Determining Whether Mass Campaigns With Fractional Dose PCV10 Would Accelerate Herd Protection Against Pneumococcal Transmission in Sub-Saharan Africa
Phase: PHASE4
Conditions: Pneumococcal Carriage
Sponsor: Epicentre

Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection against pneumococcal transmission in 
Sub-Saharan Africa 
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Study Protocol  
 
Determining whether mass campaigns with fractional dose PCV10 would accelerate herd 
protection against pneumococcal transmission in Sub-Saharan Africa 
 
Primary Sponsor  
 
Rebecca F. Grais  
Sponsor’s Investigator  
Matthew E. Coldiron 
Co-investigators 
Ousmane Guindo 
Issaka Soumana 
Aitana Juan-Giner 
Rabiou Dare 
Hassan Abdoul Nasser 
Katherine Gallagher 
Wangeci Kagucia 
John Ojal 
Eric Adehossi 
Anthony Scott 
Angela Karani  
Souleymane Brah 
 
Manufacturer 
 
 Serum Institute of India Pvt. Ltd., Pune, India  
Registration 
Clinicaltrials.gov NCT05175014 
PACTR Number: PACTR20211257448484 
 
 
 
 
Declaration of Confidentiality 
The information contained herein is confidential and therefore are provided in confidence as a 
potential examiner or investigator. 
It is understood that this information will not be disclosed to others without the written permission 
of the Sponsor, except to the extent necessary to achieve the consent of those who can participate in 
the study. 
 
 
 
 

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General Information  
 
 
Type of study  
Clinical trial 
Registration of Study 
Clinicaltrials.gov NCT05175014 
PACTR Number: PACTR20211257448484 
 
Study product 
PCV10 vaccine (Pneumosil®) 
Sponsor and Sponsor representative 
Epicentre, Rebecca F. Grais 
Sponsor’s Investigator 
Matthew E. Coldiron, Epicentre 
Manufacturer 
Serum Institute of India Pvt Ltd., Pune, India 
Funding 
EDCTP 
Principal Investigator 
Matthew E. Coldiron, Epicentre 
Co-Investigators 
Ousmane Guindo, Epicentre 
Issaka Soumana, Epicentre 
Aitana Juan-Giner, Epicentre 
Rabiou Dare, Niger Ministry of Public Health  
Hassan Adboul Nasser, National Immunization Program 
Katherine Gallagher, KWTRP and LSHTM 
Wangeci Kagucia, KWTRP 
John Ojal, KWTRP and LSHTM 
Eric Adehossi, Université Abdou Moumouni 
Anthony Scott, KWTRP and LSHTM 
Angela Karani, KWTRP 
Souleymane Brah, Université Abdou Moumouni 
 
Site of Study 
Madarounfa District, Niger 
Consortium of partners 
Epicentre Paris and Niger 
London School of Hygiene and Tropical Medicine, UK 
African Research Collaboration for Health Limited 
(KWTRP), Kenya  
Université Abdou Moumouni, Niger 
 
Data Monitoring Committee 
 
 
DSMB  
 
 
 

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1 
Signature page ........................................................................................................... 6 
2 
Trial Registration Information .................................................................................... 7 
3 
Abbreviations .......................................................................................................... 10 
4 
Background .............................................................................................................. 11 
5 
Rationale ................................................................................................................. 12 
6 
Study Objectives ...................................................................................................... 14 
6.1 
Definition of outcomes ................................................................................................ 14 
7 
Methodology ........................................................................................................... 15 
7.1 
Overall study design .................................................................................................... 15 
7.2 
Description of the investigational product .................................................................... 17 
 
Summary of vaccine safety ............................................................................................ 17 
 
Storage and handling ..................................................................................................... 17 
7.3 
Site selection ............................................................................................................... 17 
7.5 
Cross sectional survey procedures ................................................................................ 19 
 
Inclusion and exclusion criteria ..................................................................................... 19 
 
Screening procedures and enrolment ........................................................................... 19 
 
NP carriage sampling and analysis ................................................................................ 20 
7.6 
Vaccination ................................................................................................................. 21 
 
Eligibility criteria for mass vaccination campaigns ........................................................ 21 
 
Community mobilization and eligibility screening ........................................................ 21 
 
Administration of vaccine .............................................................................................. 21 
 
Dose modifications ........................................................................................................ 22 
 
Labelling ......................................................................................................................... 22 
7.7 
Qualitative study ......................................................................................................... 22 
 
Recruitment, inclusion criteria and exclusion criteria ................................................... 22 
 
Sample size .................................................................................................................... 24 
 
Interview procedures .................................................................................................... 24 
7.8 
Early withdrawal from study ........................................................................................ 25 
7.9 
Concomitant interventions .......................................................................................... 26 
7.10 
Provision of medical care ............................................................................................. 26 
7.11 
Randomization and blinding procedures ...................................................................... 26 
7.12 
Sample size for surveys ................................................................................................ 26 
8 
Safety reporting for Adverse Events and Serious Adverse Event ................................ 28 
8.1 
Causality Assessment ................................................................................................... 29 
8.2 
Procedure for recording Serious Adverse Events ........................................................... 29 
 
General information about SAEs ................................................................................... 29 
 
Recording SAEs .............................................................................................................. 30 
 
Management of SAEs .................................................................................................... 30 
8.3 
Expectedness ............................................................................................................... 30 
8.4 
Reporting of SAEs ........................................................................................................ 30 

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Initial Reporting ............................................................................................................. 30 
 
Follow Up Reporting ...................................................................................................... 30 
8.5 
SAE Reporting to relevant bodies ................................................................................. 31 
9 
Ethical and regulatory aspects .................................................................................. 31 
9.1 
Ethical considerations particular to cluster randomized trials ........................................ 31 
9.2 
Definition of research participants and identification of gatekeepers ............................ 32 
9.3 
Community engagement .............................................................................................. 32 
9.4 
Summary of known and potential risks......................................................................... 32 
9.5 
Risk minimization and benefits .................................................................................... 33 
9.6 
Expenses and reimbursements ..................................................................................... 33 
9.7 
Ethics review and approvals ......................................................................................... 34 
 
Declaration of Helsinki .................................................................................................. 34 
 
ICH Guidelines for Good Clinical Practice ...................................................................... 34 
 
Approvals ....................................................................................................................... 34 
9.8 
Study registration ........................................................................................................ 34 
9.9 
Informed consent ........................................................................................................ 34 
 
Community consent ...................................................................................................... 34 
 
Individual consent ......................................................................................................... 35 
9.10 
Participant privacy and confidentiality ......................................................................... 35 
10 
Administrative aspects ......................................................................................... 36 
10.1 
Protocol amendments ................................................................................................. 36 
10.2 
Protocol deviations and violations ............................................................................... 36 
10.3 
Insurance .................................................................................................................... 36 
10.4 
Funding and other support for the trial ........................................................................ 36 
11 
Data handling and record keeping......................................................................... 37 
11.1 
Overview ..................................................................................................................... 37 
11.2 
Investigator site file (ISF).............................................................................................. 37 
11.3 
Source Documents and CRFs ........................................................................................ 37 
11.4 
Record keeping ............................................................................................................ 38 
11.5 
Data management ....................................................................................................... 38 
 
Hardware and software ................................................................................................. 38 
 
Data security, access, and back-up ................................................................................ 38 
 
Archiving ........................................................................................................................ 39 
12 
Data Analysis ........................................................................................................ 39 
13 
Quality assurance and control ............................................................................... 40 
13.1 
Electronic and central data validation .......................................................................... 40 
13.2 
On-site monitoring ...................................................................................................... 40 
 
Framework for monitoring ............................................................................................ 40 
 
Implementing monitoring and audits at study sites ..................................................... 40 
 
Training to ensure quality of the study ......................................................................... 41 
13.3 
Data Safety Monitoring Board ...................................................................................... 41 
13.4 
Inspections .................................................................................................................. 41 
13.5 
Completion or termination of the study ....................................................................... 41 

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13.6 
Publication policy and final report ................................................................................ 41 
14 
Study Organization ............................................................................................... 42 
14.1 
Study Team ................................................................................................................. 42 
14.2 
Trial Steering Committee ............................................................................................. 42 
14.3 
Study timeline ............................................................................................................. 42 
15 
References ........................................................................................................... 43 
 
 
 
 

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1 
Signature page 
By my signature below, I hereby confirm that I will conduct the study described in this protocol in 
compliance with ICH/GCP and the version of such protocol agreed to by the applicable regulatory 
authorities and approved by all Institutional Review Board and Ethical Committees. 
 
Sponsor, Rebecca F. Grais 
 
____________________________ 
 
 
 
 
 
13 December 2021 
Signature 
 
 
 
 
 
 
 
 
Date 
 
 
 
Principal Investigator, Matthew E. Coldiron 
 
  
 
 
 
 
 
 
13 December 2021 
____________________________ 
 
 
 
 
 
_______________ 
Signature 
 
 
 
 
 
 
 
 
Date 
 
Please note that study responsibilities are documented in the Trial Master and Investigator Site Files. 
 
 
 

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Trial Registration Information 
Primary Registry and Trial Identifying Number  
ClinicalTrials.gov NCT05175014 
 
Date of Registration in Primary Registry 
13th December 2021 
 
Secondary Identifying Numbers 
PACTR20211257448484 
 
Sources of Monetary and Material Support 
EDCTP 
 
Sponsor  
Epicentre 
 
Primary Sponsor contact 
Rebecca F. Grais, 14-34 Avenue Jean Jaurès, 75019 Paris, rebecca.grais@epicentre.msf.org 
 
 
Contacts for Queries 
The following individuals will provide responses to general queries including information about 
current recruitment status: 
Matthew Coldiron, Epicentre:  matthew.coldiron@epicentre.msf.org  
Issaka Soumana, Epicentre, Maradi, Niger:  Issaka.soumana@epicentre.msf.org 
 
Public Title 
Mass campaigns with fractional dose pneumococcal vaccines in sub-Saharan Africa 
 
Scientific Title 
Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
against pneumococcal transmission in Sub-Saharan Africa 
 
Site of Recruitment 
Madarounfa District of Niger 
 
Health Condition(s) or Problem(s) Studied 

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Pneumococcal carriage 
 
Intervention 
Mass vaccination campaign with one single dose PCV10 vaccine administered as a full dose or 
fractional dose 
 
Key Inclusion and Exclusion Criteria 
For participation in pneumococcal carriage surveys 
Inclusion criteria:  
(1) Aged 1-9 years  
(2) Residing in the villages included in the study  
(3) Parent or caretaker provides informed consent for the child to participate in the study 
 
Exclusion criteria:  
(1) Head or facial injuries that contraindicate nasopharyngeal swabbing 
(2) Any condition or criteria, including acute or chronic clinically significant abnormality that in 
the opinion of the investigator might compromise the wellbeing of the participant or 
interfere with the outcome of the study 
 
For participation in mass vaccination campaigns (with full or fractional dose PCV10) 
Inclusion criteria:   
(1) Aged 1-9 years  
(2) Residing in the villages included in the study and allocated to vaccination  
(3) Head of the household or main caretaker provides consent for the child to be vaccinated  
 
Exclusion criteria:  
(1) Hypersensitivity to any component of the vaccine, including diphtheria toxoid 
(2) Vaccination with a PCV vaccine within the previous 4 weeks, as there should be a minimum 
of 4 weeks between doses 
(3) Moderate or severe febrile illness (temperature ≥39°C) is a temporal contraindication and 
the child should not be vaccinated until improvement 
(4) Any condition or criteria, including acute or chronic clinically significant abnormality that in 
the opinion of the clinical staff might compromise the wellbeing of the volunteer 
 
 
Study Type 
Phase IV cluster-randomized controlled trial 
 
Date of First Enrolment  
November 2021 
 
Target Sample Size 

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63 clusters with a total population between 500 and 4000 will be randomized in a 3:3:1 ratio to 
receive either (1) mass campaigns targeting children aged 1-9 years with a single full dose of PCV10, 
(2) mass campaigns targeting children aged 1-9 years with a single fractional (1/5) dose of PCV10, or 
(3) no mass campaigns (control arm). It is estimated that approximately 32 000 children will be 
targeted by the campaigns. 
Cross-sectional surveys conducted at baseline prior to the vaccination campaign, and approximately 
6 months after the vaccination campaign, will collect nasopharyngeal swabs from children aged 1-9 
years. Simple random sampling will be used to select 36 households from each of the 63 clusters. 
One child aged 1-9 will be randomly selected from each household to participate. A total of 2268 
children will be targeted in each survey.  
 
Recruitment Status 
Not yet recruiting 
 
Primary Objective 
To evaluate whether a mass vaccination campaign targeting children approximately 1-9 years of age 
with a full dose of PCV is superior to the absence of vaccine in reduction of VT carriage prevalence at 
6 months post-campaign, and subsequently to evaluate if a single 20% dose of PCV is non-inferior to 
a full dose.  
Secondary Objectives 
• 
To measure the age-stratified prevalence of NP carriage of S. pneumoniae in children 1-9 years of 
age in the study area.  
• 
To determine the effect of a mass vaccination campaign with one full dose of PCV in children 1 to 
9 years of age on VT pneumococci carriage 6 months after vaccination  
• 
To assess the occurrence of adverse events (AE) during 7 days and serious adverse events (SAE) 
during 28 days after administration of fractional and full doses of PCV. 
• 
To model the potential effect of fractional dose PCV campaigns in other contexts using the 
results of the clinical trial.  
• 
To develop recommendations on how a potential future fractional dose PCV mass campaign 
could be successfully planned, communicated, delivered and integrated into national 
immunization programmes using qualitative analysis.  
 
