The Effect of Fractional Doses of Pneumococcal Conjugate Vaccines (PCV10 and PCV13) on Immunogenicity and Vaccine-serotype Carriage in Kenyan Infants
Phase: PHASE4
Conditions: Pneumococcal Infection, Streptococcus Pneumoniae Infection, Invasive Pneumococcal Disease, Protection Against
Sponsor: London School of Hygiene and Tropical Medicine

KEMRI- Wellcome Trust Research Programme (KWTRP) 
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KWTRP    
CLINICAL TRIAL PROTOCOL 
The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and PCV13) 
on immunogenicity and vaccine-serotype carriage in Kenyan infants 
GENERAL INFORMATION 
 
Protocol Number: 
QA1075 
Trial Registration Number: 
 
Investigational Product(s): 
Pneumococcal 
Conjugate 
Vaccines: 
Synflorix (PCV10; GlaxoSmithKline plc.) 
and Prevnar13 (PCV13; Pfizer Inc.) 
Funder: 
The Bill & Melinda Gates Foundation;  
500 Fifth Avenue North; Seattle, WA 
98109; USA. 
Tel: +1 (206) 709-3100 
Sponsor:  
London School of Hygiene & Tropical 
Medicine; Keppel Street, London, WC1E 
7HT, United Kingdom. 
Tel: +44 (0) 20 7636 8636 
Email: Patricia.Henley@lshtm.ac.uk 
Product Manufacturer(s): 
1. GlaxoSmithKline plc., 980 Great West 
Road, Brentford, Middlesex, TW8 
9GS, United Kingdom. Tel: +44 (0)20 
8047 5000 
2. Pfizer Inc., 235 East 42nd Street NY, 
NY 10017, USA. Tel: +12127332323  
 
 
 

KEMRI- Wellcome Trust Research Programme (KWTRP) 
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Confidentiality Statement 
The information contained herein is privileged or confidential and may not be disclosed unless 
such disclosure is required by applicable laws or regulations. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential 
and may not be further disclosed by them. These restrictions on disclosure will apply equally 
to all future information supplied to you, which is indicated as privileged or confidential. This 
confidentiality statement also applies to data generated during the course of the study. 
 

KEMRI- Wellcome Trust Research Programme (KWTRP) 
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INVESTIGATOR’S APPROVAL OF THE PROTOCOL 
 
The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and PCV13) 
on immunogenicity and vaccine-serotype carriage in Kenyan infants 
 
Protocol Number: 
 
The undersigned acknowledge possession of and have read the Fractional Dose PCV Trial 
protocol versions 1.0 (dated 16th October 2017), 2.0 (dated 09th January 2018) and 3.0 (dated 
01st May 2018). Having fully considered all the information available, the undersigned 
consider that it is ethically justifiable to give pneumococcal conjugate vaccines in fractional 
doses to the selected participants according to the agreed protocol. 
 
I understand that all information concerning fractional doses of pneumococcal conjugate 
vaccines supplied to me by the London School of Hygiene and Tropical Medicine (LSHTM) 
and their agents/partners in connection with this study and not previously published is 
confidential information. This includes the Investigators’ Brochure, Clinical Trial Protocol, 
Case Report Forms and any other preclinical and clinical data provided by LSHTM. 
I understand that no data are to be made public or published without prior knowledge 
and written approval by LSHTM. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all 
the conditions, instructions and restrictions contained in the Fractional dose PCV trial 
protocol and in accordance with the most recent Declaration of Helsinki and Good Clinical 
Practice and all applicable regulatory requirements. 
I acknowledge that the Sponsor of the study, LSHTM, has the right to discontinue the study 
at any time. 
 
 
Principal Investigator Signature 
Date 
[Principal Investigator name and title/position/role] 
 
 
 

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CONTENTS 
GLOSSARY OF TERMS AND ABBREVIATIONS: .......................................................... 6 
1 
LAY SUMMARY .......................................................................................................... 7 
2 
TITLE OF THE PROJECT ......................................................................................... 9 
3 
LIST OF INVESTIGATORS....................................................................................... 9 
4 
ABSTRACT ................................................................................................................. 10 
5 
INTRODUCTION/ BACKGROUND ....................................................................... 11 
6 
JUSTIFICATION ....................................................................................................... 12 
7 
HYPOTHESIS............................................................................................................. 14 
8 
AIM & OBJECTIVES ................................................................................................ 14 
8.1 
AIM .............................................................................................................................. 14 
8.2 
Primary objective ........................................................................................................ 14 
8.3 
Secondary objectives ................................................................................................... 15 
9 
TRIAL DESIGN .............................................................................................................. 15 
9.1 
Overall Study Design .................................................................................................. 15 
9.2 
Description of the study population .......................................................................... 16 
9.3 
Trial procedures .......................................................................................................... 18 
9.3.1 Recruitment ................................................................................................................. 18 
9.3.2 Screening ...................................................................................................................... 19 
9.3.3 Inclusion & exclusion criteria .................................................................................... 20 
9.3.4 Enrolment .................................................................................................................... 21 
9.3.5 Randomisation & blinding ......................................................................................... 21 
9.3.6 Vaccination .................................................................................................................. 22 
9.3.7 
Follow-up Visits ................................................................................................ 26 
9.3.8 
Unscheduled Visits ........................................................................................... 27 
9.3.9 
End of study visit .............................................................................................. 27 
9.3.10 Study participant withdrawal criteria ...................................................................... 27 
9.3.11 Managing withdrawals ............................................................................................... 28 
9.3.12 Replacing withdrawn participants ............................................................................ 28 
10 TREATMENT OF STUDY PARTICIPANTS ............................................................. 28 
10.1 The Product(s) ............................................................................................................. 28 
10.2 Dose selection ............................................................................................................... 29 
10.3 Product management & storage ................................................................................ 29 
10.4 Dispensing Procedures................................................................................................ 30 
10.5 Unblinding ................................................................................................................... 30 
10.6 Prior/Concomitant Therapy ...................................................................................... 31 
10.7 Rescue vaccination ...................................................................................................... 31 
11 LAB PROCEEDURES ................................................................................................... 32 
12 ASSESSMENT OF SAFETY ......................................................................................... 33 
12.1 Identification of Adverse Events (AEs) and Severe Adverse Events (SAEs) ........ 33 
12.2 Definitions and monitoring of AEs and SAEs .......................................................... 33 
12.3 Reporting AEs and SAEs ........................................................................................... 34 
12.4 Reporting SUSARs...................................................................................................... 35 
12.5 Emergency Procedures ............................................................................................... 36 
12.6 Procedures for reporting any protocol violation(s) ................................................. 37 
13 STATISTICAL ANALYSES .......................................................................................... 37 
13.1 Primary analyses and Sample size............................................................................. 37 
13.2 Secondary analyses ..................................................................................................... 38 

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13.3 
General statistical methods ................................................................................. 40 
14 
DATA MANAGEMENT ..................................................................................... 41 
14.1 
Hardware and software....................................................................................... 41 
14.2 
Data security, access and back-up...................................................................... 41 
14.3 
Direct access to source data/documents ................................................................ 41 
15 QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 41 
15.1 Choice of investigators ................................................................................................ 41 
15.2 Monitoring ................................................................................................................... 41 
15.3 Training to ensure quality of the study ..................................................................... 42 
16 INTELLECTUAL PROPERTY .................................................................................... 42 
17 TIME FRAME/DURATION OF THE TRIAL ............................................................ 43 
18 ETHICS ............................................................................................................................ 43 
18.1 Human Subjects .......................................................................................................... 43 
18.2 Community Considerations ....................................................................................... 45 
18.3 Informed Consent ....................................................................................................... 45 
18.4 Compensation .............................................................................................................. 46 
18.5 Patient Data Protection/Confidentiality ................................................................... 46 
18.6 Data Sharing ................................................................................................................ 46 
18.7 Safety ............................................................................................................................ 47 
18.8 Material Transfer Agreement (if applicable) ........................................................... 47 
19 ARCHIVING AND RECORD RETENTION .............................................................. 47 
19.1 
Overview .................................................................................................................. 47 
19.2 
Investigator site file (ISF) ....................................................................................... 47 
19.3 
Source documents .................................................................................................... 48 
19.4 
Record keeping and retention ................................................................................ 49 
20 FINANCING AND INSURANCE ................................................................................. 49 
20.1 
Budget ....................................................................................................................... 49 
20.2 
Justification of the Budget ...................................................................................... 50 
20.3 
Insurance .................................................................................................................. 51 
21 TRIAL MANAGEMENT ............................................................................................... 51 
21.1 
The Sponsor ............................................................................................................. 51 
21.2 
The Data and Safety Monitoring Board (DSMB) ................................................ 51 
22 REPORTING, DISSEMINATION AND NOTIFICATION OF RESULTS ............. 51 
22.1 
The Clinical Trial Report ....................................................................................... 51 
22.2 
Publications .............................................................................................................. 51 
22.3 
Dissemination ........................................................................................................... 52 
REFERENCES ....................................................................................................................... 53 
APPENDICES ........................................................................................................................ 59 
Appendix 1: Roles of Investigators ....................................................................................... 59 
Appendix 2: Informed consent form in English .................................................................. 61 
Appendix 3: Non-KEMRI Investigator CVs ....................................................................... 68 
 
 
 
 
 

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GLOSSARY OF TERMS AND ABBREVIATIONS: 
AE   
 
 
Adverse Event 
ATP  
 
 
According-to-protocol 
CI 
 
 
 
Confidence Interval 
CRF   
 
 
Case Report Form 
DSMB 
 
 
Data and Safety Monitoring Board 
EPI  
 
 
Expanded Programme on Immunization  
ERC  
 
 
Ethics Review Committee 
GCP   
 
 
Good Clinical Practice 
GMC 
 
 
Geometric Mean Concentration 
GMT  
 
 
Geometric Mean Titre 
GMFI 
 
 
Geometric Mean Fold Increase 
IB 
 
 
 
Investigator Brochure  
ICF  
 
 
Informed Consent Form 
ICH  
 
 
International Conference on Harmonization 
ID 
 
 
 
Intradermal 
IgG  
 
 
Immunoglobulin G 
IM 
 
 
 
Intramuscular 
IRB   
 
 
Institutional Review Board 
ISF  
 
 
Investigator site file 
ITT  
 
 
Intention to treat 
IU 
 
 
 
International Units 
NRA  
 
 
National regulatory authority 
PI 
 
 
 
Principal Investigator 
PIS  
 
 
Patient information sheet 
SAE   
 
 
Serious Adverse Event 
SAP  
 
 
Statistical Analysis Plan 
SC 
 
 
 
Subcutaneous 
SOP  
 
 
Standard operating procedure 
SUSAR 
 
 
Suspected unexpected serious adverse reaction 
 

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1 
LAY SUMMARY 
Formal Title: The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and 
PCV13) on immunogenicity and vaccine-serotype carriage in Kenyan infants. 
Lay Title: A trial to compare the immune response and the proportion of infants still carrying 
bacteria in their nose after varying doses of the pneumonia vaccines (‘PCV10’ and ‘PCV13’) 
in Kenyan infants. 
What is the problem/background? Before the introduction of pneumonia vaccines in 2000, 
around 700,000- 1 million children died each year as a result of infection with the bacteria 
Streptococcus pneumoniae and the resulting diseases, namely, meningitis, sepsis and 
pneumonia. Most of the deaths were in Africa and Asia. Where the vaccines have been 
introduced, they have been highly effective and have already reduced disease. However, at 
USD 10 per child, they are not affordable to most low-income countries without financial 
support from Gavi, the Vaccine Alliance. In Kenya, a 10-valent PCV has been implemented 
since 2011. The greater part of the vaccine cost is subsidized by Gavi. However, in 2022 Gavi 
will begin to reduce its subsidies to Kenya over a 5-year period so that by 2027 Kenya will be 
paying the whole cost alone. A reduction in the cost of the PCV programme may be necessary 
for Kenya to keep delivering its PCV programme. 
What questions are we trying to answer? This project aims to assess whether lower doses 
of the two commercially available pneumonia vaccines can protect Kenyan infants as well as 
the full dose and can be delivered safely. The results could be used to enable countries unable 
to afford the full cost of the pneumonia vaccine, to continue delivering it in the childhood 
immunisation programme in the absence of Gavi support. 
 
Where is the study taking place, how many people does it involve and how are they 
selected? The study will take place at multiple health facilities in Kilifi County. A total of 2100 
infants will be involved. Infants will be selected from those eligible for routine immunisations. 
Infants with acute illness will be excluded from enrolment into the study. HIV infection will 
be recorded but not used as an exclusion criterion.   
 
What does the study involve for those who are in it? Participants will be randomised in 
equal numbers to one of seven groups to receive either PCV10 or PCV13 at the full dose or 
lower dose schedules.   
Infants will receive the first dose of the three-dose schedule at 6 weeks of age and then mothers 
and infants will be invited back to the study clinic 6 further times during the course of the 
study. Infants will receive the 2nd and third doses of the vaccine, at 10 and 14 weeks or at 14 
weeks and 9 months of age. They will have a small amount of blood taken at their first visit, 
and 4 weeks after the 2nd and 3rd doses, some participants will also have a small amount of 
blood drawn at the time of the 3rd dose and at their last study visit at 18 months of age. Two 
swabs will be taken from the mucous in the nose to look for the presence of the bacteria.  

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What are the benefits and risks/costs of the study for those involved?  There is a small risk 
that the children in this study who receive the lower dose schedules will be less well protected 
than those who receive the full dose. However, because the vaccine has been in use for 6 years 
already in Kenya and will continue to be in use in the routine immunization system throughout 
the study, the bacteria is much less common than it was and the likelihood of developing 
disease is very low. As participants in the study, infants will have access to the study medical 
staff and will be able to present with any illness at an early stage and receive free treatment 
and/or referral to the sub-district hospital up until the age of 18 months (when the study ends). 
If, after final analyses, the lower doses are found to not give a good enough immune response, 
all infants in those groups will be given a single booster vaccination with the full dose.  
If a low dose of the vaccine stimulates a protective immune response, infants who were 
randomly selected to be given the PCV13 will have the added benefit of immunization against 
three additional pneumococcal bacterial types (3, 6A, 19A) contained in the study vaccine 
(PCV13) but not contained in the vaccine used in the national programme (PCV10). 900 of the 
2100 children recruited into the study will receive PCV13. 
How will the study benefit society?  If the pneumonia vaccines are effective at lower doses, 
the whole community may benefit. If lower doses can be administered the cost of the vaccine 
will fall meaning it may continue to be delivered by the government for longer.  
When does the study start and finish? The study will start upon receipt of ethical clearance. 
Data collection, analysis and write up will take place over 42 months. 

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2 
TITLE OF THE PROJECT  
The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and PCV13) 
on immunogenicity and vaccine-serotype carriage in Kenyan infants  
3 
LIST OF INVESTIGATORS 
KEMRI Investigators:  
Dr. Ifedayo Adetifa, Infectious Disease Epidemiologist, KEMRI-Wellcome Trust 
Research Programme (KWTRP) Centre for Geographic Medical Research - Coast 
(CGMRC), Kilifi, Kenya 
Dr. Mary Kaniu, Research Medical Officer, KEMRI-Wellcome Trust Research 
Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), 
Kilifi, Kenya.    
Angela Karani, Assistant Research Officer/Laboratory Coordinator, KEMRI-Wellcome 
Trust Research Programme (KWTRP) Centre for Geographic Medical Research - Coast 
(CGMRC), Kilifi, Kenya.  
Jimmy Shangala, Programme Pharmacist, KEMRI-Wellcome Trust Research 
Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), 
Kilifi, Kenya.  
Daisy Mugo, laboratory technician, KEMRI-Wellcome Trust Research Programme 
(KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), Kilifi, Kenya. 
Elizabeth Gardiner, laboratory technician, KEMRI-Wellcome Trust Research 
Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), 
Kilifi, Kenya. 
Mark Otiende, Statistician, KEMRI-Wellcome Trust Research Programme (KWTRP) 
Centre for Geographic Medical Research - Coast (CGMRC), Kilifi, Kenya. 
Dr Mainga Hamaluba; acting Chair of Clinical Research, KEMRI-Wellcome Trust 
Research Programme (KWTRP) Centre for Geographic Medical Research - Coast 
(CGMRC), Kilifi, Kenya.  
Professor Anthony Scott (Principal Investigator); Professor of Vaccine Epidemiology, 
Wellcome Trust Senior Research Fellow in Clinical Medicine, KEMRI-Wellcome Trust 
Research Programme (KWTRP) Centre for Geographic Medical Research - Coast 
(CGMRC), Kilifi, Kenya & London School of Hygiene and Topical Medicine.  
Non-KEMRI Investigators: 
Dr. Katherine Gallagher (Lead Co-Investigator); Assistant Professor in Epidemiology, 
London School of Hygiene and Tropical Medicine.  
Professor Frederick Were; Professor of Paediatrics at the University of Nairobi, Chair of 
the Kenyan NITAG. 
Dr. Christian Bottomley; Associate Professor in Medical Statistics and Epidemiology, 
London School of Hygiene and Tropical Medicine. 
Professor David Goldblatt; Professor of Vaccinology and Immunology, University 
College London.  

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Professor Peter Smith; Professor of Tropical Epidemiology, London School of Hygiene 
and Tropical Medicine. 
 
