be critical to communicate the non-traditional age group vaccination schedule, reinforcing 
any links to other preventive services proposed from age five months onwards. It will also be 
important to explain that the vaccine is less effective and for a relatively shorter duration 
compared to other vaccines. IEC will need to continually reinforce the need to continue the use of 
other malaria control interventions (LLINs, SMC, etc).  
Immunization programmes and partners have previous communications experience with other 
vaccines that do not protect against all causes of a particular illness, such as for the introduction of 
pneumococcal conjugate vaccine and Rotavirus vaccine against pneumonia and diarrhoea, 

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respectively, which also require other control interventions17. There are also established resources 
for communication strategies for the introduction of new vaccines, including those developed by 
UNICEF, that could be applied to RTS,S. 
 
As RTS,S/AS01 vaccination will be deployed at a sub-national level it will also be necessary to have 
IEC efforts address the potential for misunderstanding/rumours that RTS,S/AS01 vaccine 
introduction is an experimental research trial. 
 
Given the safety signals for RTS,S/AS01 vaccine, it will be very important (as it is for all new vaccine 
introductions) to have communication plans and systems in place for handling any adverse events 
following vaccination. WHO has a wealth of materials, trainings and guidance available to support 
countries.18 
 
Details of the communication and social mobilization plans for the MVIP can be found in the 
accompanying document on communication and social mobilization. 
 
Training 
Health care staff in the MVIP pilot areas will receive specific training before introducing the 
RTS,S/AS01 vaccine. If prepared well, a three-day training should be sufficient to cover the 
necessary background information on the pilot implementation of RTS,S/AS01, the vaccine, its role 
in malaria control, operational issues, communication and key messages, pharmacovigilance and 
hands-on practice. If possible, the training for RTS,S/AS01 vaccine introduction could be included 
as a part of a regular annual or refresher training for health workers.  Linking training with an 
annual micro-planning activity can also build efficiencies and allow for more integrated planning of 
vaccine delivery. 
 
Service Delivery 
Vaccination sessions for RTS,S/AS01 vaccine will be integrated into the routine vaccine 
immunization sessions. The main recording tools that are used for immunization will be adapted 
to include RTS,S/AS01 vaccine.  At the service delivery level these include: 
• Immunization register 
• Tally sheet 
• Immunization card or mother-child card or health passport 
• Defaulter tracking system 
• Vaccine stock record 
• Integrated monthly report 
As with other vaccines, immunization sessions should have all the necessary supplies and 
materials for effective delivery. Supplies include chair and table, water and soap or hand sanitizer, 
                                                     
17 WHO. (2013) Ending preventable child deaths from pneumonia and diarrhoea by 2025. The integrated Global Action Plan for 
Pneumonia and Diarrhoea (GAPPD). 
http://www.who.int/maternal_child_adolescent/documents/global_action_plan_pneumonia_diarrhoea/en/ 
18 Vaccine Safety Basics: WHO On-line e-Learning Course in Vaccine Safety (http://vaccine-safety-training.org/home.html) and 
Vaccine Safety Events: Managing the Communication Response (www.euro.who.int/data/assets/pdf_file/0007/187171/Vaccine-
Safety-Events-managing-the-communications-response-final.pdf) 

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safety boxes with closed lids, waste bags for garbage, and IEC materials. All forms and monitoring 
tools should be available at every vaccination session, including the vaccination logbook or 
register, tally sheets, vaccination cards, and AEFI forms in case of immediate reactions. 
 
In addition to following all the basic requirements for any injectable vaccine, a few additional 
steps before and after are required to properly administer RTS,S/AS01 vaccine.  
Safe injection practices 
RTS,S/AS01 vaccine is freeze-dried and needs to be reconstituted before administration.  The 
diluent attached to the vaccine vial must only be used. Each reconstituted vial contains 2 doses. 
 
As with all other immunizations, RTS,S/AS01 vaccine should be delivered with good technique and 
following the best practices for safe injections: 
• Always follow manufacturer recommendations for use, storage, and handling 
• To minimize risk of injury, prepare work area so that: 
• A trained vaccine administrator is on site 
• Monitoring tools and safety boxes are easily accessible 
• Each vaccinator has a designated safety box and can see the entrance hole when discarding 
needle 
• Wash hands with soap and water and drip dry 
• Prepare each dose immediately before administering. Do not prepare several syringes in 
advance 
• Check the vaccine and diluent vials for condition, Vaccine vial monitor (VVM) status, and 
expiry date. Do not use if VVM has changed colour and indicates vaccine should not been 
used, packaging is punctured, torn, or damaged, or if vial contains particles or if there is 
discoloration 
• Use a new reconstitution syringe for each vial of vaccine and diluent; Reconstitute only one 
vaccine vial at a time. 
• After reconstitution, shake the vial gently upside down a few times, holding the neck for 
mixing appropriately. Do not hold the vial with the finger on the vial’s septum. 
• After reconstitution, immediately dispose of the reconstitution syringe in the safety box 
WITHOUT RECAPPING 
• Record time of reconstitution on RTS,S/AS01 vaccine vial label. Use the reconstituted 
vaccine within 6 hours of reconstitution. Any unused reconstituted vaccine must be 
discarded after 6 hours. 
• Using a new auto-disable syringe for each child fill the dose accurately  
• DO NOT pre-fill syringes in advance – fill them only prior to each vaccine administration. 
• Do not touch any part of the needle 
• Inject entire content of the syringe by intramuscular injection, preferably in the deltoid 
muscle of the upper arm, using a perpendicular 90 degree angle 

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• Discard the syringe and needle directly (no recapping) into a safety box immediately after 
administering the vaccine   
• Safety box should be a water-proof and tamper-proof container that is securely closed with 
only a small hole at the top large enough for syringe and needle to enter 
• Do not overfill the safety box. Close the container and seal the opening when the box is ¾ 
full 
• Keep safety boxes in a dry, safe place until they can be safely disposed 
• Do not dispose of used syringe and needles in an open box or container 
 
Adverse events following immunization (AEFI) monitoring 
An adverse event following immunization is any untoward medical occurrence which follows 
immunization and which does not necessarily have a causal relationship with the use of the 
vaccine. If not rapidly and effectively dealt with, AEFIs can undermine confidence in a vaccine and 
ultimately have dramatic consequences for immunization coverage and disease incidence.  
 
Although an AEFI can be caused by the vaccine itself, reported AEFIs are more commonly either a 
coincident event that is not related to the vaccine, due to programmatic or human errors that 
compromise the vaccine quality, or allergic reactions to components in the vaccine. 
 
AEFIs can be classified into 5 categories: 
1. Vaccine product-related reaction 
• Caused or precipitated by inherent properties of the vaccine product 
2. Vaccine quality defect-related reaction 
• Caused or precipitated by a vaccine due to one or more quality defects of the 
vaccine product, including the administration device, as provided by the 
manufacturer 
3. Immunization error-related reaction 
• Caused by inappropriate vaccine handling, prescribing or administration and that 
thus, by its nature, is preventable 
4. Immunization anxiety-related reaction 
• Arising from anxiety about the immunization 
5. Coincidental event 
• Caused by something other than the vaccine product, immunization error or 
immunization anxiety 
The most commonly reported adverse reactions for RTS,S/AS01 vaccination were fever (27%), 
irritability (14%) and injection site reactions such as pain (16%) and swelling (7%). In clinical 
studies, the most serious adverse reaction associated with Mosquirix was febrile seizures (within 7 
days post-vaccination) (0.1%). 
 

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The additional safety signals noted in the analysis from the large multi-country phase 3 trial, 
although causality is unknown, also needs to be monitored. These are specifically meningitis and 
cerebral malaria. 
Monitoring and reporting of AEFI 
Monitoring vaccine safety is of particular importance because RTS,S/AS01 is a new vaccine that 
has not been deployed in other settings.  Consolidating the safety profile of the RTS,S/AS01 
vaccine is an important outcome of the MVIP, and a three tiered approach is used as part of the 
MVIP to collect information on vaccine safety.  This includes strengthening of the 
pharmacovigilance system, the establishment and support of sentinel hospitals in the pilot areas, 
and a community based mortality surveillance system.  A functional pharmacovigilance system can 
provide the added effect of reassuring the public of a vaccine’s safety, especially if effective 
groups opposed to vaccines for any reason initiate or perpetuate rumours of vaccine safety and 
spurious associations with coincident adverse events to discourage vaccination in the population. 
 
The monitoring and reporting of AEFI should be included in the regular AEFI reporting and 
monitoring system. A system in place should facilitate prompt reporting and investigation of AEFIs. 
The NRA and the National Immunization Technical Advisory Group (NITAG) should take a proactive 
role in investigation of reports of serious adverse events to verify any link to vaccine and develop 
communication messages to address rumours. Clear procedures for what should be reported and 
how are necessary elements of any AEFI reporting system should be in place. Health workers will 
be trained on the recognition of adverse events, completion of the AEFI reporting form, and 
appropriate notification of supervisors and the district/county health officer, according to 
established protocols. Countries should ensure that vaccine adverse event monitoring is fully 
incorporated within the national AEFI guidelines prior to national introduction. 
 
Supportive supervision 
Once the RTS,S/AS01 vaccine is introduced, implementation should be monitored through 
supportive supervision, which includes “on-the-job training.” Supportive supervision strengthens 
the capacities of health workers and improves performance; visits can be used to provide 
feedback, update health staff on this and other vaccinations, enhance motivation, and identify 
training needs. 
 
Supervisor schedules and integrated checklist tools will be adapted to include the RTS,S/AS01 
vaccine. During supervisory visits, staff should be specifically asked about vaccine coverage and 
any problems (supply or demand) that they face with this vaccine. 
 
Administrative method to calculate vaccine coverage 
Calculating RTS,S/AS01 vaccine coverage is necessary for monitoring the impact of vaccine on a 
population, as well as for evaluating the performance of a vaccine programme toward meeting 
objectives. As with other EPI vaccines, administrative coverage will be supplemented by coverage 
surveys that will be conducted as part of the MVIP. 
 
RTS,S/AS01 vaccine coverage monitoring will rely on the monthly data compilation of number of 
doses, dose number and  age.  Following established practices, the child’s date of birth or age, 
date of vaccine administration, and the dose should be recorded in the immunization register and 

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on the child’s home-based vaccination record (immunization card) each time a vaccine is 
administered.   
 
A coverage monitoring wall chart for RTS,S/AS01 vaccination should be maintained and displayed 
in the health facility.  This chart should include the target population of children at the health 
facility or catchment area, and record the number of children vaccinated per month, per dose, 
over time, until the target is reached.   
 
 

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Annex 5: Governance and coordination structure for the RTS,S/AS01 
Malaria Vaccine Pilot Evaluation  
 
 
Abbreviations  
 
ADGs  
Assistant Director Generals in WHO 
FWC 
 
Family, Women’s and Children’s health cluster 
HTM  
HIV, TB and Malaria cluster in WHO 
AFRO  
WHO Regional Office for Africa  
DIRs 
 
Directors in WHO 
IVB 
 
Department of Immunizations, vaccines and biologicals 
GMP  
Global Malaria Programme 
CRO 
 
Clinical Research Organization 
EMP 
 
Essential Medicines and Health Products 
EPI 
 
Expanded Programme on Immunization 
GACVS  
Global Advisory Committee on Vaccine Safety 
MoH  
Ministry of Health 
MPAC  
Malaria Policy Advisory Committee 
NMCP  
National Malaria Control Programme 
NPV 
 
National Pharmacovigilance  
NRA 
 
National Regulatory Agency 
RD AFRO 
Regional Director of the WHO Regional Office for Africa 
SAGE  
Strategic Advisory Group of Experts on immunization 
 
WHO  
World Health Organization 
 
 
 

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Entity 
Function (high-level 
description) 
Composition 
Programme 
Leadership Team 
Decision-making on design, 
management and 
implementation of the MVIP, 
informed by progress reports 
from PCT and guidance from 
the PAC. 
WHO: Assistant Director-Generals of FWC and HTM 
and AFRO RD; Directors of IVB and GMP and AFRO 
Directors 
 
PATH leadership 
 
GSK leadership* 
Programme 
Coordination Team 
Coordinates and provides 
technical, managerial and 
administrative support to the 
Programme.  
 
Sets up and coordinates 
technical working groups 
 
Receives, processes and 
delivers information from 
countries to PLT and PAC. 
Mid-senior level technical staff  
 
WHO: IVB, GMP, EMP + AFRO 
 
PATH  
Country Co-
ordination Group 
Coordinates activities across 
all MVIPcomponents within a 
country - regulatory, vaccine 
implementation, evaluations 
-to ensure progress according 
to plans and protocols 
 
Reviews reports from 
national safety data review 
committee 
Mid-senior level technical staff  
 
Chaired by MoH 
 
Representatives from national EPI, NMCP, 
evaluation partners, NPV/NRA, and others as 
appropriate 
 
WHO and PATH country offices focal points 
Programme 
Advisory Group 
Monitors programme 
activities and provides 
scientific, technical and 
programmatic advice to PLT  
 
No executive, regulatory or 
decision-making function. 
 
Reports to SAGE & MPAC  
~10 people, including members of SAGE, MPAC, 
GACVS. 
 