Data Safety and Monitoring Board 
To be named 
 

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3 
Abbreviations  
AE  
  
Adverse Event 
CRF    
Case Report Form 
DSMB  
Data and Safety Monitoring Board 
EC 
  
Institutional Ethical Committee 
ERC   
Ethics Review Committee 
GCP    
Good Clinical Practice 
ICF 
  
Informed Consent Form 
ICH 
  
International Conference on Harmonization 
IRB    
Institutional Review Board 
ISF 
  
Investigator site file 
LMIC   
Low and middle-income countries  
MOH   
Ministry of Health 
MSF   
Doctors Without Borders 
NP 
  
Nasopharyngeal  
NRA   
National regulatory authority 
PI 
  
Principal Investigator 
PIS 
  
Patient information sheet 
SAE    
Serious Adverse Event 
SII 
  
Serum Institute of India Pvt. Ltd 
SSL 
  
Secure Sockets Layer 
SOP   
Standard operating procedures 
SUSAR  
Suspected unexpected serious adverse reaction 
VT 
  
Vaccine-type 
WHO    
World Health Organization  
 
 

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4 
Background 
In 2015, there were an estimated 8.9 million cases (uncertainty range 7.7-10.6 million) of clinical 
pneumococcal pneumonia globally, with 2.4 million cases estimated in Africa alone (uncertainty 
range 2.1-3.1 million) (1). These figures represent a global reduction of 37% from 14.2 million cases 
(12.3 million–16.9 million) in 2000. However, pneumococcal disease continues to be a leading cause 
of severe disease and death representing 10% of all death in children under 5 years of age (1). These 
deaths occur disproportionally in low- and middle-income countries (LMICs), with approximately 50% 
of global pneumococcal deaths estimated to occur in 4 countries: India, Nigeria, Pakistan and the 
Democratic Republic of Congo (1).  
Streptococcus pneumoniae is part of the normal bacterial flora in the nasopharynx (NP) (2). 
Colonization with S. pneumoniae is generally asymptomatic, but in some cases it spreads and causes 
disease, including sinusitis, otitis media, bacteraemia and meningitis, referred to as invasive 
pneumococcal disease (IPD) (3). It has been estimated that approximately 75% of cases of IPD, and 
83% of cases of pneumococcal meningitis, occur in children <2 years, although these estimates may 
vary by country, study method and socio-economic status within countries (4). There are over 90 
known pneumococcal serotypes identified throughout the world, but a small number are responsible 
for most severe disease (4). The pneumococci are easily transmitted from person to person, 
generally within families, from older to younger siblings and between households within 
communities (2). NP colonization generally occurs early in life (2), with some studies reporting a peak 
in children younger than 2 years of age (5). Studies have estimated NP carriage prevalence >70% 
among children <5 years in Kenya (6), The Gambia (7) and Uganda (8) in the period before 
introduction of pneumococcal conjugate vaccines (PCV).   
PCVs were introduced in Africa from 2011 onwards with support from Gavi, the Vaccine Alliance. At 
present there are three PCVs that are WHO-prequalified: SynflorixTM, a 10-valent vaccine (PCV10); 
Prevenar®, a 13-valent vaccine (PCV13); and the most recently prequalified PCV10, Pneumosil®. The 
vaccines contain different serotypes, though each includes serotypes most frequently responsible for 
severe disease, and are considered effective against pneumococcal disease (4,9). Vaccination with 
PCV has a direct effect reducing carriage amongst those vaccinated, but also has the capacity to 
reduce carriage amongst unimmunized populations by interrupting transmission (10). This indirect 
effect of vaccines that goes beyond individual protection is linked to the reduced exposure to S 
pneumoniae vaccine serotypes (VT) in communities where a large proportion of the population have 
been vaccinated (10), i.e., herd protection.  
To date, the majority of countries have introduced PCV into routine immunization programs (11). 
Following WHO recommendations, most LMICs have introduced the vaccine in a 3 dose schedule, 
starting at 6 weeks of age and with vaccine doses separated by 4 weeks (4). In settings with high 
disease burden and mortality, catch-up vaccination at the time of vaccine introduction has also been 
recommended to accelerate the impact of vaccination. Catch-up vaccination should ideally target 
children 1 to 5 years of age and should prioritize children <2 years of age (4). The WHO Framework 
for vaccination in humanitarian emergencies also recommends PCV mass campaigns following 
assessment of local epidemiology and other risk factors (12). In humanitarian emergencies, mass 
campaigns could rapidly establish direct and indirect protection when vulnerability is highest and 
routine health services are disrupted (13).  

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Coverage of PCV vaccination through routine immunization has been heterogenous. Some countries 
achieved >80% coverage quickly after introduction of the vaccines and have been able to sustain this 
over time. Other countries, however, have difficulties and continue to have low coverage (<50%) 
years after vaccine introduction (14). Carriage studies conducted in LMICs with high vaccination 
coverage have shown some level of residual VT carriage. For instance, in Malawi, 7 years after the 
introduction of PCV13, VT carriage is reported at 16.6% VT amongst 3-5 years old vaccinated children 
(15). In a study conducted in Kilifi, Kenya, 5 years after PCV10 introduction,  VT pneumococci is 
identified in 6% of children aged less than 5 years and 8% of infants(16). However, it has been 
considered that current vaccination strategies are unlikely to reduce this further (17). Further 
complicating this, although decreasing VT colonization with PCV decreases subsequent IPD, the exact 
nature of the relationship is not well-described, and a target threshold necessary to establish her 
protection has not been established. Regardless, in countries with low vaccination coverage, the 
beneficial effects of PCVs have yet to be fully realised.  Mass campaigns as a strategy to boost herd 
protection in areas of low routine vaccination coverage, could have a role in these different settings. 
However, a barrier to PCV vaccination strategies is their cost. From 2001 to 2017, the cost to fully 
immunize a child in LMICs has increased from USD 1.00 to approximately USD 32.001, with vaccines 
against rotavirus and pneumococcal disease accounting for three quarters of the total cost of 
vaccinating a child (11). These high costs also impact considerations of PCV for mass vaccination 
campaigns (13).  
 
5 
Rationale  
Vaccination campaigns targeting children up to 5 years of age, in addition to routine vaccination in 
infancy, have been shown to have an effect in the reduction of VT carriage and disease (18,19). 
However, the benefits of catch-up campaigns are reduced if they delay or affect coverage of routine 
vaccination activities, and if those in the catch-up age cohort have only moderate vaccine serotype 
carriage and disease (4). Moreover, there is limited evidence on the optimal deployment strategies 
for mass campaigns (4,13). Some programs, for instance, have used a single dose while others have 
considered that two PCV doses are needed for children 12-23 months of age (4). The target age 
group for mass vaccination has also varied. WHO recommendations for catch-up vaccination target 
children <5 years of age. However, this target has been questioned as there is no clear rationale for 
this limit (13). Whilst it has been considered that children <5 years of age usually bear the heaviest 
burden of pneumococcal pneumonia, this is not necessarily the case in all settings. In crisis situations 
or in settings with high prevalence of malnutrition, the high pneumococcal carriage prevalence is 
likely to extend to older age groups and vaccination of a larger age group might be needed to control 
VT circulation (13). Consequently, the inclusion of older children in campaigns might be beneficial in 
particular settings where older children contribute substantially to the transmission of pneumococci 
(18).  
Niger introduced PCV13 into the routine vaccination program in 2014, with doses given at 6, 10, and 
14 weeks of age, without catch-up campaigns. Administrative coverage with 3 doses was estimated 
to be 81% in 2019, however, coverage estimated directly in the Maradi region is considered to be 
 
 
1 Excluding HPV vaccine.  

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around 48%2, suggesting a heterogeneity in the reach of the program. Currently, for Gavi-supported 
countries, such as Niger, PCV13 vaccine has a cost of US$3 per dose. The most recently WHO 
prequalified PCV vaccine (Pneumosil®) has, however, the lowest price at US$2 per dose. The vaccine 
cost is also far below current market prices offered by the other manufacturers for uses outside Gavi 
support (20). Consequently, as the overall cost to health systems is lower, this provides more 
opportunities to countries and organizations supporting countries on the choice of how to use the 
vaccine. Pneumosil® is a PCV10 manufactured by Serum Institute of India Ltd (SIIL), tailored 
specifically to African, Asian, and Latin American countries by including serotypes 6A and 19A, two 
serotypes available in PCV13 but not in the SynflorixTM PCV10 (21). Although Pneumosil® is a PCV10, 
which has fewer serotypes than PCV13, there is currently insufficient evidence to show any 
difference in impact between PCV10 and other PCV vaccines (4,9). Moreover, although product 
switching, in this case from PCV13 to PCV10, has not been recommended (4), a mass campaign 
would be directed to children older than the routine vaccination target group (infants), and for many 
this would be done years after they received their primary schedule.  
Although a relatively low cost PCV (Pneumosil®) is currently available, mass campaigns targeting 
large age groups with a full dose of vaccine would require a large quantity of vaccine and might not 
be sustainable over time. Fractional dosing of licensed vaccines have been considered for situations 
of high vaccine costs and/or supply chain shortages (22). Fractional doses administered through the 
intradermal route have been assessed for several vaccines including influenza, rabies, hepatitis B, 
inactivated polio vaccine (IPV) (23) and through the standard subcutaneous route for yellow fever 
vaccine (24). Following available evidence, fractional doses of IPV, rabies and yellow fever vaccines 
are recommended by WHO and used routinely in several countries and for outbreak response 
(25,26). Data from the original dose-finding studies for a pentavalent PCV indicate that a dose as low 
as 1/4th of the current dose in PCV10 could elicit adequate immunogenicity (27). A non-inferiority 
trial of fractional doses of PCV10 and PCV13 is currently underway in Kenya (ClinicalTrials.gov 
Identifier: NCT03489018; PI Anthony Scott). Following this, fractional doses of PCV could be a 
solution to overcome the high PCV costs, increase vaccine access and expand vaccination benefits 
through alternative strategies.  
This study aims to assess the impact of a mass campaign with a single, fractional dose of Pneumosil®, 
a PCV10, on VT carriage. A 20% fractional dose (1/5th) will be used as a practical formulation to 
prepare and administer. This study will assess whether the impact of a single fractional dose mass 
campaign on carriage is non-inferior to a single full dose mass campaign in a cluster randomized trial 
in a low coverage setting in Niger. The results would provide evidence of the population-level direct 
and indirect impact of fractional dose in older children which will be completed by mathematical 
modelling, to inform the policy debate regarding PCV dosing schedules in different contexts. This trial 
and the modelling exercises that follow, would allow for larger scale evaluation of fractional dose 
PCV strategies in multiple contexts. 
 
 
 
2 Administrative coverage from UNICEF Immunization data https://data.unicef.org/topic/child-
health/immunization/ 
Actual coverage from MSF-Epicentre data.  

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6 
Study Objectives 
Primary objective 
To evaluate whether a mass vaccination campaign targeting children approximately 1-9 years of age 
with a full dose of PCV is superior to the absence of vaccine in reduction of VT carriage prevalence at 
6 months post-campaign, and subsequently to evaluate if a single 20% dose of PCV is non-inferior to 
a full dose.  
Secondary objectives  
• 
To measure the age-stratified prevalence of NP carriage of S. pneumoniae in children 1-9 years of 
age in the study area.  
• 
To determine the effect of a mass vaccination campaign with one full dose of PCV in children 1 to 
9 years of age on VT pneumococci carriage 6 months after vaccination  
• 
To assess the occurrence of adverse events (AE) during 7 days and serious adverse events (SAE) 
during 28 days after administration of fractional and full doses of PCV. 
• 
To model the potential effect of fractional dose PCV campaigns in other contexts using the 
results of the clinical trial.  
• 
In the setting of a qualitative study, to develop recommendations on how a potential future 
fractional dose PCV mass campaign could be successfully planned, communicated, delivered and 
integrated into national immunization programmes using qualitative analysis.  
6.1 
Definition of outcomes 
Effect of PCV10 campaign 
The effect of a single dose PCV10 campaign in the reduction of VT carriage will be assessed by: first, 
assessing the superiority of a campaign using full doses of PCV10 compared to control group without 
vaccination; and second, by establishing the non-inferiority of a campaign using fractional doses of 
PCV10 compared to a campaign using full doses.    
NP carriage will be measured in the 3 study arms (full dose arm, fractional dose arm and control arm) 
in a baseline survey implemented prior to the vaccination campaign and in a post-vaccination survey 
conducted 6 months post-vaccination campaign.  
The NP carriage of VT S. pneumoniae will be measured as the proportion of participants that are 
colonized with any of the 10 serotypes covered by PCV10 at each time point. The reduction in NP 
carriage will be calculated by comparing the proportion of children carrying VT pneumococci 6 
months post-vaccination to baseline, at the time of vaccination. Prevalence of colonization of non-VT 
serotypes will also be described at both timepoints.  
Vaccine safety 
Vaccine safety will be monitored up to 28 days after vaccination and all AEs and SAEs will be 
recorded.   
Cost-effectiveness and modelling study 
An age-structured, dynamic, deterministic model of pneumococcal transmission will be constructed 
to estimate the impact of mass fractional dose PCV campaigns on VT carriage. The model will use the 

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data on social interactions between age groups and PCV coverage estimates collected during the 
baseline survey as well as the results of the VT carriage from the baseline survey.  
Based on the modelled epidemiological impact of PCV10 mass campaigns, with both full and 
fractional doses, a cost-effectiveness analysis will be performed to estimate the incremental cost-
effectiveness ratio of routine PCV10 mass campaigns. 
The modelled epidemiological impact and cost-effectiveness of a fractional dose mass campaign will 
be used to inform ongoing discussions of dose-sparing strategies and the use of single-dose fractional 
PCV in acute humanitarian emergencies. 
Facilitators and barriers to implementing mass campaigns of fractional dose PCV  
A qualitative study will be conducted among parents, healthcare workers, national and international 
stakeholders to develop insights and recommendations on how a potential future fractional dose 
PCV mass campaign could be successfully planned, communicated, delivered and integrated into 
national immunization programmes. 
 
7 
Methodology 
7.1 
Overall study design  
A Phase IV, 3-arm, observer-blinded, cluster-randomized controlled trial will be implemented in rural 
villages of the Madarounfa District of Niger. A schematic representation of the trial is presented in  
After results of the baseline survey are known, clusters will be randomized to full dose, fractional 
dose or control arm in 3:3:1 allocation ratio. The trial will be conducted in 63 clusters, with 27 
randomized to full dose arm, 27 randomized to fractional dose arm and 9 randomized to a control 
arm. Clusters will be composed of a village or group of closely-neighbouring villages that share a 
school or market, and will be limited to a population of between 500 and 4000 persons. Stratified 
randomization will be used to account for proximity to the nearest health centre (<5 km vs ≥5 km). In 
the event of significant imbalance in carriage of VT pneumococci between clusters in the baseline 
survey, randomization will also be stratified by baseline prevalence. Vaccination will target all 
children aged 1 to 9 years of age residing in the selected villages. (If baseline survey data 
unexpectedly shows very low prevalence of carriage at the extremes of this age range, the target age 
group may be adjusted upon recommendation of the trial steering committee.) We estimate that 
children eligible for the vaccination campaigns will represent 30% of the total population.  With an 
estimated average of 2000 people per cluster, vaccination will target 600 children 1-9 years of age in 
each cluster receiving vaccine. In total, in the 54 clusters receiving vaccine, the mass vaccination 
campaign with single full- or fractional-dose PCV will target approximately 32,400 children 1-9 years 
of age.  
Prior to the mass vaccination campaign, a cross-sectional survey will be implemented to estimate 
community-level carriage of VT pneumococci, as well as to collect data on household composition, 
social interactions and PCV vaccination coverage in the routine EPI. A total of 36 households in each 
cluster will be invited to participate in the cross-sectional survey. This sample size may be re-
evaluated based on the results of the baseline survey.  
Selection of households will be based on probability sampling. The required number of households in 
each cluster will be randomly selected using simple random sampling based on an exhaustive list of 
heads of household in the cluster. Six months after the mass vaccination campaign, the post-

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vaccination cross-sectional survey will be implemented. This will be used to estimate community-
level carriage of VT pneumococcus after a single-dose PCV delivered as full or fractional dose as well 
as carriage in the clusters that received no vaccination. The survey will target the same number of 
children as the baseline survey and will follow the same methodology with the households selected 
by simple random sampling from the sampling frame.  
For the qualitative component of the study, focus groups discussions and key informant interviews 
will be conducted with immunisation stakeholders, community members and healthcare workers. 
 
   
Follow-up survey in 63 
clusters 
Mass campaign among 1-9 
year olds with  
full-dose PCV10 
Mass campaign among 1-9 
year olds with  
fractional-dose PCV10 
27 clusters randomized to 
full-dose arm 
9 clusters randomized to 
control arm 
27 clusters randomized to 
fractional-dose arm 
Baseline survey in 63 clusters 
Randomization stratified on 
distance to health center +/- 
baseline prevalence
Figure 1: Schematic representation of cluster-randomized trial 

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7.2 
Description of the investigational product  
In this study we will use Pneumosil®, the PCV10 vaccine manufactured by SII. Pneumosil® is a WHO-PQ 
vaccine licensed for use in infants and toddlers from 6 weeks up to 2 years of age. 
Each dose of PCV10 (Pneumosil®; SIIL) contains 2mcg of saccharide for each serotype 1, 5, 9V, 14, 19A, 
19F, 23F, 7F and 6A; and 4 mcg of saccharide for serotype 6B.  
Vials containing 5 full doses will be used. Following manufacturer’s instructions, each full dose has a 
volume of 0.5ml and is administered by intramuscular injection.  
A fractional dose of 1/5 of a dose will be defined as 0.1ml and will be administered via intramuscular 
injection using a graduated syringe. For the fractional dose PCV dose arm, each vial will contain 
approximately 25 fractional doses. 
 