 
4 
ABSTRACT 
Currently, two pneumococcal conjugate vaccines (PCV) are licensed for inclusion in routine 
immunisation schedules in low- and middle-income countries (LMICs). Both vaccines have 
proven highly effective in stimulating vaccine-serotype-specific immune responses, reducing 
vaccine-serotype carriage and reducing the incidence of invasive pneumococcal disease 
(IPD) and hospitalised pneumonia. Worldwide, over 50 LMICs have introduced PCV with 
the support of Gavi, the Vaccine Alliance; however, as economies grow and countries 
transition out of Gavi support, the sustainability of their PCV programmes is at risk. PCV is 
currently the most expensive vaccine in the routine immunisation schedule in Gavi-supported 
countries. This study aims to provide evidence which may enable a substantial decrease in the 
cost of PCV programmes, therefore increasing the sustainability of PCV programmes in 
LMICs. We propose to assess whether fractional (20% and 40%) doses of pneumococcal 
conjugate vaccine (PCV10 and PCV13) in a 2p+1 schedule (2 primary doses followed by a 
booster dose) induce non-inferior immunogenicity and effects on vaccine-serotype carriage 
when compared to the full dose. These lower doses would convert new 4-dose vials of PCVs 
into 10- or 20-dose vials, ready for immediate implementation in LMIC programmes.  
 

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5 
INTRODUCTION/ BACKGROUND 
Pneumococcal conjugate vaccines (PCVs) have proven to be highly effective in stimulating 
vaccine-serotype specific immune responses[1-3], reducing vaccine-serotype carriage[4-7] 
and causing significant declines in invasive pneumococcal disease (IPD)[8, 9]. In 2004, four 
years after the introduction of PCV7 in the USA, the incidence of Invasive Pneumococcal 
Disease (IPD) among children aged <5 years had declined by 84% and the incidence of 
vaccine-serotype IPD had declined by 92%[6]. These findings are supported by similar 
surveillance figures in Western Australia[8], Northern Canada[10] and England, where 
further declines were apparent after the switch from PCV7 to PCV13[11].  
Currently, two PCVs are available for introduction into the routine immunisation schedules 
of low- and middle-income countries (LMICs), Synflorix® (GlaxoSmithKline plc.) covers 10 
pneumococcal serotypes and Prevnar 13® covers 13 serotypes (Pfizer Inc.). Although there is 
now evidence that immune correlates of protection for vaccine serotype-specific IgG 
responses may vary by serotype[2], both vaccines have been licensed based on the immune 
correlate of protection for vaccine serotype-specific IgG responses of 0.35 mcg/ml IgG 
established using PCV7[12, 13]. There is little evidence of cross-protection against non-
vaccine pneumococcal serotypes[9, 12]. The World Health Organization (WHO) currently 
recommends PCV10 or PCV13 for use in routine immunisation programmes in a three dose 
schedule: in a primary series at 6, 10 and 14-20 weeks of age (the ‘3p+0’ schedule), or two 
primary doses at 6-8 weeks and 14-16 weeks with a booster at least 6 months after the 2nd 
dose (e.g. 11-15 months of age; the ‘2p+1’ schedule)[12]. In high income countries, where 
disease incidence generally peaks later in childhood than in LMICs[14], the 2p+1 schedule 
has demonstrated effective direct protection against carriage and IPD and additionally 
stimulates strong herd protection at the population level[11, 15, 16]. In most LMICs, 
including Kenya, rates of pneumococcal disease peak in the first 6 months of life, and uptake 
of vaccines scheduled for the second year of life is low, so a 3p+0 schedule has been adopted 
to ensure direct protection from disease as early in life as possible[14]. However, there is 
evidence that the IgG concentrations after 2 primary doses delivered with a 2 month interval 
are equivalent to those produced after 3 doses that are each 1 month apart[17, 18]. 
Additionally, data from Australia indicate that a 3p+0 schedule of PCV13 may have resulted 
in less substantial declines in IPD compared to those seen in the UK or USA, where 2+1 and 
3+1 schedules have been used respectively[19]. As PCV programmes mature and evidence 
accrues, schedules in LMICs may also change to 2p+1 in order to take advantage of the 
potential additional benefits of herd protection[19-21]. This approach is supported by recent 
data from South Africa, a relatively high transmission setting, where a 2p+1 schedule of 
PCV7 has demonstrated a 48-60% reduction in carriage prevalence at 12 months of age 
compared to a PCV-unvaccinated historical cohort[22, 23]. IgG concentrations pre-boost 
were greater than 0.35 mcg/ml for all 7 vaccine types indicating that, importantly, direct 
protection may have been maintained in the period between the primary series and boost 
dose[24]. Persistence of high IgG concentrations could be due to the persistence of the 
vaccine-induced immune response and/or natural boosting through exposure to circulating 

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vaccine-types[25].In the UK, 2.5 years after vaccination in a 2p+1 schedule, >75% of 
children had circulating IgG to 5 of the 7 PCV7 serotypes at concentrations >0.35 
mcg/mll[26]. Protection from carriage has been demonstrated out to at least 4 years post-
vaccination in some studies for at least some PCV7 serotypes[27].   Further data are needed 
on the duration of protection after a 2p+1 schedule in LMIC settings, both between the 
primary series and boost dose and after the booster into the 2nd year of life[16, 27]. 
Safe and immunogenic co-administration of PCV7/9/13 with routine childhood 
immunisations has been demonstrated for all antigens in the schedule, including Diphtheria-
Tetanus- acellular Pertussis vaccine with or without Inactivated Polio Vaccine and hepatitis B 
vaccine components,  Measles-Mumps-Rubella, Varicella, Haemophilus influenzae Type b 
(Hib) and meningococcal conjugate vaccines [28-32]. Immunological responses to PCV in 
Kenyan infants are high; over 90% of a cohort of children following the routine 
immunisation schedule of 3p+0 achieved the immune correlate of protection 4 weeks after 
the third dose for all PCV7 serotypes[33].    
 
6 
JUSTIFICATION 
Since 2010, Gavi, the Vaccine Alliance, has supported PCV introduction in over 50 ‘Gavi-
eligible’ LMICs (countries with a gross national income (GNI) per capita <1580 USD). At 
the current cost of US$3.10-3.50 per dose, PCV is the most expensive vaccine in the EPI 
schedule for many LMICs[34]. At US$10 per fully immunised child, PCV is one of the 
biggest barriers to countries self-financing their routine vaccination schedules and the 
sustainability of the PCV programme is of concern in countries that are transitioning out of 
Gavi support. Gavi predicts that Kenya will enter the ‘accelerated transition phase’ in 2022, 
at which point vaccine co-financing commitments will increase sharply for 5 years until 
Kenya’s routine immunisation (RI) programme is fully self-financed. In 2015, the Kenyan 
government funded just 10% of their RI programme expenditure[35]; the EPI programme is 
anticipating potentially dropping antigens from their vaccination schedule to meet the 
funding shortfall. Both the EPI programme and the Kenya National Immunisation Technical 
Advisory Group are actively examining alternative policy options for prevention of 
pneumococcal disease. Furthermore, for those middle-income countries ineligible for Gavi 
support, a reduction in the cost of PCV may enable vaccine introduction where currently it is 
prohibitively expensive. In 2016, only 56% of MICs had introduced PCVs compared with 
76% of low-income countries (LICs)[36]. As of September 2017, only 57% of the world’s 
infants lived in countries that had introduced PCV[37, 38]. 
One approach to reducing the financial cost of PCV programmes is to use a fractional dose of 
antigen at each vaccination. Fractional doses of antigen have been shown to induce non-
inferior immune responses in trials of vaccines against Haemophilus influenzae type b 
(Hib)[39-44], Neisseria meningitidis[45] and Yellow Fever[46-49] and are under 
investigation for Inactivated Polio Vaccine (IPV) using novel injection devices for 
intradermal delivery[50-54]. Both the diphtheria CRM197 and tetanus toxoid-conjugated Hib 
vaccines with antigen doses as low as 1.25 mcg (1/8th of the marketed dose) stimulated non-

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inferior immune responses when compared to the full dose[39]. Intramuscular doses of 2.5 
mcg (1/4th of the full dose) of Neisseria meningitidis serogroups A and C polysaccharide 
within a conjugate vaccine elicited high geometric mean titres of antibody in Filipino 
infants[45]. A 0.1 ml dose of Yellow Fever vaccine (1/5th of the standard dose), delivered via 
subcutaneous or intramuscular injection, is now endorsed by WHO as a preventative measure 
in areas at risk of epidemics[55, 56].  
Specific to pneumococcal vaccines, an early trial of a pentavalent pneumococcal conjugate 
vaccine (pentavalent PCV) documented serotype-specific immune responses that reached the 
immune correlate of protection (0.35 mcg/ml – established following later efficacy trials) 
after a dose of just 0.5 mcg of antigen without adjuvant (approximately 1/5th of the current 
dose in PCV13 – see Table 1)[57]. Pentavalent PCV was administered to 400 infants in the 
USA in the 1990s in formulations of 5, 2 or 0.5 mcg of polysaccharide; 1 month after the 
third vaccine dose all three formulations elicited adequate serotype-specific immune 
responses for protection (>0.35 mcg IgG/ml)[57]. Additionally, there is some evidence that 
African children elicit higher antibody responses than European or American children[58], 
which may mitigate against any potential diminution in immunogenicity with reducing dose. 
Following the request by Gavi-eligible countries to reduce the cold-chain requirements of 
PCV[59], Pfizer and GlaxoSmithKline (GSK) have developed 4-dose presentations of PCV 
containing a preservative, which will be available for ministries of health to purchase from 
Unicef from 2018. The presence of a preservative in these 4-dose vials, which is not in the 2-
dose vials of PCV10, reduces the risk of contamination during multi-dose administration and 
enables multi-dose vials to be used for up to 28 days following first puncture, minimising 
vaccine wastage. The 4-dose presentations are not available for use in this study; the trial will 
use single dose formulations to deliver a single full or fractional dose as a proof of concept. 
However, if this trial provides evidence that fractional doses elicit non-inferior 
immunogenicity to full doses using the single dose formulations, LMICs could operationalise 
fractional dose delivery by using the 4-dose vials as 10 or 20 dose vials, as soon as the trial 
results are known. Vaccine implementers in LMICs are familiar with multi-dose vials, 
particularly 10-dose/20-dose vials that are used to deliver BCG, and re-classifying a 4-dose 
vial of PCV as either a 10-dose or 20-dose vial would effectively deliver 40% or 20% 
fractional doses. Here we propose to evaluate whether fractional doses of PCV10/13 induce 
non-inferior immunogenicity in a proof of concept study, if the trial yields propitious results, 
a further small study could be conducted to document the feasibility of delivering 10 or 20 
doses from a single 4-dose vial. A 20% dose of PCV13 in 0.1 ml volume would deliver a 
dose of saccharide similar to the lowest dose previously found to elicit an adequate immune 
response in the pentavalent PCV trial. This study was performed without the advantage of an 
adjuvant[57]. The 20% dose of PCV10 would deliver a lower dose of antigen than published 
in previous studies; however, PCV10 has demonstrated broadly equivalent effectiveness to 
PCV13 despite using saccharide doses approximately half those of PCV13. The different 
vaccines use different carrier proteins[60, 61] and therefore both the 40% and 20% doses 
need to be tested for both products to allow results to be generalizable to Kenya and/or other 

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LMICs currently using PCV13. A 20% doses, at a volume of 0.1ml represents the smallest 
volume currently thought to be feasible to deliver as an intramuscular injection in infants[55].  
Table 1. The available vaccine formulations and proposed fractional (20% and 40%) 
dose of PCV10 and PCV13 
 
Serotype 
saccharide 
dose (μg)  
1 
3 
4 
5 
6A 
7F 
9V 
14 
18C 
19A 
19F 
23F 
6B 
PCV13 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
4.4 
40%-PCV13  
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
1.76 
20%-PCV13 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.88 
PCV10 
1.0 
 
3.0 
1.0 
 
1.0 
1.0 
1.0 
3.0 
 
3.0 
1.0 
1.0 
40%-PCV10 
0.40 
 
1.2 
0.40 
 
0.40 
0.40 
0.40 
1.20 
 
1.20 
0.40 
0.40 
20%-PCV10 
0.2 
 
0.6 
0.2 
 
0.2 
0.2 
0.2 
0.6 
 
0.6 
0.2 
0.2 
 
If fractional doses generate non-inferior vaccine serotype-specific immune responses and 
similar impact on vaccine serotype carriage as the full dose, the cost of PCVs could be 
reduced by 50-75%. This would represent a substantially greater cost reduction than that 
achieved in recent price reductions (10% reduction in 2017)[62], or by reducing to a two-
dose schedule (33%).  
 
7 
HYPOTHESIS 
The null hypothesis is that there is a difference in the geometric mean concentrations of IgG 
elicited by Kenyan infants following three fractional doses of PCV10/ PCV13 (at 20% or 40% 
dose) in a 2p+1 schedule compared to full doses in a 2p+1 schedule.  
8 
AIM & OBJECTIVES 
8.1 
AIM 
To assess whether fractional doses (20% or 40%) of 10 or 13-valent Pneumococcal 
Conjugate Vaccine (PCV13/ PCV10), administered in a schedule consisting of two primary 
doses and one booster dose, induce serotype-specific immunogenicity and carriage 
prevalence at 18 months of age, that are non-inferior to the effects achieved with full doses.  
 
8.2 
Primary objective 
To determine whether fractional doses of PCV13/ PCV10 elicit non-inferior immunogenicity 
compared to full doses when delivered in a 2p+1 schedule with primary analyses at 4 weeks 

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after the booster dose (10 months of age) and secondary analyses at 4 weeks after the primary 
series (18 weeks of age). For the primary objective, immunogenicity will be assessed as the 
ratio of the geometric mean concentrations of IgG in the fractional/full dose arms. Secondary 
analyses will assess the proportion of infants achieving antibody levels above the threshold 
for protection (0.35 mcg IgG/ ml).  
 
8.3 
Secondary objectives 
• To determine the functionality of the immune response to full and fractional doses 
at the 1-month post-boost time point using an opsonophagocytic assay. 
• To compare vaccine efficacy against carriage of non-PCV10 serotypes 6A and 19A 
in the full dose PCV13 arms when compared to the fractional dose arms, using the 
full dose PCV10 2p+1 arm as a control, with primary analyses at 18 months of age 
and secondary analyses at 9 months of age. The carriage prevalence of the common 
vaccine serotypes (PCV10 serotypes) in the fractional dose arms will also be 
compared against the carriage prevalence in the full dose arms.  
• To compare frequency and severity of local injection-site reactions and vaccine-
related adverse events in the 28 days following immunization after fractional dose 
delivery and a full dose delivery.  
• To determine the concentration of circulating IgG after the primary series of the 
2p+1 schedule, prior to boost, at 9 months of age and after the boost at 18 months 
of age, estimate the duration of direct protection conferred by full and fractional 
dose schedules and use seroepidemiology to monitor acquisition rates. 
• To compare carriage prevalence at 9 and 18 months of age and IgG concentrations 
at 4 weeks after the primary series after full dose of PCV10 in a 3p+0 schedule, 
and full/ fractional doses of PCV10/13 in a 2p+1 schedule.  
 
 
9 
TRIAL DESIGN 
9.1 
Overall Study Design 
A phase IV individually-randomised controlled trial of full or fractional (20% or 40%) doses 
of PCV10/ PCV13, given as a 3-dose schedule to infants: 2 doses at 6 and 14 weeks of age 
and a booster dose at 9-12 months (the 2p+1 schedule) or 3 full doses at 6, 10 and 14 weeks 
of age (the 3p+0 schedule) (Figure 1.).  
At 6-8 weeks of age, 300 infants will be enrolled at random into each of the seven trial arms 
and followed until 18 months of age. The seven trial arms: 
A. Full dose PCV13 vaccination in a 2p+1 schedule. This arm will demonstrate 
immunogenicity and carriage endpoints for an alternative schedule to 3p+0 as 
recommended by WHO, in the Kenyan population.  
B. 40% fractional dose PCV13 vaccination in a 2p+1 schedule. 

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C. 20% fractional dose PCV13 vaccination in a 2p+1 schedule.  
 
D. Full dose PCV10 vaccination in a 2p+1 schedule. This arm will demonstrate 
immunogenicity and carriage endpoints for an alternative schedule to 3p+0 as 
recommended by WHO, in the Kenyan population.  
E. 40% fractional dose PCV10 vaccination in a 2p+1 schedule. 
F. 20% fractional dose PCV10 vaccination in a 2p+1 schedule.  
 
G. Full dose PCV10 vaccination in a 3p+0 schedule. This arm would represent the 
current vaccine and schedule in the Kenyan routine immunisation programme and 
would act as an additional comparison arm.  
 
Figure 1. Clinical trial flow 
 
 
1 Immunogenicity samples at 9 and 18 months of age will only be drawn from 150/300 participants in each arm.  
RI = routine immunisation. 
 