Experts shall serve in their personal capacity. 
Funders Forum 
Reviews progress, including 
financial monitoring 
 
Advises on funding outlook  
 
Facilitates coordination of 
MVIP with other ongoing or 
Representatives of donor organizations financially 
contributing to MVIP (Gavi, UNITAID, Global Fund , 
BMGF) 
 
Observers: key donors to immunization / malaria 
without direct contribution to MVIP 

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future activities by funding 
agencies 
Data and Safety 
Monitoring Board 
Reviews safety data from the 
MVPE and the GSK Phase IV 
study on an ongoing basis in 
order to monitor and rapidly 
identify any accumulating 
safety signals from across the 
programme.  
Provides updates to the 
GACVS 
 
Can recommend to the PLT 
for the pilots to be stopped 
or altered in the event there 
is evidence of harm 
Experts in cerebral malaria and meningitis, as well as 
experts in vaccine safety 
 
Involves representatives of the safety monitoring 
groups in each country.  
 
 
 

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Annex 6. Community engagement in the MVIP 
 
Engagement and sensitization of community stakeholders will be an essential component of the 
Malaria Vaccine Implementation Programme (MVIP).  Community engagement will be important 
both for the vaccine introduction and implementation activities, and for the various components 
of the evaluation. In all efforts, the principles of the Good Participatory Practicei guidelines will 
guide efforts to ensure communities are engaged respectfully to build mutual understanding, to 
ensure integrity, transparency, accountability and ensure the autonomy of the community 
stakeholders.  
 
Comprehensive communication plans are under development by Ministries of Health in the three 
MVIP pilot countries to support vaccine introduction, including plans to guide community 
engagement. Community engagement will be focused at all relevant levels, including at the 
community and district/county levels within the MVIP pilot areas.  In accordance with WHO 
guidance on implied consent for vaccination,ii community engagement procedures will be 
designed to provide sufficient information to allow parents and caretakers to make informed 
decisions on whether to bring age-eligible children to clinics to receive the RTS,S/AS01 vaccine or 
whether to “opt-out” of RTS,S/AS01 vaccination.  
 
Engagement within the MVIP will be informed by data-driven communications plans and 
strategies that emphasize interactive communication approaches. For increased effectiveness, 
these plans will be informed by sociocultural data collected from African communities where 
malaria is a major public health issue. Working with countries and in collaboration with WHO, 
PATH has supported literature reviews that summarized sociocultural factors influencing decisions 
around the use of malaria prevention tools and care seeking behavior and vaccination uptake in 
sub-Saharan Africa. Additionally, PATH and country partners have conducted formative research, 
including within the MVIP countries of Ghana, Kenya and Malawi, to understand perceptions of 
malaria and vaccines and how those perceptions might affect the acceptability and uptake of a 
malaria vaccine.iii   Findings from the literature review and from the formative research are 
informing national communications and community mobilization strategies and the development 
of key messages.  
 
Communication plans under development include the identification of key stakeholders, especially 
those groups who will constitute critical audiences for community engagement within the MVIP. 
Key among these groups are those who make decisions on whether to bring young children for 
vaccination (parents and other caregivers). Other main audiences include those who have the 
potential to inform vaccination decisions (including health care workers, community health 
workers, grandparents, religious and traditional leaders, traditional healers, local government 
administrators, and nongovernmental organization representatives). Health workers will receive 
training on how to communicate effectively with caregivers, and will be provided information so 
that they accurately relay information on the benefits and risks of vaccination with RTS,S.   
 
Communication activities will address information gaps related to the RTS,S/AS01 malaria vaccine 
and will aim to increase understanding of the MVIP. Simple, evidence-based messages that 
provide information about the vaccine in the local languages will be developed. This information 
will include an explanation of who is the target population for vaccination and why that group; the 

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potential health benefits of the vaccine; the possible side effects; and simple information on how 
the vaccine works, what it does, and its role in the overall malaria control strategy. Messages will 
emphasize the partial efficacy of the vaccine (specifically, that vaccinated child will have fewer 
episodes of malaria, but still can become sick with malaria) and the need to continue to use 
malaria preventive measures, including insecticide treated bednets, and to seek care promptly for 
fever.  Messages to community members and health workers will emphasize the need to continue 
to test for malaria with a diagnostic tool, even among children who have received the RTS,S/AS01 
vaccine.  Where possible, messages will be packaged within the context of established child 
welfare programs. 
 
Communications plans and strategies for the MVIP will build on familiar practices already in use to 
engage communities and deliver information. Countries will have their own distinct processes for 
delivering health information, but familiar, interactive channels across countries include the use of 
gatherings called by chiefs and other senior community members (such as durbars in Ghana and 
barazas in Kenya), workshops, and vehicles with megaphone message-delivery.  
 
In conclusion, the community engagement activities supported as part of the MVIP are designed 
to ensure that caregivers of eligible children have the necessary information to make decisions on 
whether to receive the RTS,S/AS01 malaria vaccine. Communication plans are being developed in 
the three MVIP pilot countries to ensure effective delivery of key messages that will support 
families to make informed decisions on vaccination with RTS,S.  Activities will be conducted by 
MoH staff involved in the vaccination programs, and will be carried out within a timeframe that 
allows adequate time to address concerns and misconceptions. 
 
 
 
 
 
 
 
 
ihttps://www.avac.org/good-participatorypractice  
iiWorld Health Organization (WHO). (2014) Considerations regarding consent in vaccinating children and adolescents 
between 6 and 17 years old. WHO Press: Geneva. 
iiiOjakaa DI, Ofware P, Machira YW, Yamo E, Collymore Y, et al. (2011) Community perceptions of malaria and vaccines in the South Coast and Busia 
Regions of Kenya. Malar J 10: 147. doi:10.1186/1475-2875-10-147. 
iv Menaca A, Tagbor H, Adjei R, Bart-Plange C, Collymore Y, et al. (2014) Factors Likely to Affect Community Acceptance of a Malaria Vaccine in Two 
Districts of Ghana: A Qualitative Study. PLoS ONE 9(10): e109707. doi:10.1371/journal.pone.0109707. 

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Annex 7. 2014 cause of death list for verbal autopsy with corresponding 
ICD-10 codes 
 
Source: Verbal autopsy standards. The 2014 WHO verbal autopsy instrument.17 
Appendix 1. Column 1 contains the code for the verbal autopsy entity. Column 2 lists the related 
titles. Column 3 lists the ICD-10 codes that would be used if the condition labeled by column 2 
were coded to ICD-10. Column 4 lists the ICD-10 categories that need to be grouped to match the 
content of the relevant VA entity. 
Verbal 
autopsy code Verbal autopsy title 
ICD-10  
code (to  
ICD) 
ICD-10 
codes (from 
ICD) 
VAs-01 Infectious and parasitic diseases 
VAs-01.01 
Sepsis 
A41 
A40-A41 
VAs-01.02 
Acute respiratory infection,  
including pneumonia 
J22/J18 
J00-J22 
VAs-01.03 
HIV/AIDS related death 
B24 
B20-B24 
VAs-01.04 
Diarrheal diseases 
A09 
A00-A09 
VAs-01.05 
Malaria 
B54 
B50-B54 
VAs-01.06 
Measles 
B05 
B05 
VAs-01.07 
Meningitis and encephalitis 
G03;G04 
A39; G00-  
G05 
VAs-01.08 
Tetanus 
Excludes: Neonatal tetanus VAs-10.05 
A35 
(obstetrical 
A34) 
A33-A35 
VAs-01.09 
Pulmonary tuberculosis 
A16 
A15-A16 
VAs-01.10 
Pertussis 
A37 
A37 
VAs-01.11 
Haemorrhagic fever 
A99 
A92-A99 
VAs-01.12 
Dengue fever 
A90;A91 
A90-A91 
VAs-01.99 
Unspecified infectious disease 
B99 
A17-A19 
A20-A38; 
A42-A89; 
B00-B19; 
B25-B-49; 
B55-B99 
 

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Non-communicable diseases 
Note: 
This group covers all non-communicable conditions. Any infection of the systems that are listed 
in this section should be assigned to the suitable infectious disease category. Any maternal and 
perinatal condition should be assigned to the maternal and perinatal causes below. 
VAs-98 
Other 
and 
unspecified 
non-
communicable disease 
Note: 
This group covers all non-communicable 
conditions that could not be assigned to 
another category in this section. There is a 
separate category for cases where the 
cause of death is unknown. 
R99 
D55-D89; 
E00-E07; 
E15-E35; 
E50-E90; 
F00-F99; 
G06-G09 
G10-G37; 
G50-G99; 
H00-H95; 
J30-J39; 
J47-J99; 
K00-K31; 
K35-K38 
K40-K93; 
L00-L99; 
M00-M99; 
N00-N16; 
N20-N99; 
R00-R09 
R11-R94 
VAs-02 Neoplasms 
VAs-02.01 
Oral neoplasms 
C06 
C00-C06 
VAs-02.02 
Digestive neoplasms 
C26 
C15-C26 
VAs-02.03 
Respiratory neoplasms 
C39 
C30-C39 
VAs-02.04 
Breast neoplasms 
C50 
C50 
VAs-02.05 
Female reproductive neoplasms 
C57 
C51-C58 
VAs-02.06 
Male reproductive neoplasms 
C63 
C60-C63 
VAs-02.99 
Other and unspecified neoplasms 
C80 
C07-C14  
C40-C49  
C60-D48 
 
 
VAs-03 Nutritional and endocrine disorders 
VAs-03.01 
Severe anaemia 
D64 
D50-D64 
VAs-03.02 
Severe malnutrition 
E46 
E40-E46 
VAs-03.03 
Diabetes mellitus 
E14 
E10-E14 

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VAs-04 Diseases of the circulatory system 
VAs-04.01 
Acute cardiac disease 
I24 (acute 
ischemic) 
I20-I25 
VAs-04.02 
Stroke 
I64 
I60-I69 
VAs-04.03 
Sickle cell with crisis 
D57 
D57 
VAs-04.99 
Other and unspecified cardiac 
disease 
I99 
I00-I09 
I10-I15 
I26-I52 
I70-I99 
VAs-05 Respiratory disorders 
VAs-05.01 
Chronic obstructive pulmonary 
disease (COPD) 
J44 
J40-J44 
VAs-05.02 
Asthma 
J45 (J46) 
J45-J46 
VAs-06 Gastrointestinal disorders 
VAs-06.01 
Acute abdomen 
R10 
R10 
VAs-06.02 
Liver cirrhosis 
K74 
K70-K76 
VAs-07 Renal disorders 
VAs-07.01 
Renal failure 
N19 
N17-N19 
VAs-08 Mental and nervous system disorders 
VAs-08.01 
Epilepsy 
G40 
G40-G41 
 
 
 

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VAs-09 Pregnancy-, childbirth and puerperium-related  
disorders 
VAs-09.01 
Ectopic pregnancy 
O00 
O00 
VAs-09.02 
Abortion-related death 
O06 
O03-O08 
VAs-09.03 
Pregnancy-induced hypertension 
O13 (or 
O15 for 
eclampsia) 
O10-O16 
VAs-09.04 
Obstetric haemorrhage 
O46 (ante  
partum)  
O72 (post  
partum) 
O46; O67;  
O72 
VAs-09.05 
Obstructed labour 
O66 
O63-O66 
VAs-09.06 
Pregnancy-related sepsis 
O75.3 (ante 
partum)O85 
(post partum) 
O85; O75.3 
VAs-09.07 
Anaemia of pregnancy 
O99 
O99.0 
VAs-09.08 
Ruptured uterus 
O71 
O71 
VAs-09.99 
Other and unspecified maternal 
cause 
O05 
O01-O02; 
O20-O45; 
O47-O62; 
O68-O70; 
O73-O84; 
O86-O99 
VAs-10 Neonatal causes of death 
VAs-10.01 
Prematurity 
P07 
P05-P07 
VAs-10.02 
Birth asphyxia 
P21 
P20-P22 
VAs-10.03 
Neonatal pneumonia 
P23 
P23-P25 
VAs-10.04 
Neonatal sepsis 
P63 
P36 
VAs-10.05 
Neonatal tetanus 
A33 
A33 
VAs-10.06 
Congenital malformation 
Q89 
Q00-Q99 
VAs-10.99 
Other and unspecified perinatal 
cause of death 
P96 
P00-P04;  
P08-P15;  
P26-P35;  
P37-P94;  
P96 
 
 
 

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VAs-11 Stillbirths 
VAs-11.01 
Fresh stillbirth 
P95 
P95 
VAs-11.02 
Macerated stillbirth 
P95 
P95 
VAs-12 External causes of death 
Note: 
The list of questions contains sub 
questions that allow for more specificity  
for accidents. 
VAs-12.01 
Road traffic accident 
V89 
V01-V89 
VAs-12.02 
Other transport accident 
V99 
V90-V99 
VAs-12.03 
Accidental fall 
W19 
W00-W19 
VAs-12.04 
Accidental drowning and  
submersion 
W74 
W65-W74 
VAs-12.05 
Accidental exposure to smoke, fire 
and flames 
X09 
X00-X19 
VAs-12.06 
Contact with venomous animals and 
plants 
X29 
X20-X29 
VAs-12.07 
Accidental poisoning and exposure 
to noxious substance 
X49 
X40-X49 
VAs-12.08 
Intentional self-harm 
X84 
X60-X84 
VAs-12.09 
Assault 
Y09 
X85-Y09 
VAs-12.10 
Exposure to force of nature 
X39 
X30-X39 
VAs-12.99 
Other 
and 
unspecified 
external 
cause of death 
X59 
S00-T99; 
W20-W64; 
W75-W99; 
X50-X59; 
Y10-Y98 
 
VAs-99 
Cause of death unknown  
R99 
R95-R99 
 
 
 

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Annex 8: Verbal Autopsy for children aged four weeks to 11 years, 
adapted for MVIP impact evaluation 
 
Source: Verbal autopsy standards. The 2016 WHO verbal autopsy instrument.17 
 
 
2016 WHO VERBAL AUTOPSY 
SAMPLE QUESTIONNAIRE  
V1.4 
 
 
 