Summary of vaccine safety 
The most frequently reported adverse reactions include fever, irritability, injection site reactions 
including pain, erythema, swelling or induration, decreased appetite, drowsiness and diarrhoea. 
Serious reactions are rare.  
Extending the use of the 5-dose multi-dose vial to provide 25 administrations may increase the risk of 
injection site reactions e.g. swelling and localised inflammation due to contamination. The 
preservative contained in the vial should minimise this risk. 
 
Storage and handling 
Following manufacturer’s recommendations, vaccines will be stored at a temperature ranging 
between +2°C and +8°C.  A fine white deposit with clear colourless supernatant may be observed 
upon storage of the vial. This does not constitute a sign of deterioration.  
Because Pneumosil is a suspension containing an adjuvant, vaccinators will vigorously shake vials 
immediately prior to use to obtain a homogenous, whitish turbid liquid in the vaccine container.  
Once opened, multi-dose vials will be kept between +2ºC and +8ºC. Following the conditions stated 
on the WHO policy statement on handling of multi-dose vials after opening (WHO/IVB/14.7), opened 
multi-dose vials may be used up to a maximum of 28 days.  
7.3 
Site selection  
The study will take place in the Madarounfa Health District, situated in the Maradi Region of south-
central Niger along the Nigerian border. Madarounfa District had an approximate population of 
540,000 inhabitants and covers a rural area of 4700 km2 largely representative of the Sahel region of 
Niger and sub-Saharan Africa. The main economic activity is subsistence agriculture, and the region is 
generally peaceful without any underlying political or social tension. The Madarounfa Health District 
has one district hospital and 25 health centres, of which 2 are led by full-time doctors, and 23 of 
which are led by nursing staff. Each of the health centres is the first-level care facility for a Health 
Area, which is usually composed of 10-20 villages. 
The villages to be included in the study will be purposefully selected from different health areas of 
the Madarounfa Health District. Health areas will be selected based on access and security. To avoid 
contamination of the different interventions, a minimum radius of 2 km will be kept between 
clusters. In some cases, two or more closely neighbouring villages sharing a school or market may be 

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combined to form a single cluster. Clusters will be limited in size to a total population of between 500 
and 4000 persons.  
Epicentre has been conducting research studies in the Maradi region, and the Madarounfa District 
specifically, since 2008. Main themes have included childhood malnutrition, meningitis, malaria, and 
rotavirus, and antimicrobial resistance among many other subjects. Clinical, laboratory and logistical 
staff, as well as a dedicated community engagement team, are present.  
7.4 
Obtaining informed consent  
Informed consent will be obtained from parent or guardian before any study specific procedures are 
undertaken. Separate consent will be sought for the cross-sectional surveys, the vaccination 
campaign and the qualitative interviews. Informed consent will be taken by study personnel specially 
trained for the informed consent process. It will be made clear from the outset that refusal to 
participate will not jeopardize any of the other health services or care participants and families 
receive.  
An information notice will be used to present the exact nature of the study; the implications and 
constraints of the protocol; the known side effects and any risks involved in taking part in the study. 
It will be clearly stated that participation is voluntary and that the participant or their 
parent/guardian is free to withdraw from the study at any time for any reason without prejudice to 
future care, and with no obligation to give the reason for withdrawal. The information notice will be 
available in French and Hausa.  
The potential participant or representative will be allowed as much time as necessary to consider the 
information and to take the opportunity to question the person taking the informed consent and to 
decide whether they will allow their charge to participate in the study.  
Written informed consent will be needed for the participation in the different components of the 
study. This will be obtained by means of the participant’s or participant’s representative dated 
signature or thumb print (if unable to write), and the consent form must be signed and dated by a 
literate witness and dated signature of the person who presented and obtained the informed 
consent.  
Different informed consent documents will be used:  
1. Consent form for the head of the village to provide consent for the village to participate in 
the cluster randomized trial 
2. Consent form for overall participation in the surveys and for nasopharyngeal sampling of a 
randomly selected household member aged 1-9 years 
3. Consent form for the head of the household for vaccination of children of the target age 
group living in the household 
4. Consent form for participants in qualitative study 
 
Other considerations regarding informed consent are detailed below in section 9.9 “Informed 
Consent”. 

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7.5 
Cross sectional survey procedures  
Households selected at random will be invited to participate in the cross-sectional surveys. Sampling 
will be independent between the two surveys, and there will be no longitudinal follow-up. Survey 
procedures will be conducted at a single visit to each household, unless the members are absent, in 
which case there will be a second attempt to reach the potential participants. There will be no 
follow-up after this visit.  
For the purposes of this study, a household is defined as a group of people living under the authority 
of a head of household, sleeping under the same roof, and sharing at least one meal per day, for at 
least two weeks, independent of any family ties. 
 
Inclusion and exclusion criteria  
Households containing at least one member aged 1-9 years whose head of the household or main 
caretaker provides consent to participate will be eligible to participate.  
To participate in the carriage surveys, children meeting the following inclusion criteria are eligible for 
enrolment:  
(4) Aged 1-9 years  
(5) Residing in the villages included in the study  
(6) Parent or caretaker provides informed consent for the child to participate in the study 
 
Exclusion criteria for participating in the carriage survey will include the following:  
(3) Head or facial injuries that contraindicate nasopharyngeal swabbing  
(4) Any condition or criteria, including acute or chronic clinically significant abnormality that in 
the opinion of the investigator might compromise the wellbeing of the participant or 
interfere with the outcome of the study  
 
 
 
Screening procedures and enrolment 
The baseline and 6-months post-vaccination surveys will follow similar screening and enrolment 
procedures. Survey teams will visit randomly selected households and will go through the informed 
consent process with the head of the household (see sections 7.4 and 9.9).  
In the pre-vaccination survey we will:  
1) Administer a household questionnaire to the head of the household to collect information on 
the number of members who live in the household, their age and sex, school or other day 
care attendance of the children living in the household, PCV vaccination status of children 
living in the household, exposure to solid fuel smoke, and smoking habits.  
2) Select a household member at random (using a simple lottery system) to collect information 
on the number of contacts with people of different age groups in the last 24h. This 
information will be collected using the social interactions questionnaire. If this person is 
absent from the household, a second attempt at a pre-scheduled time will be arranged. If the 
person is still unreachable after a second attempt the social contact questionnaire will not be 
completed. 

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3) Select a child aged 1 to 9 years of age at random (using a simple lottery system) for 
nasopharyngeal sampling. A short questionnaire will be used to collect the child’s recent 
symptoms of an upper respiratory tract infection, including receiving any antimicrobials in 
the previous two weeks. If the selected child is temporarily absent from the household, a 
second attempt of inclusion will be made at another agreed upon time. In the rare event that 
the child is not eligible to participate another member will be randomly selected from the 
list. In the unlikely event that no child in the household is eligible to participate in the survey, 
the household will not be replaced.  
In the post-vaccination survey we will: 
1) Administer a household questionnaire to the head of the household to collect information on 
the number of members who live in the household, their age and sex, school or other day 
care attendance of the children living in the household, PCV vaccination status of children 
living in the household in the EPI, exposure to solid fuel smoke, smoking habits, and PCV 
vaccination during the study campaign from all children of the target age group. 
2) Select a child of the target age group for vaccination at random for nasopharyngeal swab. A 
short questionnaire will be used to collect the child’s recent symptoms of an upper 
respiratory tract infection, including receiving any antimicrobials in the previous two weeks. 
If the selected child is absent from the household, a second attempt of inclusion will be made 
at another agreed upon time. In the rare event that the child is not eligible to participate 
another member will be randomly selected from the list.  In the unlikely event that no child 
in the household is eligible to participate in the survey, the household will not be replaced. 
 
NP carriage sampling and analysis 
The NP swab will be taken by trained study nurses following the WHO standard method described by 
Satzke et al (31) for detecting upper respiratory carriage of S. pneumoniae. Briefly, a study team 
member trained in standard procedures for nasopharyngeal sample collection will sample the 
nasopharynx of participants using a flocked swab. The sample will be immersed in skim milk, tryptone, 
glucose, glycerol (STGG) media prior to being transported to the lab. 
Samples will be processed, aliquoted and temporarily stored at ultra-low temperature (≤-70°C) until 
shipment to African Research Collaboration for Health Limited (KWTRP), Kilifi, Kenya.  
Culture and serotyping of NP samples will be done at the KWTRP laboratory in Kenya. At the KWTRP 
laboratory, samples will be cultured on gentamicin-blood agar and S pneumoniae identified by 
optochin susceptibility testing. Serotyping will be done by latex agglutination and the Quellung 
reaction. Confirmatory pathogen and serotype testing will be done on 10% of culture positive samples 
by PCR. 
To assure the quality of sample collection, culture positivity data will be stratified by various 
characteristics such as study staff performing sample collection, date of collection, date of shipping 
and age category to assess the quality of samples to identify any unexpected patterns that may 
indicate low quality of sample collection. To support transfer of skills and capacity in laboratory 
evaluations for pneumococcus, staff from Epicentre Niger and Université Abdou Moumouni, Niger 
will participate in an in-service training program led by peers at KWTRP, Kenya. 

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7.6 
Vaccination  
Vaccination activities will occur at village level following implementation of community awareness 
activities and liaison with village leaders. Vaccination will take place on a pre-scheduled day. All 
children of the target age group for vaccination, for instance aged 1-9 years of age, residing in the 
study villages allocated to full or fractional dose arm will be targeted for vaccination. Vaccination will 
occur at fixed sites in each participating village.  
Vaccination activities will be timed to happen in the same geographical area at the same time and 
will be scheduled as to not interfere with other planned vaccination activities.  
 
Eligibility criteria for mass vaccination campaigns 
Children meeting the following inclusion criteria are eligible for vaccination:   
(4) Aged 1-9 years  
(5) Residing in the villages included in the study and allocated to vaccination  
(6) Head of the household or main caretaker provides consent for the child to be vaccinated  
 
Exclusion criteria for vaccination will include the following:  
(5) Hypersensitivity to any component of the vaccine, including diphtheria toxoid 
(6) Vaccination with a PCV vaccine within the previous 4 weeks, as there should be a minimum 
of 4 weeks between doses 
(7) Moderate or severe febrile illness (temperature ≥39°C) is a temporal contraindication and 
the child should not be vaccinated until improvement.  
(8) Any condition or criteria, including acute or chronic clinically significant abnormality that in 
the opinion of the clinical staff might compromise the wellbeing of the volunteer  
 
 
A SOP will be used to assess eligibility in accordance with the inclusion and exclusion criteria for 
vaccination listed above. 
 
Community mobilization and eligibility screening 
Prior to the mass vaccination campaigns, community information sessions will occur in each village to 
discuss the vaccination campaign, and the design, objectives and methods of the overall trial. During 
these sessions, study staff will stress the importance of vaccination in this context, but also 
underscore that parents of children are free to choose whether to have their child vaccinated. Prior 
to vaccination activities, the study team will ensure that each head of the household or main 
caretaker goes through the informed consent process and provides consent for the children of the 
target age group living in the household to participate in the study. The head of the household or 
main caretaker will be asked to accompany the children of the target age group for vaccination at the 
scheduled day.  
On the vaccination day, a nurse will screen each child for contraindications for vaccination and will 
ensure that the inclusion criteria, including written informed consent, are fulfilled.  
 
Administration of vaccine 
PCV vaccine will be administered intramuscularly following the manufacturer recommendations. The 
vaccine will be administered in the deltoid region of either arm avoiding broken skin or injuries. It is 
recommended, but not required, that the injection be administered into the non-dominant arm.   

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The necessary equipment will be in place to manage eventual hypersensitivity reactions. 
Vaccine preparation and administration as well as management of hypersensitivity reactions will be 
detailed in a study specific SOP. 
The number of doses of vaccine administered at each site will be noted on tally sheets. 
 
Dose modifications 
There are no anticipated dose modifications following enrolment since the intervention consists of a 
single dose. 
 
Labelling 
Study vaccines will be labelled specifically for the study. 
7.7 
Qualitative study  
A literature search and desk review of available reports from countries and/or NGOs that have 
introduced government-sponsored mass vaccination campaigns children under the age of 15 years 
will be conducted. 
Data gaps related to Niger and pneumococcal vaccination campaigns in particular will be filled 
through key informant interviews and focus group discussions, either in-country or by telephone. 
For the qualitative data collection on the feasibility, acceptability, and community needs regarding a 
mass PCV vaccination campaign, an exercise to map the relevant stakeholders will take place in the 
first month of the project.  
International and national stakeholders who are/would be involved in the planning, implementation, 
and/or evaluation of a mass vaccination campaign with PCV will be invited to participate in key 
informant interviews and/or focus group discussions. This will include healthcare workers who take 
an active role in vaccination campaigns (e.g., doctors, nurses, nurse aides, and any others e.g., 
community health volunteers) and community members (mothers or fathers) with children between 
1-9 years of age. The University Abdoul Moumouni of Niamey will be the lead partner for the 
implementation of this qualitative study. 
 
Recruitment, inclusion criteria and exclusion criteria 
Four groups will be targeted for qualitative data collection:  
1) Parents/ caregivers local to the area in which the trial is being implemented will be invited to 
focus group discussions on the perceived acceptability, feasibility and communication needs 
when delivering a (hypothetical) mass PCV campaign to 1–9-year-old children. Individuals will be 
identified during house-to-house visits in a mix of communities across the trial area. 
 
Inclusion criteria for parents/caregivers: 
• 
A parent/caregiver to a child under the age of 15 years  
• 
A community member from the general population in the catchment area of a selected 
health facility 

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• 
An adult able to give informed consent 
 
Exclusion criteria for parents/caregivers: 
• 
A community member not resident in the catchment area  
• 
An adult unable to give informed consent 
• 
An adult with obvious signs/symptoms of COVID-19 on the day of interview 
 
2) Healthcare workers local to the area in which the trial is being implemented will be invited to 
Focus Group Discussions on the perceived acceptability and feasibility of delivering a mass 
campaign of fractional dose PCV e.g., the requirements that would be needed for planning, 
delivery, monitoring & evaluation. Individuals will be identified through visits to a mix of 
government health facilities in the trial area.  
 
Inclusion criteria for healthcare workers in focus group discussions are: 
• 
Healthcare worker working in immunisation or in a leadership/coordination position within 
the health centre 
• 
Able to give informed consent 
 
Exclusion criteria for health care workers: 
• 
Healthcare worker working in a different service at the health facility 
• 
Healthcare worker with obvious signs or symptoms of COVID-19 on the day of the interview 
• 
Unable/ unwilling to give informed consent 
 
3) Immunisation programme managers and stakeholders at the regional and national level will be 
invited to key informant interviews on the feasibility, cost, and sustainability of using mass 
campaigns of fractional dose PCV in older children to enhance herd protection. Interviewees may 
be members of the Ministry of Health or other implementing partner organisations (e.g., non-
governmental organizations or research institutes). 
 