9.2 
Description of the study population   
 
The proposed trial will be conducted out of the KEMRI Wellcome Trust Research Programme 
(KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), with approximately 8 
clinics in Kilifi, Ganze, Malindi, Magarini sub-counties in Kilifi County. The final selection of 
clinics will depend on the agreement of the County and Sub-County health management teams. 
The following clinics are proposed, in the first instance:  
Randomisation (n=300 per arm)
G. PCV10 Full dose 
3p+0 
(RI schedule)
A. PCV13 
Full dose
2p+1
B. PCV13 
40% dose
2p+1
C. PCV13 
20% dose
2p+1
D. PCV10 
Full dose
2p+1
E. PCV10
40% dose
2p+1
F. PCV10
20% dose
2p+1
RI visit 10 weeks of age: DTP-HepB-Hib [no PCV]  
RI visit 6 weeks of age: DTP-HepB-Hib  + PCV (1st dose)
RI visit 14 weeks of age: DTP-HepB-Hib + IPV + PCV (2nd dose)
18 weeks of age: immunogenicity sample
RI visit 9 months of age: MCV1 + PCV (3rd dose) + carriage sample + immunogenicity sample1
1 month post boost – immunogenicity sample
RI visit 18 months of age: MCV2 + carriage sample + immunogenicity sample1
Subset of 50 immunogenicity samples per arm analysedfor OPA 
DTP-HepB- Hib+ PCV
DTP-HepB-Hib + IPV + PCV
MCV1 + Carriage sample
No visit
DTP-HepB- Hib+ PCV
MCV2 + Carriage sample

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- 
Ganze Health Centre & Bamba Sub-District Hospital (Ganze sub-county) 
- 
Gongoni Health Centre, Mambrui Dispensary, Marikebuni dispensary (Magarini sub-
County) 
- 
Gede Health Centre ((Malindi sub-county) 
- 
Matsangoni health centre and Kilifi County Hospital (Kilifi North sub-county) 
 
A further 1-2 other health facilities may be utilised if the above health centres cannot be used 
or if recruitment is slower than expected, including: Malindi General Hospital (Malindi Town 
sub-county), Vitengeni Health Centre (Ganze sub-county) and Chasimba health centre (Kilifi 
South sub-county).  
 
KWTRP CGMR-Coast has significant experience in recruitment of infants and young children 
to vaccine trials in a variety of different areas including past trials including 300 infants in 
Kilifi[33], 600 toddlers in Malindi[63] and 447 infants in Mtwapa/Pinglikani[64]. 
 
PCV10 was introduced in the national EPI programme in Kenya in 2011 in a three-dose 
schedule at 6, 10 and 14 weeks of age, with no booster dose (the ‘3p+0’ schedule). In Kilifi 
County, a catch-up campaign in under 5-year olds was completed. PCV10 is delivered 
concomitantly with DTP-HepB-Hib (pentavalent) vaccine and oral Polio vaccine[65]. In 
Kilifi, the median age at receipt of the first dose of PCV10 in 2013-2016 was 6.1-6.3 weeks 
(personal communication I. Adetifa). At 14 weeks of age, IPV is also administered. In an 
evaluation of the impact of the new vaccine introduction in 2013 it was estimated that S. 
pneumoniae vaccine-serotype carriage had been reduced from 34% to 13% in children under 
5 years of age in Kilifi[4]. This had been further decreased to 7% in 2016 but may be higher 
in areas outside of Kilifi in which no catch-up campaigns were conducted. It is expected that 
the fractional doses will be effective in preventing the acquisition of vaccine-serotype (VT) 
carriage, but if they are not, this will be apparent within the trial as study infants will be 
exposed (by contact with older children) to the vaccine serotypes. Furthermore, the reduction 
in vaccine type carriage prevalence over time has been matched by a commensurate increase 
in carriage of non-vaccine serotypes, particularly those contained in PCV13 but not in 
PCV10 (3, 6A and 19A) which are now found in 22% of all children under 5 years (cross 
sectional survey in Kilifi 2016; unpublished observation).  
Although Kenya currently delivers PCV in a 3p+0 schedule, there is increasing pressure for 
LMICs to switch to a 2p+1 schedule to take advantage of the hypothesised increased herd 
protection with a booster dose[20].  In preparation for a potential future change in schedule 
we have designed the study to deliver fractional doses in a 2p+1 schedule; however, we are 
also incorporating a single arm of 3p+0 to ‘bridge’ the findings to the existing schedule. 
PCV7, PCV9 and PCV13 can be delivered concomitantly with DTP-HepB-Hib (pentavalent 
vaccine) and other routine immunisations including measles with no effect on the 
immunological responses to any of the antigens [29, 32, 60, 61, 66, 67]. There is currently no 
routine vaccination visit at 11-15 months of age in Kenya; however, measles vaccine first 
dose (MCV1) is delivered to children at 9 months of age and measles second dose was 

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introduced in 2015 for children 15-18 months of age (MCV2). In future, the delivery of the 
booster dose in the 2p+1 schedule could be integrated with MCV1 or MCV2 or other health 
interventions e.g. vitamin A supplementation. In Kenya, 75% of children received MCV1 in 
2015[68] and 88% of children were fully vaccinated with the three doses of pentavalent 
vaccine by 1 year of age[69]. The National Vaccines and Immunization Program (NVIP) 
have begun to strengthen second year of life vaccinations and increase uptake of Measles 
second dose at 15-18 months of age. The World Health Organization also proposed to SAGE 
(April 2016) a new focus on the second year of life in the integration of immunisation and 
child-health services[70]. However, the most recent data for MCV2, from the first year of its 
introduction in Kenya in 2015, indicated only 28% coverage[68]. Therefore, for the purposes 
of this study, we will integrate the booster dose with MCV1 at 9 months of age.  
Across the coastal region of Kenya, 97% of women attend at least 1 ANC appointment at 
their local health facility, at a median of 5 months of gestation[69]. In 2014, 85% of women 
attending ANC nationally were tested for HIV and PMTCT programmes were available in 
>95% of health facilities[71]. HIV prevalence in women who had had at least 1 child was 
6.1% with an estimated mother-to-child transmission rate of 15% leaving 0.9% of infants 
with HIV infection[71]. We intend to execute the study as a pragmatic trial, including all 
infants regardless of HIV status; however, the prevalence of HIV in infants will be too low to 
permit a sub-group analysis of the impact of fractional doses among HIV-infected (or even 
HIV-exposed but uninfected) infants. 
 
9.3 
Trial procedures  
9.3.1 Recruitment   
Participants will be recruited from approximately 8 clinics in Kilifi, Ganze, Malindi, Magarini 
sub-counties in Kilifi County (see Section 9.2). The county and sub-county health management 
teams and relevant departments of the national Ministry of Health will be consulted regarding 
the choice of clinic sites. Community meetings will be organized with advice and input from 
the Ministry of Health staff at each clinic, local community health volunteers, community 
representatives and community liaison staff, to explain the need for a study of fractional doses 
of PCVs, the study requirements, and the risks and benefits of participation.  These community-
wide meetings will be used to sensitise the families and relatives of any mothers and infants 
who may be interested in participating. There will be time for question and answer sessions. 
Information sheets will be distributed, and any mothers considering participation will be asked 
to register their names and contact details with the community health volunteer and/or the study 
fieldworkers so that they can be contacted by phone or at home prior to their infant becoming 
6 weeks of age. 
With advice and input from the Ministry of Health staff, community representatives, 
community liaison staff and the agreement of local health facilities, information sessions will 
be organised in the waiting areas of antenatal care clinics and/or invitations to meetings about 
the study will be distributed to mothers waiting for their antenatal care appointment. Any 

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mother considering participation will be asked to register their name and contact details with 
the Ministry of Health staff at the clinic and/or our fieldworkers so that they can be contacted 
by phone or at home prior to their infant becoming 6 weeks of age.  
Community health volunteers may be employed to identify women who are pregnant or have 
recently given birth so that they and/or the study’s fieldworkers can contact them and their 
families at home to give them information about the study prior to their infant’s visit to the 
health centre at 6 weeks of age.  
It will be stated explicitly that participation may result in the parent’s child attaining inadequate 
immunity to pneumococcal vaccine serotypes; however, the results of the trial will be reviewed 
by an Independent Data and Safety Monitoring Board and if there is evidence of inadequate 
immunity all children in the fractional dose arms will receive a ‘top-up’ full dose of PCV10.  
9.3.2 Screening  
With the agreement of Ministry of Health staff at each clinic, the MOH staff will identify 
parents who are bringing their infants for their birth or 6 week of age vaccination visit and 
approach these parents and infants with information about the study. Ministry of Health or 
study staff will assess whether the family has been previously mobilised in the community 
and assess interest in enrolment onto the study. Before any study specific procedures are 
conducted the study team will explain the material contained in the information sheet and the 
parent(s) will be given an opportunity to discuss the material and ask questions. The parent 
will be required to read the full consent or receive a full oral explanation in an appropriate 
language. Parents will be asked individually by the study team if they understand all parts of 
the consent and will be given another opportunity to ask any questions and seek clarification. 
The parent will be asked to sign the informed consent form (ICF) or if unable to sign, to place 
a thumbprint on the ICF in the presence of an impartial witness.  
 
The information sheet will include details of the potential risks/ benefits to the parent’s child 
of participating in the study, the study requirements, the use of the blood samples and their 
right to refuse and/or withdraw from the study at any point without affecting any of the other 
health services or care they receive and without having to disclose a reason for their refusal or 
withdrawal.  
During the informed consent, parents will be given the contact details of a designated study 
staff member and the MOH staff at their local clinic and will be advised to contact either the 
MOH staff member or the study team (by telephone or by coming to the study site) if their 
child has a health problem. Parents may be contacted by phone by a member of the study team 
to be reminded about their child’s participation in the study and the follow-up visits. The 
contact details of the parent will be taken by the study team at the screening visit.  A copy of 
the consent form and participant information sheet (PIS) will be provided to the parent.  

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Mothers and infants will then be screened for eligibility. Mothers and infants will undergo a 
medical history, physical examination, and the mother will be either asked for her ANC HIV 
test result or tested for HIV using a rapid HIV diagnostic test as per the national guidelines. If 
the mother is HIV+ the clinic MOH and study team will organise for her infant to be tested for 
HIV using PCR as per the national guidelines, if they have not already been tested under the 
routine testing programme in Kenya. At this initial visit the investigator will assess the 
likelihood of compliance with protocol requirements prior to enrolment. HIV positive mothers 
and their infants will be referred to the health facility’s HIV testing and treatment services at 
the end of the study visit.  
9.3.3 Inclusion & exclusion criteria 
The study will recruit infants in Kilifi, Ganze, Malindi, Magarini sub-counties in Kilifi County, 
who are healthy and whose parents are willing to participate in the study. Inclusion/exclusion 
criteria will mimic those of the routine immunisation programme. The trial is aiming to emulate 
national vaccine policy in order to generate data to support policy decisions, so all healthy 
infants will be enrolled irrespective of HIV status. Infants with acute illness at the time of 
enrolment will be excluded from the trial.  
 
Inclusion criteria:  
- 
Healthy infants aged 6-8 weeks of age 
- 
HIV positive or negative but with no symptoms of current clinical 
immunosuppression i.e. HIV infection at WHO clinical stage 1 [72].  
- 
Parents are willing to provide informed consent for their child to participate in the 
study 
- 
Parents and infant are likely to remain in the study area until the infant is 18 months 
of age and comply with study requirements including the requirement to return to the 
same health facility to obtain all other childhood vaccines.  
 
Exclusion criteria:  
- 
Infants >8 weeks of age at time of enrolment  
- 
Signs or symptoms of immunosuppression or HIV infection clinical stage 2 or above.   
- 
Acute illness (e.g. febrile disease) on the day of vaccination 
- 
Contraindications precluding vaccination (e.g.  hypersensitivity to any component of 
the vaccine, including diphtheria toxoid)  
- 
Previous PCV vaccination 
- 
Family are planning to migrate out of the study areas before the end of the study 
follow-up 
- 
Family are planning to obtain the subsequent vaccine doses of the routine 
immunisation schedule elsewhere and therefore their child may receive a full dose 
under the routine vaccination programme. 
 
 

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9.3.4 Enrolment  
If parents and their infants meet the inclusion and none of the exclusion criteria above, the 
infant will be enrolled on the study by study staff at each clinic. If the infant is 6-8 weeks of 
age, randomisation will be completed the same day. After randomisation, a baseline 
questionnaire requesting information on sociodemographic characteristics, behavioural and 
environmental factors influencing pneumococcal transmission will be administered. A blood 
sample will be taken from the infant to perform a full blood count, screen for anaemia and 
assess HIV status as necessary. The results of the blood tests will not be used for the 
eligibility assessment but may inform the clinical care of the participant. An aliquot of this 
sample will be stored frozen in case there is any reason to suppose (from the final analyses) 
that the randomisation did not lead to three groups with equivalent starting concentrations of 
anti-capsular IgG. 
 
9.3.5 Randomisation & blinding  
The infant will be randomised to one of the seven vaccine schedules and dosages by the study 
team at the clinic. At randomisation, half of the participants randomised to arms A-F (150 of 
every 300 in each arm) will be allocated to a sub-group with an additional blood draw at 9 
and 18 months of age. This blood draw will be analysed to assess IgG persistence (Table 2a). 
 
Infants will be randomised using pre-prepared sealed envelopes containing randomisation 
codes.  Randomization codes will be prepared before recruitment starts by a person outside of 
the study. Allocations will be concealed until the envelope is opened by a member of the 
unblinded study team at each clinic during vaccine preparation.  Participants will not be 
informed of the allocated vaccine and vaccine will be prepared by the unblinded team who will 
mask the barrel of the syringe to avoid observation of the volume.  This will be important to 
avoid differential loss to follow up across the trial arms. Participants will be told that this is to 
avoid them becoming aware of the vaccination type before the end of the trial. Other than the 
vaccination team, other study personnel e.g. those observing reactogenicity and laboratory 
personnel will be blinded to the type of vaccine received by each participant. The study 
personnel preparing and administering the vaccine will not be blind to allocation in order to 
administer the vaccine, but will then not participate in safety assessments and will not reveal 
vaccination allocations to other trial personnel. 
 
Blinding of the seventh, control, arm of vaccination with the full dose of 3p+0 schedule will 
be broken when participants return for their second visit at 10 weeks of age and those in the 
seventh arm (arm G) receive their 2nd PCV dose. This break in blinding is not expected to affect 
rates of withdrawal from the study or assessment of the study outcome measures. Participants 
in the other 6 arms will remain blinded as to full/fractional PCV10/PCV13 allocation and 
participants in the seventh arm will not contribute local injection site reaction data (See Table 
2a and 2b: Time and events Schedule).  
 

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9.3.6 Vaccination  
Each infant will be assigned a study ID card/ sticker which will be fixed (stuck/ stapled) to 
the front of their routine immunisation vaccination booklet in order to clearly identify the 
infant as a trial participant, stickers with text to that effect will be inserted next to the relevant 
space for PCV administration in the routine immunisation booklet. Health workers in the 
surrounding area will be mobilised and informed about the trial and pictures of the study ID 
card/sticker will be circulated to them to attempt to avoid mistaken administration of full 
dose PCV in routine immunisation.  
 
The study team vaccinating nurse, or ‘vaccinator’, will be responsible for preparation and 
administration of the vaccines as randomised.  They will be responsible for the 
accompanying documentation. The vaccinator will prepare and administer the specified dose 
of vaccine intramuscularly (IM) in the anterolateral thigh muscle, as far as possible the 
routine immunisation guidelines will be followed, which state the right anterolateral thigh 
muscle. The location (Left versus Right) of the IM injection will be confirmed in the source 
documents.  
Other routine immunisations required will be administered as per Kenya routine 
immunisation schedule recommendations e.g. DTP-HepB-Hib (pentavalent vaccine), at an 
alternative site.   
MOH staff (blinded) and/or blinded study staff will conduct safety surveillance that will 
include 30 minutes of observation directly after vaccination. During the observation time, all 
parents who enrol their child onto the study will be counselled on: 
- the importance of returning to the same health facility for all subsequent infant 
vaccinations; 
- information regarding adverse events and parents will be asked to observe infants 
in the following seven days e.g. injection site reactions;  
- the signs and symptoms of respiratory distress in an infant as outlined also in the 
informed consent form e.g. cough, fast breathing, abnormal noise or movements 
when breathing;  
- how to contact study staff for help;  
- general points to reduce their child’s risk of respiratory disease i.e. the importance 
and benefits of breastfeeding and good nutrition, and the potential harm to their 
child of exposure to tobacco smoke and fumes from solid fuel cooking stoves. 
Personnel assessing safety outcomes and laboratory personnel will be blinded to the type of 
vaccine received by each participant. The study personnel preparing and administering the 
vaccine will not be blind to allocation in order to administer the vaccine, but will then not 
participate safety assessments and will not reveal vaccination allocations to other clinic or 
trial personnel. 

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Parents will be told they will be contacted and either invited back to the clinic 7 days after 
vaccination to report any adverse events/ reactions or visited at home (whichever preferred) 
by a study fieldworker. Parents will be able to telephone study staff at any point to report 
possible adverse events, which will initiate an examination at the clinic, as appropriate. 