Death of a child aged four weeks to 11 years 
 
 
DK= answer means ‘don’t know’ 
Ref= answer means ‘refused to answer’ 
 
 
 
 

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No. 
Questions and filters 
Answer 
  
Ski
p 
  
 
1) INFORMATION ABOUT THE PREVALENCE OF MALARIA AND HIV  
 
 
 
 
10002 Is this an area of high HIV/AIDS prevalence? 
High 
   
  
  
  
Low 
   
  
  
  
Very low 
 
  
  
10003 Is this a region of high malaria prevalence? 
High 
   
  
  
  
Low 
   
  
  
  
Very low 
 
  
  
10004 During which season did (s)he die 
Wet 
   
  
  
  
Dry 
   
  
 
 
DK 
  
 
  
2) 
INFORMATION ABOUT THE RESPONDENT, CONSENT AND TIME OF 
INTERVIEW  
  
10007 What is the name of the VA respondent? 
  
  
  
  
  
____________________________________ 
  
  
  
  
10008 What is the respondent’s relationship to the deceased? 
Parent 
   
  
  
  
Child 
   
  
  
  
Other  
   
  
  
  
family 
member 
   
  
  
  
Friend 
   
  
  
  
Health 
worker 
   
  
  
  
Public 
official 
   
  
  
  
Another 
relationshi
p 
   
  
10009 Did the respondent live with the deceased in the 
period leading to her/his death? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10010 What is the name of the VA interviewer 
  
 
  
   
  
__________________________________________________ 
  
 
  
   
10011 Time at start of interview 
hh:mm 24h 
_________
  
  
  

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__ 
10012 Date of interview 
DAY                 
   
  
  
  
MONTH 

   
  
  
  
YEAR 

   
  
10013 Did the respondent give consent? 
YES 
   
  
  
  
NO 
   
  
  
3) 
INFORMATION ABOUT THE DECEASED 
  
  
  
  
  
3a) Socio-demographic information 
  
  
  
  
10017 What was the first or given name(s) of the deceased? 
  
  
  
  
  
________________________________________ 
  
  
  
  
10018 What was the surname or family name(s) of the deceased? 
  
  
  
  
  
__________________________________________ 
  
  
  
   
10019 What was the sex of the deceased? 
MALE 
   
  
  
  
FEMALE 
   
  
10020 Is the date of birth known? 
YES 
   
  
  
  
NO 
 ➡ 10022 
  
  
REF 
 ➡ 10022 
10021 When was the deceased born? 
DAY                    
  
  
  
MONTH 
   
  
  
  
YEAR 
   
  
10022 Is the date of death known? 
YES 
  
 
 
 
NO 
 ➡ AAAA 
 
 
REF 
 ➡ AAAA 
10023 When did (s)he die? 
DAY                 
   
  
  
  
MONTH 

   
  
  
  
YEAR 

   
  
AAAA Please indicate the age of the child in months or years 
Months 

   
   
    
Years 

  
   

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126 
 
age_g
roup 
What age group corresponds to the deceased? 
Neonate 
   
  
  
  
Child 
   
  
  
  
Adult 
   
  
10058 Where did the deceased die? 
Hospital 
  
 
  
  
Other 
health 
facility 
  
 
  
  
Home 
  
 
  
  
On route to 
facility or 
hospital 
  
 
  
  
Other 
  
 
  
  
DK 
  
 
  
  
Ref. 
  
 
10051 Is there a need to collect civil registration data on the 
deceased? 
YES 
   
  
  
  
NO 
 ➡ 10069 
 
10052 What was her/his citizenship / nationality? 
Citizen at 
birth 
   
  
  
  
Naturalized 
citizen 
   
  
  
  
Foreign 
national 
   
  
  
  
DK 
   
  
10053 What was her/his ethnicity? 
  
  
  
  
  
____________________________________ 
  
  
  
  
10054 What was his/her place of birth? 
  
  
  
  
  
_____________________________________ 
  
  
  
  
10055 What was his/her place of usual residence (the place where 
the person lived most of the year)? 
  
  
  
  
  
_________________ 
  
  
  
  
10056 
What was his/her place of usual residence 1 to 5 years 
before death? 
  
  
  
  
  
_________________ 
  
  
  
  
10057 Where did death occur?(specify country, province, district, 
village) 
  
  
  
  
  
_________________ 
  
  
  
  

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127 
10061 What was the name of the father? 
  
  
  
  
  
Surname 
  
  
  
  
  
_________________ 
  
  
  
  
  
Name  
  
  
  
  
  
_________________ 
  
  
  
  
10062 What is the name of the mother? 
  
  
  
  
  
Surname 
  
  
  
  
  
_________________ 
  
  
  
  
  
Name  
  
  
  
  
  
_________________ 
  
  
  
  
10063 What was her/his highest level of schooling? 
no formal 
education 
   
  
  
  
primary 
school 
   
  
  
  
Doesn't 
know 
   
  
  
  
Refused to 
answer 
   
  
10064 
Was (s)he able to read and write? (select 'yes' also if only 
one of either reading or writing is known to the 
respondent) 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10065 What was her/his economic activity status in year prior to 
death? 
Mainly 
unemploye
d 
   
  
  
  
Mainly 
employed 
   
  
  
  
Home-
maker 
   
  
  
  
Pensioner 
   
  
  
  
Student 
   
  
  
  
Other 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10066 What was her/his occupation, that is, what kind of work d 
(s)he mainly do? 
  
  
  
  
  
______________________________________________ 
  
  
  
  

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128 
  
3b) Civil registration information 
  
  
  
  
10069 Is there a need to collect civil registration numbers on the 
deceased? 
YES 
   
  
  
  
NO 
 ➡ 10077 
10070 Death registration number/certificate 
  
  
  
  
  
_________________ 
  
  
  
  
10071 Date of registration 
DAY                
   
  
  
  
MONTH 

   
  
  
  
YEAR 

   
  
10072 Place of registration 
  
  
  
  
  
_________________ 
  
  
  
  
10073 National identification number of deceased 
  
  
  
  
  
_________________ 
  
  
  
  
  
4) HISTORY AND DETAILS OF INJURIES/ ACCIDENTS 
  
  
  
  
10077 Did (s)he suffer from any injury or accident that led to 
her/his death? 
YES 
   
  
  
  
NO 
 ➡ 10120 
  
  
DK 
 ➡ 10120 
  
  
Ref. 
 ➡ 10120 
10079 Was it a road traffic accident? 
YES 
   
  
  
  
NO 
 ➡ 10082 
  
  
DK 
 ➡ 10082 
  
  
Ref. 
 ➡ 10082 
 
10080 What was her/his role in the road traffic accident? 
 Driver or 
passenger 
in bus or 
heavy 
vehicle 
 
  
  
  
  
Driver or 
passenger 
in a car or 
light 
vehicle 
 
  
  
  
  
Driver or 
passenger 
on a 
   
  

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129 
motorcycle 
  
  
Driver or 
passenger 
on a pedal 
cycle 
 
  
  
  
  
 Pedestrian    
  
10081 What was the counterpart that was hit during the road 
traffic accident? 
Pedestrian 
   
  
  
  
Stationary 
object 
   
  
  
  
Car or light 
vehicle 
   
  
  
  
Bus or 
heavy 
vehicle 
   
  
  
  
Motorcycle    
  
  
  
Pedal cycle    
  
  
  
Other 
   
  
10082 Was (s)he injured in a non-road traffic accident? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10083 Was (s)he injured in a fall? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10084 Was there any poisoning? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10085 Did (s)he die of drowning? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10086 Was (s)he injured by a bite or sting of venomous animal? 
YES 
 ➡ 10088 
  
  
NO 
   
  

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130 
  
  
DK 
   
  
  
  
Ref. 
   
  
10087 Was (s)he injured by an animal or insect (non-venomous) 
YES 
   
  
  
  
NO 
 ➡ 10089 
  
  
DK 
 ➡ 10089 
  
  
Ref. 
 ➡ 10089 
10088 What was the animal/insect? 
Dog 
   
  
  
  
Snake 
   
  
  
  
insect or 
scorpion 
   
  
  
  
Other 
   
  
  
  
DK 
   
  
10089 Was (s)he injured by burns/fire? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10090 Was (s)he subject to violence (homicide, abuse)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10091 Was (s)he injured by a fire arm? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10092 Was (s)he stabbed, cut or pierced? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10093 Was (s)he strangled? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 

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10094 Was (s)he injured by a blunt force? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10095 Was (s)he injured by a force of nature? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10096 Was it electrocution? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10097 Was (s)he injured by some other injury? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10098 Was the injury accidental? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10099 Was the injury or accident self-inflicted? 
YES 
   
   
  
  
NO 
   
   
  
  
DK 
   
   
  
  
Ref. 
   
  
10100 Was the injury or accident intentionally inflicted by 
someone else? 
Yes 
   
  
  
  
No 
   
  
  
  
DK 
   
  
  
  
Ref 
   
  
  
5) 
MEDICAL HISTORY ASSOCIATED WITH THE FINAL ILLNESS  
  
  
  
5a) Duration of final illness 
  
  
  
  
10120 For how long was (s)he ill before (s)he died? 
Days: 

   
  

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132 
    
Weeks: 

   
  
    
Months: 

   
  
 
10123 Did (s)he die suddenly? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
  
5b) History of diseases likely to be associated with or the cause of death  
  
  
10125 Was there any diagnosis by a health professional of 
tuberculosis? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10126 Was a HIV test ever positive? 
YES 
  
 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10127 Was there any diagnosis by a health professional of AIDS? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10128 Did (s)he have a recent positive test by a health 
professional for malaria? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10129 Did (s)he have a recent negative test by a health 
professional for malaria? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10130 Was there any diagnosis by a health professional of dengue 
fever? 
YES 
   
  
  
  
NO 
   
  

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DK 
   
  
  
  
Ref. 
   
  
10131 Was there any diagnosis by a health professional of 
measles? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10133 Was there any diagnosis by a health professional of heart 
disease? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10134 Was there any diagnosis by a health professional of 
diabetes? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10135 Was there any diagnosis by a health professional of 
asthma? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10136 Was there any diagnosis by a health professional of 
epilepsy? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10137 Was there any diagnosis by a health professional of cancer? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10142 Was there any diagnosis by a health professional of sickle 
cell disease? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  

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10143 Was there any diagnosis by a health professional of kidney 
disease? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10144 Was there any diagnosis by a health professional of liver 
disease? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
  
5c) General signs and symptoms associated with final 
illness 
  
  
  
  
10147 Did (s)he have a fever? 
YES 
  
 
  
  
NO 
 ➡ 10152 
  
  
DK 
 ➡ 10152 
  
  
Ref. 
 ➡ 10152 
10148 For how many days did the fever last? 
Days: 

   
  
10149 Did the fever continue until death? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10150 How severe was the fever? 
Mild 
   
  
  
  
Moderate 
   
  
  
  
Severe 
   
  
10151 What was the pattern of the fever? 
Continuous    
  
  
  
On and off 
   
  
  
  
Only at 
night 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10152 Did (s)he have night sweats? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  

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10153 Did (s)he have a cough? 
YES 
   
  
  
  
NO 
 ➡ 10159 
  
  
DK 
 ➡ 10159 
  
  
Ref. 
 ➡ 10159 
10154 For how many days did (s)he have a cough? 
DAYS 

   
  
10155 Was the cough productive, with sputum? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10156 Was the cough very severe? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10157 Did (s)he cough up blood? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10158 Did (s)he make a whooping sound when coughing? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10159 Did (s)he have any difficulty breathing? 
YES 
   
  
  
  
NO 
 ➡ 10166 
  
  
DK 
 ➡ 10166 
  
  
Ref. 
 ➡ 10166 
10161 For how many days did the difficulty breathing last? 
DAYS 

   
  
10165 Was the difficulty continuous or on and off? 
Continuous    
  
  
  
On and off 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  

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10166 During the illness that led to death, did (s)he have fast 
breathing? 
YES 
   
  
  
  
NO 
 ➡ 10168 
  
  
DK 
 ➡ 10168 
  
  
Ref. 
 ➡ 10168 
10167 For how many days did the fast breathing last? 
DAYS 

   
  
10168 Did (s)he have breathlessness? 
YES 
   
  
  
  
NO 
 ➡ 10172 
  
  
DK 
 ➡ 10172 
  
  
Ref. 
 ➡ 10172 
10169 For how many days did (s)he have breathlessness? 
DAYS 

   
  
10172 Did you see the lower chest wall/ribs being pulled in as the 
child breathed? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
 

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10173 During the illness that led to death did his/her breathing 
sound like any of the following:  
Stridor 
   
  
  
  
Grunting 
   
  
  
  
Wheezing 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10174 Did (s)he have chest pain? 
YES 
   
  
  
  
NO 
 ➡ 10181 
  
  
DK 
 ➡ 10181 
  
  
Ref. 
 ➡ 10181 
10176 How many days before death did (s)he have chest pain? 
DAYS 

   
  
10181 Did (s)he have more frequent loose or liquid stools than 
usual? 
YES 
   
  
  
  
NO 
 ➡ 10186 
  
  
DK 
 ➡ 10186 
  
  
Ref. 
 ➡ 10186 
10182 For how many days did (s)he have frequent loose or liquid 
stools? 
DAYS 

   
  
10183 How many stools did the baby or child have on the day that 
loose liquid stools were most frequent? 
NUMBER 
OF STOOLS: 

   
  
10184 How many days before death did the frequent loose or 
liquid stools start? 
DAYS 

   
  
10185 Did the frequent loose or liquid stools continue until death? YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10186 At any time during the final illness was there blood in the 
stools? 
YES 
   
  
  
  
NO 
 ➡ 10188 
  
  
DK 
 ➡ 10188 
  
  
Ref. 
 ➡ 10188 
10187 Was there blood in the stool up until death? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  

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Ref. 
   