Inclusion criteria for healthcare workers in focus group discussions are: 
• Able to give informed consent 
 
Exclusion criteria for health care workers: 
• Unable/ unwilling to give informed consent 
 
4) Stakeholders at Gavi, the Bill & Melinda Gates Foundation and WHO will be invited to key 
informant interviews on the perceived facilitators and barriers to implementing a mass PCV 
campaign both in countries with established routine immunisation programmes and in fragile or 

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crisis-affected states. Individuals will be identified from relevant documents and websites and 
informal collaborators at the international level within WHO, Gavi and BMGF. 
 
Inclusion criteria for external stakeholders in focus group discussions are: 
• 
Able to give informed consent 
 
Exclusion criteria for external stakeholders: 
• 
Unable/ unwilling to give informed consent 
 
 
Sample size 
Dependent on the number and availability of key informants, we will aim to conduct: 
• 
4-10 focus group discussions with parents/ caregivers (maximum 6 participants each)  
• 
4-10 focus group discussions with healthcare workers (maximum 6 participants each)  
• 
4-10 key informant interviews with national immunization programme stakeholders  
• 
4-10 key informant interviews with international level immunization stakeholders 
 
 
Interview procedures  
 
Focus groups with healthcare workers and parents/caregivers 
If a healthcare worker or parent/caregiver agrees to participate in a focus group discussion and 
meets the inclusion and none of the exclusion criteria above, they will be given a time, date and 
place for discussion. At the beginning of the discussion the purpose will be described clearly again. 
Confidentiality and anonymity will be assured. Once the participant has understood the information, 
informed consent and permission to record the interview will be obtained. The informed consent 
form will describe the purpose of the study, the procedure to be followed (interview or focus group 
discussion), and the extent that the information obtained will be used.  
Participants will be given the participant information sheet and consent form to read (or will have 
the information sheet read out to them) and they will be asked to sign stating that they consent to 
taking part. If the volunteer is illiterate or unable to fully understand the written information in the 
consent form an independent witness will be invited to accompany the volunteer and sign the 
consent form, the participants will be asked to put their thumb print on the consent form. Adequate 
time for each potential participant to ask questions will be allowed.  
Focus group discussions with parents/caregivers and healthcare workers will be carried out by a 
trained interviewer and facilitator using topic guides. 
During the focus group discussion each member of the group will be given a placard with a number 
on it, they will be asked to say that number before inputting into the discussion, for the purpose of 
the recording. 

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Key informant interviews with national and international stakeholders 
Key informants will be approached by phone or email. Once they agree to the interview, the 
interviewer will explain the purpose of the interview and will identify a private area in which to 
conduct the interview at the interview site or ask the participant over the phone to ensure they are 
in a private area to ensure confidentiality. Signed written informed consent and permission to record 
the interview will be obtained either in person or this will be organized prior to the phone interview 
by email.  
Each participant will be assigned a unique identification number which will be used throughout the 
interview in recordings and written records. The identity of interviewees will be confidential and will 
remain non-identifiable in project outputs released into the public domain. Participants will be able 
to opt-in or opt-out of being anonymously quoted. All interviews will be recorded, if the participant 
consents. If the participant consents to interview but declines to have the interview recorded, 
handwritten notes will be taken at the time of interview by the interviewer and typed up in full 
immediately afterwards. All relevant information in the interview recordings/ notes will be 
transcribed and entered into the data extraction template. 
Interviews with national and international immunization stakeholders will be conducted by 
telephone or in-person using the interview topic guides. The topic guide will be piloted prior to the 
start of data collection. As far as possible, an informal interview style will be used, including open 
ended questions, in order to gain as much information as possible. 
The topic guide will include relevant questions on the following topics: questions will be selected 
based on the gaps in the literature specific to Niger and/or pneumococcal vaccine campaigns: 
• 
The decision to conduct a campaign 
• 
The planning, implementation, and timing of the social mobilization  
• 
Training and preparation of implementing staff 
• 
Vaccine management and cold chain capacity 
• 
Delivery strategy 
• 
Effectiveness data 
• 
Vaccine coverage 
• 
Funding for vaccine supply and implementation  
• 
Integration of the campaign with other health services/ the impact on routine health service 
provision 
 
7.8 
Early withdrawal from study  
In accordance with the principles of the current revision of the Declaration of Helsinki1 and any other 
regulations, a participant has the right to withdraw from any part of the study at any time and for 
any reason and is not obliged to give their reasons for doing so.  
The mass vaccination consists of a single dose while outcomes are at the community level measured 
through two cross-sectional surveys. However, individual participants (in surveys or the qualitative 

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study) may withdraw their consent and in that case their data will not be included in the data 
analysis. 
7.9 
Concomitant interventions 
Any interventions required to treat a disease or condition in an enrolled participant will be allowed.  
7.10 
Provision of medical care 
Immediate reactions post-vaccination will be treated free of charge on-site by trained clinical staff. 
Free referrals to the nearest health center will be provided for any participants presenting to 
vaccination campaign sites with acute medical conditions necessitating clinical evaluation. Likewise, 
during the two cross-sectional surveys, household members with acute illness who need medical 
attention will be provided free referrals to the nearest health center.  
7.11 
Randomization and blinding procedures 
Following the results of the baseline survey, clusters will be randomized in a 3:3:1 ratio, with 27 
clusters randomized to receive a campaign with the full dose, 27 clusters randomized to receive a 
campaign with the fractional dose and 9 clusters randomized to the control arm.  Randomization will 
be stratified by proximity to nearest health center (<5 km vs. ≥5km). In the event of significant 
imbalance in carriage of VT pneumococci between clusters in the baseline survey, randomization will 
also be stratified by baseline prevalence. An equal or proportional number of clusters will be 
randomized to each study arm from each stratum. 
The randomization list will be generated by an independent statistician with no other contact with 
trial participants.  
Study implementation will be blinded to the extent possible. Vaccination nurses will not be blinded 
to the vaccine they are giving, but they will not communicate vaccine allocation to other members of 
the team or to participating villages. Villages randomized to the control arm will not receive any 
“dummy” intervention, so will not be blinded to their group allocation. The trial will be observer-
blind in that personnel at KWTRP will be blinded to group allocation until after the completion of 
culture and serotyping in each survey. 
7.12 
Sample size for surveys 
The sample size has been calculated to respond to the objective of determining whether community-
level prevalence of VT pneumococci after a fractional dose PCV mass campaign among children aged 
1-9 years is non-inferior to that seen after a mass campaign among children aged 1-9 years using full-
dose PCV as well as determining the superiority of a full dose PCV mass campaign compared to no 
vaccination.   
Based on NP carriage studies conducted in Sub-Saharan Africa settings  (7,28–30) and considering an 
estimated coverage of 3 doses of PCV in children <12 months of age of 48% in the study area, we 
estimate the prevalence of VT carriage, among 1-9 year olds, to be between 25 and 35% and take the 
middle value, 30%, as an initial estimate. We assume a 50% reduction in PCV10 VT carriage after 
vaccination with a full dose and consider the prevalence of VT carriage amongst vaccinated children 
with a full dose 6 months after the vaccination campaign to be 15%.  

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Based on a previous cluster randomized trial assessing meningococcal carriage in the same study 
area, we consider an intra-cluster correlation coefficient of 0.02(20).   
To test the non-inferiority of a mass campaign using fractional doses compared to a mass campaign 
using full doses, we have chosen a non-inferiority margin of 7.5% to ensure that a campaign with 
fractional doses provide at least half of the benefits provided by a campaign using full doses. We 
consider a 2.5% level of significance for a one-sided test and 90% power. With these assumptions, 27 
clusters with 36 households sampled per cluster would provide a power of at least 90% (1944 
individuals, with 972 in the full dose and 972 in the fractional dose arm). Non-inferiority will be 
achieved if the lower limit of the 95% confidence interval (CI) around the difference in the proportion 
of children with VT carriage (full dose group – fractional dose group) is >-7.5%.  
Given the sample size of the full-dose arm to test non-inferiority as described above, to test the 
superiority of a mass campaign to the control (non-vaccinated) arm, and considering a 5% level of 
significance for a two-sided test and 90%, we would need to sample 9 clusters with 30 households 
apiece in both the full-dose and control arms. Since the non-inferiority evaluation requires a larger 
sample size, the control arm will include the larger number of participants per cluster (36), which will 
lead to >90% power to detect superiority.  
For the NP carriage survey, one participant will be sampled from each household. We consider that 
most households will have a child aged 1 to 9 years of age, but account for 20% refusal to participate 
and/or absences and increase the number of households to be invited to participate by 20%. All 
selected households, even if they do not have a child of the target age group, will be invited to 
participate in the social contacts survey. Table 1 summarizes the number of cluster and households 
to be included in each survey.  
Table 1. Initial estimates of clusters and households to be invited to participate in each survey 
Allocation 
N° clusters  
N° households  
Total participants 
Control arm 
9 
36 
324 
Full dose arm* 
27 
36 
972 
Fractional dose arm 
27 
36 
972 
Total 
63 
108 
2268 
*Adjustment for multiplicity will be done at the analysis phase if necessary 
In order to adjust the initial estimates, sample size will be recalculated with VT carriage data 
obtained from the baseline survey.    
The sample size calculations were performed using PASS 14 (Power Analysis and Sample Size 
Software (2015). NCSS, LLC. Kaysville, Utah, USA).  
7.13 
Expected Results 
The overall project will present results for each of the primary and secondary objectives. For the 
main trial, results of prevalence of vaccine-serotype pneumococcus will be presented and compared. 
The results of the qualitative study will be presented in the form of a report. All results will be 
communicated as described below in section 13.6. 

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8 
Safety reporting for Adverse Events and Serious Adverse Event 
Data on Adverse Events (AEs) will be collected in a passive surveillance system for 7 days following 
vaccination. Data on Serious Adverse Events (SAEs) will be collected in a passive surveillance system 
for 28 days following vaccination.   
A health professional from the study team will be based in the nearest health centre to the 
vaccinated villages for 28 days after vaccination activities, and will be the key notifiers of AEs and 
SAEs to the study team. Moreover, the community health workers from the vaccinated villages will 
be asked to act as a focal point and communicate to the study team any events that occur during the 
follow-up period. During the vaccination activities, caretakers will be informed about vaccine safety 
and will be asked to contact the community health worker or to attend the nearest health centre in 
case of a health problem.  
Following, the International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice, 
an adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject to 
whom a vaccine has been administered; it does not necessarily have a causal relationship with the 
vaccine/vaccination.  
Definitions of AEs and grading will be specified in an SOP. In this trial, the recording of AEs will be 
limited to the evaluation of injection-site reactions (pain, tenderness, induration, infection, etc). 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life threatening: if the participant was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe. 
• 
Results in persistent or significant disability/incapacity: if the event results in a substantial 
disruption of the participant's ability to carry out normal life functions.  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization: In general, 
hospitalization signifies that the participant has been detained (usually involving at least 24h 
stay) at the hospital or emergency ward for treatment that would not have been appropriate 
in an outpatient setting. 
• 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
• 
Is an important medical event that may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed above.  
 
Hospitalization for either elective surgery related to a pre-existing condition, which did not increase 
in severity, or frequency following initiation of the study, or for routine clinical procedures (including 
hospitalization for "social" reasons) are not considered as SAEs. When in doubt as to whether 
hospitalization occurred or was necessary, the AE will be considered serious.  
The definition of a routine clinical procedure is a procedure, which may take place during the study 
period and should not interfere with the study vaccine administration or any of the on-going protocol 
specific procedures. If anything untoward occurs during an elective procedure and satisfies any of the 
criteria for SAE, this will be documented and reported. 

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8.1 
Causality Assessment 
If an event meets the criteria to be determined "serious" (see definition of SAE); it will be examined 
by the investigator (and DSMB) to determine all contributing factors applicable to each SAE. These 
contributing factors will be documented and reported appropriately. Every effort will be made by the 
investigator to explain each SAE and assess its causal relationship, if any, to administration of the 
study vaccine. 
In case of concomitant administration of multiple drugs, it will not be possible to determine the 
causal relationship of SAEs to the individual drugs administered. The investigator will, therefore, 
assess whether the SAE could be causally related to vaccination rather than to the individual drugs. 
The degree of certainty with which an SAE can be attributed to administration of the intervention (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be 
determined by how well the event can be understood in terms of one or more of the following: 
• 
Reaction of similar nature having previously been observed with Pneumosil or other PCV. 
• 
The event having often been reported in literature for similar interventions. 
• 
The event being temporally associated with Pneumosil vaccination.  
 
The Investigator will assess the causality of all SAEs, using the following question: “Is there a 
reasonable possibility that the SAE may have been caused by vaccine administration?” After 
assessment of causality, the investigator will classify the SAE as related or unrelated, as defined 
below: 
• 
Related: there is suspicion that there is a relationship between vaccine and SAE (without 
determining the extent of probability); there is a reasonable possibility that the vaccine 
contributed to the SAE. 
• 
Unrelated: there is no suspicion that there is a relationship between vaccine and SAE, there 
are other more likely causes and administration of the study vaccine is not suspected to have 
contributed to the SAE. 
 
8.2 
Procedure for recording Serious Adverse Events  
 
General information about SAEs 
The investigator will document all SAEs according to the detailed guidelines set out below. All 
participants will be instructed to contact the investigator immediately, either directly or via the 
community representative should the participant show any signs or symptoms perceived as serious 
during the period extending from enrolment to the study to the study end. Whenever possible, SAEs 
will be documented in terms of a diagnosis or syndrome rather than multiple symptoms that are 
clearly manifestations of the same diagnosis/syndrome. In case the participant reports signs and 
symptoms, the investigator will obtain a medical diagnosis. If a diagnosis cannot be obtained, then 
enter each sign or symptoms as separate events. Pre-existing conditions or signs and/or symptoms 
(including any which are not recognized at study entry but are recognized during the study period) 
present in a participant prior to enrolment will be recorded in the medical history in the participant's 
CRF.  

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Recording SAEs  
Information regarding SAEs will be collected through an SAE CRF as soon as the investigator is made 
aware of an SAE. SAEs will be followed up to resolution, and cessation of treatment or end of study, 
irrespective of severity or whether they are considered vaccination-related. 
The diagnosis, date and time (where appropriate) of onset, outcome, severity and relationship to 
vaccination will be established. Details of any treatment (all concomitant interventions) given will be 
recorded appropriately. Where applicable, information from relevant hospital case records and 
autopsy reports will be obtained.  
SAEs will be coded following MedRA coding conventions.  
 
Management of SAEs 
SAE will be managed in line with current Good Medical Practice. Management of any SAE will be 
recorded in the CRF. Participants will be referred to an approved health clinic and will be treated 
according to national and/or MSF standards. 
SAEs will be followed to their conclusions. Possible conclusions of an SAE will include followed up to 
resolution (participant’s health has returned to baseline status); followed up to stabilization (no 
further improvement or worsening of the event is expected) or the event is otherwise explained.    
8.3 
Expectedness 
SAEs will be considered as unexpected if the nature, seriousness, severity or outcome of the event is 
not consistent with the current information available for the vaccine as documented in the Reference 
Safety Information.  
8.4 
Reporting of SAEs  
 
Initial Reporting 
Any SAE (whether or not considered to be related to the study vaccine) will be reported to the 
Sponsor (or designee) by telephone or in writing or by email within 24 hours (1 calendar day) of 
becoming aware of the event. If the SAE is fatal or life threatening, the Sponsor (or designee) will be 
informed immediately by telephone, in addition to the duly completed form. The PI (or designee) will 
ensure that the information provided on the form, is legible, does not have abbreviations or personal 
and institutional identifiers, and is as complete as possible. 
The following is the minimum information required for the initial SAE report: 
• Description of the event 
• Date of vaccination  
• Reporter information 
• Preliminary causality assessment  
• Severity 
 
Follow Up Reporting 
A more detailed record of the Serious Adverse Event must follow the initial SAE within 5 days after 
receipt of the new information.  