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Table 2a: Time and Events Schedule – Trial arms A, B, C, D, E, F (the 2p+1 schedule)  
Study visit +/-window 
D01  
 
(dose 1) 
D7 
D28  
+/- 3d 
D56  
+/- 3d 
(dose 2) 
D63 /+ 
2d 
D84 +/- 
1wk 
D228 +/- 
2 wks 
(Boost) 
D235 
D256 +/- 
1wk 
D502 +/- 2 
wks 
 
Infant’s approx. age  
6wk 
7wk 
10wk 
14wk 
15wk 
18wk 
9m 
9m 
10m 
18m 
Clinic visit code 
V1 
 
V2 
V3 
 
V4 
V5 
 
V6 
V7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Maternal medical history and infant clinical exam 
X 
 
 
 
 
 
 
 
 
 
HIV testing (if necessary) 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria checked  
X 
 
 
 
 
 
 
 
 
 
Completion of questionnaire 
X 
 
 
 
 
 
 
 
 
 
Blood sample2 
X 
 
 
 
 
X 
(X3) 
 
X 
(X3) 
Randomization  
X 
 
 
 
 
 
 
 
 
 
Full/ fractional dose PCV administration (IM 
injection) 
X 
 
 
X 
 
 
X 
 
 
 
Administration of other routine vaccinations  
DTwP-
HepB-
Hib 
 
DTwP-
HepB-
Hib 
DTwP-
HepB-Hib; 
IPV 
 
 
MCV1 
 
 
 
MCV2 
Observation for immediate post-vaccination 
reactions (within 30 minutes of vaccination) 
X 
 
 
X 
 
 
X 
 
 
 
Home visit by fieldworkers - active assessment of 
all local injection site reactions, adverse events and 
severe adverse events in the 7 days following 
vaccination 
 
(X) 
 
 
(X) 
 
 
(X) 
 
 
Active assessment of all adverse events and severe 
adverse events in the past 28 days at the clinic 
 
 
X 
 
 
X 
 
 
X 
 
Nasopharyngeal swab for analysis of carriage 
prevalence  
 
 
 
 
 
 
X 
 
 
X 
Total Blood Volume (ml)4 
2ml 
 
 
 
 
2ml 
(2ml3) 
 
2ml 
(2ml3) 
1 D0= Screening & enrolment; 2 On vaccination visits, blood will be drawn before vaccination; 3 At randomisation, 150/300 (half) the participants in each arm will be 
allocated to have an additional blood draw at 9 and 18 months of age in order to assess IgG persistence; 4 Volume to not exceed 1ml/kg. 

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Table 2b: Time and Events Schedule – Trial arm G (the 3p+0 schedule) 
Study visit +/-window 
D01  
(dose 1) 
D7 
D28 +/- 3d 
(dose 2) 
 
D35  
D56 +/- 
3d 
(dose 3) 
 
D63 
/+ 2d 
D84 +/- 
1wk 
D228 
+/- 2 
wks 
D256 +/- 
1wk 
D502 
+/- 2 
wks 
 
Infant’s approx. age  
6wk 
7wk 
10wk 
11wk 
14wk 
15wk 
18wk 
9m 
10m 
18m 
Clinic visit code 
V1 
 
V2 
 
V3 
 
V4 
V5 
V6  
(no visit) 
V7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Maternal medical history and infant clinical exam 
X 
 
 
 
 
 
 
 
 
 
HIV testing (if necessary) 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria checked  
X 
 
 
 
 
 
 
 
 
 
Completion of questionnaire 
X 
 
 
 
 
 
 
 
 
 
Blood sample2 
X 
 
 
 
 
 
X 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
Full dose PCV administration (IM injection) 
X 
 
X 
 
X 
 
 
 
 
 
Administration of other routine vaccinations e.g. 
DTP-HepB-Hib, OPV, IPV and MCV1.  
DTwP-
HepB-Hib 
 
DTwP-
HepB-Hib 
 
DTwP-
HepB-
Hib; IPV  
 
 
MCV1 
 
 
MCV2 
Observation for immediate post-vaccination 
reactions (within 30 minutes of vaccination) 
X 
 
X 
 
X 
 
 
 
 
 
Home/clinic visits - active assessment of all local 
injection site reactions, adverse events and severe 
adverse events in the 7 days following vaccination 
 
(X) 
 
(X) 
 
(X) 
 
 
 
 
Active assessment of all adverse events and severe 
adverse events in the past 28 days  
 
 
X 
 
 
 
X 
 
 
 
Nasopharyngeal swab for analysis of carriage 
prevalence  
 
 
 
 
 
 
 
X 
 
X 
Blood volume (ml)3 
2ml 
 
 
 
 
 
2ml 
 
 
 
1D0= Screening & enrolment; 2before vaccination; 3To not exceed 1ml/kg  

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9.3.7 Follow-up Visits 
Parents and infants will attend 6 or 7 scheduled facility visits during the trial including screening 
and enrolment (Table 2a and 2b). 
For trial arms A-F:  
- 
At D7, D63 and D7PB (7 days after the booster dose) i.e. 7 days after each vaccination 
with full or fractional doses of PCV in a 2p+1 schedule home visits will be made by 
fieldworkers; injection site reactions will be assessed, parents will be asked about 
symptoms since vaccination.  
- 
At D28 parents will be asked to return to the health facility for routine vaccinations 
according to the EPI schedule (2nd dose of pentavalent vaccine and OPV), no PCV 
vaccine will be administered but adverse events in the 28 days since vaccination will be 
solicited.  
- 
At D56, or at approximately 14 weeks of age, the infant will receive their 2nd full or 
fractional dose of PCV. Allocation will be indicated to the vaccinator by the participant 
number and a randomization log and concealed from the parent by using blinding tape 
over the barrel of the syringe. The location of the IM injection will be noted in source 
documents. At the same visit to the health facility, the third dose of pentavalent vaccine 
will be administered alongside IPV at different sites as per the routine immunisation 
schedule. 
- 
At D84, or approximately 18 weeks of age, and at the D28PB visit, a blood sample will 
be drawn for immunogenicity analyses by study staff and adverse events will be 
solicited for the 28 days since vaccine administration.    
- 
At D228 or approximately 9 months of age, infants will be invited to the clinic for their 
third and final PCV vaccination. Before vaccination, half of the participants in each arm 
will have an additional small blood draw at this visit, as allocated during randomisation. 
The vaccine will then be administered and the location of the IM injection will be noted 
in the source documents. The infant’s first dose of measles vaccine will be administered 
into the upper arm as per the routine immunisation schedule. A single nasopharyngeal 
swab will be taken for the carriage analyses.  
 
For trial arm G:  
- 
At D7, D35 and D63 i.e. 7 days after each vaccination with full doses of PCV in a 3p+0 
schedule home visits will be made by fieldworkers; injection site reactions will be 
assessed and site noted, parents will be asked about symptoms since vaccination.  
- 
At D28 parents will be asked to return to the health facility for routine vaccinations 
according to the EPI schedule (2nd dose of pentavalent vaccine and OPV), and a second 
dose of PCV10 vaccine will be administered. Allocation will be indicated to the 
vaccinator by the participant number and a randomization log. At this point the blind is 
broken.   
- 
At D56, or at approximately 14 weeks of age, the infant will receive their 3rd full dose 
of PCV10. Allocation will be indicated to the vaccinator by the participant number and 

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a randomization log. At the same visit to the health facility, the third dose of pentavalent 
vaccine will be administered alongside IPV at different sites as per the routine 
immunisation schedule. 
- 
At D84, or approximately 18 weeks of age, a blood sample will be drawn by study staff 
for immunogenicity analyses and adverse events will be solicited for the 28 days since 
vaccine administration.    
- 
At D228 or approximately 9 months of age, infants will be invited to the clinic for the 
infant’s first dose of measles vaccine as per the routine immunisation schedule. A single 
nasopharyngeal swab will be taken for the carriage analyses. 
 
9.3.8 Unscheduled Visits 
Parents will be reminded to contact the study team or MOH clinic team if their infant 
experiences any symptoms of illness between scheduled study assessments. 
Any interventions required to treat a disease or condition in an enrolled participant will be 
allowed. Concomitant administration of other vaccines included in the Expanded Programme 
of Immunization (EPI) is accepted. All concomitant interventions will be determined by asking 
the participant at the scheduled visits and recorded in the appropriate CRF pages. 
The study team or MOH clinic staff will provide medical care to participants during the study 
follow-up period for acute illnesses.  The study team will not become responsible for long-
standing chronic conditions that were present before vaccination, or that are unrelated to 
vaccination, and medical care will be provided within Government of Kenya guidelines, but 
will help to facilitate treatment in national primary or secondary care where that is judged 
clinically appropriate. 
9.3.9 End of study visit 
At 18 months of age, the parent and child will be invited back to the health facility for their 
final study visit. A single nasopharyngeal swab will be taken for analyses of carriage 
prevalence. Half of the participants in each of the trial arms A-F will have an additional small 
blood draw at this visit, as allocated during randomisation. The contact details of the parent will 
be updated and they will be informed that if results indicate that the fractional dose elicited an 
inferior immune response to the full dose, they will be asked to return to the study clinic one 
last time for a full dose to ‘top-up’ protection (if this is not known already).   
To reduce loss to follow-up at the 18-month of age visit, the study team will contact participants 
by phone at around 13-17 months of age to remind them about their participation in the study 
and about the remaining final study visit. 
9.3.10 Study participant withdrawal criteria 
In accordance with the principles of the current revision of the Declaration of Helsinki, a parent 
has the right to withdraw their child from the study at any time and for any reason, and is not 

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obliged to give his or her reasons for doing so. In addition, the participant may be withdrawn 
for any of the following reasons: 
- 
Participant non-compliance with study requirements (for example follow-up visits) 
despite reminders and attempts to make contact 
- 
Participant/ family moves out of the study area and cannot be traced 
- 
A SAE, which requires discontinuation of the study involvement or results in inability 
to continue to comply with study procedures e.g. a case of pneumococcal vaccine-type 
disease 
- 
Participant receives full dose(s) of PCV vaccine within the routine immunisation system 
in Kenya.  
9.3.11 Managing withdrawals 
The study team will continue to follow up all vaccine recipients until the end of the study 
wherever possible. The reason for withdrawal will be recorded in the Case Report Form (CRF) 
if given. If withdrawal is due to a SAE, appropriate follow-up visits or medical care will be 
arranged, with the agreement of the participant, until the event has resolved, stabilized or a non-
study related causality has been established. Any child who develops vaccine type invasive 
pneumococcal disease will be unblinded and withdrawn from the study. If the child was 
allocated to a reduced dose arm, they will be given full dose PCV10 in three doses 4 weeks 
apart (if aged <12 months) or 1 dose (if aged≥12 months). 
Following Good Clinical Practice (GCP) guidelines, data on participants who specifically 
withdraw their consent for use of their data will not be included in the data analysis. However, 
participants who withdraw from follow up without withdrawing consent for use of their data 
will be included.  
9.3.12 Replacing withdrawn participants 
No withdrawn subjects will be replaced in the dataset.  
10 TREATMENT OF STUDY PARTICIPANTS  
10.1 The Product(s)  
Where possible, the 4-dose vial formulations of two licensed products, Synflorix and 
Prevnar13, will be used in this study (Table 3).  
 
If the 4-dose vial formulation is not available in time for the study to start due to reasons out of 
the investigators’ control e.g. in the manufacture and/or supply of the 4-dose vials, single dose 
formulations will be used as specified below.  
 

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Table 3. Specifications of the two vaccines included in the study.  
 
Manufacturer 
Commercial 
name 
Target 
serotypes 
Conjugate protein(s)  
Adjuvant 
Presentation 
GlaxoSmithKline 
plc. 
Synflorix; 
PCV10 
1, 4, 5, 7F, 
9V, 14, 
18C, 19F, 
23F, 6B 
Protein D (outer membrane 
protein from Non-Typeable 
Hib), or Diphtheria Toxoid 
(serotype 19F only), or 
Tetanus Toxoid (serotype 
18C only) 
Aluminum 
phosphate   
 
Suspension for 
intramuscular 
injection;  
1, 2 or 4 dose vials 
Pfizer Inc.  
Prevnar13; 
PCV13 
1, 4, 5, 7F, 
9V, 14, 
18C, 19F, 
23F, 6B, 3, 
6A, 19A 
Diphtheria CRM197 
Aluminum 
phosphate  
 
Suspension for 
intramuscular 
injection;  
1 dose pre-filled 
syringe or 4 dose 
vials  
 
10.2 Dose selection 
Fractional doses will be administered according to specific vaccine preparation and 
administration SOPs. The antigen doses included in each full and fractional dose administration 
are documented in Table 4. 
Table 4. The antigen dose in the available full dose vaccine formulations and the 
estimated antigen dose in the proposed fractional (20% and 40%) dose formulations. 
 
Vaccine 
formulation 
Vaccine-serotype specific saccharide dose per administration (μg) 
 
1 
3 
4 
5 
6A 
7F 
9V 
14 
18C 
19A 
19F 
23F 
6B 
PCV13 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
2.2 
4.4 
40%-PCV13  
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
0.88 
1.76 
20%-PCV13 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.44 
0.88 
PCV10 
1.0 
 
3.0 
1.0 
 
1.0 
1.0 
1.0 
3.0 
 
3.0 
1.0 
1.0 
40%-PCV10 
0.40 
 
1.2 
0.40 
 
0.40 
0.40 
0.40 
1.20 
 
1.20 
0.40 
0.40 
20%-PCV10 
0.2 
 
0.6 
0.2 
 
0.2 
0.2 
0.2 
0.6 
 
0.6 
0.2 
0.2 
 
10.3 Product management & storage 
Vaccine stocks will be obtained from appointed distributors of the manufacturers. For each 
batch documentary evidence will be obtained to ascertain origin of products, and to 
demonstrate maintenance of cold chain from manufacturer to the distributor. The vaccine will 
be held at a central store, refrigerated at +2 °C to +8 °C, and dispensed to clinic sites as 
necessary. Vaccine will be continually temperature monitored and the number of excursions 
and cumulative time outside of the refrigerator will be recorded.  

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Vials will be discarded if total time between 8°C and 25°C exceeds 4 days (96 hours) as 
indicated by the vaccine vial monitor (VVM)[60, 61]. 
Vials will be discarded if the vaccine ever freezes.   
 
The 4-dose vials will be used until the 28th day following the first puncture as per WHO 
recommendations[73], provided that: 
- 
The expiry date has not passed. 
- 
The vaccines are stored under appropriate cold chain conditions. 
- 
The vaccine vial septum has not been submerged in water. 
- 
Aseptic technique has been used to withdraw all doses.  
- 
The vaccine vial monitor (VVM), if attached, has not reached the discard point (see 
package insert or study specific vaccine preparation and administration SOPs).  
The date of first puncture and number of administrations from each vial will be recorded by 
vaccinating nurses according to vaccine preparation and administration SOPs.  
 
If single dose formulations are used, which do not contain preservative, a single full/ 
fractional dose will be administered as per vaccine preparation and administration SOPs and 
the remaining volume will be discarded on the day of first puncture as per WHO 
recommendations[73]. 
 
10.4 Dispensing Procedures 
The study vaccinating nurse will be responsible for preparation and administration of the 
vaccines as randomised.  They will be responsible for the accompanying documentation.  
 
The vaccine dose to be administered will be guided by the randomization process. The dose 
will be a full dose (0.5ml), a 40% dose (0.2ml) or a 20% dose (0.1ml) administered 
intramuscularly in the anterolateral thigh. 
 
Any concomitant routine immunisations will be administered according to the routine 
immunisation schedule instructions. Site of all vaccinations will be recorded in clinical source 
documents.    
 
10.5 Unblinding 
The primary endpoint of immunogenicity will be assessed at 4 weeks post-third dose 
administration. The trial data and safety monitoring board (DSMB) will review the results and 
if the non-inferiority criteria are not met as per the statistical analysis plan, the DSMB will 
authorise unblinding in order to allow a full dose of vaccine to be administered to fractional 
dose recipients.  
 

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Prior to this time point, unblinding will not be necessary unless as per DSMB request for SAE 
review; apart from those participants in trial arm G. Study staff and parents of participants 
enrolled in trial arm G will become unblinded to the allocation at the clinic visit at 10 weeks of 
age, due to the difference in the PCV schedule. Blinding beyond 10 weeks could be maintained 
through a placebo injection given to the other 6 arms, however, the discomfort to the 
participants would outweigh any benefit to the participant or the study. As long as blinding is 
maintained among trial arms A-F, the unblinding of arm G is unlikely to impact the main 
outcome assessments (objective assessments of immunogenicity and carriage) or retention 
(participants in trial arms A-F would remain with a 33% chance of being allocated to the full 
dose arms).  
 
10.6 Prior/Concomitant Therapy 
Concomitant therapy will be documented, the site of administration of concomitant vaccines 
will be documented.  Previous PCV vaccination or planned PCV uptake under the routine 
immunisation programme, outside of the trial, will be noted for exclusion.  
 
10.7 Rescue vaccination  
The primary endpoint of immunogenicity will be assessed at 4 weeks post-third dose 
administration. The DSMB will review the immunogenicity results from the time point at 4 
weeks post-third dose and if the non-inferiority criteria are not met as per the statistical analysis 
plan, the DSMB will authorize unblinding in order to allow a full dose of vaccine to be 
administered to fractional dose recipients as a rescue dose.  
 