  
10188 Did (s)he vomit? 
YES 
   
    
  
  
NO 
 
  
  
DK 
 
  
  
Ref. 
 
10189 Did (s)he vomit in the week preceding death? 
YES 
   
  
  
  
NO 
 ➡ 10193 
  
  
DK 
 ➡ 10193 
  
  
Ref. 
 ➡ 10193 
10191 
Did (s)he vomit blood? 
YES 
   
  
  
  
NO 
 
  
  
DK 
 
  
  
Ref. 
 
10192 Was the vomit black? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10193 
Did (s)he have any belly (abdominal) problem? 
YES 
   
  
  
  
  
NO 
   
  
  
  
  
DK 
   
  
  
  
  
Ref. 
   
  
  
10194 Did (s)he have belly (abdominal) pain? 
YES 
   
  
  
  
NO 
 ➡ 10200 
  
  
DK 
 ➡ 10200 
  
  
Ref. 
 ➡ 10200 
10195 Was the belly (abdominal) pain severe? 
YES 
   
  
  
  
NO 
 ➡ 
10200 
  
  
  
DK 
 ➡ 
10200 
  
  
  
Ref. 
 ➡ 
10200 
  
10196 For how long before death did (s)he have severe abdominal 
pain? 
HOURS 

   
  

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10197 For how many days before death did (s)he have severe 
abdominal pain? 
DAYS 

  
 
  
WEEKS 

  
 
10198 For how many months before death did (s)he have severe 
abdominal pain? 
MONTHS 

  
 
 
10199 Was the pain in the upper or lower abdomen? 
Upper 
abdomen 
  
 
  
  
Lower 
abdomen 
   
  
  
  
Upper and 
lower 
abdomen 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10200 Did (s)he have a more than usually protruding abdomen? 
YES 
   
  
  
  
NO 
 ➡ 10204 
  
  
DK 
 ➡ 10204 
  
  
Ref. 
 ➡ 10204 
10201 For how many days did (s)he have a more than usually 
protruding abdomen? 
DAYS 

   
  
10202 For how many months did (s)he have a more than usually 
protruding abdomen? 
MONTHS 

   
  
10203 How rapidly did (s)he develop the protruding abdomen? 
Rapidly 
   
  
  
  
Slowly 
   
  
10204 Did (s)he have any mass in the abdomen? 
YES 
   
  
  
  
NO 
 ➡ 
1020
7 
  
  
DK 
 ➡ 
1020
7 
  
  
Ref. 
 ➡ 10207 
10205 For how many days before death did (s)he have a mass in 
the abdomen? 
DAYS 

   
  
10206 For how many months before death did (s)he have a mass 
in the abdomen? 
MONTHS 

   
  
10207 Did (s)he have a severe headache? 
YES 
   
  

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140 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10208 Did (s)he have a stiff neck during illness that led to death? 
YES 
   
  
  
  
NO 
 ➡ 
1021
0 
  
  
DK 
 ➡ 
1021
0 
  
  
Ref. 
 ➡ 10210 
10209 For how many days before death did (s)he have stiff neck? 
DAYS 

   
  
10210 Did (s)he have a painful neck during the illness that led to 
death? 
YES 
   
  
  
  
NO 
 ➡ 
1021
4 
  
  
DK 
 ➡ 
1021
4 
  
  
Ref. 
 ➡ 
1021
4 
 
10211 For how many days before death did (s)he have a painful 
neck? 
DAYS 

   
  
10214 Was (s)he unconscious during the illness that led to death? 
YES 
   
    
  
  
NO 
 ➡ 
1021
9 
  
  
DK 
 ➡ 
1021
9 
  
  
Ref. 
 ➡ 
1021
9 
10215 Was (s)he unconscious for more than 24 hours before 
death? 
YES 
 ➡ 
1021
7 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
141 
10216 How many hours before death did unconsciousness start? 
Hours 

   
  
10217 Did the unconsciousness start suddenly, quickly (at least 
within a single day)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10218 Did the unconsciousness continue until death? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10219 Did (s)he have convulsions? 
YES 
   
  
  
  
NO 
 ➡ 
1022
3 
  
  
DK 
 ➡ 10223 
  
  
Ref. 
 ➡ 10223 
10220 Did (s)he experience any generalized convulsions or fits 
during the illness that led to death? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10221 For how many minutes did the convulsions last? 
MINUTES: 

   
  
10222 Did (s)he become unconscious immediately after the 
convulsion? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
 

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
142 
10223 Did (s)he have any urine problems? 
YES 
   
  
  
  
NO 
 ➡ 10227 
  
  
DK 
 ➡ 10227 
  
  
Ref. 
 ➡ 10227 
10224 Did (s)he stop urinating? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10225 Did (s)he go to urinate more often than usual? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10226 During the final illness, did (s)he ever pass blood in the 
urine? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10227 Did (s)he have sores or ulcers anywhere on the body? 
YES 
   
  
  
  
NO 
 ➡ 10230 
  
  
DK 
 ➡ 10230 
  
  
Ref. 
 ➡ 10230 
10229 Did the sores have clear fluid or pus? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10230 Did (s)he have an ulcer (pit) on the foot? 
YES 
   
  
  
  
NO 
 ➡ 
1023
3 
  
  
DK 
 ➡ 10233 
  
  
Ref. 
 ➡ 10233 
10231 Did the ulcer on the foot ooze pus? 
YES 
   
  
  
  
NO 
 ➡ 
1023
3 

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
143 
  
  
DK 
 ➡ 10233 
  
  
Ref. 
 ➡ 10233 
10232 For how many days did the ulcer on the foot ooze pus? 
DAYS 

   
  
 
10233 During the illness that led to death, did (s)he have any skin 
rash? 
YES 
   
  
  
  
NO 
 ➡ 
1023
8 
  
  
DK 
 ➡ 
1023
8 
  
  
Ref. 
 ➡ 
1023
8 
10234 For how many days did (s)he have the skin rash? 
DAYS 

   
  
10235 Where was the rash? 
Face 
   
  
  
  
Trunk or 
abdomen  
   
  
  
  
Extremities    
  
  
  
Everywhere    
  
10236 Did (s)he have measles rash (use local term)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10238 During the illness that led to death did his/her skin flake off 
in patches? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10239 During the illness that led to death did he/ she have areas 
of skin that turned black? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10240 During the illness that led to death did he/ she have areas 
of the skin with redness or swelling? 
YES 
   
  
  
  
NO 
   
  

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144 
  
  
DK 
   
  
  
  
Ref. 
   
  
10241 During the illness that led to death, did (s)he bleed from 
anywhere? 
YES 
   
  
  
  
NO 
 ➡ 10243 
  
  
DK 
 ➡ 10243 
  
  
Ref. 
 ➡ 10243 
10242 Did (s)he bleed from the nose, mouth or anus? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10243 Did (s)he have noticeable weight loss? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10244 Was (s)he severely thin or wasted? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10245 During the illness that led to death, did s/he have a whitish 
rash inside the mouth or on the tongue? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10246 Did (s)he have stiffness of the whole body or was unable to 
open the mouth? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10247 Did (s)he have puffiness of the face? 
YES 
   
  
  
  
NO 
 ➡ 
1024
9 
  
  
DK 
 ➡ 
1024
9 

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
145 
  
  
Ref. 
 ➡ 
1024
9 
10248 For how many days did (s)he have puffiness of the face? 
DAYS 

   
  
10249 During the illness that led to death, did (s)he have swollen 
legs or feet? 
YES 
   
  
  
  
NO 
 ➡ 
1025
2 
  
  
DK 
 ➡ 
1025
2 
  
  
Ref. 
 ➡ 
1025
2 
10250 How many days did the swelling last? 
DAYS 

   
  
10251 Did (s)he have both feet swollen? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10252 Did (s)he have general puffiness all over his/her body? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10253 Did (s)he have any lumps? 
YES 
   
  
  
  
NO 
 ➡ 
1025
8 
  
  
DK 
 ➡ 
1025
8 
  
  
Ref. 
 ➡ 
1025
8 
10255 Did (s)he have any lumps on the neck? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
146 
10256 Did (s)he have any lumps on the armpit? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10257 Did (s)he have any lumps on the groin? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10258 Was (s)he in any way paralysed? 
YES 
   
  
  
  
NO 
 ➡ 10261 
  
  
DK 
 ➡ 10261 
  
  
Ref. 
 ➡ 10261 
10259 Did s(he) have paralysis of only one side of the body? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10260 Which were the limbs or body parts paralysed? 
Right side 
   
  
  
  
Left side 
   
  
  
  
Lower part 
of body 
   
  
  
  
Upper part 
of body 
   
  
  
  
One leg 
only 
   
  
  
  
One arm 
only 
   
  
  
  
Whole 
body 
   
  
  
  
Other 
   
  
 
 

RTS,S/AS01 Malaria Vaccine Pilot Evaluation            RTS,S MVIP v9.0 22 Apr2020 
 
147 
10261 Did (s)he have difficulty swallowing? 
YES 
   
  
  
  
NO 
 ➡ 10264 
  
  
DK 
 ➡ 10264 
  
  
Ref. 
 ➡ 10264 
10262 For how many days before death did (s)he have difficulty 
swallowing? 
DAYS 

   
  
10263 Was the difficulty with swallowing with solids, liquids, or 
both? 
Solids 
   
  
  
  
Liquids 
   
  
  
  
Both 
   
  
10264 Did (s)he have pain upon swallowing? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10265 Did (s)he have yellow discoloration of the eyes? 
YES 
   
  
  
  
NO 
 ➡ 10267 
  
  
DK 
 ➡ 10267 
  
  
Ref. 
 ➡ 10267 
10266 For how many days did (s)he have the yellow discoloration? DAYS 

   
  
10267 Did her/his hair change in colour to a reddish or yellowish 
colour? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10268 Did (s)he look pale (thinning/lack of blood) or have pale 
palms, eyes or nail beds? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10269 Did (s)he have sunken eyes? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10270 Did (s)he drink a lot more water than usual? 
YES 
   
  

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148 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
 
5d) Signs and symptoms relevant for neonatal and child deaths 
 
 
 
NOTE THE NEXT SECTION UP TO ID10418 
SHOULD ONLY BE ASKED IF THE DECEASED 
WAS ONE YEAR OLD OR LESS 
 
 
 
 
10271 Was the baby able to suckle or bottle-feed within the first 
24 hours after birth? 
YES 
   
  
    
NO 
   
  
    
DK 
   
  
    
Ref. 
   
  
10272 Did the baby ever suckle in a normal way? 
YES 
   
  
    
NO 
   
  
    
DK 
   
  
    
Ref. 
   
  
10273 Did the baby stop suckling? 
YES 
   
  
    
NO 
 ➡ 
1027
5 
    
DK 
 ➡ 
1027
5 
    
Ref. 
 ➡ 
1027
5 
10274 How many days after birth did the baby stop suckling? 
Days:  

   
  
10275 Did the baby have convulsions in the first 24 hours of life? 
YES 
 ➡ 
1027
7 
    
NO 
   
  
    
DK 
   
  
    
Ref. 
   
  
10276 Did the baby have convulsions starting more than 24 hrs 
after birth? 
YES 
   
  
    
NO 
   
  
    
DK 
   
  

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149 
    
Ref. 
   
  
10277 Did the baby's body become stiff, with the head arched 
backwards? 
YES 
   
  
    
NO 
   
  
    
DK 
   
  
    
Ref. 
   
  
10278 During the illness that led to death did the baby have a 
bulging or raised fontanelle? 
YES 
 ➡ 
1028
1 
  
 
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10279 During the illness that led to death did the baby have a 
sunken fontanelle? 
YES 
   
  
  
 
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10281 During the illness that led to death, did the baby become 
unresponsive or unconscious? 
YES 
  
 
  
NO 
  
 
  
DK 
  
 
  
Ref. 
  
 
10282 Did the baby become unresponsive or unconscious soon 
after birth, within less than 24 hours? 
YES 
  
 
  
NO 
  
 
  
DK 
  
 
  
Ref. 
  
 
10283 Did the baby become unresponsive or unconscious more 
than 24 hours after birth? 
YES 
  
 
  
NO 
  
 
  
DK 
  
 
  
Ref. 
  
 
10352 How many years old was the child when the fatal illness 
started? 
YEARS: 

   
  
10354 Was the child part of a multiple birth? 
YES 
   
  
  
  
NO 
 ➡ 10356 
  
  
DK 
 ➡ 10356 

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150 
  
  
Ref. 
 ➡ 10356 
10355 Was the child the first, second, or later in the birth order? 
First 
   
  
  
  
Second or 
later 
   
  
10356 Is the mother still alive? 
YES 
 ➡ 
1036
0 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10357 Did the mother die during or after the delivery? 
During 
delivery 
 
 
➡ 
1036
0 
  
  
After 
delivery 
   
  
10358 How many months after delivery did the mother die? 
Months: 

   
  
10359 How many days after delivery did the mother die? 
Days:  

   
  
 
10360 Where was the deceased born? 
Hospital 
   
  
  
  
Other 
health 
facility 
   
  
  
  
Home 
   
  
  
  
On route to 
hospital or 
facility 
   
  
  
  
Other 
   
  
  
  
DK 
   
  
  
  
Ref 
   
  
10361 Did the mother receive professional assistance during the 
delivery? 
YES 
 
  
(ask only up to one year) 
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10362 At birth was the baby of usual size? 
YES 
 ➡ 
1036
5 
  
  
NO 
  
 
  
  
DK 
  
 

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151 
  
  
Ref. 
  