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A follow-up report will contain new, updated or corrected information. The follow-up report will 
describe whether the event has resolved or continues, if and how it was treated including 
documentation of all supportive actions taken.  
8.5 
SAE Reporting to relevant bodies 
The Sponsor (or designee) will coordinate the safety monitoring and reporting in the study. SAEs will 
be reported to local ERBs following local laws and requirements. SAEs will be reported to the Data 
Safety and Monitoring Board (DSMB) according to the schedule and transmission flow set forth in the 
DSMB charter. Notification of SAE to concerned National Regulatory Authorities will follow national 
law requirements. Table 2 summarizes SAE reporting timelines. 
Table 2.  SAE reporting timelines. 
Reported To 
Reported By 
Timeline 
Sponsor (or designee)  
PI (or designee) 
Within 24 hours for all SAEs 
Local IRB and MSF-ERB 
PI (or designee) 
Within the delay established by local procedures/laws 
DSMB 
Sponsor (or designee) 
Within 24 hours for fatal and life threatening events or 
SUSARs, and within 7 days for other SAEs (according to 
DSMB charter) 
 
9 
Ethical and regulatory aspects 
9.1 
Ethical considerations particular to cluster randomized trials 
The design and implementation of cluster randomized trials raises a variety of ethical questions.  
These include who is considered a research subject; from whom, how and when informed consent 
should be obtained; whether clinical equipoise exists; the determination of risks and benefits; the 
protection of vulnerable groups; and the roles and responsibilities of “gatekeepers” (32). In response, 
a series of recommendations for the ethical design and conduct of cluster randomized trials were 
developed by a consensus group in 2012, referred to as the Ottawa Statement (33).  
Two general types of cluster-randomized trials have been described (34). The first is a “cluster-
cluster” trial, where the intervention necessarily takes place at the cluster level (such as treatment of 
a community well). The second is an “individual-cluster”, where the intervention takes places at the 
individual or household level.  The proposed cluster randomized trial can be classified as an 
“individual-cluster” trial, as the intervention, i.e. vaccination, is delivered at the individual level but 
the outcome measurement will be reported at the cluster level. In “individual-cluster” trials, as the 
intervention occurs at the individual level, the individual can provide consent to receiving that 
intervention (34). However, consent necessitates the special consideration of the role of political and 
administrative authorities as gatekeepers, as well as the nature of individual consent for 
participation. 
The following sections will address some of the important ethical considerations of the proposed trial 
design, taking into account the guidance of the Ottawa Statement and other important documents 
from the medical/ethical literature on the subject of cluster-randomized trials. 

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9.2 
Definition of research participants and identification of gatekeepers 
Given that the primary outcome of interest is the effect of a single-dose mass campaigns on NP 
carriage in the different arms, and knowing that vaccination has a direct effect amongst those 
vaccinated as well as an indirect effect, all residents of randomized villages should be considered as 
research participants (32,35). Following the principles stated in the Ottawa Statement, permission for 
the villages to take part in the study will be sought from “gatekeepers”.  This will include health and 
political/administrative leaders.  For the purposes of this study, the gatekeepers who will be asked 
for permission will be the village chief and his/her deputies for the villages eligible for inclusion. 
9.3 
Community engagement 
Appropriate engagement with the communities in the study area is crucial. We will follow use 
guidelines developed by UNAIDS for clinical trial research, Good Participatory Practices to ensure 
participation and mutual respect of values and actions. Open meetings will be routinely held with 
community representatives to discuss this research project. Moreover, the existing Community 
Advisory Boards in Niger will be convened to facilitate open communication between targeted 
communities and study personnel and inform adaptations to procedures and communication around 
the trial. 
Community representatives will be asked for advice before, during and after trial, ensuring a 
transparent and meaningful participatory process.  
9.4 
Summary of known and potential risks 
This study is considered to be of minimal risk to participants. The main three risks are related to 
vaccination, sample collection and confidentiality.  
The study product vaccine is an already approved and pre-qualified by WHO. There have not been 
any safety concerns regarding PCV10 and is considered safe (20). In a study assessing lower doses of 
a pentavalent PCV, doses close to what will be used in this study were not associated with increased 
frequency of local reactions (27). Administration of fractional doses will result, however, in an 
increased number of piercings of vial stoppers compared with what they are validated for. Possible 
stopper failures could include loss of self-sealing capacity, increasing the risk of contamination or 
leakage, and fragmentation of the stopper material, which could increase the risk of syringe blockage 
or injection of particles (36). However, a study assessing different vials stoppers found that all  
stoppers maintained their self-sealing capacity even after 100 punctures (36). Considering this and 
the presence of a preservative in the vaccine, the risk of multiple piercings is minimal. However, 
vaccination will be performed following a study specific SOP and vaccinated children will be followed-
up to monitor and treat any reactions to the vaccine. A pharmacovigilance officer is permanently in 
place at the Epicentre Niger research center and with the Sponsor.  
If one dose of PCV has an effect in the reduction of VT carriage, serotype replacement could 
eventually occur. However, the serotypes included in the PCV10 vaccine used in this study are the 
most common cause of IPD. Consequently, VT carriage is likely to be replaced by non-VT pathogenic 
serotypes, preventing cases of IPD.  

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All clinical procedures, including administration of the vaccine and collection of the NP swab, will be 
performed by adequately trained and experienced personnel under regular supervision to minimize 
any risk or discomfort to participants.   
Data management and confidentiality will all be conducted according to the EU General Data 
Protection Regulations (GDPR).  
9.5 
Risk minimization and benefits 
The introduction of the swab through a nostril might be particularly uncomfortable to young 
children. The procedure will be carefully explained to the parent/guardian and if the age of the child 
allows it will also be explained to the child in an adapted language. The procedure will be carried out 
by medical study personnel specifically trained to perform this procedure and following a study SOP. 
Should the COVID-19 pandemic be circulating in the region at the time of the study, a SOP will be in 
place to ensure proper use of personal protection equipment (PPE), which will be provided, as well as 
alignment with all public health regulations issued by the Nigerien government and as recommended 
by international regulators. 
At the individual level, children will benefit from immunization with a booster dose of PCV. Increased 
vaccine coverage will contribute to reduction of pneumococcal associated disease.  
At the population-level, the increase in PCV vaccination might have a positive effect on the uptake of 
other vaccines increase the overall protection against vaccine-preventable diseases. If PCV mass 
campaigns have an effect in reduction of VT carriage, this will be a benefit for the entire community. 
The data obtained from this study will be used to inform mass campaigns targeting a large age group 
in different settings, including emergency situations. 
WHO policy regarding handling of multi-dose vaccine vials (WHO/IVB/14.07) will be followed and 
used to minimize any risk from injections during vaccine campaigns. 
Relying on passive surveillance of AEs and SAEs may lead to underreporting, but this will be mitigated 
by having study staff dedicated to safety follow-up in health centers in the study area. 
9.6 
Expenses and reimbursements 
Participants will not receive any direct financial benefit from participating in the study.  
Clinic and treatment costs due to serious adverse events will be covered by the study for all 
participants during a period of 28 days post-vaccination.  
It is not anticipated that participants will travel for any study visits, as they will be home visits. 
However, if they should occur, reasonable travel expenses for any visits additional to normal care will 
be reimbursed or a mileage allowance provided as appropriate. 
Households participating in the surveys will be offered two bars of soap as a gesture of thanks and to 
compensate for time taken to participate, a practice that has been commonly accepted in the study 
area.  

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9.7 
Ethics review and approvals 
 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
 
ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this trial is conducted in full conformity with relevant regulations 
and with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) E6(R2) 2016.   
 
Approvals  
The protocol, informed consent form, and participant information sheet will be submitted for ethical 
review to the MSF Ethical Review Board, the Kenya Medical Research Institute Scientific Ethics 
Review Unit, and the Comité National d’Ethique pour la Récherche en Santé in Niger.  
The Investigators will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
Study authorization will be obtained by the Ministry of Public Health in Niger, and from the drug and 
pharmacy regulatory authorities “Autorité Nationale de Réglementation des Médicaments” in Niger 
for approval of the importation of the product.  
9.8 
Study registration 
Before study start, the study will be registered on clinicaltrials.gov and PACTR. 
9.9 
Informed consent 
 
Community consent 
The community engagement process will map the willingness and requirements of the community 
for involvement in the study, to ensure participation and mutual respect of values and actions. A 
study team will visit the selected villages to discuss community consent with gatekeepers as defined 
above.  
Before study activities, villages will be visited, and information sessions will be held to inform about 
study activities and assignment of villages to the different study arms. During these sessions, 
information will be given on the study vaccine, and it will be explained that the vaccination campaign 
is part of a larger study and that some individuals will be selected to participate in pre and post-
vaccination surveys.  
Information sessions will be planned to reach the highest number of household’s representatives. 
The involvement of community leaders will be key in assessing the reach of the information sessions. 
During these sessions the Information notice will be distributed, and parents/caretakers will have the 
opportunity to ask questions.  

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Individual consent 
During the information sessions, the household representative will be asked to sign an informed 
consent form if they wish that the children of the target age group living in their household 
participate in the vaccination activities. On the day of the vaccination activities in a given village, a 
study team will continue to deliver information about the study and the nature of the vaccination 
activity, highlighting that participation is voluntary.  Children will be asked to come to the vaccination 
site with a parent or guardian. Households who present to vaccination sites who have not previously 
signed informed consent documents will be given the opportunity to do so at the vaccination site 
with dedicated study staff. 
Written informed consent will be sought prior to inclusion in the pre- and post-vaccination surveys. 
The potential participants and their parent(s)/guardian(s) will have the study explained in depth to 
them and, in addition, will receive a patient information sheet. They will have the opportunity to ask 
questions to study staff prior to giving consent. Informed, witnessed, written consent will be 
recorded (ICF) from each participant and applicable parent(s)/guardian(s) for study participation, and 
other specific aspects of the trial.  
The ICFs designed for this study are based on the description in the 2013 Revision of the Helsinki 
Declaration and other documents related to GCP.  
Designated study staff will review the consent form with potential participants or representatives. 
The consent form will also be verbally explained in the appropriate local language. The informed 
consent process will ensure with high confidence that potential participants have an understanding 
of the potential risks and benefit of participation in the study, the study procedures, their right to 
refuse and/or withdraw from the study at any point without affecting the health services or care they 
receive, and without having to disclose a reason for their refusal or withdrawal.  
9.10 
Participant privacy and confidentiality 
The study staff will ensure that the participants’ privacy is maintained.  
No individual information will be collected at vaccination sites.  
Pre- and post- survey participants will be identified by initials, age (and date of birth if known), sex 
and a unique ID number. All documents and electronic data will be stored securely and only 
accessible by study staff and authorized personnel. The study will make the information anonymous 
as soon as it is practical to do so. 
The Investigator Site File and associated source documents will be retained for at least 10 years after 
the completion of the study. Written approval from the Sponsor will be obtained prior to destroying 
records. 
All study related documents will be kept in locked cabinets at the study site. Filing cabinets with the 
study data and the participant information will be locked and accessed only by authorized persons 
from the Sponsor and Regulatory Authorities.  
Participant personal data will be kept confidential and the privacy of all participants will be protected 
as far as permitted by law and following GDPR regulations. To ensure traceability and following 

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standard practice, nasopharyngeal samples will be labelled with participant initials, in addition to a 
unique ID number, sex and age. Only staff involved with the study conduct and local and 
international regulatory agencies may review these records.  
 
10 
Administrative aspects 
10.1 
Protocol amendments 
The Sponsor will amend the study protocol as needed to ensure that the clinical investigations are 
always conducted according to appropriate and up-to-date protocols. Amendments will be submitted 
for approval to the regulatory authorities and Ethics Committees. Changes requiring amendments 
will be defined according to guidance from regulators and include any significant change in the 
design of the study or the addition of a new test or procedure.  
10.2 
Protocol deviations and violations 
A protocol violation is any departure from the approved protocol, trial documents or any other 
information relating to the conduct of the study, which may affect the safety of trial participants or 
the study outcomes. Examples include failure to obtain informed consent (i.e. no documentary 
evidence) or enrolment of participants that do not meet inclusion/exclusion criteria.   
A protocol deviation is any departure from the approved protocol, trial documents or any other 
information relating to the conduct of the trial that does not result in harm to the trial participants 
and does not significantly affect the study outcomes. Examples of deviations include missed study 
visits or a visit date outside the study visit window or an isolated incident of a missed or incomplete 
study procedure or study evaluation. Serious or repeated protocol violations or deviations will 
require assessment of the root cause and implementation of corrective and preventive action plans. 
They may constitute grounds to interrupt the trial.  
Any changes from protocol-specified procedures and study-related SOPs occurring during the 
conduct of the trial will be documented and reported as protocol violations or deviations. Protocol 
violations will be reported to the Sponsor and reviewing ethical committees, as appropriate and in 
accordance with the requirements of the involved committees. 
10.3 
Insurance 
ICH GCP defines the extent of the responsibility of the Sponsor.  
The involved volunteer participants will be insured, in accordance with applicable laws and 
regulations, against financial loss resulting from personal injury and/or other damages, which may 
arise because of this study. 
10.4 
Funding and other support for the trial 
EDCTP will fund the study. The manufacturer will provide vaccines free of charge and other support 
will be provided by Epicentre in the area of deployment. 
 

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11 
Data handling and record keeping 
11.1 
Overview 
A Data Management team will be located at the study site. For surveys, all data will be collected on 
tablet computers using electronic CRFs (eCRF). Information about AE and SAE will be collected at 
health centers on paper CRFs. 
11.2 
Investigator site file (ISF) 
The investigators will maintain appropriate medical and research records for this study, in 
compliance with ICH E6 GCP and regulatory and institutional requirements for the protection of 
confidentiality of participants. The principal investigator, co-investigator, and clinical research staff 
will have access to records. The investigators will permit authorized representatives of the Sponsor, 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and progress. 
The ISF will be maintained at the study site containing at least the following documents and 
information: 
• 
Signed protocol and amendments 
• 
Electronic questionnaires and paper case report forms (CRF)  
• 
Current informed consent form and all revisions 
• 
Current participant information sheet and all revisions 
• 
Any other written information given to the study team 
• 
Financial aspects of the study 
• 
Insurance statement 
• 
All signed agreements/contracts 
• 
Dated and documented approval of ethics committee and regulatory authorities 
• 
Signed CV’s of all investigators and any study personnel (updated regularly as changes occur) 
• 
Instructions for handling of investigational product and study related materials 
• 
Monitoring reports 
• 
Relevant communication 
• 
Signed informed consent forms 
• 
Signed, dated, and completed CRFs 
• 
SAE reporting 
• 
Notification by Sponsor of safety information 
• 
Annual reports to ethics committee and regulatory authorities 
• 
Investigational product accountability 
• 
Authorization/signature sheet 
• 
Documentation of investigational product destruction 
• 
Clinical study report 
11.3 
Source Documents and CRFs 
In this study the following documents have been designated as source documents: 

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1. Vaccination cards 
2. Survey questionnaire responses 
3. Hospital records in case of hospitalization  
4. Paper versions of AE and SAE CRFs 
5. Tally sheets from vaccination sites 
 
If information is collected from different sources other than those specified above, then they will be 
recorded and documented. 
The only paper CRFs will be used to document AEs and SAEs. For the purposes of the surveys, all 
information will be collected on password-protected tablet computers (see below). A guide for filling 
in survey questionnaires will be developed and tested with study staff. Data about AE/SAE from 
paper CRF will be double-entered by data entry clerks using password protected laptops 
The study Data Managers are responsible for data management, integrity and security of paper and 
electronic data. Epicentre Research Department’s Data Protection and Compliance Officer supervises 
those activities. The study's data management plan will describe all activities that will be conducted 
to ensure the safety and quality of data. 
11.4 
Record keeping 
The ISF including a copy of the final completed CRFs, as well as all source documentation is retained 
by the investigator and one copy will be maintained by the Sponsor, who will ensure that it is stored 
with other study documents, such as the signed informed consent forms, protocol, the investigator’s 
brochure and any protocol amendments, in a secure place for 10 years. 
11.5 
Data management 
 
Hardware and software 
The survey questionnaires will be saved directly from tablet computers into a REDCap database. 
Information about AE/SAE recorded on paper CRFs will be entered directly into REDCap. The REDCap 
system uses a MySQL database via a secure web interface with data checks used during data entry to 
ensure data quality. It also includes a complete suite of features to support HIPAA compliance, 
including a full audit trail and user-based privileges and will conform to ICH GCP requirements. The 
REDCap system will be activated for the study only after successfully passing a formal design and test 
procedure. The primary study database will be located on the REDCap server in Paris. Responsibility 
for implementing the REDCap system lies with the Epicentre. Management and maintenance of the 
REDCap server lies with the data manager at the study site. 
 