The study is not powered to allow non-inferiority to be assessed in a subset of the 
immunogenicity samples therefore results from all participants will be required prior to DSMB 
review. The timing of the shipments of samples to UCL, the immunological analyses and the 
DSMB review meeting will mean that the outcome of the DSMB’s review may only be 
available when some of the trial participants have already exited trial follow-up. If participants 
undergo their last study visit before the DSMB has reviewed all the data, the contact 
information for the participant’s parents will be updated by study staff at their last study visit 
and they will be told they will be contacted by study staff in the near future and may be asked 
to return to the clinic for an additional vaccination.   Fieldworkers and/or community health 
volunteers (CHVs) will be employed to keep in touch with any participants who have already 
exited the trial before the DSMB review in order to invite them back to the clinic if necessary. 
All participants will be recruited in Kilifi County where the risk of morbidity attributable to 
pneumococcal vaccine types is very low (see Ethics section 18).  
 
Any child who develops vaccine type invasive pneumococcal disease will be unblinded and 
withdrawn from the study. If the child was allocated to a reduced dose arm, they will be given 
full dose PCV10 in three doses 4 weeks apart (if aged <12 months) or 1 dose (if aged≥12 
months). 

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11 LAB PROCEEDURES 
11.1 Blood sample management & testing 
Venous blood samples will be collected at baseline (2ml), the D84 visit (approximately 18 
weeks of age; 2ml) and, in trial arms A-F, at the 1-month post-boost visit (10-13 months of 
age; 2ml). Half of the participants enrolled onto trial arms A-F (150 in each arm) will have 
additional blood draws at 9 months and 18 months of age (2ml at each visit). A cumulative 
total of 4-10mls of blood will be collected from each participant by the end of the trial, 
depending on randomisation and allocation. The sample at baseline will be tested for anaemia 
in order to inform clinical care of the infant. All serum will be separated within 48 hours of 
sample collection and stored at -20 degrees Celsius at the KWTRP CGMR-Coast laboratories. 
All samples will be shipped to the UCL WHO Reference Laboratory for Pneumococcal 
Serology based at the Great Ormond Street Institute of Child Health. If any remaining volume 
is not shipped to UCL, samples will be stored at the KWTRP CGMR-Coast laboratories. 
Sample management will include monitoring of the number of freeze-thaw cycles 
experienced by each sample in a laboratory database.    
At the UCL WHO Reference Laboratory for Pneumococcal Serology, sera will be assayed for 
antibodies to all vaccine-type capsular polysaccharides using the WHO reference ELISA 
following adsorption with cell wall polysaccharide and 22F polysaccharide at a concentration 
of 10 mcg/ ml (Details available at http://www.vaccine.uab.edu/ELISA%20Protocol.pdf). 
This assay is based on the original Wyeth assay used to generate the correlate of protection of 
0.35 mcg/ml.  
A subset of 50 sera from each of the trial arms A-F, at the 1 month post-boost time point will 
be used to estimate the functionality of the immune response to all vaccine serotypes using 
the multiplexed Opsono-Phagocytic Assay (MOPA; details available at 
http://www.vaccine.uab.edu/UAB-MOPA.pdf).  
 
The result of the mother’s most recent HIV test will be recorded at the study screening visit 
using the information in their ‘Mother & Child Health Handbook’ or alternative clinical source 
notes, if unavailable, rapid diagnostic tests will be performed according to Government of 
Kenya guidelines. If a mother is living with HIV, a dry blood spot will be taken from the infant 
in order to process with PCR as per Government of Kenya guidelines. The result of the HIV 
test, performed at the national testing laboratory in Mombasa, will be recorded in the ‘Mother 
& Child Health Handbook’ or alternative clinical records and study clinical source documents, 
when the result becomes available.  
 
11.2 Nasopharyngeal swab sample management & testing   
 

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Standard methods for administering and processing nasopharyngeal swabs for culture will be 
used to ensure that results are comparable with previous studies[74, 75]. A single, deep, 
nasopharyngeal rayon swab will be taken at 9 and 18 months of age and transported in 1 ml 
skim milk-tryptone-glucose-glycerin (STGG) transport medium to the KWTRP CGMR-Coast 
laboratories. A primary culture will be prepared on blood agar with gentamicin before the 
sample is frozen at -70C. One colony on the plate will be selected at random for serotyping by 
latex agglutination and confirmatory Quellung reaction. Polymerase Chain Reaction (PCR) 
will be performed for quality control purposes on 10% of the samples and as a confirmatory 
test for samples that have ambiguous or negative Quellung tests. Minor serotypes, relative 
abundance and density may be assessed at a later date using the stored samples should the 
initial culture results prove difficult to interpret. Carriage will be defined if a serotype is 
isolated by latex agglutination and confirmatory Quellung reaction[75]. Swab medium will be 
stored at the KWTRP CGMR-Coast laboratories. 
 
 
12 ASSESSMENT OF SAFETY 
12.1 Identification of Adverse Events (AEs) and Severe Adverse Events (SAEs) 
 
Measures will be put in place to identify any adverse or serious adverse events (including any 
cases of pneumococcal disease) in study participants:  
- 
Study staff will assess the general health of the child at every study visit;  
- 
Fieldworkers based in the communities around each study clinic will be educated 
in the signs and symptoms of respiratory distress in infants and will visit every child 
at home for their 7-day post vaccination check-up. They will also be points of 
contact in the community to help parents access study staff for medical advice and 
referral if necessary. 
- 
Parents will be told verbally and it is written in the informed consent form that they 
should contact study staff for free medical consultation and treatment in case of any 
illness in their child. Parents will be given the phone number of the clinical officers 
on the trial and their local fieldworker.  
- 
Hospital staff at the Kilifi and Malindi referral hospitals will be sensitised about the 
trial and asked to notify study staff if they suspect a child presenting to the hospital 
(for any reason) is a study participant. 
 
Any AE will be evaluated for seriousness (see section 12.2), relatedness, severity and 
expectedness by the treating physician. Solicited and unsolicited AE and SAE will be recorded 
in all participants in the CRF. If further medical attention is needed, the study team will organise 
referral and emergency admission to Kilifi County Hospital. 
 
12.2 Definitions and monitoring of AEs and SAEs 
 

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AEs and SAEs will be defined in accordance with the International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (38).  
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, when applicable, to be followed 
in the study sites will be specified in an SOP.  
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. This 
definition is not intended to include experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhoea, influenza, injection site reactions and 
accidental trauma (e.g. sprained ankle) 
- 
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.  
 
12.3 Reporting AEs and SAEs  
Both PCV10 and PCV13 are licensed products and had been administered to over 109 million 
children in LMICs by the end of 2016[34].  

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All AEs that are not serious will not be reported individually but will be recorded in the CRF 
and summarised in an annual safety report. 
All SAEs will be reported individually using an SAE form including an assessment of 
relatedness, severity and expectedness. The treating physician will ensure that as much 
information as possible is provided in the SAE form and if necessary will discuss with the PI 
or designee prior to submission. The PI will receive the SAE form within 24 hours of the event. 
If the event is life threatening, and/or suspected to be related to the vaccination the PI (or 
designee) will be informed by telephone within 24 hours of the event. Specimens from study 
participants presenting with respiratory disease will be cultured in order to detect whether the 
respiratory disease is pneumococcal and whether any pneumococcal disease is vaccine-type.  
The minimum information required for the initial SAE report: 
- 
Participant’s study number, age and sex 
- 
Description of the event 
- 
Date of vaccination (s) 
- 
Reporter information 
- 
Preliminary assessment of relatedness 
- 
Severity 
- 
Preliminary assessment of expectedness  
 
The principal investigator (PI) (or designee) will ensure that the information provided on the 
SAE form, is legible, does not have abbreviations or personal and institutional identifiers, and 
is as complete as possible. The PI (or designee) is responsible for safety monitoring and 
reporting SAEs and updates of SAEs to the DSMB, Sponsor, IRB/IEC and regulatory 
authorities as appropriate (Table 6). Those that are life-threatening or suspected to be causally 
related to vaccination will be reported to the DSMB, Sponsor and vaccine manufacturers, this 
will include any cases of suspected vaccine-type pneumococcal disease at any time point in the 
study follow-up.  
All SAEs identified will be tabulated and reported annually in summary form to Kenyan 
Regulatory Authorities and the LSHTM ethics committee.  
12.4 Reporting SUSARs 
 
Any SAE that are suspected to be causally related to vaccination and are unexpected will be 
defined as SUSARs and will require expedited reporting to the DSMB, Sponsor, IRB/IEC and 
regulatory authorities which have approved the clinical trial and other organisations as 
required under the terms of the individual contracts (e.g. relevant pharmaceutical companies).  
A detailed description of DSMB functions and responsibilities and guidelines on the 
transmission flow of SAEs /SUSARs will be provided in the DSMB charter. Table 6 provides 
details on the person responsible of reporting and timelines.  

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Table 6: Safety assessments reporting responsibilities 
 
12.5  Emergency Procedures 
During vaccination, staff trained in basic life support will be available in case of adverse 
reactions around vaccination. An emergency kit will also be available and checked at each 
vaccination visit.  
 
There will be no mandated pauses of vaccination triggered by SAEs unless the investigators, 
sponsors, or DSMB express concern. 
Safety event  
Reported to 
Reported by 
The form of the 
report  
Timeline  
All SAEs 
 
PI (or designee) 
Treating 
physician 
SAE form  
Within 24 hours of 
awareness of event. 
KEMRI Scientific and 
Ethics Review Unit  
PI (or 
designee) 
Annual AE/SAE 
summary report 
Annually 
Kenya Pharmacy and 
Poisons Board  
PI (or 
designee) 
Annual AE/SAE 
summary report 
Annually 
LSHTM Research 
Ethics Committee 
(Sponsor) 
PI (or 
designee) 
Annual AE/SAE 
summary report 
Annually 
All life threatening 
SAEs and/or those 
suspected to be 
causally related to 
the vaccine 
KEMRI Scientific and 
Ethics Review Unit  
PI (or 
designee) 
SAE form 
Within one working day of 
notification of the event. 
Kenya Pharmacy and 
Poisons Board  
PI (or 
designee) 
SAE form 
Within one working day of 
notification of the event. 
LSHTM Research 
Ethics Committee 
(Sponsor) 
PI (or 
designee) 
SAE form 
Within one working day of 
notification of the event. 
DSMB 
PI/ Sponsor 
(or designee) 
SAE form 
Within one working day of 
notification of the event. 
Pfizer Inc.  
PI/ Sponsor 
(or designee) 
SAE form 
Within the delay established 
by their procedures 
GlaxoSmithKline plc.  
PI/ Sponsor 
(or designee) 
SAE form  
Within the delay established 
by their procedures 

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12.6 Procedures for reporting any protocol violation(s) 
Protocol violations will be reported to the sponsor and IRB/IEC and regulatory authorities as 
specified in their guidelines. 
 
13 STATISTICAL ANALYSES 
13.1 Primary analyses and Sample size  
The primary endpoint of non-inferiority will be reached if the lower CI around the ratio of 
geometric mean concentration (GMC) of IgG (fractional/full dose) is >0.5 (i.e. the 2-fold 
criterion) at 1-month post-boost dose (10 months of age). 
A secondary endpoint will assess the proportion of ‘responders’, defined as those with 
serotype-specific IgG antibody concentration 0.35 mcg/ml[13] at 4 weeks after the primary 
series (18 weeks of age). Non-inferiority will be achieved if the lower limit of the 95% 
confidence interval (CI) around the difference in the proportion of ‘responders’ (fractional 
dose group – full dose group) is >-10%[76] post-primary series (18 weeks of age) for at least 
8 of the 10 vaccine types in the PCV10 arms and at least 10 of the 13 vaccine types in the 
PCV13 arms. Assessments of non-inferiority will be made separately for each of the vaccine 
type serotypes. Our primary endpoint will be reached across all arms if non-inferior 
immunogenicity is achieved for the 10 serotypes in PCV10 as this is the standard of care in 
Kenya currently.  
The required sample size for the trial was calculated in order to ensure good power to detect 
both the primary and secondary immunogenicity endpoints, this approach is recommended in 
trials where both primary and secondary endpoints are important to determine the success of 
the intervention[77]. The proportion of children achieving the correlate of protection (IgG 
0.35 g/ml) varies across PCV10/13 serotypes after the primary vaccination series and by 
schedule (range 63.5-98.4%)[33, 76, 78-80]. In a prior study of PCV7 in Kilifi, the average 
proportion of children reaching the threshold antibody concentration across serotypes at 18 
weeks of age was 87%[33]. The average proportion reaching the threshold antibody 
concentration at 18 weeks of age after 2 primary doses, 2 months apart, in European[81], 
Israeli[17, 82] and South African children[24]  was also approximately 87% across 10 
serotypes but serotype specific responses ranged between 63-97%. On this basis, to detect 
non-inferior immunogenicity (% responders) to 10 of the 13 serotypes in the PCV13 arms or 
8 of the 10 serotypes in the PCV10 arms at 18 weeks of age with 90% power, we would need 
to enrol 300 infants per arm to declare non-inferiority using a margin of 10%, accounting for 
serotype-specific response rates, multiple serotype-specific comparisons and 5% loss to 
follow up at 4 weeks after the booster dose. Additionally, this sample size would allow us to 
perform an analysis on all vaccine types with a 12% non-inferiority margin with 84% power.  

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The 10-12% non-inferiority margin has been determined considering the public health 
consequences of a commensurate loss of protection, assuming 87% of infants achieve 
protection with the full dose.   
There will be >99% power to declare non-inferiority using the criterion that the lower limit of 
the 95% CI for the ratio of GMCs (fractional/full dose) is >0.5. Based on the IgG GMCs 
elicited post boost in South Africa, which ranged between 13 and 35 mcg/ml for the PCV7 
serotypes[24], we hope to be able to estimate GMCs with precision  +/- 2-4 mcg/ml. 
There will therefore be four pairwise comparisons of each vaccine type serotype for the 
primary endpoint of non-inferiority (i.e. full dose vs 20% dose; and full dose vs. 40% dose for 
each vaccine). 
A co-primary analysis, which has a precedent in PCV licensure analyses[83], will determine 
whether the immune responses elicited by the fractional doses (20% and 40% doses) are non-
inferior to the lowest serotype-specific immune response elicited by the full dose PCV, 4-
weeks after the primary series. In PCV13 licensure analyses, the immunogenicity of new 
PCV13 serotypes, not included in PCV7, were assessed in non-inferiority comparisons with 
the lowest response observed among the PCV7 serotypes in PCV7 recipients, the response to 
serotype 6B, for which there was existing evidence of both efficacy and programmatic 
effectiveness[83]. In adapting this approach to our study, non-inferiority will be achieved if 
the lower limit of the 95% confidence interval (CI) around the difference in the proportion of 
‘responders’ (fractional dose serotype ‘x’ – full dose 6B) is >-10%. 
The timing of the primary endpoint, at 4 weeks after the booster dose, aligns with the aim to 
assess the effectiveness of the whole three dose schedule (rather than partial vaccination with 
1 or 2 doses). It will give an indication of protection in the second year of life, this is 
clinically relevant as it is thought that the enhanced protection in the second year of life, as a 
result of a booster dose, has an important impact on carriage and transmission in toddlers, 
which may enhance herd protection, compared to a 3p+0 schedule[20]. In a 2p+1 schedule in 
Kenya, a smaller proportion of children may reach the protective threshold of antibodies after 
the 2 primary doses in early infancy, compared to after three primary doses, but in the context 
of low rates of disease after 6 years of PCV10 implementation, young infants would be 
protected by the indirect protection afforded by the reduced transmission of pneumococci. 
The timing of the endpoint corresponds to previous literature analysing 2p+1 schedules and is 
in line with standard practice to analyse non-inferiority trials in the ATP population. 
 