 
10363 At birth was the baby smaller than usual (weighing under 
2.5 kg)? 
YES 
   
  
  
  
NO 
 ➡ 
1036
5 
  
  
DK 
 ➡ 
1036
5 
  
  
Ref. 
 ➡ 
1036
5 
10364 At birth was the baby very much smaller than usual 
(weighing under 1 kg)? 
YES 
 ➡ 
1036
6 
  
  
NO 
 ➡ 
1036
6 
  
  
DK 
 ➡ 
1036
6 
  
  
Ref. 
 ➡ 
1036
6 
10365 At birth was the baby larger than usual (weighing over 4.5 
kg)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10366 What was the weight in grammes of the deceased at birth? 
GRAMMES 


   
  
  Note 1kg = 1000 grammes 
Don't Know    
  
  
10367 How many months long was the pregnancy before birth? 
Months: 

   
  
  
(ask only up to one year) 
Don't Know    
  
 
 

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152 
10368 Were there any complications in the late part of the 
pregnancy (defined as the last 3 months before labour)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10369 Were there any complications during labour or delivery? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10370 Was any part of the baby physically abnormal at time of 
delivery? 
YES 
   
  
  
(for example body part too large or too small) 
NO 
 ➡ 10418 
  
  
DK 
   
  
  
  
Ref. 
   
  
10371 Did the baby/child have swelling or a defect on the back at 
time of birth? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10372 Did the baby/child have a very large head at time of birth? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10373 Did the baby/child have a very small head at time of birth? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
 
  
  
Ref. 
 
10408 Before the illness that led to death was the baby/ child 
growing normally? 
YES 
 
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
  
5e) Health service and contextual factors 
  
  
  
  
10418 Did (s)he receive any treatment for the illness that led to 
death? 
YES 
   
  
  
  
NO 
 ➡ 10428 

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153 
  
  
DK 
 ➡ 10428 
  
  
Ref. 
 ➡ 10428 
 
10419 Did (s)he receive oral rehydration salts? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10420 Did (s)he receive (or need) intravenous fluids (drip) 
treatment? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10421 Did (s)he receive (or need) a blood transfusion? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10422 Did (s)he receive (or need) treatment/food through a tube 
passed through the nose? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10423 Did (s)he receive (or need) injectable antibiotics? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10424 Did (s)he receive (or need) antiretroviral therapy (ART)? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10425 Did (s)he have (or need) an operation for the illness? 
YES 
   
  
  
  
NO 
 ➡ 10427 
  
  
DK 
 ➡ 10427 
  
  
Ref. 
 ➡ 10427 
10426 Did (s)he have the operation within 1 month before death? 
YES 
   
  

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NO 
  
 
  
  
DK 
  
 
  
  
Ref. 
  
 
 
10427 Was (s)he discharged from hospital very ill? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10428 Had (s)he received immunisation? 
YES 
   
  
  
  
NO 
 ➡ 10432 
  
  
DK 
 ➡ 10432 
  
  
Ref. 
 ➡ 10432 
10429 Do you have the child's vaccination card? (If no vaccination 
card, ascertain vaccinations through verbal recall) 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10430 
Can I see the vaccination card (and note the vaccines the 
child received)? (If vaccination card can not be seen, 
ascertain vaccinations through verbal recall) 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10431 Note vaccines here (including RTS,S) 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
10432 Was care sought outside the home while (s)he had this 
illness? 
YES 
   
  
  
  
NO 
 ➡ 10450 
  
  
DK 
 ➡ 10450 
  
  
Ref. 
 ➡ 10450 
 
10433 Where or from whom did you seek this care? 
traditional 
healer 
   
  

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homeopath    
  
  
  
religious 
leader 
   
  
  
  
governmen
t hospital 
   
  
  
  
governmen
t health 
centre or 
clinic 
 
  
  
  
  
private 
hospital 
   
  
  
  
community
-based 
practitioner 
associated 
with health 
system 
 
  
  
  
  
trained 
birth 
attendant 
   
  
  
  
private 
physician 
   
  
  
  
Relative, 
friend 
(outside 
household) 
 
  
  
  
  
pharmacy 
   
  
  
  
Doesn't 
know 
   
  
  
  
Refused to 
answer 
   
  
10434 Record the name and address of any hospital health centre 
or clinic where help was sought: 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
10435 Did a health care worker tell you the cause of death? 
YES 
   
  
  
  
NO 
 ➡ 
1043
7 
  
  
DK 
 ➡ 10437 
  
  
Ref. 
 ➡ 10437 
10436 What did the health care worker say? 
  
  
  
  
  
__________________________________ 
  
  
  
  

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__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
  
__________________________________ 
  
  
  
  
 
10437 Do you have any health care records that belonged to the 
deceased? 
YES 
   
  
  
  
NO 
 ➡ 
1044
5 
  
  
DK 
 ➡ 
1044
5 
  
  
Ref. 
 ➡ 
1044
5 
10438 Can I see the health records? 
YES 
   
  
  
  
NO 
 ➡ 
1044
5 
  
  
DK 
 ➡ 
1044
5 
  
  
Ref. 
 ➡ 
1044
5 
10439 Record the date of the most recent (last) visit 
Day 

   
  
  
  
Month 

   
  
  
  
Year 

   
  
10445 Has the deceased's (biological) mother ever been tested for 
HIV? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10446 Has the deceased’s (biological) mother ever been told she 
had HIV/AIDS by a health worker? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10450 In the final days before death, did s/he travel to a hospital 
or health facility? 
YES 
   
  

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NO 
 ➡ 10455 
  
  
DK 
 ➡ 10455 
  
  
Ref. 
 ➡ 10455 
10451 Did (s)he use motorised transport to get to the hospital or 
health facility? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10452 Were there any problems during admission to the hospital 
or health facility? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
10453 
Were there any problems with the way (s)he was treated 
(medical treatment, procedures, interpersonal attitudes, 
respect, dignity) in the hospital or health facility? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10454 Were there any problems getting medications, or 
diagnostic tests in the hospital or health facility? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10455 Does it take more than 2 hours to get to the nearest 
hospital or health facility? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10456 in the final days before death were there any doubts about 
whether medical care was needed? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10457 in the final days before death, was traditional medicine 
used? 
YES 
   
  
  
  
NO 
   
  

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DK 
   
  
  
  
Ref. 
   
  
10458 In the final days before death, did anyone use a telephone 
or cell phone to call for help? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
10459 Over the course of illness, did the total costs of care and 
treatment prohibit other household payments? 
YES 
   
  
  
  
NO 
   
  
  
  
DK 
   
  
  
  
Ref. 
   
  
 
  
5f) Information from death certificate 
YES 
   
  
10462 Was a death certificate issued? 
NO 
 ➡ 10481 
  
  
DK 
 ➡ 10481 
  
  
Ref. 
 ➡ 10481 
10463 Can I see the death certificate? 
YES 
   
  
  
  
NO 
 ➡ 10481 
  
  
DK 
 ➡ 10481 
  
  
Ref. 
 ➡ 10481 
10464 Record the immediate cause of death from the certificate 
(line 1a) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10465 Duration (1a) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10466 Record the first antecedent cause of death from the 
certificate  (line 1b) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10467 Duration (1c) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10468 Record the second antecedent cause of death from the 
certificate (line 1c) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10469 Duration (1c) 
  
  
  
  
  
__________________________________ 
  
  
  
  

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10470 Record the third antecedent cause of death from the 
certificate (line 1d) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10471 Duration (1d) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10472 Record the contributing cause(s) of death from the 
certificate (part 2) 
  
  
  
  
  
__________________________________ 
  
  
  
  
10473 Duration (part 2) 
  
  
  
  
  
__________________________________ 
  
  
  
  
 
 
6) NARRATIVE DESCRIPTION OF FINAL ILLNESS 
 
 
 
 
10476 NARRATIVE DESCRIPTION 
  
  
 
 
  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________ 
 _______________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________ 
  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________ 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7) CHECK LIST OF KEY INDICATORS FROM THE NARRATIVE DESCRIPTION 
 
 
10478 Are any of the following words of interest mentioned in the 
above narrative? 
Abdomen 
 
 
 
  
  
Cancer 
  
 
  
  
Dehydration   
 
  
  
Dengue 
fever 
  
 
  
  
Diarrhoea 
  
 

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Fever 
  
 
  
  
Heart 
problems 
  
 
  
  
Jaundice 
(yellow skin 
or eyes) 
  
 
 
 
Pneumonia 
  
 
 
 
Rash 
  
 
 
 
None of the 
above 
words were 
mentioned 
 
 
 
 
 
Don’t know 
  
 
10481 
Time at end of interview ____________________ 
 
 
 
 
 
 
 
 
 

Pilot implementation of RTS,S/AS01 
 
161 
Annex 9. Village Reporter CRF 
 
 
A. DETAILS OF THE DECEASED  
 
0. 
District / Sub-District /Community  
1. 
Serial number 
 
2. 
Full name of deceased 
 
 
3. 
Date of birth (day/month/year) 
 
4. 
Sex of deceased 
 
5. 
Date of death (day/month/year) 
 
 
 
6. 
Place of death 
 
7. 
Usual place of residence 
 
8. 
RTS,S status (if feasible) 
 
 
B. DETAILS OF THE INFORMANT 
 
1. 
Full name of informant 
 
 
2. 
Address 
 
3. 
Telephone number 
 
4. 
Date of reporting 
 
 
Note: This is not a burial permit or a death certificate. 
 
DECLARATION 
 
I ……………………………………………………………………….. do hereby declare  
 
that I have been notified of the death of  
 
………………………………………………………………… and permission is hereby  
 
granted for the burial of the deceased  after the registration of the death with the Birth  
 
and Death Registry. 
Name:  
 
………………………………………………………………………. 
Title:   
 
………………………………………………………………………… 

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162 
Signature 
 
……………………………………………………………………. 
Date (D 
AY/MONTH/YEAR)  …………………………………………

Pilot implementation of RTS,S/AS01 
 
163 
Annex 10. CRF for impact evaluation 
Variable format/type  
Question  
Select one GHA/KEN/MLW 
Country 
Select one YES or NO 
Was consent obtained ? 
Alphanumeric 
If Y, then include unique identifier of 
consent form 
Death reported  
day/month/year 
Date death reported  
Alphanumeric 
ID of the VR  
Demographics  
Drop down  
Cluster  
Drop down list  
Village name  
Text  
Name of respondent  
Drop down list  
Relation of respondent  
Date 
Date of VA interview  
XX:XX hrs  
Time of VA interview  
Text  
Compound head name (KENYA ONLY) 
Text  
 What was the first or given name(s) of 
the deceased? 
Text  
 What was the surname (or family name) 
 of the deceased? 
Text  
Initials of the deceased  
Select one MALE or FEMALE  
What was the sex of the deceased? 
Select one YES or NO 
Is the date of birth known? 
Date 
When was the deceased born? 
Select one YES or NO 
Is the date of death known? 
Date 
When did (s)he die? 
Number  
How old was the deceased when they 
died (Age at death in months) 
Select LOCATION from drop down list  
What was her/his place of death? 
Select HOME or HEALTH FACILITY or OTHER  
Where was her/his place of death? 
Select IMPLEMENTING or COMPARATOR cluster  
What was her/his place of usual 
residence? (the place where the person 
lived most of the year) 
Drop down list  
Cluster of residence  
Period (months) 
How long had the deceased lived there?  
Longitude  
Longitude GPS coordinates of the 
household  

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Latitude  
Latitude GPS coordinates of the 
household  
Select one YES or NO 
 Did the deceased receive any 
vaccinations since birth? 
Select one YES or NO 
Is there a vaccination record available  
Photo taken YES or NO 
If YES to vaccination record available, 
take a photograph of the vaccine record  
Select one HEALTH RECORD OR MATERNAL RECALL or 
HEALTH FACILITY REGISTER  
Record vaccines received  
Date  
BCG 
Date  
OPV 0 
Date  
OPV 1 
Date  
OPV 2 
Date  
OPV 3 
Date  
IPV 
Date  
Pentavalent 1 
Date  
Pentavalent 2 
Date  
Pentavalent 3 
Date  
PCV 1 
Date  
PCV 2 
Date  
PCV 3 
Date  
RTS,S 1 
Date  
RTS,S 2 
Date  
RTS,S 3 
Date  
RTS,S 4 
Date  
Rotavirus vaccine 1 
Date  
Rotavirus vaccine 2 
Date  
Measles 1 
Date  
Measles 2 
Date  
Meningitis A vaccine  
Date  
Yellow fever vaccine  
Select one YES or NO 
Was VA form completed  
Number  
Provide the VA form ID  
Alphanumeric 
Unique ID of person conducting VA  

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Alphanumeric 
Unique ID of person reviewing VA  
Select one YES or NO 
If YES to death registration certificate, 
take a photograph 
Photo taken YES or NO 
Do you have a death registration 
certificate? 
Select one YES or NO 
Was VA form coded 
Select interVA or SmartVA or InsilicoVA  
If coded, provide name of algorithm  
Select one YES or NO 
Was cause of death classified  
Select ICD group  
What was the ICD 10 group 
Select ICD cause of death  
What was the ICD 10 cause of death  
Notes for mortality CRF 
Question on the variable 
list  
Instructions and notes  
Time of VA start  
For QA purposes  
Time of VA end  
For QA purposes  

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 What was the surname 
(or family name) 
 of the deceased? 
Only record for data triangulation exercise on the ground, but strip 
before sending data further up the chain 
When was the deceased 
born? 
Use local event calendar?? Verify date of birth using card/some other 
documentation? This variable should allow for month/year as well (in 
case doesn't know day) 
How old was the deceased 
when they died (Age at 
death in months) 
Use local event calendar?? Verify date of birth using card/some other 
documentation? This variable should allow for month/year as well (in 
case doesn't know day) 
Record vaccines received  
If not available on MCH or maternal record, get from health facility 
register and indicate source of register 
Was VA form completed  
The VA form completed should be the 2016 WHO verbal autopsy 
instrument for children aged 4 weeks to 11 years  

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Annex 11. Vaccination Registry  
 
 
 

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168 
Annex 12. Sentinel hospital CRF  
Type  
Question  
Select one GHA/KEN/MLW 
Country 
Select one YES or NO 
Has consent been obtained ? 
Alphanumeric 
If Y, then include unique 
identifier of consent form 
Drop down list  
Name of sentinel hospital  
Number  
Indicate the inpatient number for 
this admission  
Text  
What is the first or given name(s) 
of the child ? 
  