Data security, access, and back-up 
The REDCap server will be kept in a locked server-room. Only the system administrators have direct 
access to the server and back-up tapes. A role concept with personal passwords (site investigator, 
statistician, monitor, administrator etc.) regulates permission for each user to use the system and 
database, as he/she requires. 
All data are transferred to the database using Secure Sockets Layer (SSL) encryption. Each data point 
has attributes attached to it identifying the user who entered it with the exact time and date. 

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Retrospective alterations of data in the database are recorded in an audit table. Time, table, data 
field and altered value, and the person are recorded (audit trail). 
A multi-level back-up system is implemented. Back-ups of the whole system including the database 
are run internally several times per day and on external tapes once a day. The back-up tapes are 
stored in a secure location. 
 
Archiving 
The Sponsor will securely store the final study database for at least 10 years. The Sponsor will also 
keep the Trial Master File and interim and final reports both in electronic and in hard copy form for 
at least 10 years.  
 
12 
Data Analysis 
Analysis of all endpoints will be described in a Statistical Analysis Plan. This SAP will include all 
conventions on data, descriptive and statistical analyses to be performed on collected data during 
the conduct of the study. A brief overview is provided below.  
Information on the total number of individuals per cluster for each of the following categories will be 
presented: screened individuals, screen failures (together with reasons for screen failure), consented 
participants for the baseline survey, the vaccination and the follow up survey. 
Participant demographics and baseline characteristics will be described at the cluster level. For each 
arm of the trial the number of clusters, the average number of clusters by demographic and baseline 
characteristics, such as household composition, average prevalence of exposure to indoor smoke, etc 
will be described and compared to ensure comparability.   
All analyses of outcome will be performed at the cluster level, controlling for clustering effects. For 
each cluster we will calculate the prevalence of NP carriage and present VT carriage in clusters 
allocated to full dose, fractional dose and control arm, including the 95% confidence interval. 
Proportions will be compared using chi square or Fisher’s exact test, as appropriate and adjusting for 
the clustering effect accounting for the intracluster correlation coefficient.  
For the analysis of superiority of the full dose vaccination arm compared to the control arm, the 
comparisons will be done using a chi square test at the 0.05 significance level. 
For the non- inferiority analysis, the 95%CI around the difference in the in the proportion of children 
with VT carriage (full dose group – fractional dose group) will be calculated and the non-inferiority 
will be achieved if the lower limit of this 95%CI is >-7.5%.  
All sensitivity analyses and adjusted analyses will be described in the SAP. Sensitivity analyses will 
include, but not be limited to, analyses investigating potential seasonal differences in NP carriage of 
pneumococci.  
Safety analysis will be based on the entire study population. Safety and tolerability of PCV10 will be 
assessed by comparing the frequency (%) of AEs and SAEs in full-dose and fractional-dose arms to the 
control arm using the Fisher’s exact test. Safety data will be presented in tabular and/or graphical 

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CONFIDENTIAL  v2.1 28 October 2021  
format and summarized descriptively. Data will be analyzed according to an intention-to-treat 
approach. In the unlikely event of clusters receiving incorrect interventions, or being only partially 
vaccinated, per-protocol analyses will be repeated on the primary endpoint.   
13 
Quality assurance and control 
13.1 Electronic and central data validation 
A designated person will supervise data collection and entry on a regular basis. The data manager will 
support onsite data entry teams. This process will be defined in the Data Management SOP. 
13.2 On-site monitoring   
 
Framework for monitoring 
The study will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and standard operating procedures. A monitoring plan will be finalized prior to study 
initiation. 
Monitoring will be performed according to ICH GCP including but not limited to regular visits during 
the clinical study and a closeout visit. Data will be evaluated for compliance with the protocol and 
accuracy in relation to source documents. Following written standard operating procedures, the 
monitors will verify that the clinical study is conducted and data are generated, documented and 
reported in compliance with the protocol, GCP and the applicable regulatory requirements. 
 
Implementing monitoring and audits at study sites 
Monitors will participate in all key, planned activities, collaborating with implementation of the 
study. They will therefore comply with all the planned monitoring visits.  
The monitoring plan will detail the frequency of monitoring visits and audits at the study site. The 
Study Monitoring Plan will cover instructions for monitoring the main aspects of the implementation 
of the study, including at least: 
• 
Study authorizations and approvals and communication with the ethics committees 
• 
Duties and Responsibilities of the Investigator/Institution 
• 
Suitable resources 
• 
Medical care for the participants 
• 
Clinical Study compliance with the agreed protocol  
• 
Laboratory aspects 
• 
Informed consent of participants 
• 
Data management, records and reports 
• 
Stopping rules, early termination, or suspension of the study 
• 
Sponsor 's Responsibilities  
• 
Responsibilities of the Monitors 
• 
Auditor's Responsibilities 

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Training to ensure quality of the study 
Study staff will receive specific training focused on the activities they will be performing. Specific 
training will be conducted prior to the cross-sectional surveys, mass campaign and interviews. The 
objective of this training program is to ensure that investigators are well prepared and trained, and 
understand the details and design of the study prior to implementation of the study.  
GCP training or GCP refresher training will be provided to pre-identified staff. 
13.3 Data Safety Monitoring Board 
The remit and functions of the DSMB will be described in the DSMB Charter.  
The aim of this committee is to protect the safety of trial participants while maintaining the study’s 
scientific goals according to the protocol and in accordance with international and local standards. A 
first DSMB meeting will be convened before the study commences and the DSMB Charter and Terms 
of Reference will be set at this first meeting. Thereafter, DSMB meetings will be conducted every 3 
months.  
13.4 
Inspections 
The investigators and institutions involved in the study will ensure that regulatory authorities may 
conduct monitoring and auditing and inspection of the study implementation. This includes official 
reviews of documents, facilities, records, and any other resources that are deemed by the authorities 
to be related to the study and that may be located at the study site or the Sponsor ’s and/or contract 
research organization’s facilities, or at other establishments deemed appropriate by the regulatory 
authority. 
13.5 
Completion or termination of the study 
Upon completion of the study, a summary of the study’s outcome and any required reports, if 
relevant, will be provided to the ERBs where required, and any reports will be provided to the 
regulatory authorities if applicable.  
 
After completion or termination of the study all documents, summaries, and reports for ERBs or the 
regulatory authorities should be kept in the investigator site file (ISF).   
13.6 
Publication policy and final report 
Timely reports of progress will be made available to MOH and health officials and other stakeholders, 
including communities.  
A final report of the study will be prepared and shared with relevant partners as described above. 
The project will publish overall results in international peer-reviewed scientific journals and in 
relevant national journals and media. The results of the cluster randomized trial will be reported 
following the CONSORT extension for cluster-randomized trials.3  
 
 
3 http://www.consort-statement.org/extensions/overview/cluster-trials 

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14 
Study Organization 
14.1 
Study Team 
A field study team will consist of nurses, communication officers, laboratory personnel, data 
management personnel, monitors, administrator and logistician. The field study team in Niger will be 
overseen by the Site Principal Investigator. He will be supported by a Project Coordinator, who will 
be responsible for maintaining communications between the field and office study teams. 
The field team will be supported by a clinical study and project administration team located in Paris.  
The qualitative component of this project will have their own dedicated team and will be led by 
qualitative researchers from the Université Abdou Moumouni.  
14.2 
Trial Steering Committee  
A Trial Steering Committee (TSC) will be put in place, with members comprised of a relevant mix of 
people with experience in pneumococcal disease prevention and epidemiology, as well as knowledge 
in data management, ethics, and knowledge of the local community.  
The overall task of the committee is to provide guidance and independent expertise on study design 
and conduct and ensure proper execution of the study. The Committee will meet prior to study 
initiation and at regular intervals thereafter to review study progress, consider recommendations of 
the DSMB and relevant ethics committees, and to agree on communications regarding the study.  
14.3 
Study timeline 
The overall duration of the study will be 18 months and major milestones are shown in Table 3.  
Table 3: Study timeline
 
8
9
10
11
12
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
6
Clinical Trial Implementation
Preparatory work 
Ethical and medical approvals
Baseline survey
Vaccination campaign
Follow-up survey 
Monitoring visits
Clinical study report
Laboratory Analysis
Lab preparatory work 
Monthly stock reports
Monthly sample reports
Cost-effectiveness and Modelling
Analysis Plan
Analysis 
Reports 
Policy Uptake and Access
Prepatory work 
Literature Review
Informant Interviews
Qualitative database closure
Report and briefing 
Year 1 (2021)
Year 2 (2022)
Year 3 (2023)

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15 
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Millar E V., O’Brien KL, Watt JP, Bronsdon MA, Dallas J, Whitney CG, et al. Effect of community-wide 
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http://dx.doi.org/10.1016/S0140-6736(18)33005-8 
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/pmc/articles/PMC5571437/ 
18.  
Flasche S, Ojal J, Le Polain de Waroux O, Otiende M, O’Brien KL, Kiti M, et al. Assessing the efficiency of 
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26];15(1):113. Available from: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-
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Predicting the impact of pneumococcal conjugate vaccine Programme options in Vietnam. Hum 
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Danaiya Usher A. Low-cost pneumonia vaccine breaks into global market. Lancet [Internet]. 2019 [cited 
2021 Jun 16];393(May 18):2025–6. Available from: www.thelancet.com 
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Alderson M, Dhere R. A new pneumococcal vaccine is here! Why this matters. | PATH [Internet]. 2019 
[cited 2021 Mar 15]. Available from: https://www.path.org/articles/new-pneumococcal-vaccine/ 
22.  
Schaumburg F, De Pijper CA, Grobusch MP. Intradermal travel vaccinations-when less means more. 
Travel Med Infect Dis. 2019;28(March):3–5.  
23.  
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intramuscular and subcutaneous vaccination - A systematic review and meta-analysis Jenny. Travel 
Med Infect Dis. 2020;37(101868).  
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Juan-Giner A, Kimathi D, Grantz KH, Hamaluba M, Kazooba P, Njuguna P, et al. Immunogenicity and 
safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial. 
Lancet [Internet]. 2021 Jan 9 [cited 2021 Mar 10];397(10269):119–27. Available from: 
www.thelancet.com 
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26.  
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Secretariat information paper [Internet]. 2016 [cited 2021 Mar 15]. Available from: http://www.who.int 
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Pneumococcal CRM 197 Vaccines: Effect of Saccharide Size on Immunogenicity and Interactions with 
Simultaneously Administered Vaccines. J Infect Dis [Internet]. 1997 Aug 1 [cited 2021 Mar 
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Adetifa IMO, Antonio M, Okoromah CAN, Ebruke C, Inem V, Nsekpong D, et al. Pre-vaccination 
nasopharyngeal pneumococcal carriage in a Nigerian population: Epidemiology and population biology. 
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The Gambia. Vaccine. 2015;33(51):7144–51.  
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Verani JR, Massora S, Acácio S, dos Santos RT, Vubil D, Pimenta F, et al. Nasopharyngeal carriage of 
Streptococcus pneumoniae among HIV-infected and – uninfected children <5 years of age before 
introduction of pneumococcal conjugate vaccine in Mozambique. PLoS One [Internet]. 2018 Feb 1 
[cited 2021 Jun 1];13(2):e0191113. Available from: https://doi.org/10.1371/journal.pone.0191113 
31.  
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detecting upper respiratory carriage of Streptococcus pneumoniae: Updated recommendations from 
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Weijer C, Grimshaw J, Taljaard M, Binik A, Boruch R. Ethical issues posed by cluster randomized trials in 
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Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, et al. The Ottawa Statement on the 
Ethical Design and Conduct of Cluster Randomized Trials. PLoS Med [Internet]. 2012 Nov 1 [cited 2021 
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Van Der Graaf R, Koffijberg H, Grobbee DE, De Hoop E, Moons KGM, Van Thiel GJMW, et al. The ethics 
of cluster-randomized trials requires further evaluation: A refinement of the Ottawa Statement. Vol. 
68, Journal of Clinical Epidemiology. Elsevier USA; 2015. p. 1108–14.  
36.  
Jarrahian C, Myers D, Creelman B, Saxon E, Zehrung D. Vaccine vial stopper performance for fractional 
dose delivery of vaccines. Hum Vaccines Immunother [Internet]. 2017 Jul 3 [cited 2021 Jun 
3];13(7):1666–8. Available from: https://pubmed.ncbi.nlm.nih.gov/28463054/ 
 
 
 
 
 

Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
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1
 
Statistical Analysis Plan 
 
Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
against pneumococcal transmission in Sub-Saharan Africa 
 
Primary Sponsor  
 
Rebecca F. Grais (Epicentre) 
Sponsor’s Investigator
 
 
Matthew E. Coldiron, Epicentre 
Co-investigators 
 
 
 
 
Ousmane Guindo, Epicentre  
Issaka Soumana, Epicentre  
Aitana Juan-Giner, Epicentre  
Rabiou Dare, Niger Ministry of Public Health  
Hassan Adboul Nasser, National Immunization Program  
Katherine Gallagher, KWTRP and LSHTM  
Wangeci Kagucia, KWTRP  
John Ojal, KWTRP and LSHTM  
Eric Adehossi, Université Abdou Moumouni  
Anthony Scott, KWTRP and LSHTM  
Angela Karani, KWTRP  
Souleymane Brah, Université Abdou Moumouni 
 
Data management  
Souna Garba et Chaibou Louali, Epicentre 
Statistical analysis 
Elisabeth Baudin, Epicentre 
Funding
EDCTP 
 
 

Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
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Version 1.1, 18Sep2023 
 
2
Declaration of Confidentiality 
The information contained herein is confidential and therefore are provided in confidence as a potential 
examiner or investigator. 
 
It is understood that this information will not be disclosed to others without the written permission of the 
Sponsor, except to the extent necessary to achieve the consent of those who can participate in the study. 
 