13.2 Secondary analyses 
We will present the serotype-specific difference in proportions of children with evidence of 
vaccine serotype carriage by trial arm. In Kilifi, residual carriage of PCV10 serotypes under 
the routine immunisation schedule has been estimated in 2016 at 6%; assuming 300 per arm, 
we expect to estimate the combined prevalence of PCV10 serotypes in each arm with an 
accuracy of ±2.7%. Carriage of the 3 additional PCV13 serotypes in children aged under 5 

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years in Kilifi in 2016 was 22%; assuming 300 per arm, we expect to estimate combined 
prevalence of PCV13 serotypes in each arm with an accuracy of ±5.0%.  
The indirect effect of the PCV10 programme, which has been implemented in Kenya for 6 
years, has reduced the carriage prevalence of PCV10 serotypes in Kilifi to 6% among children 
<5 years; this limits the power to examine the direct effect of different doses of PCV13 on 
carriage of the serotypes contained in PCV10. However, the population impact of the PCV10 
programme has also led to an increase in the carriage prevalence of the serotypes that are 
contained in PCV13 but not in PCV10 (3, 6A and 19A). We will use carriage of these 
serotypes in the PCV10 full dose arm as a control against which to test of the direct effect of 
the full and fractional doses of PCV13. The effectiveness of PCV13 against carriage of 
serotype 3 is limited22 67 so we will concentrate in this analysis on serotypes 6A and 19A; the 
combined carriage prevalence of these serotypes among children aged <5 years in Kilifi is 
19%. Assuming this prevalence at 18 months of age among the children receiving full dose 
PCV10, 300 infants per arm would confer 92% power to detect a 50% reduction in carriage in 
any of the PCV13 arms (leading to a prevalence of 9.5%); and 78% power to detect a 40% 
reduction in any of the PCV13 arms (leading to a prevalence of 11%). These effect estimates 
would be in line with previous literature on the direct effect of PCV13 on carriage 
prevalence64-66. A total of 290-300 per arm at 18 months of age would confer just over 80% 
power to determine whether full and fractional dose arms exhibit non-inferior prevalence of 
PCV10 vaccine-type carriage using a non-inferiority margin of 5%. 
The results from the multiplex opsono-phagocytic assay (MOPA) to all vaccine serotypes 
plus 6C will be used to compare IgG functionality after 3 full doses of PCV10 or PCV13 with 
that after 3 fractional doses of PCV10 or PCV13 at 1-month post boost. Antibody function 
will also be compared between products for comparable schedules. The correlation between 
IgG concentration and functional activity following a third dose of PCV delivered in a 2+1 
schedule will be assessed. Exploratory analyses will derive a functional correlate of protection 
against carriage using the post booster MOPA titre and vaccine type carriage at 18 months of 
age for serotypes 19A and 6A. 
To evaluate the safety of the fractional dose delivery we will describe: 
• the proportion of infants in each trial arm experiencing specified local vaccination site 
reactions (e.g. redness, swelling) within the 30 minutes immediately after vaccination as 
observed by study personnel; 
• the proportion experiencing local/systemic adverse reactions, e.g. injection site abscess, in 
the 7 days after vaccination, as reported by mother or the legal guardian who accompanied 
the infant to the vaccination session at a day 8 visit.  
We do not expect to have the statistical power to determine a difference in the risks of 
injection site abscess between arms as the risk of injection site abscess is expected to be low. 
Pentavalent vaccine delivered in 10-dose vials in Kenya resulted in 128 abscesses per 100,000 
injections[84]. If this baseline level of risk applies to the 3 immunisations given to 1200 

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children in the fractional dose groups we would expect to see no more than 5 abscesses 
throughout the whole study. 
The sera of all participants in the seventh trial arm (Arm G) will be assayed for 
immunogenicity to 7 serotypes (the PCV7 vaccine types) at 4-weeks post-primary series only. 
The proportion of responders in Arm G at 4-weeks post-primary series will be compared to 
that of the PCV10/13 2p+1 arms at 4-weeks post-primary series. Non-inferiority will be 
achieved if the lower limit of the 95% confidence interval (CI) around the difference in the 
proportion of ‘responders’ (2p+1 - 3p+0) is >-10%[76]. Assuming the proportion of children 
reaching the threshold antibody concentration across serotypes at 18 weeks of age is on 
average 87%[33], with 300 per arm, we would have 85% power to declare non-inferiority 
using a margin of 10%, accounting for 7 serotype-specific comparisons. 
IgG GMCs in a random selection of half the participants in trial arms A-F at 9 months of age 
(pre-boost) and at 18 months of age (9 months post-boost) will be used to 1) estimate the 
duration at which GMCs remain above the threshold for protection in the first 2 years of life 
after a 2p+1 schedule of full or fractional doses and 2) to monitor carriage acquisition rates. 
 
13.3 General statistical methods 
The total number of individuals for each of the following categories will be presented: screened 
for eligibility, screen failures, consented individuals, vaccinated individuals with 1, 2 and 3 
doses, participants completing the study follow-up period, and reason for follow-up 
discontinuation. Participant demographics and baseline characteristics will be described and 
compared between trial arms.  
The ATP population will comprise randomized participants in arms A-G who received three 
doses of their allocated study vaccine in the allocated schedule and have at least one post-third 
dose vaccination blood sample (for immunogenicity analyses) or at least one carriage sample 
at 18 months of age (for carriage analyses).  This population will be used for the primary 
endpoint analysis of non-inferiority.  
The ITT population will include all randomized participants who received at least 1 dose of 
their allocated vaccine schedule, who submitted at least one immunological/carriage sample 
and for whom the eligibility criteria were correctly applied. 
The safety population will include all subjects in trial arms A-F who received a study vaccine. 
Adverse events occurring during the study follow up period will be analysed and compared 
between groups. This will be a descriptive analysis and will include adverse events which 
started on or after the day of vaccine administration for each dose up to and including 28 days 
later.  
A detailed statistical analysis plan (SAP) will be finalized after the study has started (and before 
the database lock).  

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14  DATA MANAGEMENT 
14.1  Hardware and software 
The CRFs in this study will be entered into an electronic database, e.g. OpenClinica, that is 
compliant with Good Clinical Data Management guidelines and 21 CFR Part 11 regulations on 
clinical data management systems for use in clinical trials. This will be done via secure web 
interface with data checks used during data entry to ensure data quality. The database will be 
activated for the study only after successfully passing a formal design and test procedure.  
Computers will be used for data entry of paper forms. Management and maintenance of 
computers will lie with the operational support and data managers at the study site. 
14.2  Data security, access and back-up 
The database will be kept in a locked server-room. Only the system administrators have direct 
access to the server and back-ups. Passwords (site investigator, statistician, monitor, 
administrator etc.) will regulate permission for each user to use the system and database, as 
he/she requires. 
All data entered into the CRFs has identifiers attached to it identifying the user who entered it 
with the exact time and date. Retrospective alterations of data in the database are recorded in 
an inbuilt audit function. Time, table, data field and altered value, and the person are recorded. 
Back-ups of the whole system including the database will be run internally several times per 
day. Back-ups will be stored in a secure location.  
14.3 Direct access to source data/documents 
Source documentation will be held securely by the trial team in KWTRP CGMR-Coast.  Access 
will be granted to monitors responsible for quality assurance, for data entry staff and for 
purposes of medical care.  Access will also be granted for audit by statutory authorities and 
others.  Non-study team members will not be granted access. Qualified staff will supervise data 
collection and entry on a regular basis. Data managers will support onsite data entry teams.  
15  QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 Choice of investigators  
Investigator CVs are detailed in Appendix 3. 
 
15.2 Monitoring  
The study will be conducted in accordance with the current approved protocol, ICH GCP, 
relevant regulations and standard operating procedures. 

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Internal monitoring by the KWTRP CGMR-Coast monitoring team will be performed 
according to ICH GCP including but not limited to visits to the clinical sites for study initiation, 
during the 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. 
Monitors will participate as detailed in a monitoring plan that will be prepared prior to the 
study. This will cover instructions for monitoring the main aspects of the implementation of the 
clinical studies, as follows: 
• 
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 
• 
Sponsor 's Responsibilities  
• 
Responsibilities of the Monitors 
• 
Records of GCP training 
 
15.3 Training to ensure quality of the study 
GCP training and protocol-specific training will be delivered to the whole study team. The 
objective will be to ensure that the study team members are well prepared and trained, and 
understand the details of the study, the design and the study procedures. A training plan will be 
maintained, GCP and GDP will be topics of annual refresher training for all staff. 
 
16  INTELLECTUAL PROPERTY 
The vaccine products assessed in the clinical trial are all licensed and in routine use, and 
therefore no product-related IP will arise from this trial. In the unexpected event that other 
findings lead to IP then KEMRI guidelines will be followed in terms of registering and 
exploiting the IP. 
However, any intellectual property rights that arise from the work will be safeguarded 
according to the current KEMRI guidelines and the Industrial Property Act of 2001, sections 
32, 58 and 80. The scientific and intellectual contributions of all persons involved in the 
research will be appropriately acknowledged in all publications and presentations arising from 
the work. 

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17  TIME FRAME/DURATION OF THE TRIAL 
Total study duration is 42 months; timelines will 
be determined by the receipt of approval from 
KEMRI ethics committee and the Kenyan 
Pharmacy and Poisons Board but are estimated as 
follows, by activity:  
Time period following 
ethical approval 
Study staff recruitment, procurement etc.  
Month 1 - 6 
Community engagement and mobilization 
Month 3 - 6 
Screening, and vaccinations for main study. 
Month 6 - Month 25 
Follow Up for main study (overlaps with vaccinations) 
Month 6 - Month 34 
Feedback to study participants, complete laboratory 
analyses, complete data analysis and write up 
Month 34 – month 42 
 
18  ETHICS 
18.1 Human Subjects 
Ethical approval will be sought from KEMRI Scientific & Ethics Review Unit (SERU) and 
the LSHTM Ethics Committee. Written informed consent will be obtained from at least one 
parent of all infants enrolled onto the study. 
 
The potential risks to participants include risks related to administration of the vaccine:  
- 
The vaccines are licensed products.  In children under 5 years, the most frequently reported 
adverse reactions to PCVs are those associated with all vaccines, these can include one or 
multiple of the following symptoms: injection site reaction, fever, irritability, drowsiness, 
restless sleep, decreased appetite, vomiting, diarrhoea and rash.  
- 
Extending the use of the 4-dose multi-dose vial to provide 10 or 20 administrations may 
increase the risk of injection site reactions e.g. swelling and localised inflammation due to 
contamination. If 4-dose vials are used, this will be closely monitored.  
- 
Serious reactions to PCV injection are rare and include hypersensitivity reaction generally 
associated with diphtheria toxin.   
Other potential risks are that despite the small dose-ranging study of a pentavalent PCV 
showing good responses to saccharide doses as small as 0.5 mcg/ml, there is a small risk that 

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the 20% and the 40% doses may elicit inferior immunogenicity to the full dose in the fractional 
dose study arms [57]. The unprotected/partially protected children would then not benefit from 
direct protection of the vaccine but would benefit from the indirect protection generated by the 
continued routine administration of PCV10 in the national EPI programme, which has led to 
dramatic decreases in vaccine type carriage[85] and IPD[86]. In the Kilifi Health and 
Demographic Surveillance System (KHDSS) in 2016, there were 3.2 cases of vaccine-type IPD 
per 100,000 person years (pyo) in under 5s[87]. This amounts to 1 case every 31,250 person 
years. Among the 2100 trial participants followed for 1.5 years, we will observe a total of 3,150 
pyo – which means there is a 10% chance that we will see one case of vaccine-type IPD in the 
study, and a 90% change we will see no vaccine-type IPD. one of the advantages of undertaking 
this study at KWTRP CGMR-Coast is that it has a strong history of IPD surveillance and we 
will therefore be able to detect IPD if it occurs in the trial population. Any cases observed will 
be reported to the DSMB. Although the risk of IPD is very small we will establish procedures 
to detect it at an early stage when treatment can avert a severe outcome; this will be done by 
providing participants with easy access to study medical staff. Children with signs of sepsis, 
pneumonia or meningitis will be investigated with bacterial culture of blood and/or 
cerebrospinal fluids as appropriate to detect the serotype of pneumococcus causing IPD. If any 
case of IPD occurs, it will be referred to the DSMB as an SAE. Members of staff at the hospitals 
in Kilifi and Malindi will be engaged by the study team to enable treatment of referrals if 
necessary and to notify the study team if a participant presents to the hospital in an unscheduled 
visit. Any child who develops vaccine type invasive pneumococcal disease will be unblinded 
and withdrawn from the study. If the child was allocated to a reduced dose arm, they will be 
given full dose PCV10 in three doses 4 weeks apart (if aged <12 months) or 1 dose (if aged≥12 
months). 
If, after final analyses, the fractional doses are found to be inferior, all children in those groups 
will be given a single, full dose booster PCV. 
The potential benefits of participation are as follows:  
- 
Participants will be given the phone numbers of study clinicians and local fieldworkers 
and/or will be able to present at the clinic with any illness and receive free treatment and 
referral throughout the course of the study. This is in contrast to government-funded care at 
local clinics, where waiting times may be lengthy and care is not always free of charge. 
Rapid referral will be made to Hospital in Kilifi or Malindi in case of any serious illness. 
- 
There will be periodic follow up by phone or by home visits in between the study visits near 
the end of follow up in order to maintain contact with the participant and actively follow up 
on their health. For trial participants the benefit of increased access to medical care is likely 
to outweigh the extremely low risk of IPD caused by vaccine type infection.  
- 
If the vaccine is efficacious at low dose, participants in the PCV13 arms will have the added 
benefit of immunization against three additional serotypes (3, 6A, 19A) contained in the 

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study vaccine (PCV13) but not contained in the 10-valent vaccine used in the national 
programme.  
18.2 Community Considerations 
If fractional dose administration delivers inadequate protection, the risk to the community is 
limited due to the low prevalence of vaccine types and established herd protection since the 
national introduction of PCV10 in 2011. If the vaccine is efficacious at low dose, the potential 
benefits to the community are significant. PCV is one of the most expensive vaccines in the 
routine immunisation schedule, a 50-75% reduction in its cost may mean it can be sustained in 
the routine immunisation schedule after transition from Gavi co-funding. 
We will use existing community engagement strategies to inform communities about the study. 
A community engagement plan specific for the study will be developed between the CLG team 
and the investigators.  We will organize community barazas in towns and surrounding areas, 
meetings with chiefs, sub-chiefs, community representatives, and the Department of Health in 
Kilifi County and surrounding areas to inform them about the study.  
Research findings will be disseminated to participants and the participating communities upon 
completion of the study in dissemination meetings.  
18.3 Informed Consent 
The rationale for the study, its aims, the study requirements and potential outcomes will be 
discussed with chiefs, community leaders and community representatives in specific meetings. 
Subsequent meetings will be organized with potential parents/ guardians of trial participants; 
the study, its rationale, its aims, the study requirements and potential outcomes including the 
risks and benefits of participation and potential inconvenience and procedures required for 
participation will be described in detail. 
One parent will sign and date the informed consent form before any study specific procedures 
are performed on infants. All informed consent documents will be translated into Kiswahili and 
Giriama.  
We will emphasize the following; 
- 
Participation in the study is entirely voluntary. 
- 
Declining to participate involves no penalty or loss of medical benefits. 
- 
If the parent agrees for their child to participate they may not know which study vaccine 
the child receives for the length of the study.  
- 
The parent may withdraw their child from the study at any time. 
- 
A volunteer is free to ask questions at any time to allow him or her to understand the 
purpose of the study and the procedures involved. 

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- 
There is no direct benefit from participating. The benefits will be realized in the long-
term for the community by contributing towards the sustained delivery of a 
pneumococcal vaccine. 
- 
Volunteers will be compensated for travel, time and inconvenience of participating. 
 
18.4 Compensation 
We will compensate participants for travel required to attend study visits and for lost time using 
the standard figures determined by the Community Liaison Group and stipulated in the 
informed consent form. Fieldworkers and the Community Liaison Group will devise a standard 
set of travel times/distances and expenses likely to be incurred by parents bringing their child 
to each facility, which will be recorded in an SOP and will govern the amount each parent 
receives. 
As such, the amount of compensation a parent receives will be based on:  
- Compensation for loss of wage - this is a set amount based on KEMRI-Wellcome 
Trust research Programme guidelines for benefits and payments to research 
participants. Given the timing and potential length of visits and the time it may take 
for parents to travel to the clinic and return home, Ksh350 will be given in 
compensation for 1 day of lost wages.  
- Reimbursement for travel costs - this will be based on reported distance between 
the parent’s home and the health facility and local fieldworker knowledge. 
Fieldworkers will develop a local list of standard distances and costs for the areas 
around each of the health facilities in this study. Given previous projects it is 
anticipated the costs could be between Ksh200-1000 per return journey. 
 
All compensation received by parents will be documented and the parent will be required to 
sign or thumbprint to confirm receipt.   
 
18.5 Patient Data Protection/Confidentiality 
Paper based clinical records will be kept in locked cabinets in the study clinics and subsequently 
at KWTRP CGMR-Coast. All electronic data, including immunological and carriage data will 
be kept in anonymized databases linked by a unique participant identification number to clinical 
data. 
18.6 Data Sharing 
After the trial ends, a clean final database(s) of anonymized, de-identified individual-level 
clinical, laboratory and safety data will be produced by KWTRP CGMR-Coast.  This will be 
shared with LSHTM statistician and trial team in order for the final analyses to take place as 
per the statistical analysis plan. A clean de-identified database will be provided as publically 

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available (‘open access’) or upon reasonable request, after the final study publication is 
published, as per the relevant medical journal regulations.   
Information collected or generated during this study may be anonymised for use to support 
PCV policies and/or further research. Any further research using information from this study 
must first be approved by a local or national expert committee to make sure that the interests 
of participants and their communities are protected. 
18.7 Safety 
The study team will provide medical care to participants during the study follow-up period for 
acute illnesses.  The study team will not become responsible for long-standing chronic 
conditions that were present before vaccination, or that are unrelated to vaccination. Medical 
care will be provided within Government of Kenya guidelines. 
 
18.8 Material Transfer Agreement (if applicable) 
Where samples will be shipped to the WHO reference laboratory for pneumococcal serology at 
University College London, U.K., a Material Transfer Agreement (MTA) will be developed. 
This will include the following information. 
• Identification of the provider and recipient 
• Identification of the material and the volume of material 
• Definition of the trial and how the material will and will not be used 
• Maintenance of confidentiality of background or supporting data or information, if 
provided.  
 