Text  
What is the surname (or family 
name) of the child? 
  
Text  
Initials of the child (use 3 letters) 
Demographics  
Select IMPLEMENTING or COMPARATOR 
cluster  
What is her/his place of usual 
residence? (the place where the 
person lived most of the year) 
Text or drop down  
Cluster of residence  
Select one YES or NO 
Have the child been resident in 
this location during this illness? 
Select one MALE or FEMALE  
What is the sex of the child? 
 
Select one YES or NO 
Is the date of birth known? 
YYYY 
When is the child born? 
MMM 
When is the child born? 
DD 
When is the child born? 
DDMMMYYYY 
What is the date of this 
admission ? 
Number  
Age at admission (months) 
 
Select one YES or NO 
Is this the first admission ? 
Number  
If not the first admission, indicate 
number of previous admissions in 
the last 12 months  
YYYY 
If not the first admission, indicate the date of the 
last admission  
MMM 
If not the first admission, indicate the date of the 
last admission  
DD 
If not the first admission, indicate the date of the 
last admission  
Select one YES or NO 
Is the child enrolled in a clinical 
or intervention trial ? 
 

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Select one YES or NO 
Does the child  have a bed net ? 
 
Select one YES or NO 
Does the child sleep under a  bed net on the night 
before admission? 
Select one YES or NO 
At any time in the last 12 months 
has anyone sprayed the interior 
walls of your dwelling against 
mosquitoes ? 
 
Vaccinations  
For all children, just record RTS,S 
status; then if there is a 
meningitis or cerebral malaria, 
record all vaccines.   
Select one YES or NO 
Did the child receive any 
vaccinations since birth? 
Select one YES or NO 
Is there a vaccination record 
available  
Confirm if photo taken YES or NO  
If vaccination record is available, 
take a photograph  
Select one HEALTH RECORD OR MATERNAL 
RECALL 
Record vaccines received  
Date  
BCG 
Date  
OPV 0 
Date  
OPV 1 
Date  
OPV 2 
Date  
OPV 3 
Date  
IPV 
 
Date  
Pentavalent 1 
Date  
Pentavalent 2 
Date  
Pentavalent 3 
Date  
PCV 1 
Date  
PCV 2 
Date  
PCV 3 
Date  
RTS,S 1 
Date  
RTS,S 2 
Date  
RTS,S 3 
Date  
RTS,S 4 
Date  
Rotavirus vaccine 1 
Date  
Rotavirus vaccine 2 
Date  
Measles 1 or Measles Rubella 1 
Date  
Measles 1 or Measles Rubella 2 
Date  
Meningitis A vaccine  
Date  
Yellow fever vaccine  
 

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This admission  
History 
Select one YES or NO 
Has the child had fever in the last 
7 days ? 
Date  
Indicate the date the fever 
started  
Number  
How many days has the child had 
fever  
Select one YES or NO 
Have you sought treatment for 
the fever in the last 7 days ? 
Select one YES or NO 
If sought treatment, was an 
antibiotic given? 
Drop down list  
If Yes to antibiotic, which 
antibiotic was used ? 
Select one YES or NO 
If sought treatment, was an 
antimalarial given? 
Drop down list  
If Yes to antimalarial, which 
antimalarial was used ? 
Select one YES or NO 
Does this child have any pre-
existing illnesses?  
Select one  HIV, Congenital heart disease, 
Sickle cell disease, Severe malnutrition, other  
Indicate the pre-existing illnesses 
Select one YES or NO 
Has the child had difficulty in 
breathing  during this illness? 
Select one YES or NO 
Has the child had altered 
consciousness during this illness? 
 
Select one YES or NO 
Has the child had convulsions 
during this illness? 
Select one YES or NO 
If yes to convulsions, number in 
the last 24 hours? 
 
Number  
Has the child had more than 1 
convulsion or atypical convulsion 
during this illness? 
if yes, do LP.  
Examination 
Number ( _ _._ C) 
What was the body temperature 
on admission? 
Number ( _ _ Breaths per min ) 
What was the respiratory rate  on 
admission? 
Number ( _ _._ kg) 
What was the weight taken on 
admission? 
Number ( _ _._ cm) 
What was the MUAC taken on 
admission? 
Number (1-5) 
What was the total Blantyre 
coma score on admission? 
if total score is 
3 or less,  do LP 
Number (0, 1 or 2) 
Motor component  
Number (0, 1 or 2) 
Verbal  component  
 

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Number (0 or 1) 
Eye component  
 
Select one YES or NO 
Was there presence of deep 
breathing on admission? 
Select one YES or NO 
Was there presence of lower 
chest indrawing on admission? 
 
Select one YES or NO 
Was there a bulging fontanelle on 
admission? For children less than 
12 months of age  
if yes, do LP 
Select one YES or NO 
Was there neck stiffness on 
admission? 
if yes, do LP 
Select one YES or NO 
Was the child eligible for a 
lumbar puncture ?  
Contraindications for LP include 
needing resusitation, 
Poor pupillary responses to light, 
papilloedema, cranial nerve 
lesions, lateralising signs,  
Skin infection at LP site   
  
Review for 
contraindicatio
ns to LP, then if 
not present, do 
LP 
Text  
If eligible for LP but not done, 
describe reasons.  
Tests  
Select one YES or NO or not done 
Was an RDT or malaria slide 
performed ? 
Select one YES or NO or not done 
Results of the RDT or malaria 
slide  
Select one YES or NO or not done 
Was an Haemoglobin or 
haematocrit test performed ? 
 
Number (_ _._   or _ _ %) 
Results of the haemoglobin or 
haematocrit test  
Select one YES or NO or not done 
Was an Blood glucose test 
performed ? 
If BCS is less 
than 3 
Number (_ _._  mmol/L) 
Results of the blood glucose test  
  
Select one YES or NO or not done 
Was a lumbar puncture 
performed ? 
Review criteria 
for LP 
Date 
Date of lumbar puncture  
Alphanumeric  
ID of person performing LP 
Select one YES or NO 
Had antibiotics been used in the 
7 days before LP? 
If yes, refer to 
question above 
for antibiotics 
used  
Select reason:  Contraindication for LP, 
parental refusal, dead, absconded, discharge 
against medical advice, referral to another 
facility, no resources 
If no LP was performed with 
criteria present 
 
Select one YES or NO or not done 
Was CSF collected ? 
 

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Alphanumeric  
CSF sample number  
 
Select CLEAR, TURBID, PURULENR, BLOODY, 
OTHER  
Macroscopic appearance of the 
CSF  
Select one YES or NO or not done 
Was CSF WCC counted ? 
 
Number (_ _ _ ) 
Results of CSF WCC count  
Select one YES or NO or not done 
Was a CSF aliquot frozen? 
To be inputted from the ref lab  
CSF result from reference 
laboratory  
Diagnosis  
ICD 10 classification code  
Final primary diagnosis  
If final primary diagnosis is not consistent with 
clinical algorithm, record reason for 
discrepancy (e.g. severe malaria anemia or 
cerebral malaria with negative blood slide 
because treated confirmed malaria prior day, 
or low BCS with parasites, but not CM) 
 
 
ICD 10 classification code  
Secondary diagnosis 1 
If final secondary diagnosis 1 is not consistent 
with clinical algorithm, record reason for 
discrepancy 
 
 
ICD 10 classification code  
Secondary diagnosis 2 
If final secondary diagnosis 2 is not consistent 
with clinical algorithm, record reason for 
discrepancy 
 
 
ICD 10 classification code  
Secondary diagnosis 3 
 
If final secondary diagnosis 3 is not consistent 
with clinical algorithm, record reason for 
discrepancy 
 
 
Select ALIVE; DEAD, REFERRED  or 
ABSCONDED  
Outcome  
 
QA  
Alphanumeric  
ID of person completing 
admission form 
 
Alphanumeric  
ID of person reviewing/finalising 
inpatient form 
 
Notes for safety CRF 
 
Question for safety variables  
Notes  
Has consent been obtained ? 
Who and how is consent attained. 
What is the first or given name(s) of the 
child ? 
Only record for data linkage but strip before sending 
data further up the chain 

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What is the surname (or family name) of 
the child? 
Only record for data linkage but strip before sending 
data further up the chain 
Initials of the child (use 3 letters) 
Only record for data linkage but strip before sending 
data further up the chain 
Vaccinations  
Record all vaccines. Enter only DPT3/Pentavalent 3 doses  
and all RTSS doses  
If sought treatment, was an antimalarials 
given? 
Possibility to have a picture of common antibiotics for 
parents to identify. Refer to the health record  
If sought treatment, was an antibiotic 
given? 
Possibility to have a picture of common antimalarials for 
parents to identify. Refer to the health record  
Was an RDT or malaria slide performed ? 
Malaria test to be performed on all admissions.  
Results of the RDT or malaria slide  
Important if BCS less than 3 to rule out malaria as well. 
ID of person performing LP 
Only record for QA on the ground, but strip before 
sending data further up the chain 
ID of person completing admission form 
Only record for QA on the ground, but strip before 
sending data further up the chain 
ID of person reviewing/finalising 
inpatient form 
Only record for QA on the ground, but strip before 
sending data further up the chain 
 
 
 

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Annex 13. Household Survey CRF 
 
Reference is DHS/ questionnaires for samples  
Type  
Question  
Select one GHA/KEN/MLW 
Country 
Select one YES or NO 
Has consent been obtained ? 
Alphanumeric 
If Y, then include unique identifier of consent 
form 
X X:X X hrs  
Interview start time  
Demographics  
Select one GHA/KEN/MLW 
Country 
Drop down list from the randomisation list  
Region/ County/ District 
Alphanumeric  
Randomisation cluster ID  
Drop down list from the randomisation list  
Randomisation cluster name  
Date  
Interview date  
Alphanumeric  
Household number  
Alphanumeric  
Survey cluster ID 
Longitude  
Longitude GPS coordinates of the household  
Latitude  
Latitude GPS coordinates of the household  
Select one Completed/Refused/No person to 
consent  
Outcome  
Number  
Household members children aged 5-  48 months  
Number  
TOTAL ELIGIBLE CHILDREN AGED 12-23 MONTHS 
Number  
TOTAL ELIGIBLE CHILDREN AGED 27-38 MONTHS  
Wealth quintile  
Each country should include validated PCA 
variables for this section to calculate wealth 
quintiles  
Select one YES or NO 
  
Does your household have:  
Select one YES or NO 
Electricity  
Select one YES or NO 
A radio 
Select one YES or NO 
A television  
Select one YES or NO 
A mobile phone  
Select one YES or NO 
A bicycle  
Select one YES or NO 
A car or truck  
Select one YES or NO 
A motor bike  
Select one YES or NO 
A boat with a motor  
Select one YES or NO 
Does any member of this household own a bank 
account ? 

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Select one YES or NO 
Does any member of this household own any 
agricultural land ? 
Use the DHS drop list  
Observe the main material of the floor of the 
dwelling. Record  
Use the DHS drop list  
Observe the main material of the roof of the 
dwelling. Record  
Use the DHS drop list  
Observe the main material of the exterior walls of 
the dwelling. Record  
Select POOR or LOW , AVERAGE, ABOVE 
AVERAGE, WEALTHY  
In relation to others in this community, what 
would you say is your wealth status in this 
community  
Malaria control  
Select one YES or NO 
At any time in the last 12 months has anyone 
sprayed the interior walls of your dwelling against 
mosquitoes ? 
Months (number ) 
How many months ago did your household get 
sprayed against mosquitoes? 
Select one YES or NO 
Does your household have any mosquito nets? 
Name  
DID (NAME of eligible child sleep under this 
mosquito net last night? if yes, show the net, 
then record the specifics of that net  
Select LLIN or OTHER  
Observe or ask the type of mosquito net ? 
Mother  
Name 
Identify mother of target child  
MM YYYY 
In what month and year were you born? 
select one  YES or NO 
Have you ever attended school? 
Select PRIMARY or SECONDARY or HIGHER  
What is the highest level of school you attended? 
Number  
What is the highest [GRADE/FORM/YEAR] you 
completed at that level? 
Check highest level of school attended, if PRI or 
SEC, perform reading test below  
Use the DHS drop list  
Now I would like you to read this sentence to me. 
SHOW CARD TO RESPONDENT. 
IF RESPONDENT CANNOT READ WHOLE 
SENTENCE, 
PROBE: Can you read any part of the sentence to 
me? 
Use the DHS drop list  
What is your ethnic group? 
Use the DHS drop list  
What is your religion? 