 
 
 

Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
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Version 1.1, 18Sep2023 
 
3
Version control and signature page: 
SAP 
Effective Date: 18Sep2023 
Version Number and Date: 1.1, 18Sep2023 
Revision  
List of changes: 
V1.1, 18Sep2023 
Correction in the section 4.3 Statistical analysis: Statistical analyses 
to demonstrate superiority and non-inferiority will be performed at 
the individual level instead of the cluster level, as described in the 
section 4.3.2.1 Primary Analysis    
Name and function 
Date (DD-MMM-YYYY) 
Signature 
Author 
Elisabeth 
Baudin, 
Epicentre, 
Biostatistician 
 
 
Reviewed by
Rebecca F. Grais, Epicentre, Sponsor 
representative 
 
Matt 
Coldiron, 
Epicentre, 
Sponsor’s  
investigator 
 
 
 
 
 

Determining whether mass campaigns with fractional dose PCV10 would accelerate herd protection 
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Table of Contents 
1. Introduction 
6 
1.1 Statistical Analysis Plan 
6 
1.2 
Rationale 
6 
2. Study Objectives 
6 
2.1 Primary Objective 
6 
2.2 Secondary Objectives 
6 
3. Study Design and Assessment 
7 
3.1 Study Design 
7 
3.1.1 Study cohorts 
7 
3.1.2 Sample Size and Power Considerations 
8 
3.1.3 Randomization and Blinding 
10 
3.1.4 Schedule of Study Visits and Procedures 
10 
3.1.5 Analysis Populations 
11 
3.1.6. Protocol Violation and Deviations 
11 
3.2 Assessment of Objectives 
12 
3.2.1 Efficacy Assessments 
12 
3.2.2 Safety Assessments 
12 
3.2.3 Other Assessments 
13 
4. Statistical Methods 
13 
4.1 Timing of Analysis 
13 
4.1.1 Primary Analysis Time Point 
14 
4.2 Methods for Handling Missing Data 
14 
4.3 Statistical Analysis 
14 
4.3.1 Baseline Characteristics 
14 
4.3.2 Primary Analysis 
15 
4.3.3 Safety Analysis 
16 
5. Statistical Tables to be Generated 
16 
5.1 Demographic and Baseline 
16 
5.2 Primary and Secondary Analyses 
16 
5.3 Safety Analysis 
16 
6. Statistical Listings to be Generated 
17 
7. Statistical Graphs to be Generated 
17 
 

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Abbreviations 
 
AE  
  
Adverse Event 
CI 
  
Confidence Interval 
CRF  
  
Case Report Form 
DSMB   
Data and Safety Monitoring Board 
GCP 
  
Good Clinical Practice 
GEE 
  
Generalized Estimating Equation 
IAE 
  
Immediate Adverse Event 
IRB  
  
Institutional Review Board 
ITT 
  
Intent-to-treat 
KWTRP  
KEMRI Wellcome Trust Research Programme 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
  
Principal Investigator 
PP 
  
Per-protocol 
PT 
  
Preferred Term 
SAE  
  
Serious Adverse Event 
SAP 
  
Statistical Analysis Plan 
SOC 
  
System Organ Class 
SOP 
  
Standard operating procedure 
SUSAR   
Suspected unexpected serious adverse reaction 
WHO   
World Health Organization 
 
 

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1. Introduction 
1.1 Statistical Analysis Plan 
A statistical analysis plan (SAP) is a comprehensive and detailed description of the methods for data analyses to 
be used in a clinical trial. A clear, detailed SAP will avoid post hoc decisions that may affect the interpretation of 
the data. This SAP includes details on the procedures for creating Tables, Listings, and Graphs from the results 
of a Phase IV study, which will be carried out to determine whether mass campaigns with fractional dose PCV10 
would accelerate herd protection against pneumococcal transmission in Sub-Saharan Africa. 
 
This is a separate document from statistical section of the protocol. Any changes in the statistical methods 
presented in the protocol and any additional statistical analysis not included in the protocol will be explained in 
this detailed statistical analysis plan of the study. This SAP includes a statement of the objectives of the trial, as 
stated in the protocol; identifies all primary and secondary end-points; specifies the hypotheses to be tested 
and any parameters that are to be estimated, in order to meet the trial objectives; defines the analysis 
populations to be used; and provides a full and detailed description of the methods of analysis including details 
of handling of missing data, dropouts, derived variables, etc. 
 
1.2 Rationale 
Pneumococcal vaccination campaigns targeting children up to 5 years of age with a full three-dose primary series 
have been shown to have an effect in the reduction of VT carriage and disease. However, in crises or settings 
with high prevalence of malnutrition, the high pneumococcal carriage prevalence is likely to extend to older age 
groups. Therefore, a single dose vaccination of a larger age group might be needed to control VT circulation. 
Currently, for Gavi-supported countries, such as Niger, PCV13 vaccine has a cost of US$3 per dose. Pneumosil®, 
a PCV10 manufactured by Serum Institute of India Ltd, has the lowest price at US$2 per dose of all WHO 
prequalified vaccines. 
Even at the lower price point, mass campaigns targeting larger age groups would require many doses and might 
not be sustainable over time. 
Mass campaigns using fractional doses of PCV could be a solution to overcome the high PCV costs, increase 
vaccine access and expand vaccination benefits through alternative strategies.  
 
2. Study Objectives 
2.1 Primary Objective 
The primary objective is to evaluate whether a mass vaccination campaign targeting children approximately 1-
9 years of age with a full dose of PCV is superior to the absence of vaccine in reduction of VT carriage prevalence 
at 6 months post-campaign, and subsequently to evaluate if a single 20% dose of PCV is non-inferior to a full 
dose. 
 
2.2 Secondary Objectives 
Analysis of the following secondary objectives will be described in this SAP: 
 
To measure the age-stratified prevalence of NP carriage of S. pneumoniae in children 1-9 years of age 
in the study area.  

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 
To determine the effect of a mass vaccination campaign with one full dose of PCV in children 1 to 9 
years of age on VT pneumococci carriage 6 months after vaccination  
 
To assess the occurrence of adverse events (AE) during 7 days and serious adverse events (SAE) 
during 28 days after administration of fractional and full doses of PCV.  
The analyses of the two following secondary objectives will be described elsewhere:  
 
To model the potential effect of fractional dose PCV campaigns in other contexts using the results of 
the clinical trial.  
 
In the setting of a qualitative study, to develop recommendations on how a potential future fractional 
dose PCV mass campaign could be successfully planned, communicated, delivered and integrated into 
national immunization programmes using qualitative analysis. 
3. Study Design and Assessment 
3.1 Study Design 
 
This is a Phase IV, 3-arm, observer-blinded, cluster-randomized controlled trial, implemented in rural villages of 
the Madarounfa District of Niger.  
 
3.1.1 Study cohorts 
Clusters will be randomized to full dose mass vaccination campaigns, fractional dose mass vaccination campaigns 
or the control arm in 3:3:1 allocation ratio. Clusters will be composed of a village or group of closely-
neighbouring villages that share a school or market, and will be limited to a population of between 500 and 4000 
persons. Stratified randomization will be used to account for proximity to the nearest health centre (<5 km vs 
≥5 km).  In the event of significant imbalance in carriage of VT pneumococci between clusters in the baseline 
survey, randomization may also be stratified by baseline prevalence upon the decision of the Trial Steering 
Committee. For this reason, randomization will happen after the results of the baseline survey are known. 
 
Vaccination will target all children aged 1 to 9 years of age residing in the selected villages. (If baseline survey 
data unexpectedly shows very low prevalence of carriage at the extremes of this age range, the target age 
group may be adjusted upon recommendation of the trial steering committee.) We estimate that children 
eligible for the vaccination campaigns will represent 30% of the total population. With an estimated average of 
2000 people per cluster, vaccination will target approximately 600 children 1-9 years of age in each cluster 
receiving vaccine. In total, in the 54 clusters receiving vaccine, the mass vaccination campaign with single full- 
or fractional-dose PCV is expected to target approximately 32,400 children 1-9 years of age.  
 
Prior to the mass vaccination campaign, a cross-sectional survey will be implemented to estimate community-
level carriage of VT pneumococci, as well as to collect data on household composition, social interactions and 
PCV vaccination coverage in the routine EPI. A total of 36 households in each cluster will be invited to participate 
in the cross-sectional survey. For the purposes of this study, a household is defined as a group of people living 
under the authority of a head of household, sleeping under the same roof, and sharing at least one meal per 
day, for at least two weeks, independent of any family ties. Selection of households will be based on probability 
sampling. The required number of households in each cluster will be randomly selected using simple random 
sampling based on an exhaustive list of heads of household in the cluster.  
 
Six months after the mass vaccination campaign, the post- vaccination cross-sectional survey will be 
implemented. This will be used to estimate community level carriage of VT pneumococcus after a single-dose 
PCV delivered as full or fractional dose as well as carriage in the clusters that received no vaccination. The survey 

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will target the same number of children as the baseline survey and will follow the same methodology with the 
households selected by simple random sampling from the sampling frame. 
 
Sampling will be independent between the two surveys. 
 
3.1.1.1 Inclusion and Exclusion Criteria 
To participate in each cross-sectional surveys (baseline and post vaccination), one child per household will be 
randomly selected for the nasopharyngeal sampling if he is eligible for enrolment after meeting the following 
inclusion criteria:   
- 
Aged 1-9 years 
- 
Residing in the villages included in the study 
- 
Parent or caretaker provides informed consent for the child to participate in the study 
Exclusion criteria for participating in the surveys will include the following:  
- 
Head or facial injuries that contraindicate nasopharyngeal swabbing  
- 
Any condition or criteria, including acute or chronic clinically significant abnormality that in the 
opinion of the investigator might compromise the wellbeing of the participant or interfere with the 
outcome of the study 
For mass vaccination campaigns, all children of the target age group for vaccination, for instance aged 1-9 years 
of age, residing in the study villages allocated to full or fractional dose arm will be targeted for vaccination.  
Children meeting the following inclusion criteria will be eligible for vaccination:  
- 
Aged 1-9 years 
- 
Residing in the villages included in the study and allocated to vaccination 
- 
Head of the household or main caretaker provides consent for the child to be vaccinated  
Exclusion criteria for vaccination will include the following:  
- 
Hypersensitivity to any component of the vaccine, including diphtheria toxoid 
- 
Vaccination with a PCV vaccine within the previous 4 weeks, as there should be a minimum of 4 
weeks between doses  
- 
Moderate or severe febrile illness (temperature ≥39°C) is a temporal contraindication, and the child 
should not be vaccinated until improvement.  
- 
Any condition or criteria, including acute or chronic clinically significant abnormality that in the 
opinion of the clinical staff might compromise the wellbeing of the volunteer 
3.1.1.2 Withdrawal/Discontinuation Criteria 
In accordance with the principles of the Declaration of Helsinki a participant has the right to withdraw from any 
part of the study at any time and for any reason and is not obliged to give their reasons for doing so.  
 
The mass vaccination consists of a single dose while outcomes are at the community level measured through 
two cross-sectional surveys. However, individual participants (in surveys or the qualitative study) may withdraw 
their consent and in that case their data will not be included in the data analysis.   
 
3.1.2 Sample Size and Power Considerations 
The sample size has been calculated to respond to the objective of determining whether community level 
prevalence of VT pneumococci after a fractional dose PCV mass campaign among children aged 1-9 years is non-

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inferior to that seen after a mass campaign among children aged 1-9 years using full dose PCV as well as 
determining the superiority of a full dose PCV mass campaign compared to no vaccination. Based on NP carriage 
studies conducted in Sub-Saharan Africa settings and considering an estimated coverage of 3 doses of PCV in 
children < 12 months of age of 48% in the study area, we estimate the prevalence of VT carriage, among 1-9 
year old, to be between 25 and 35% and take the middle value, 30%, as an initial estimate. We assume a 50% 
reduction in PCV10 VT carriage after vaccination with a full dose and consider the prevalence of VT carriage 
amongst vaccinated children with a full dose 6 months after the vaccination campaign to be 15%. 
 
Based on information from a study conducted in the area, we consider an intra-cluster correlation coefficient of 
0.02. To test the non-inferiority of a mass campaign using fractional doses compared to a mass campaign using 
full doses, we have chosen a non-inferiority margin of 7.5% to ensure that a campaign with fractional doses 
provide at least half of the benefits provided by a campaign using full doses. We consider a 2.5% level of 
significance for a one-sided test and 90% power. With these assumptions, 27 clusters with 36 households 
sampled per cluster would provide a power of at least 90% (1944 individuals, with 972 in the full dose and 972 
in the fractional dose arm). Non-inferiority will be achieved if the lower limit of the 95% confidence interval (CI) 
around the difference in the proportion of children with VT carriage (full dose group – fractional dose group) is 
> -7.5%. 
 
Given the sample size of the full-dose arm to test non-inferiority as described above, to test the superiority of a 
mass campaign to the control (non-vaccinated) arm, and considering a 5% level of significance for a two-sided 
test and 90%, we would need to sample 9 clusters with 30 households apiece in both the full-dose and control 
arms. Since the non-inferiority evaluation requires a larger sample size, the control arm will include the larger 
number of participants per cluster, which will lead to >90% power to detect superiority. 
 
For the NP carriage survey, one participant will be sampled from each household. We consider that most 
households will have a child aged 1 to 9 years of age, but account for 20% refusal to participate and/or absences 
and increase the number of households to be invited to participate by 20%. All selected households having a 
child of the target age group will be invited to participate in the social contacts survey. Table 1 summarizes the 
number of cluster and households to be included in each survey.  
 
Table 1. Initial estimates of clusters and households to be invited to participate in each survey 
Allocation 
N° clusters  
N° households  
Total participants 
Control arm 
9 
36 
324 
Full dose arm 
27 
36 
972 
Fractional dose arm 
27 
36 
972 
Total 
63 
108 
2268 
The baseline prevalence of VT carriage is expected to be between 25 and 35% as described below. In case the 
results from the baseline survey differ significantly, the sample size may be re-evaluated.  Once baseline survey 
results are available, they will be presented to TSC with simulation on power calculations outlining various 

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scenarios for the follow-up survey. Sample size may be re estimated and the number of children may be 
increased following this review.  
 
3.1.3 Randomization and Blinding 
 
Following the results of the baseline survey, clusters will be randomized in a 3:3:1 ratio, with 27 clusters 
randomized to receive a campaign with the full dose, 27 clusters randomized to receive a campaign with the 
fractional dose and 9 clusters randomized to the control arm. Randomization will be stratified by proximity to 
nearest health center (<5 km vs ≥5 km). In the event of significant imbalance in carriage of VT pneumococci 
between clusters in the baseline survey, randomization will also be stratified by baseline prevalence, after a 
decision by the trial steering committee. An equal or proportional number of clusters will be randomized to each 
study arm from each stratum. The study statistician randomization will prepare the material to generate the list 
(blocked randomization with fixed block size if only one stratum, by minimisation if more than one stratum), and 
the final list will be generated by an independent statistician who has no contact with study participants. Study 
implementation will be blinded to the extent possible. Vaccination nurses will not be blinded to the vaccine they 
are giving, but they will not communicate vaccine allocation to other members of the team or to participating 
villages. Villages randomized to the control arm will not receive any “dummy” intervention, so will not be blinded 
to their group allocation. The trial will be observer-blind in that personnel at KWTRP will be blinded to group 
allocation until after the completion of culture and serotyping in each survey. 
 