19  ARCHIVING AND RECORD RETENTION 
19.1 Overview 
Data collection will occur at each clinic using paper or electronic CRFs. Any paper or electronic 
data in source documents will be transported by designated study staff. Data entry clerks will 
use password protected computers and double enter any data collected on paper forms onto an 
electronic database, e.g. OpenClinica, that is compliant with Good Clinical Data Management 
guidelines and 21 CFR Part 11 regulations on clinical data management systems for use in 
clinical trials.  
19.2 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 the records. The investigators will permit authorized 
representatives of the Sponsor, and regulatory agencies to examine (and when required by 

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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 
- 
CRFs 
- 
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) 
- 
Monitoring reports 
- 
Relevant communication 
- 
SAE reporting processes and other relevant SOPs 
- 
Annual reports to ethics committee and regulatory authorities 
- 
Participant screening log 
- 
Participant identification code list (mapping patient onto anonymized study ID) 
- 
Participant enrolment log 
- 
Product accountability information 
- 
Clinical study report 
 
19.3 Source documents  
All protocol required procedures along with information necessary to report the observations 
and tests described in this protocol are recorded in CRFs. Any entries captured on CRFs that 
are derived from source documents e.g. hospital record, will have the source documents 
included as part of the participant’s file. Where source documents for specific entries are not 
available, this must be explicitly mentioned. Any requested information that is not obtained as 
specified in the protocol should have an explanation noted on the CRF or in a note to file as to 
why the required information was not obtained.  
CRFs will be completed and signed and authorized in a timely and accurate manner by 
designated study staff. All data on the CRFs must be legibly recorded. The investigator or a 
designated, qualified individual must review all CRFs for accuracy and consistency with any 
relevant source documentation, and sign the CRFs upon completion. Any corrections will be 
made on the CRFs by striking through the incorrect entry with a single line and entering the 
correct information adjacent to it. The correction will be initialled and dated by the investigator 

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or a designated, qualified individual. Any corrections made after data entry has begun will be 
notified to data managers for correction of electronic databases. 
19.4 Record keeping and retention 
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 following 
local regulations. 
The Sponsor will securely store the final study database with all archive tables for at least 10 
years. The Sponsor also keeps the central Trial Master File and interim and final reports both 
in electronic and in hard copy form for at least 10 years. KWTRP CGMR-Coast will archive 
paper CRFs and study files following local laws. 
 
20 FINANCING AND INSURANCE 
20.1 Budget 
 
USD $ 
Kenya Shilling (Ksh) 
a) Personnel, salaries and benefits disbursements 
  
1,456,065  
 
  
131,045,863  
 
b) Participant related costs  
 
 217,231  
 
 19,550,808 
 
c) Equipment 
  
73,407  
  
6,606,601  
d) Supplies 
 
 
Laboratory consumables 
127,713  
11,494,188  
 
Clinical consumables 
 
  
225,924  
20,333,177 
e) Travel and accommodation 
 
 
Local (return Nairobi)  
 2,700.00  
 243,000.00  
international  
0 
0 
f) Transportation and running costs etc. 
293,684  
26,431,560  
g) Operating expenses  
249,928  
22,493,490  
h) Animals acquisition etc. 
0 
 

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i) Consultancy fees  
0 
 
j) Contingency fees (15% of above) 
 
 
k) Institutional administrative overheads  
  
396,998  
35,729,803  
Total 
  
3,049,650  
274,468,500 
 
20.2 Justification of the Budget 
This work is funded by the Bill & Melinda Gates Foundation and the National Institute of 
Health Research Mucosal Pathogens Research Unit in the UK. The study is part of the KEMRI-
Wellcome Trust Research Programme; costs for staff time, patients and supplies are based on 
those incurred by similar vaccine trials.  
Details on the costings provided above are as follows: 
- 
Personnel, to ensure the smooth operation of the trial: 1 trial coordinator, 1 finance and 
admin support officer, 2 clinical officers, 8 nurse vaccinators, 16 fieldworkers, 1 
pharmacist, 2 drivers, 1.2 FTE lab technicians, 1 FTE data entry clerks and 0.5 FTE 
Data manager, 0.05 FTE senior clinical trials support for 2.5-3 years. 
- 
Participant related costs include: Compensation and reimbursement for travel, 
refreshments and stationary (average Ksh1,750 per participant assuming 10 visits plus 
1 unscheduled visit per participant), patient referral costs to hospital in the event of SAE 
(allow an additional 30 USD per participant, assuming not all participants will require 
this service), stakeholder engagement and dissemination meetings. 
- 
Equipment are small items for the clinics (assuming 8 clinics): Additional fridges for 
clinics (8), physical examination equipment (weighing scales, stadiometers; 8), portable 
emergency kits (8), cabinets/ desks, vaccine carriers, blood sample carriers (16), data 
entry equipment (14 tablets and 1 desktop computer) 
- 
Laboratory supplies include all consumables and reagents for: a full heamogram on all 
baseline blood samples, HIV testing of 6% of baseline samples via PCR if national 
testing is not available, serum separation and preparation for shipping, nasopharyngeal 
swab processing, culture, quellung and 10% PCR. 
- 
Clinic supplies include: blood collection sets (3 per participant plus wastage), 
nasopharyngeal swabs (2 per participant plus wastage), vaccine supply (3 doses per 
participant plus wastage), vaccination consumables, gloves etc. 
- 
Travel and accommodation costs will include some KWTRP team travelling to Nairobi 
for meetings with key stakeholders and to disseminate the results  
- 
Transportation costs include the purchase of 2 vehicles, 8 motorbikes and running costs 
(tax, fuel, insurance and servicing) for all items for 3 years. 
- 
Operating expenses include: GCP training/ refresher training, communications for field 
staff (phone credit), contribution to clinic utilities bills, contribution to Malindi hospital 
office space, transport coordination costs and community liaison coordination costs, 

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LSHTM staff work permit (1), ethics and regulatory authority submissions fees, data 
management software and Microsoft licencing, postage, printing etc. 
- 
Institutional overheads are charged at 15% as per funder guidelines.  
 
20.3 Insurance 
The vaccine manufacturers are liable for any harm arising from negligent manufacture but have 
not undertaken to sponsor the trial.  The sponsor, LSHTM, provides insurance to cover the 
clinical trial and KWTRP CGMR-Coast will provide indemnity for study staff. 
21 TRIAL MANAGEMENT 
21.1 The Sponsor 
LSHTM takes responsibility for initiating, registering and conduct of the trial, and as such, will 
be involved in the study design, data collection, management and analysis, and interpretation 
of data, and writing of the report.  LSHTM takes responsibility for ensuring the trial is 
monitored properly and results made available.   
Lead staff based at KWTRP CGMR-Coast will communicate regularly with the LSHTM PI on 
general trial progress, challenges experienced and any necessary amendments requiring ethical 
review.   
21.2 The Data and Safety Monitoring Board (DSMB) 
A DSMB will be convened by the Sponsor, and will receive safety data as described above. A 
detailed description of DSMB functions and responsibilities and guidelines on the 
transmission flow of SAEs /SUSARs will be provided in the DSMB charter. 
 
22 REPORTING, DISSEMINATION AND NOTIFICATION OF RESULTS 
22.1 The Clinical Trial Report  
The results of the trial will be reported in a Clinical Study Report generated by the Sponsor, 
containing CRF data, laboratory data and safety data. The Sponsor will register and disclose 
the existence of the results of the clinical trial on an international clinical trials registry in 
accordance with good practice. Individual participant identifiers will not be used in any 
publication of results. 
  
22.2 Publications 
Results will be published in an open access format, consistent with Good Publication 
Practices, the International Committee of Medical Journal Editors guidelines and funder 
requirements. The primary trial results will be published including all investigators currently 

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listed on the protocol as authors. Local investigators and Programme members will take 
prominent roles in the primary trial results write-up.  Secondary analyses will also be 
developed as part of KWTRP's commitment to capacity development to ensure that co-
investigators have additional opportunities for individual scientific output. 
 
22.3 Dissemination 
Results will be disseminated to the Kenyan Ministry of Health and KENITAG (the Kenyan 
National Immunisation Technical Advisory Group) and other relevant stakeholders in vaccine 
policy.   
Results will be disseminated locally in the areas where the study was conducted and participants 
will be invited to meetings to receive feedback on the trial outcomes. 
 

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Cadorna-Carlos J, Vidor E, Bonnet MC. Randomized controlled study of fractional doses of inactivated 
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58. 
Park DE, Johnson TS, Nonyane BA, Chandir S, Conklin L, Fleming-Dutra KE, et al. The differential 
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CONFIDENTIAL 
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Carriage and Reactogenicity of 10-Valent Pneumococcal Non-Typeable Haemophilus influenzae Protein D 
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Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, et al. Seven-Year Efficacy of 
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2016/06/30. doi: 10.1056/NEJMoa1515257. PubMed PMID: 27355532; PubMed Central PMCID: 
PMCPMC4962898. 
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Ministry of Public Health and Sanitation K. Kenya Division of Vaccines and Immunisation 
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66. 
Kieninger DM, Kueper K, Steul K, Juergens C, Ahlers N, Baker S, et al. Safety, tolerability, and 
immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal 
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http://dx.doi.org/10.1016/j.vaccine.2010.04.008. 
67. 
Gimenez-Sanchez F, Kieninger DM, Kueper K, Martinon-Torres F, Bernaola E, Diez-Domingo J, et al. 
Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular 
pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 
13-valent pneumococcal conjugate vaccine. Vaccine. 2011;29(35):6042-8. Epub 2011/06/28. doi: 
10.1016/j.vaccine.2011.06.026. PubMed PMID: 21704105. 
68. 
World Health Organization. WHO vaccine-preventable diseases: monitoring system. 2016 Global 
Summary. http://apps.who.int/immunization_monitoring/globalsummary/ 2017 [cited 2017 30 April]. 
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Kenya National Bureau of Statistics (KNBS), Ministry of Health, National AIDS Control Council, Kenya 
Medical Research Institute, National Council of Population and Development, The DHS Program ICF 
International. Kenya Demographic and Health Survey. 2014. 
70. 
SAGE meeting of 12-14 April 2016. Establishing a 2nd year of life health child visits as a platform for 
vaccination and other health interventions (2YL) Concept Note Geneva2016 [cited 2017 12 March]. Available 
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http://www.who.int/immunization/sage/meetings/2016/april/1_SAGE_2YL_concept_note_ye
llow_book_v160318b.pdf. 
71. 
Sirengo M, Muthoni L, Kellogg TA, Kim AA, Katana A, Mwanyumba S, et al. Mother-to-child 
transmission of HIV in Kenya: results from a nationally representative study. Journal of acquired immune 
deficiency syndromes (1999). 2014;66 Suppl 1:S66-74. Epub 2014/04/16. doi: 10.1097/qai.0000000000000115. 
PubMed PMID: 24732822; PubMed Central PMCID: PMCPMC4790087. 
72. 
World Health Organization. Manual on Paediatric HIV Care and Treatment for District Hospitals: 
Addendum to the Pocket Book of Hospital Care of Children. . Geneva: World Health Organization, 2011. 
73. 
World Health Organization. WHO Policy Statement: The use of opened multi-dose vials of vaccine in 
subsequent immunization sessions (WHO_IVB_14.07) issued in 2014. Geneva: 2014. 
74. 
O'Brien KL, Nohynek H. Report from a WHO Working Group: standard method for detecting upper 
respiratory carriage of Streptococcus pneumoniae. The Pediatric infectious disease journal. 2003;22(2):e1-11. 
Epub 2003/02/15. doi: 10.1097/01.inf.0000049347.42983.77. PubMed PMID: 12586987. 
75. 
Satzke C, Turner P, Virolainen-Julkunen A, Adrian PV, Antonio M, Hare KM, et al. Standard method 
for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World 
Health Organization Pneumococcal Carriage Working Group. Vaccine. 2013;32(1):165-79. Epub 2013/12/18. doi: 
10.1016/j.vaccine.2013.08.062. PubMed PMID: 24331112. 
76. 
Gadzinowski J, Tansey SP, Wysocki J, Kopinska E, Majda-Stanislawska E, Czajka H, et al. Safety and 
immunogenicity of a 13-valent pneumococcal conjugate vaccine manufactured with and without polysorbate 80 
given to healthy infants at 2, 3, 4 and 12 months of age. The Pediatric infectious disease journal. 2015;34(2):180-
5. Epub 2014/08/16. doi: 10.1097/inf.0000000000000511. PubMed PMID: 25126854. 
77. 
U.S. Department of Health and Human Services Food and Drug Administration (FDA). Multiple 
Endpoints in Clinical Trials. Guidance for Industry. U.S. Department of Health and Human Services Food and 
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Research (CBER), 2017. 
78. 
Yeh SH, Gurtman A, Hurley DC, Block SL, Schwartz RH, Patterson S, et al. Immunogenicity and safety 
of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126(3):e493-505. Epub 
2010/08/25. doi: 10.1542/peds.2009-3027. PubMed PMID: 20732948. 

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CONFIDENTIAL 
Fractional Dose PCV Trial Protocol Version 3.0 dated 01 May 2018 
 
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79. 
Payton T, Girgenti D, Frenck RW, Patterson S, Love J, Razmpour A, et al. Immunogenicity, safety and 
tolerability of 3 lots of 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in the 
United States. The Pediatric infectious disease journal. 2013;32(8):871-80. Epub 2013/04/16. doi: 
10.1097/INF.0b013e3182906499. PubMed PMID: 23584582. 
80. 
Wijmenga-Monsuur AJ, van Westen E, Knol MJ, Jongerius RM, Zancolli M, Goldblatt D, et al. Direct 
Comparison of Immunogenicity Induced by 10- or 13-Valent Pneumococcal Conjugate Vaccine around the 11-
Month 
Booster 
in 
Dutch 
Infants. 
PloS 
one. 
2015;10(12):e0144739. 
Epub 
2015/12/15. 
doi: 
10.1371/journal.pone.0144739. PubMed PMID: 26658902; PubMed Central PMCID: PMCPMC4690595. 
81. 
Silfverdal SA, Hogh B, Bergsaker MR, Skerlikova H, Lommel P, Borys D, et al. Immunogenicity of a 2-
dose priming and booster vaccination with the 10-valent pneumococcal nontypeable Haemophilus influenzae 
protein D conjugate vaccine. The Pediatric infectious disease journal. 2009;28(10):e276-82. Epub 2010/02/02. 
doi: 10.1097/INF.0b013e3181b48ca3. PubMed PMID: 20118683. 
82. 
Givon-Lavi N, Greenberg D, Dagan R. Immunogenicity of Alternative Regimens of the Conjugated 7-
Valent Pneumococcal Vaccine: A Randomized Controlled Trial. The Pediatric infectious disease journal. 
2010;29(8):756-62. doi: 10.1097/INF.0b013e3181d99345. PubMed PMID: 00006454-201008000-00019. 
83. 
Vaccines and Related Biological Products Advisory Committee. FDA Briefing Document. Prevnar 13 
(13vPnC): Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein). CBER/FDA, 2009. 
84. 
Burton DC, Bigogo GM, Audi AO, Williamson J, Munge K, Wafula J, et al. Risk of Injection-Site 
Abscess among Infants Receiving a Preservative-Free, Two-Dose Vial Formulation of Pneumococcal Conjugate 
Vaccine in Kenya. PloS one. 2015;10(10):e0141896. doi: 10.1371/journal.pone.0141896. 
85. 
Hammitt LL, Akech DO, Morpeth SC, Karani A, Kihuha N, Nyongesa S. Population effect of 10-valent 
pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable 
Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies. Lancet Glob Heal. 
2014;2. doi: 10.1016/s2214-109x(14)70224-4. 
86. 
Scott A, Hammitt L, Morpeth S, Shariff S, Kamau T, Etyang A, et al. Pneumococcal Conjugate Vaccine 
Impact Study (PCVIS) [Internet]. 2017. http://kemri-wellcome.org/programme/pcvis-2/. Accessed 20 
Feb 2017. 
87. 
Anthony Scott, Laura Hammitt, Susan Morpeth, Shahnaaz Shariff, Tatu Kamau, Anthony Etyang, et al. 
Pneumococcal Conjugate Vaccine Impact Study PCVIS http://kemri-wellcome.org/programme/pcvis-2/ 
2017 [cited 2017 20 Sept]. 