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Use the DHS drop list  
What is your occupation? 
Father  
Name 
Identify father of target child ( Is this the natural 
father of NAME?) 
MM YYYY 
In what month and year were you born? 
select one  YES or NO 
Have you ever attended school? 
Select PRIMARY or SECONDARY or HIGHER  
What is the highest level of school you attended? 
Number  
What is the highest [GRADE/FORM/YEAR] you 
completed at that level? 
Check highest level of school attended, if PRI or 
SEC, perform reading test below  
Use the DHS drop list  
Now I would like you to read this sentence to me. 
SHOW CARD TO RESPONDENT. 
IF RESPONDENT CANNOT READ WHOLE 
SENTENCE, 
PROBE: Can you read any part of the sentence to 
me? 
Use the DHS drop list  
What is your ethnic group? 
Use the DHS drop list  
What is your religion? 
Use the DHS drop list  
What is your occupation? 
 
Reference is DHS/ questionnaires for samples  
Type  
Question  
Select one GHA/KEN/MLW 
Country 
Select one YES or NO 
Has consent been obtained ? 
Alphanumeric 
If Y, then include unique identifier of consent 
form 
Demographics  
Select one GHA/KEN/MLW 
Country 
Drop down list from the randomisation list  
Region/ County/ District 
Alphanumeric  
Randomisation cluster ID  
Drop down list from the randomisation list  
Randomisation cluster name  
Date  
Interview date  
Alphanumeric  
Household number  

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Alphanumeric  
Survey cluster ID 
Select one Completed/Refused/No person to 
consent /postponed / dwelling not found  
Response outcome  
Number  
Household members children aged 5-  48 months  
Number  
TOTAL ELIGIBLE CHILDREN AGED 12-23 MONTHS 
Number  
TOTAL ELIGIBLE CHILDREN AGED 27-38 MONTHS  
Enumerate each child aged 5-48 months 
separately to collect the following information  
Text  
Name of the child  
Text  
Relationship to Head of Household  
Name 
Identify mother of target child  
Select one YES or NO 
Are you the primary caregiver of target child  
YYYY 
Date of birth  
MMM 
Date of birth  
DD  
Date of birth  
Number  
Age  
Select one MALE or FEMALE  
Gender  
Malaria control  
Name  
DID (NAME of eligible child sleep under this 
mosquito net last night? if yes, show the net, 
then record the specifics of that net  
Select LLIN or OTHER  
Observe or ask the type of mosquito net ? 
Child health  
Vaccine status  
5-48 months  
Name of the child in the target age group  

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Hospital OR Clinic OR Outreach  
In which facility/clinic does this child receive their 
vaccines? 
 YES or NO or DK 
Do you have a card or other document where 
(NAME)'s vaccinations are written down? 
 YES or NO or DK 
Did you ever have a vaccination card for (NAME)? 
Card/record  seen YES or NO 
May I see the card or other document where 
(NAME)'s vaccinations are written down? 
Confirm if photo has been taken 
Take a photo of the card or record if available  
Vaccine record OR Maternal recall 
How is vaccination status ascertained? 
The following questions will be asked in the 
following circumstances:  1) In a subset of 
children where the card is available to assess the 
comparability of maternal recall and card history. 
Ask the questions first, then request the card and 
take a picture and fill in the dates.  2) If the 
vaccine record is not available.  
 YES or NO or DK 
Has (NAME) ever received a BCG vaccination 
against tuberculosis, that is, an injection in the 
arm or shoulder that usually causes a scar? 
 YES or NO or DK 
Within 24 hours after birth, did (NAME) receive a 
Hepatitis B vaccination, that is, an injection in the 
thigh to prevent Hepatitis B? 
 YES or NO or DK 
Has (NAME) ever received oral polio vaccine, that 
is, about two drops in the mouth to prevent 
polio? 
 YES or NO or DK 
Did (NAME) receive the first oral polio vaccine in 
the first two weeks after birth or later? 

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Number  
How many times did (NAME) receive the oral 
polio vaccine? 
 YES or NO or DK 
The last time (NAME) received the polio drops, 
did (NAME) also get an IPV injection in the arm to 
protect against polio? 
 YES or NO or DK 
Has (NAME) ever received a pentavalent 
vaccination, that is, an injection given in the thigh 
sometimes at the same time as polio drops? 
Number  
How many times did (NAME) receive the 
pentavalent vaccine? 
 YES or NO or DK 
Has (NAME) ever received a pneumococcal 
vaccination, that is, an injection in the thigh to 
prevent pneumonia? 
Number  
How many times did (NAME) receive the 
pneumococcal vaccine? 
 YES or NO or DK 
Has (NAME) ever received a rotavirus vaccination, 
that is, liquid in the mouth to prevent diarrhea? 
Number  
How many times did (NAME) receive the 
rotavirus vaccine? 
 YES or NO or DK 
Has (NAME) ever received a measles vaccination, 
that is, an injection in the arm to prevent 
measles? 
Has (NAME) ever received the measles vaccine at 
1 and half years after?   
Has (NAME) ever received the measles vaccine at 
9 months or soon after?   
Number  
How many times did (NAME) receive the measles 
vaccine? 
 YES or NO or DK 
Has (NAME) ever received a yellow fever 
vaccination, that is, an injection in the arm to 
prevent YELLOW FEVER? 

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 YES or NO or DK 
Has (NAME) ever received a meningitis 
vaccination, that is, an injection in the arm to 
prevent MENINGITIS, AROUND 1 1/2 YEAR OF 
AGE? 
 YES or NO or DK 
Has (NAME) ever received a malaria vaccination, 
that is, an injection in the arm/thigh to prevent 
malaria? 
Number  
How many times did (NAME) receive the malaria  
vaccine? 
 YES or NO or DK 
In addition to what is recorded on (this 
document/these documents), did (NAME) receive 
any other vaccinations, including vaccinations 
received in campaigns or immunization days or 
child health days? 
Use drop down list  
If incomplete vaccine status for age, probe 
reasons for not receiving the vaccine - stock outs, 
illness, religious reasons, etc  
Other preventive interventions  
 YES or NO or DK 
In the last six months, was (NAME) given a 
vitamin A dose like [this/any of these]? 
 YES or NO or DK 
Was (NAME) given any drug for intestinal worms 
in the last six months? 
Health seeking behaviour  
Fever  
YES or NO or DK  
Has (NAME) been ill with a fever at any time in 
the last 2 weeks? 
YES or NO or DK  
At any time during the illness, did (NAME) have 
blood taken from (NAME)'s finger or heel for 
testing? 
use DHS drop down list  
Did you seek advice or treatment for the illness 
from any source? 
use DHS drop down list  
Where did you seek advice or treatment? 
 
Anywhere else? 

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use DHS drop down list  
If sought treatment from multiple sources, 
indicate the initial source of treatment here  
use DHS drop down list  
Where did you first seek advice or treatment? 
YES or NO or DK  
How many days after the illness began did you 
first seek advice or treatment for (NAME)? 
Treatment  
YES or NO or DK  
At any time during the illness, did (NAME) take 
any drugs for the illness? 
use DHS drop down list  
What drugs did (NAME) take? 
Any other drugs? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take an artemisinin combination therapy? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take SP/Fansidar? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take chloroquine? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take amodiaquine? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take quinine? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take artesunate? 
use DHS drop down list  
How long after the fever started did (NAME) first 
take (OTHER ANTIMALARIAL)? 
Biomarker testing  
Text 
Confirm child's name in the target age 
YES or NO  
Confirm consent for the child in the target age 
Number (months) 
Age 
Number with 1 decimal point  
Mid upper arm circumference in cm taken 
Select one POS or NEG  
Record  Rapid malaria test results here  
Initials  
Enter the measurers code here  

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Notes for Feasibility  
Questions  
Notes  or instructions  
Age  
Calculate using date of birth and interview date or 
estimate stating age if date of birth is not known.  
Identify mother of target child  
If not available, organise to meet her when 
available   
Is this the target mother? 
Is this the target/natural father ? 
Complete the mother and father module 
Total eligible children aged 27-38 months  
This should only be collected in the 3rd HHS  
Has (NAME) ever received a malaria 
vaccination, that is, an injection in the 
arm/thigh to prevent malaria? 
Only for the second and third HHS  
Take a photo of the card or record if available  
Take a photograph of the all the pages where 
vaccinations have been recorded including 
vaccination stickers  
Biomarker testing  
Only for the first HHS 
Record  Rapid malaria test results here  
If positive, provide antimalarials as per the national 
guidelines  
Within 24 hours after birth, did (NAME) 
receive a Hepatitis B vaccination, that is, an 
injection in the thigh to prevent Hepatitis B? 
Only use this question if a birth dose of Hep B is 
given in the national schedule  
Has (NAME) ever received a BCG vaccination 
against tuberculosis, that is, an injection in the 
arm or shoulder that usually causes a scar? 
Check for scar  
Was (NAME) given any drug for intestinal 
worms in the last six months? 
Age dependent. Follow country guidelines  
Wealth quintile  
Each country should include validated PCA 
variables for this section to calculate wealth 
quintiles. These questions can be adapted to 
country specific questions.  
 
 
 

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Annex 14: Model informed consent statement for verbal autopsy  
Hello. My name is _______________________________________ and I am working with 
[AGENCY]. 
I am an interviewer. I have been informed that a child in your household died. I am very 
sorry to hear this. Please accept my sympathy. 
We are collecting information on the causes of recent deaths of children aged less than 5 
years in the community. I would like to talk to the adult person in your house who took care 
of [say the child’s name] during his/her illness before death, or who was present at the time 
of his/her death. 
We would very much appreciate your participation in this effort. 
We want to ask you about the illness and events leading to the death of [say the child’s 
name]. We would also like to ask about vaccinations s/he received and take a photograph of 
his/her vaccination card. 
Confidential information, including your child’s name, will not be shared with anyone. We 
will share other information with the Ministry of Health, with investigators in [pilot country] 
and [pilot country], where similar assessments are being done, and with the World Health 
Organization, which is sponsoring this work, and with other individuals or groups approved 
by WHO. However, no information identifying you or the deceased will ever be released to 
anyone outside this information-collection activity. 
Participation in this survey is voluntary and you can choose not to answer any individual 
question or all of the questions. You may also stop the interview completely at any time 
without any consequences at all. However, we hope that you will participate in this survey. 
This will contribute to a better understanding of the causes of deaths in children in this area, 
as the authorities work to improve health services. 
At this time, do you want to ask me anything about the purpose or content of this interview? 
May I begin the interview now? 
 
Signature of interviewer 
 
 

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Annex 15: Model Informed consent form for Inpatient Surveillance 
15.1 Model ICF for Inpatient Surveillance  
Title: An evaluation of the cluster-randomised pilot implementation of RTS, S/AS01 
through routine health systems in moderate to high malaria transmission settings in sub- 
Saharan Africa 
[Institutional Letterhead] 
Informed consent for the primary caretaker of a child between the ages of 5 months and 59 
months who live in the MVIP pilot areas, who we are asking to participate in the MVIP 
sentinel hospital surveillance. 
[Name of Principal Investigator] 
[Name of Organization] 
Sponsor: World Health Organization 
[Name of Proposal and version] 
This Informed Consent Form has two parts: 
• Information Sheet (to share information about the survey with you) 
• Certificate of Consent (for signatures if you agree that your child may participate) 
You will be given a copy of the full Informed Consent Form 
PART I: Information Sheet 
Introduction 
Good morning/afternoon. I am [ ] working for [ ] research institute. The Ministry of Health, 
in collaboration with [research institutions] and the World Health Organization, are 
collecting information at this and [enter number] other hospitals in [area] to understand 
how well the malaria vaccine that is provided in some [counties/districts] works to prevent 
severe malaria and to gather more information on the vaccine’s safety. I am sorry that your 
child has been hospitalized and I understand this is a stressful time. If you are able to talk, I 
would like to give you information and invite you to have your child participate in this 
research, which will consist of some questions to you, and possibly some tests for your child. 
We will tell you about any tests we want to do before doing them. The results of any test we 
do here will be given to your child’s doctor to be used in your child’s care. You do not have 
to decide today whether or not you agree that your child may participate in the research. 
Before you decide, you can talk to anyone you feel comfortable with. There may be some 
words that you do not understand. Please ask me to stop as we go through the information 
and I will take time to explain. If you have questions later, you can ask them of me. 
Purpose 
Malaria is one of the most common and dangerous childhood diseases in this region. There 
are important ways to prevent malaria in children, including insecticide treated nets, and 
indoor residual spray, [IPTi if recommended in country]. A new vaccine against malaria is 
being introduced into some [counties/districts/areas/] in [name MVIP pilot areas] and in 
selected areas in [other MVIP countries] as part of a pilot introduction. By collecting 
information from parents of children who are admitted to hospital, and finding out whether 
or not the child received the malaria vaccine, the Ministry of Health can learn how well the 
vaccine is working to prevent severe malaria. We can also learn more about the safety of 
the malaria vaccine. This information will allow the Ministry of Health to understand 
whether the malaria vaccine should be introduced more widely in [country]. 
Surveillance 
We are gathering information through hospital surveillance, meaning that we would like to 