3.1.4 Schedule of Study Visits and Procedures 
During the baseline and 6 months post-vaccination surveys, one visit will be performed. No follow-up will be 
done after this visit. During the two surveys, a questionnaire will be filled for each selected household to collect 
socio-demographics information on the household, including the number of members who live in the household, 
their age and sex, school or other day care attendance of the children living in the household, PCV vaccination 
status of children living in the household, exposure to solid fuel smoke, and smoking habits. 
 
For each selected child aged 1 to 9 years, an additional questionnaire will be filled to collect information on the 
child’s recent symptoms of an upper respiratory tract infection, including receiving any antimicrobials in the 
previous two weeks, and a nasopharyngeal sampling will be performed. 
 
Additionally at baseline, on a selected household member, a social interactions questionnaire will be filled to 
collect information on the number of contacts with people of different age groups in the last 24h. 
 
During the post vaccination survey, additional information on the PCV vaccination during the study campaign 
from all children of the targeted age group will be collected. 
 
Vaccination activities will occur at village level and will take place on a pre-scheduled day. All children of the 
target age group for vaccination, for instance aged 1-9 years of age, residing in the study villages allocated to 
full or fractional dose arm will be targeted for vaccination. Vaccination will occur at fixed sites in each 
participating village. Vaccination activities will be timed to happen in the same geographical area at the same 

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time and will be scheduled as to not interfere with other planned vaccination activities. The number of doses of 
vaccine administered at each site will be noted on tally sheets. 
 
Data on Adverse Events (AEs) will be collected in a passive surveillance system for 7 days following vaccination 
(focusing on AEs at the injection site) and data on Serious Adverse Events (SAEs) for 28 days following 
vaccination. A health professional from the study team will be based in the nearest health centre to the 
vaccinated villages for 28 days after the vaccination activities and will be the key notifiers of AEs and SAEs to the 
study team. Moreover, the community health workers from the vaccinated villages will be asked to act as a focal 
point and communicate to the study team any events that occur during the follow-up period. During the 
vaccination activities, caretakers will be informed about vaccine safety and will be asked to contact the 
community health worker or to attend the nearest health centre in case of a health problem. 
 
Data concerning SAEs from participants in villages allocated to the control group will be collected between the 
first vaccination date up to 28 days after the last vaccination date performed in villages that were allocated to 
full or fractional dose and located in the catchment area of the same health facility.  
 
3.1.5 Analysis Populations 
 
All data from the surveys will be analysed in an intent to treat approach, ie including all data collected in the 
household of each selected child. Only data collected in the households of selected children with results of the 
nasopharyngeal swab will be analysed for the primary outcome. 
 
Analyses of the primary outcome will be repeated on the per protocol population. The per protocol population 
will include children that provided a NP sample and completed the child questionnaire as well as the household 
questionnaire and for which no protocol violation was reported and who were in clusters who received the 
intervention allocated during randomization.  
Safety analysis will be conducted in two different groups depending on study intervention:  
 
In clusters allocated to the control arm, all children aged in the target age group for vaccination 
campaigns will be considered. The denominator in this study arm will be the population of the clusters 
according to the census records used to establish the sampling frame for the cluster.  
 
In clusters allocated to receive full- or fractional-dose mass campaigns, only children who actually 
received a vaccination will be considered, and the denominator in these study arms will be the number 
of children vaccinated based on records from the vaccination sites.  
3.1.6. Protocol Violation and Deviations 
 
A protocol violation is any departure from the approved protocol, trial documents or any other information 
relating to the conduct of the study, which may affect the safety of trial participants or the study outcomes. 
Examples include failure to obtain informed consent (i.e. no documentary evidence) or enrolment of children in 
one of the two surveys that do not meet inclusion/exclusion criteria.  
 
Incorrect intervention provided during the vaccination will be considered as a protocol violation at the cluster 
level. 
 

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A protocol deviation is any departure from the approved protocol, trial documents or any other information 
relating to the conduct of the trial that does not result in harm to the trial participants and does not significantly 
affect the study outcomes. Examples of deviations include isolated incident of a missed or incomplete study 
procedure or study evaluation, cases of mis-randomization or mis-stratification will also be considered as a 
protocol deviation. 
 
A final Protocol Deviation Listing will be generated and reviewed by sponsor personnel prior to freezing the 
database to ensure that all important deviations, including those that may lead to exclusion from analysis, are 
captured and summarized.  
 
Participants or villages/clusters will be excluded entirely from analysis if they have a protocol deviation defined 
as a full exclusion that affects the validity of their data (e.g., failure to obtain informed consent).  
 
3.2 Assessment of Objectives 
3.2.1 Efficacy Assessments 
 
3.2.1.1 Primary outcome 
 
The primary outcome is the prevalence of vaccine-type NP carriage in children approximately 1 to 9 years of age. 
It will be assessed before vaccination campaign (baseline survey) and at 6 months post PCV10 vaccination 
campaign (post vaccination survey). VT pneumococci are defined as those covered by PCV10 (1, 5, 6A, 6B, 7F, 
9V, 14, 19A, 19F, 23F). 
 
3.2.1.2 Secondary outcomes 
 
The secondary outcome is the prevalence of non-VT serotypes carriage in children approximately 1 to 9 years of 
age. It will be assessed as the same timepoints than for the primary outcome, ie during both surveys. 
3.2.2 Safety Assessments 
 
The safety outcomes are AE(s) at the injection site occurring withing 7 days after vaccination and SAE(s) occurring 
within 28 days after the vaccination. SAEs from participants in clusters allocated to the control group will be 
collected during a period of time from the first vaccination date up to 28 days after the last vaccination date 
performed in clusters allocated to full or fractional dose, in the geographical area sharing the same health center.  
 
3.2.2.1 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that either results in death; is life threatening; 
results in persistent or significant disability or incapacity, requires in-patient or extended hospitalization; 
prolonged of existing hospitalization; is a congenital anomaly/birth defect in the offspring of a study participant; 
or is a medically important event that may jeopardize the participant or require intervention to prevent one of 
the above outcomes. 
Data collection on the SAE will include the diagnosis of the AE, the intensity, the start and end dates, the 
outcome, the causality assessment with the vaccine, the seriousness criterion and the actions taken. Age and 
sex of the participant experiencing the SAE(s) will also be collected. 

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3.2.2.2 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject to whom a vaccine 
has been administered; it does not necessarily have a causal relationship with the vaccine/vaccination. In this 
study, the recording AEs will be limited to injection-site reactions as site pain injection, redness, swelling, 
itchiness, infection, etc.  
In addition to the diagnostic, the intensity, the start and end dates, the outcome, the causality assessment with 
the vaccine, the seriousness criterion and the actions taken. Age and sex of the participant experiencing the 
AE(s) will also be collected. 
 
3.2.2.3 Immediate post vaccination reactions 
Immediate reactions post-vaccination will be collected as other AE(s) from previous section. 
 
3.2.2.4 Fatal adverse events 
 
Any event which results in death will be recorded in the AE CRF as other AE from previous section. 
Additional information will be reported in the Serious Adverse Event form as the expectedness of the event, the 
result of the verbal autopsy and all relevant clinical records to provide a complete narrative of the fatal event. 
 
3.2.3 Other Assessments 
 
During both surveys, other information on the households will be collected, including a household census 
including members’ age and sex, the type of residence, occupation of the head of household, highest level of 
education of the head of household, ethnicity of the head of household, and information about known risk 
factors for pneumococcal carriage, including exposure to solid fuel smoke, certain indoor cooking practices, and 
smoking habits.  
 
During the baseline survey only, one randomly-selected household member will be administered a detailed 
questionnaire about social contacts with people of different ages, their sleeping arrangements, and their level 
of educational attainment.  
 
During both surveys, one randomly-selected child aged 1 to 9 years will have a NP swab collected. Information 
will also be collected regarding this child’s age, sex, sleeping arrangements, PCV vaccination status, and recent 
medical history, including medications taken in the last 14 days. 
 
During the follow-up survey only, all children in the target age group for the vaccination campaign will be asked 
about their participation in the vaccination campaign.  
During the vaccination campaigns, the number of children vaccinated will be collected at each site.  
 
4. Statistical Methods 
4.1 Timing of Analysis 
 

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The primary endpoint will be the change from baseline in VT carriage at 6 months post-vaccination campaign. 
The reduction in VT carriage will be calculated by comparing the proportion of children carrying VT pneumococci 
6 months post-vaccination to the baseline. 
 
4.1.1 Primary Analysis Time Point 
The primary analysis time point for the primary endpoints is 6 months post vaccination campaign.  
 
4.2 Methods for Handling Missing Data 
 
In general, missing data will be considered missing at random and no imputation will be performed. 
 
4.3 Statistical Analysis 
 
All results will be displayed by intervention group (full dose, fractional dose or control).  
 
Descriptions of the study population will be provided at the individual level and at the cluster level as 
appropriate. Statistical analyses to demonstrate superiority and non-inferiority will be performed at the 
individual level. Non inferiority will be tested if the superiority of the full dose  is shown; therefore, no 
adjustment for multiplicity is necessary. 
 
Comparison between groups will be done at the cluster level using Student’s t-test for continuous variables and 
Chi square test (or Fisher’s exact test if more appropriate) for categorical variable. 
 
Safety analysis will be done at the individual level only, and comparison for categorical variables will be done 
using a Chi square test (or Fisher’s exact test if more appropriate). All comparisons will be done at the 0.05 
significance level.  
 
Prevalence of carriage will be presented with a 2 sided 95% confidence interval.  
 
All statistical analysis will be performed on the statistical software Stata version 17 or later. 
 
4.3.1 Baseline Characteristics 
Information on the total number of participants per intervention group for each of the following categories will 
be presented: screened households, screen failures (together with reasons for screen failure), consented 
participants for the baseline survey, the vaccination and the follow up survey, screen failures (with reasons for 
screen failure) for baseline and post vaccination surveys and reasons for NP not performed.  
Information on the total population and population aged 1 to 9 years from the census, as well as breakdown by 
sex and distance to nearest health facility will be also summarized by cluster. 
Number of vaccinees, by sex and age group will be summarized by intervention group. Participant demographics 
and data collected through questionnaire at baseline and during post vaccination survey (as describe in section 
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mean and standard deviation (SD) for quantitative variables, and at cluster level using means and standard 
deviation (or median and IQR if appropriate).  
 
Baseline prevalence of carriage (VT and non VT serotypes) will be measured as the proportion of participants 
that are respectively colonized with any of the 10 serotypes covered by PCV10 and colonized with any other 
serotypes, excluding non-typable SP and those confirmed as not colonized by SP. 
 
Proportions will be compared using chi square or Fisher’s exact test, as appropriate and adjusting for the 
clustering effect. 
 
4.3.2 Primary Analysis 
4.3.2.1 Primary Analysis 
 
The primary analysis is the test of the superiority of the full dose vaccination arm compared to the control arm, 
on the reduction in NP carriage. The reduction will be calculated by comparing the proportion of children 
carrying VT pneumococci 6 months post-vaccination to baseline, at the time of vaccination.  
 
This primary analysis on the primary endpoint will be performed on the intent to treat population, using 
generalised estimating equations (GEE) to estimate risk differences and their associated 95% CI for the effect of 
the full dose vaccination on the reduction in VT carriage compared to the fractional dose. GEE will be used to 
account for clustering effect. Adjusted analyses with covariates (including but not limited to age, sex, vaccination 
coverage, time between baseline survey and vaccination, time between vaccination and follow-up survey,  
baseline prevalence of VT carriage) and stratification factor will be performed.  
The administrative vaccination coverage for each site where vaccination campaign is performed, is obtained by 
the formula: 
(number of vaccinees/number of expected children from the age group 1-9 years old) x 100. 
 
The superiority will be tested at the 0.05 significance level. 
For the non-inferiority analysis, the 95%CI around the risk difference in the in the proportion of children with VT 
carriage (full dose group – fractional dose group) will be using generalised estimating equations (GEE) and non-
inferiority will be achieved if the lower limit of this 95%CI is >-7.5%. 
 
Non inferiority analyses will be repeated on the per protocol population. Sensitivity analyses on the primary 
endpoint will be repeated by analyzing clusters according to the intervention they actually received if 
misallocation occurred.  
 
 
In order to account for any potential seasonal variation seen due to timing of the surveys, additional sensitivity 
analyses will be performed, comparing the difference in prevalence between the full-dose and control arms, 
relatively to the reduction observed in the control group..  
 
 

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Multivariable logistic regression analyses will be performed to obtain adjusted estimates of risk factors for VT 
carriage at baseline and after vaccination campaign. The Odds Ratio and95% CI will be adjusted for age and sex. 
Robust SE will be used to allow for clustering at the cluster level. 4.3.2.2 Secondary Analysis. 
 
 
4.3.3 Safety Analysis 
 
Safety analysis will be based on the entire study population.  
Any adverse events occurring within 7 days after vaccination, serious adverse events, or deaths will be 
summarized as n (%) of participants having experienced the AE(s), and SAEs or death by arms. Comparisons will 
be done between full-dose and fractional-dose arms with the control arm, using a Fisher’s exact test.  
All AEs will be coded to a “Preferred Term” (PT) and primary associated “System-Organ Class” (SOC) according 
to the MedDRA dictionary (Medical Dictionary for Regulatory Activities, version 25.0).  
 
Counts and proportions will be provided overall and for each PT within each SOC. AE(s) will be tabulated overall 
and by grade, and by type of AEs:  
• 
AEs non SAEs occurring with 7 days after vaccination 
• 
SAEs 
• 
SAEs leading to death 
5. Statistical Tables to be Generated 
<Consider appropriate tables for each of these categories and some examples are provided> 
 
5.1 Demographic and Baseline  
Table 1.1 
Summary of Screening 
Table 1.2  
Summary of Participant Disposition by intervention group, Analysis Population - Randomized 
Cluster 
Table 1.4  
Summary of Protocol Deviations by intervention group - ITT Population 
Table 1.5  
Summary of Demographics and Baseline Characteristics by intervention group, participants 
and Cluster level - ITT Population 
 
 
5.2 Primary and Secondary Analyses 
 
5.3 Safety Analysis 
Adverse Events 
Table 3.1 
Summary of adverse events (AEs) by intervention group 
Table 3.2 
Adverse events (AEs) by MedDRA coding (SOC and PT) by intervention group, Safety 
population 
Table 3.3  
Severity of adverse events (AEs) , Safety population 
Table 3.6  
Relatedness of adverse events (AEs) , Safety population 
Table 3.7  
Outcome of adverse events (AEs) , Safety population 
Serious Adverse Events 

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Table 3.1 
Summary of serious adverse events (SAEs)  by intervention group 
Table 3.2 
Serious Adverse events (SAEs) by MedDRA coding (SOC and PT) by intervention group, Safety 
population 
Table 3.6  
Relatedness of serious adverse events (SAEs) , Safety population 
Table 3.7  
Outcome of serious adverse events (SAEs) , Safety population 
Deaths 
Table 3.22 
Summary of deaths by study arm, Safety population 
 
6. Statistical Listings to be Generated 
<Adapt and amend as needed> 
 
Participant Data Listings 
Listing 1.1 
Participants who are screen-failures 
Listing 1.3  
Listing of protocol deviations 
Listing 1.5 
Exclusion of villages/cluster from PP populations 
 
Safety Listings 
Listing 2.1 
Listing of Serious adverse events (SAEs) 
Listing 2.3 
Listing of Adverse events (AEs) 
Listing 2.5 
Listing of death narratives 
7. Statistical Graphs to be Generated 
<Adapt and amend as needed> 
 
Figure 1.1 
Study flowchart of study arms, and analysis populations