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gather information on your child’s current illness and the tests done. Some of this 
information will come from speaking with you, some from your child’s medical records, and 
some from the laboratory results of tests done. In addition we will ask to see the vaccination 
record of your child and to take a photograph of the vaccination record so as to have a 
record of the vaccines received and the dates they were given. We might ask for additional 
tests to be done, but will discuss this with you before doing any additional tests. 
Participant selection 
We have chosen children from 5-59 months of age, because this is the age group who is 
likely to benefit from the malaria vaccine, which will be given to children in [country] who 
are [5 or 6 months of age]. 
Voluntary Participation 
Your decision to have your child participate in this research is entirely voluntary. If you 
choose not to consent, there will be no negative consequences and your child will still 
receive the usual standard of care at this hospital. You may also choose to change your mind 
later and stop participating, even if you agreed earlier, and that is fine. 
Procedures and Protocol 
We will ask you a series of questions about your child’s recent illness, and will ask to see the 
child’s vaccination records. We will ask that you allow us to take a photograph of your 
child’s vaccination record and collect the information fromyour child’s medical records, 
including any tests done. Depending on your child’s illness, we may ask for additional tests 
to be done performed. Some of those tests will be performed here, and the results will be 
provided to your doctor to help with your child’s care. If your child needs an assessment of 
the fluid from around the spinal cord, the cerebral spinal fluid, to check to see if he or she 
has meningitis, we will send the remaining fluid to a laboratory outside [country], to a 
laboratory in either South Africa or the The Gambia. There we will be able to look closely 
for bacteria or viruses that might be causing your child’s illness. These results will be 
provided to your doctor, but will not be available in time to direct treatment. However, 
they will help us to know if your child has meningitis, and to understand the different germs 
that cause meningitis in children in this area. 
Duration 
The questions we will ask you should take about 20 minutes. 
Risks or Discomforts 
Few risks are associated with participating in hospital surveillance. The tests that will be 
done for your child are those that should usually be done for children who are sick. If we ask 
to do additional blood tests, your child may have pain where the needle enters the skin or a 
bruise. The pain usually resolves within a day and the bruise is not long lasting. 
Benefits 
If your child participates in this research, he/she will have the following benefits: he/she will 
receive diagnostic tests to help determine what is causing his/her illness free of charge. 
There may not be any other benefit for your child but his/her participation is likely to help 
us find the answer to the research question which could benefit the community. 
Reimbursements 
You will not be provided any incentive to take part in this research. Where follow-up visits 
are requested, appropriate fare compensation would be provided. 
Confidentiality 
The information that we collect from this research will be kept confidential. Information 
about your child that will be collected from the survey will be put away and no-one but the 

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researchers will be able to see it. Any information about your child will have a number on it 
instead of his/her name. Only the researchers will know what his/her number is and we will 
lock that information up. It will not be shared with or given to anyone except [name who 
will have access to the information, such as research sponsors, DSMB board, CRO, etc].) 
Sharing of the results 
[The knowledge that we get from this study will be shared through small meetings in the 
community before it is made widely available to the public]. Information collected will also 
be shared with other investigators in [pilot country] and [pilot country] where similar 
assessments are being done, as well as with the World Health Organization, which is 
sponsoring the work, and with other individuals or groups approved by WHO. Confidential 
information, including your child’s name, will not be shared. Afterwards, we will publish the 
results in order that other interested people may learn from our research. 
Right to Refuse or Withdraw 
You do not have to agree to your child taking part in this research if you do not wish to do 
so. 
You may stop your child from participating in the research at any time that you wish. 
Who to Contact 
[Provide the name and contact information of someone who is involved, informed and 
accessible (a local person who can actually be contacted.) State also that the proposal has 
been approved and how.] 
(If you have any questions you may ask them now or later, even after the study has started. 
If you wish to ask questions later, you may contact any of the following: [name, 
address/telephone number/e-mail] 
This proposal has been reviewed and approved by [name of the IRB], which is a committee 
whose task it is to make sure that research participants are protected from harm. If you 
wish to find about more about the IRB, contact [name, address, telephone number.]) 
PART II: Certificate of Consent 
Certificate of Consent 
I have been invited to have my child participate in hospital surveillance research to 
understand how well the recently introduced malaria vaccine prevents severe 
malaria, and to gather more information on the vaccine safety. I have read the 
foregoing information or it has been read to me. I have had the opportunity to ask 
questions about it and any questions that I have asked have been answered to my 
satisfaction. I consent voluntarily for my child to participate as a participant in this 
study. I consent for samples from my child to be sent to a laboratory in The Gambia or South 
Africa. 
Print Name of Participant__________________ 
Print Name of Parent or Guardian_______________ 
Signature of Parent or Guardian ___________________ 
Date ___________________________ 
Day/month/year 
If Parent or Guardian illiterate 
A literate witness must sign (if possible, this person should be selected by the participant and 
should have no connection to the research team). Participants who are illiterate should 
include their thumb print as well. 
I have witnessed the accurate reading of the consent form to the parent of the potential 
participant and the individual has had the opportunity to ask questions. I confirm that 

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the individual has given consent freely. 
Print name of witness________________________AND Thumb print of parent 
Signature of witness ______________________ 
Date ________________________ 
Day/month/year 
Statement by the researcher/person taking consent 
I have accurately read out the information sheet to the parent of the potential 
participant, and to the best of my ability made sure that the person understands the 
components of the research. 
I confirm that the parent was given an opportunity to ask questions about the study, and all 
the questions asked by the parent have been answered correctly and to the best of my 
ability. I confirm that the individual has not been coerced into giving consent and the 
consent has been given freely and voluntarily. 
A copy of this ICF has been provided to the participant. 
Print Name of Researcher/person taking the consent________________________ 
Signature of Researcher /person taking the consent__________________________ 
Date ___________________________ 
Day/month/year 
 
15.2  Model ICF for Long term storage of samples 
 
Additional Consent to an evaluation of the cluster-randomised pilot implementation of 
RTS,S/AS01 through routine health systems in moderate to high malaria transmission 
settings in sub-Saharan Africa 
This Statement of Consent consists of two parts: 
• Information Sheet (to share information about storage of unused samples with you) 
• Certificate of Consent (to record your agreement) 
You will be given a copy of the full Statement of Consent 
Part 1. Information Sheet 
As part of the information that we are collecting through hospital surveillance, we might 
collect blood, cerebrospinal fluid and other samples for tests to understand the cause of 
your child’s illness. Where necessary, we might ask for additional tests to be done, but we 
will discuss this with you before doing any additional tests. You may choose to have your 
samples only used for the current research or for research as well. Some of the samples 
might be sent abroad to laboratories in The Gambia or South Africa for further analysis 
and/or quality assurance. 
Once the tests are done, there may be a small volume of unused sample leftover. We 
request permission to store your child’s leftover samples for possible future use in research 
looking at public health problems. If any blood or body fluid samples are taken during your 
child’s hospitalization, we ask that you allow us to store any leftover samples for up to 15 
years. You can decide not to allow us to store left over samples and still participate in this 
research. For future research, we would request permission from the ethics committee, as 
appropriate 
It is possible that genetic tests may be undertaken on your child’s samples. This will not be 
linked directly to your child but may help understand the mechanisms of malaria as affected 
by inherited traits. If you do not wish for your child’s sample to be used in this or any other 
type of research, please let us know. 

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The leftover samples can be traced to your child while in the hospital and this allows us to 
feedback results which have immediate clinical relevance. However during long term 
storage, we would remove all identifying information that could trace the sample back to 
your child. This would allow us to protect your child’s identity but would not allow us to give 
back individual results in the long term. 
Your child’s sample will only be used for research purposes, where appropriate approvals 
have been obtained as described above. 
Right to Refuse and Withdraw 
Your decision to have your child’s samples kept for research is entirely voluntary. If you 
 
 I give permission for my (TYPE OF SAMPLE) sample to be stored and used in future 
research 
but only on the same subject as the current research project : [give name of current 
research] 
 I give my permission for my [TYPE OF SAMPLE] sample to be stored and used in future 
research of any type which has been properly approved 
 I give permission for my [TYPE OF SAMPLE] sample to be stored and used in future 
research 
except for research about [NAME TYPE OF RESEARCH] 
choose not to consent, there will be no negative consequences and your child will still 
receive 
the usual standard of care at this hospital and can still participate in the inpatient 
surveillance study. You may also choose to change your mind later and stop participating, 
even if you agreed earlier, and that is fine. 
Confidentiality 
We will remove all identifiers that could trace the sample back to your child in the long term. 
This means that you will not receive any further individual results. 
You can ask me any more questions about any part of the information provided above? Do 
you have any questions? 
Part II. Certificate of Consent 
Long Term Storage of samples 
If any of the blood or body fluid I have provided for this research project is unused or 
leftover when the project is completed (Tick one choice from each of the following boxes) 
 I wish my [TYPE OF SAMPLE] sample to be destroyed immediately. 
 I want my [TYPE OF SAMPLE] sample to be destroyed after ____ years. 
 I give permission for my [TYPE OF SAMPLE] sample to be stored indefinitely 
AND (if the sample is to be stored) 
AND 
 I want my identity to be removed from my (TYPE OF SAMPLE) sample. 
 I want my identity to be kept with my (TYPE OF SAMPLE) sample. 
 
I have read the information, or it has been read to me. I have had the opportunity to ask 
questions about it and my questions have been answered to my satisfaction. I consent 
voluntarily to have my samples stored in the manner and for the purpose indicated above. 
Print Name of Participant__________________ 
Signature of Participant ___________________ 
Date ___________________________ 

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Day/month/year 
If illiterate 
A literate witness must sign (if possible, this person should be selected by the participant and 
should have no connection to the research team). Participants who are illiterate should 
include their thumb-print as well. 
I have witnessed the accurate reading of the consent form to the potential participant, and 
the individual has had the opportunity to ask questions. I confirm that the individual has 
given consent freely. 
Print name of witness_____________________ AND Thumb print of participant 
Signature of witness ______________________ 
Date ________________________ 
Day/month/year 
Statement by the researcher/person taking consent 
I have accurately read out the information sheet to the potential participant, and to the best 
of my ability made sure that the participant understands that the following will be done: 
1. 
2. 
3. 
I confirm that the participant was given an opportunity to ask questions about the nature 
and manner of storage of the samples, and all the questions asked by the participant have 
been answered correctly and to the best of my ability. I confirm that the individual has not 
been coerced into giving consent, and the consent has been given freely and voluntarily. 
A copy of this ICF has been provided to the participant. 
Print Name of Researcher/person taking the consent________________________ 
Signature of Researcher /person taking the consent__________________________ 
Date ___________________________ 
Day/month/year 
 
 

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Annex 16: Model informed consent statement for household surveys 
Hello. My name is _______________________________________. I am working with [NAME 
OF ORGANIZATION]. We are conducting a survey about vaccine use, malaria and other topics 
in 
this area of [NAME OF COUNTRY]. This information will allow the Ministry of Health to 
understand whether the malaria vaccine should be introduced more widely in [country] and 
how to introduce the malaria vaccine. Your household was selected for this survey. 
I would like to ask you some questions about your household. In addition we will ask to see 
the 
vaccination record of your child and take a photograph of the vaccination record so we can 
check the dates vaccines were received. The questions usually take about 20 to 30 minutes. 
Confidentiality 
The information that we collect from this survey will be kept confidential. Information about 
your child will be put away and no-one but the researchers will be able to see it. Any 
information about people living in your household will have a number on it instead of their 
name. Only the researchers will know what their numbers are and we will lock that 
information 
up. It will not be shared with or given to anyone except [name who will have access to the 
information, such as research sponsors, DSMB board, CRO, etc].) 
Sharing of the results 
The knowledge that we get from this study will be shared through community meetings and 
government meetings before it is made widely available to the public. Information collected 
will 
also be shared with other investigators in [pilot country] and [pilot country] where similar 
assessments are being done, as well as with the World Health Organization, which is 
sponsoring 
these work, and with other individuals or groups approved by WHO. Confidential 
information, 
including peoples’ names, will not be shared. Afterwards, we will publish the results in order 
that other interested people may learn from this research. 
Right to refuse or withdraw 
You don't have to be in the survey, but we hope you will agree to answer the questions since 
your views and experiences are important. If I ask you any question you don't want to 
answer, 
just let me know and I will go on to the next question. You can stop the interview at any 
time. 
At this time, do you want to ask me anything about the purpose or content of this interview? 
In 
case you need more information about the survey, you may contact the person listed on this 
card. 
Do you have any questions? May I begin the interview now? 
 
Signature of interviewer: 
 
Signature of Parent of CHILD: 
 

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Biomarker and MUAC (for children aged 5-48 months in baseline survey only) 
As part of this survey, we are asking children aged 5 to 48 months to have a test to see if 
they 
have malaria. Malaria is a serious illness caused by a parasite transmitted by a mosquito 
bite. 
Malnutrition is a serious illness caused by not enough or unbalanced diet, problems with 
digestion or absorption or certain medical conditions. This information on nutrition status 
and 
malaria will help us understand how the population that receives routine vaccines are 
affected 
by these conditions. This information will be shared with the government to include in their 
programs to prevent and treat malaria and malnutrition. These procedures usually take 
about 5 
to 10 minutes. 
We ask that all children who are aged 5 to 48 months take part in malaria testing in this 
survey 
and give a few drops of blood from a finger or heel. The equipment used to take the blood is 
clean, safe and has not been used on anyone before: it will be thrown away after each test. 
One blood drop will be tested for malaria immediately, and the result will be told to you 
right 
away. If the malaria test is positive, appropriate treatment will be offered following the 
government’s guidelines. 
Measurement of the arm will be done using a tape measure. If your child is found to be 
malnourished, they will be referred to the nearest health facility for nutritional 
rehabilitation. 
Your child’s result will be kept strictly confidential and will not be shared with anyone other 
than members of our survey team and appropriate health care workers. 
Do you have any questions? You can say yes or no. It is up to you to decide. 
Will you allow (NAME OF CHILD) to participate in the malaria test and nutrition assessment? 
Signature of interviewer: 
 
Signature of Parent of CHILD: 

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Annex 17: Standard AEFI reporting form 
 
 

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Annex 18: AEFI investigation form 
 

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Annex 19: AEFI Causality Assessment Worksheet  
 

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