KEMRI- Wellcome Trust Research Programme (KWTRP) 
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CONFIDENTIAL 
Fractional Dose PCV Trial Protocol Version 3.0 dated 01 May 2018 
 
Page 59 of 75 
 
 
APPENDICES 
Appendix 1: Roles of Investigators 
Investigator 
Institution 
Role 
Anthony Scott  
LSHTM/KWTRP 
CGMR-Coast 
Principal Investigator: Oversight of design, 
conduct, quality assurance and interpretation of 
results and publication. 
Katherine Gallagher  LSHTM 
Co-investigator (to be based at KWTRP): 
design, conduct, data quality, sample integrity, 
organisation of lab analysis and quality control 
procedures, collation of data, analysis and 
interpretation and publication.  
Mainga Hamaluba 
KWTRP 
CGMR-
Coast 
Lead of clinical trial team in Kilifi, input into 
design, conduct, data quality control, assurance 
and analysis, interpretation of results and 
publication. 
Mary Kaniu 
KWTRP 
CGMR-
Coast 
Managing the recruitment, follow up and 
overseeing the clinical treatment of study 
participants. 
Angela Karani  
KWTRP 
CGMR-
Coast 
Laboratory sample management, processing 
and shipping and laboratory analysis plan.  
Jimmy Shangala 
KWTRP 
CGMR-
Coast 
Programme pharmacist responsible for vaccine 
import, liaison to Pharmacy and  Poisons 
Board, 
product 
storage, 
cold-chain 
management, 
product 
accountability, 
supervision of pharmaceutical technician and 
unblinded staff. 
Pharmacy 
technologist – to be 
confirmed pending 
recruitment  
KWTRP 
CGMR-
Coast 
Pharmacy technologist, maintenance of product 
storage and cold chain, product accountability 
and allocation, quality assurance of unblinded 
documentation.   
Daisy 
Mugo 
& 
Elizabeth Gardiner 
KWTRP 
CGMR-
Coast 
Laboratory 
technologists, 
storage 
and 
processing of blood samples and carriage 
analyses 

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Page 60 of 75 
 
 
Investigator 
Institution 
Role 
Mark Otiende 
KWTRP 
CGMR-
Coast 
Programme statistical support and analysis  
Clinical officers (2) 
– to be confirmed 
pending recruitment 
procedures 
KWTRP 
CGMR-
Coast 
Managing the clinical care of participants 
across clinical sites. Assisting quality control to 
ensure good clinical and documentation 
practice.  
Ifedayo Adetifa  
KWTRP 
CGMR-
Coast 
Epidemiological input into the design of the 
protocol and implications of findings.  
Fred Were 
University 
of 
Nairobi 
Oversight of trial design for relevance to 
vaccination policy questions in Kenya  
Christian Bottomley  LSHTM  
Study 
statistician: 
input 
into 
design, 
randomization and analysis plan, analysis and 
interpretation.  
David Goldblatt 
UCL 
Lead 
on 
immunological 
lab 
assays, 
interpretation of results and publication 
Peter Smith  
LSHTM  
Senior clinical trials expertise, input into the 
design, statistical analysis plan, DSMB charter 
and interpretation of final results.  
Patricia Henley  
LSHTM 
Sponsor’s Representative 
 

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
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Appendix 2: Informed consent form in English  
KEMRI-Wellcome Trust Research Programme 
Patient Information and Informed Consent Form 
Formal Title: The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and 
PCV13) on immunogenicity and vaccine-serotype carriage in Kenyan infants. 
Lay Title: A trial to compare the immune response and the proportion of infants still carrying 
bacteria in their nose after varying doses of pneumonia vaccines in Kenyan infants. 
Institutions  
Investigators  
KEMRI CGMR 
(Coast) (KWTRP) 
Anthony Scott (PI), Mainga Hamaluba, Mary Kaniu, Angela Karani, Jimmy 
Shangala, Mark Otiende, Daisy Mugo, Elizabeth Gardiner, Ifedayo Adetifa  
University of Nairobi 
and KENITAG 
Prof Fredrick Were 
LSHTM 
Katherine Gallagher, Peter Smith, Christian Bottomley  
UCL 
David Goldblatt  
 
What is KEMRI?  
KEMRI is a government organization under the Ministry of Health, which carries out medical 
research. Research is different from normal medical treatment because research aims to find 
better ways of preventing and treating illness in the future for everybody’s benefit.  One of the 
projects in KEMRI is looking for better ways to use the existing pneumonia vaccines.   
KEMRI is working on this study in collaboration with the London School of Hygiene and 
Tropical Medicine (LSHTM), the Ministry of Health in Kenya and University College London 
(UCL), UK. LSHTM and UCL are universities in the UK. This study will be taking place only 
in Kenya but if it is beneficial, the impact may reach other low-income countries also.  In Kenya 
research will be conducted by KEMRI. 
What is this research about?  
There are two pneumonia vaccines in use across the world, one protects against 10 types of 
pneumococcal bacteria (PCV10), the second protects against 13 types of pneumococcal bacteria 
(PCV13). Before governments started to deliver pneumonia vaccines many children died each 
year as a result of infection with the bacteria called Streptococcus pneumoniae. The bacteria 
cause diseases like meningitis and sepsis as well as pneumonia.  
In Kenya the pneumonia vaccine that protects against 10 types (PCV10) has been delivered to 
young babies 6 weeks old as part of the routine immunisation schedule since 2011. The 
vaccine has worked very well and has reduced the amount of pneumococcal disease in Kenya. 
However, at the moment the vaccine is expensive. Researchers are worried that when the 
external funding stops the vaccine delivery may stop in Kenya because the vaccine is so 
expensive. We think, but we do not know for sure, that a smaller dose of vaccine may work 
just as well as the full dose. We want to measure whether this is true and smaller doses of the 

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
Page 62 of 75 
 
 
two different pneumonia vaccines are enough to protect Kenyan infants and can be delivered 
safely. The results could be used to make the vaccine cheaper and allow the vaccination 
programme it to be delivered for longer in Kenya. We will measure this by giving some 
children a smaller dose of the vaccine and some children the full dose then we will compare 
how many antibodies are made in the blood to protect them from the bacteria.   
Where is the study taking place, how many people does it involve and how are they 
selected?  
The study will take place at multiple health facilities in Kilifi County, including: Ganze health 
centre, Bamba sub-district hospital, Gongoni health centre, Mambrui dispensary, Marikebuni 
dispensary, Gede health centre, Matsangoni health centre and Kilifi County Hospital, 
Additionaly Malindi General Hospital, Vitengeni health centre and Chasimba health Centre 
may be utilised. A total of 2100 infants will be involved. Infants will be selected as they come 
for routine immunisations at 6 weeks of age and all healthy infants will be eligible for enrolment 
onto the study if parents provide their consent.  
What will the study involve? 
If you agree for your child to take part in this study, you and your child will have a medical 
examination and information in your Mother & Child Handbook and/or doctors’ notes will be 
reviewed by the study staff. If you are HIV positive and your child’s HIV status is not known 
we will organise for your child to be tested, this is according to national guidelines on 
standard care in Kenya. HIV positive mothers and their infants will be referred to the health 
facility’s HIV testing and treatment services. Your HIV infection status and your child’s HIV 
infection status will be recorded for the study for information only and will not determine 
whether or not you can take part in the study. The information will be kept confidential.  
 
If you agree and your child is healthy enough to receive his/her routine vaccinations, they will 
be randomly selected to be in one of seven groups. Your child will have an equal chance of 
being selected for each one of seven groups. Neither the study staff nor you will be able to 
choose the group that your child is allocated to. Depending on which group your child is in, 
they will receive:  
1. PCV10 at the full dose according to the routine immunisation schedule of Kenya: at 
6, 10 and 14 weeks of age i.e. the standard of care in Kenya.  
2. PCV13 at a full dose (the normal dose) in a schedule of 3 doses at 6 weeks of age, 14 
weeks of age and 9 months of age  
3. PCV13 at a 40% dose (a reduced dose) in a schedule of 3 doses at 6 weeks of age, 14 
weeks of age and 9 months of age  
4. PCV13 at a 20% dose (a reduced dose) in a schedule of 3 doses at 6 weeks of age, 14 
weeks of age and 9 months of age 
5. PCV10 at the full dose (the normal dose) in in a schedule of 3 doses at 6 weeks of 
age, 14 weeks of age and 9 months of age 
6. PCV10 at a 40% dose (a reduced dose) in a schedule of 3 doses at 6 weeks of age, 14 
weeks of age and 9 months of age 

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7. PCV10 at a 20% dose (a reduced dose) in a schedule of 3 doses at 6 weeks of age, 14 
weeks of age and 9 months of age  
  
Your child will receive the first dose at 6 weeks of age then you will be invited back to this 
clinic a further 6 times until your child is 18 months of age. The vaccine will be given as 
usual via an intramuscular injection into your child’s thigh. Four of these 6 visits will be at 
the same time as their routine immunisation visits, but you will have to come back 2 more 
times in addition to these routine visits so it is important you plan to stay in this area until 
your child is 18 months of age.  
 
Using a clean needle, we will take a small amount of blood from your child at either three 
time points, or five time points, between now and 18 months of age. At their first study visit 
(today), 2ml (or half a teaspoon) will be taken to make sure he/she is healthy. We will take a 
further 2ml at 18 weeks of age and again at 10 months of age, to test whether their body has 
generated a good immune response to the vaccine at different doses. Some infants will be 
randomly chosen to have two extra blood samples taken at 9 months of age (2ml) and at 18 
months of age (2ml). A swab will be taken from the nose at 9 months of age and at their last 
study visit at 18 months of age to look for the presence of the bacteria.  
 
A summary of the study procedures:  
 
Infant’s age  
6 weeks 
10 weeks 
14 weeks 
18 
weeks 
9 months 
10 
months 
18 months 
Routine 
immunisations 
(KEPI) 
Pentavalent 
vaccine, Polio 
vaccine 
Pentavalent 
vaccine, Polio 
vaccine 
Pentavalent 
vaccine, Polio 
vaccine 
 
Measles vaccine 
 
Measles vaccine 
Study procedures  
All children 
Consent, 
medical check-
up 
 
 
 
 
 
 
1 out of every 7 
children (300 
children in total) 
randomised to the 
full dose 
pneumonia 
vaccination in the 
routine schedule 
Pneumonia 
vaccine 
 
Blood sample 
(2ml) 
Pneumonia 
vaccine 
Pneumonia 
vaccine 
 
 
 
Blood 
sample 
(2ml) 
 
 
 
Nose swab 
 
 
 
 
Nose swab 
6 out of every 7 
children (1800 
children in total) 
allocated to 
full/fractional 
dose pneumonia 
vaccination 
Pneumonia 
vaccine 
 
Blood sample 
(2ml) 
 
 
Pneumonia 
vaccine 
 
 
 
 
 
Blood 
sample 
(2ml) 
Pneumonia 
vaccine  
 
Nose swab 
 
(blood sample 
(2ml) in some 
infants only) 
 
 
 
 
 
Blood 
sample 
(2ml) 
 
 
 
Nose swab 
 
(blood sample 
(2ml) in some 
infants only) 
Total time for the 
study visit 
(maximum)  
1-2 hours  
1 hour 
1 hour 
30 
minutes 
1 hour 
30 
minutes 
30 minutes 
 
After each vaccination, your child will be observed for 30 minutes to make sure they are ok. 

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
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Seven days after each pneumonia vaccination, a member of the study team will contact you by 
phone or at your home in order to check your child is ok. They will ask about any illness since 
vaccination and any reactions around the site of injection.  
Are there any risks or disadvantages to my child for taking part in the study?  
Our priority for every child is their well-being.  
There may be some pain and bruising associated with blood drawing, which will resolve after 
a few days. There is a small risk of local infection after injection. This risk is minimized by use 
of pre-packaged sterile equipment and trained staff. We will ask you to report to us if you are 
worried or think your child has an infection. 
As with any routine vaccination, your child may feel pain at the injection site. Some children 
may have fever after the vaccine is given, other symptoms include irritability, drowsiness, 
restless sleep, decreased appetite, vomiting, diarrhoea and rash. These should disappear after a 
few days. Very rare serious side effects can be seen immediately after any vaccination. These 
include skin swelling, shortness of breath and light-headedness or fainting. Medical equipment 
necessary to treat serious reactions is available.  
We do not know for sure whether the smaller dose will work as well as the full dose of vaccine. 
There is a risk that the children in this study who are selected to receive the smaller doses (4 
out of every 7 children) will generate a less good immune response compared to those who 
receive the full dose. This means that these children may only be partially protected from 
infection and becoming sick. As participants in the study, your child will have access to the 
study medical staff and will be able to present with any illness at an early stage and receive free 
treatment and/or referral throughout the course of the study, up until they are 18 months old. If 
your child presents any of the following signs please contact a member of the study team 
immediately:  
- 
cough or fast breathing; 
- 
abnormal noise when breathing;  
- 
abnormal movements when breathing - nostril flaring in time with the breath or 
nodding of the head in time with the breath; 
- 
fever, difficulty feeding or drinking, lethargy or convulsions. 
 
Until the study is finished, neither you, nor your child will know which vaccine or dose your 
child has received. If, after the study finishes, we find out that the smaller doses do not work as 
well as the full doses, all infants in those groups will be given a single, full dose, booster 
vaccination which should leave them fully protected until later in life.  
This study will involve taking your time and you may have travel costs. In addition to 
reimbursement of transport fares based on standardized KEMRI rates (between Ksh200-1000 
per return journey dependent on distance travelled and transport expenditure), we will 
compensate you for inconvenience and time or wages lost on that day at a rate of Ksh350 for 
each time you come to the clinic. 

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
Page 65 of 75 
 
 
Are there any benefits for taking part?  
If your child participates in this study, they will receive medical care for acute illnesses from 
the day of the first dose of vaccine until the completion of the study free of charge.  Our study 
team will make a first assessment and treat any simple conditions.  If your child needs to be 
referred to a government health facility, we will help you with transport and cover initial costs.  
Treatment of chronic illnesses or long term injuries unrelated to the study procedures will not 
be paid for by the study. If your child is found to have such illnesses/injuries, they will be 
referred for treatment under the existing government programs. 
Your child may be randomly allocated to a group to receive the full dose of one of the vaccines 
(3 in every 7 children will be allocated to full dose groups); children who receive the full dose 
of PCV13 (1 in every 7 children) will have an added benefit of protection against three 
additional types of bacteria that are not contained in the vaccine used in the national programme 
(the PCV10 vaccine). 
At present we cannot be sure that the smaller doses will protect people. When we have results 
from the trial we will provide feedback to all participants. 
If the vaccines work well at a smaller dose, there are substantial potential benefits to the 
community. The vaccine is one of the most expensive vaccines in the routine immunisation 
schedule, if we are able to halve its cost, or more, this may mean it can be delivered in the 
routine immunisation schedule for many more years.  
What will happen if I refuse to allow my child to participate?  
All participation in research is voluntary. You are free to decide if you want your child to take 
part or not. You will still receive the recommended standard of care at the clinic even if you do 
not take part. If you do agree to participate, we would like you to understand that you are free 
to change your mind at any time and withdraw from the research. This will not affect your 
health care now or in the future. The clinicians running the study may withdraw you from the 
study if you are unable to comply with the study visits or for your safety.  
What happens to my child’s samples?  
The blood samples will be coded with the study identification number but no personal 
information such as name or date of birth will be included. This is to ensure that samples can 
only be linked to the participants by people closely concerned with the research. The nasal 
swab samples will be processed and stored in KEMRI-Wellcome Trust research programme, 
Kilifi, but the blood samples will be sent to London, England.  This is because we need the 
tests to be done in a WHO reference laboratory. Any remaining blood samples will be stored 
at our research laboratories in KEMRI, Kilifi. In the future, new research may be done on these 
stored samples. Any future research must first be approved by a national independent expert 
committee to ensure that participants’ safety and wellbeing are protected. 
Who will have access to information about me in this research?  

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
Page 66 of 75 
 
 
All our research records are stored securely in locked cabinets and password protected 
computers. Only the people who are closely concerned with the research will be able to view 
all the information from participants just to be sure that the study is being run correctly and the 
health of every participant is protected and they will keep the information confidential. In order 
to use the information from this study, we will share anonymized information (that is, 
information with names and personal details removed) with LSHTM and government agencies 
so as to show the comparison of immune responses for volunteers getting different doses of the 
vaccines. 
Who has allowed this research to take place?  
This study had been approved by KEMRI Scientific and Ethics Review Unit and London 
School of Hygiene and Tropical Medicine Ethics Committees to make sure the research is 
conducted properly and that participants’ safety and rights are respected. They have looked 
carefully at this work and agreed that the research is important, relevant to Kenya and follows 
nationally and internationally agreed guidelines. This includes ensuring that all participants’ 
safety and rights are respected. 
The local and international committees will be informed about any serious side effects that are 
noticed, and if we receive new information about the vaccine during the course of the trial, we 
will inform you.  
What if I have any questions?  
You may ask any of our staff questions at any time. You can also contact those who are 
responsible for this research:  
1. Katherine Gallagher Tel: 0798 899 995 
2. Mary Kaniu Tel: 0709 983 939 
  
If you want to ask someone independent anything about this research, please contact:   
The Community Liaison Manager, KEMRI – Kilifi, Tel: 041 7522 063, Mobile: 0723 342780      
OR          
The Head, KEMRI Scientific and Ethics Review Unit, P. O. Box 54840-00200, Nairobi; 
Telephone numbers: 0717 719477; 0776 399979 Email address: seru@kemri.org  
This research is supported by LSHTM, who provide insurance for any treatment or 
compensation in the unlikely event of any injury resulting from this trial. 

FPCVTrial_InformedConsent_v.3.0_01May2018 
 
Page 67 of 75 
 
 
KEMRI – Wellcome Trust Programme Informed consent form for: 
Formal Title: The effect of fractional doses of pneumococcal conjugate vaccines (PCV10 and PCV13) 
on immunogenicity and vaccine-serotype carriage in Kenyan infants. 
Lay Title: A trial to compare the immune response and the proportion of infants still carrying bacteria 
in their nose after varying doses of pneumonia vaccines in Kenyan infants. 
I,         __________________________           (Parent’s name), have had the trial explained to me. I 
have understood all that I have read and have had explained to me and had my questions answered 
satisfactorily. I understand that I can change my mind at any stage. I consent for my child 
________________________________   
(Child’s name) to take part in this study.  
        Please tick I agree for my child to take part in this research  
        Please tick I agree to my child’s samples being stored and used for future research 
         Please tick I agree to my child’s samples being exported to the United Kingdom 
        Please tick I agree to being contacted by study staff, if necessary, after the last study visit in 
order to hear the results of the trial 
Parent’s Name (print):   
Date & Time:  
Parent’s signature/ thumbprint in the presence of a witness:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Where parent/guardian cannot read, ensure a witness observes consent process and signs below: 
I attest that the information concerning this research was accurately explained to and apparently 
understood by the subject and that informed consent was freely given by the subject. 
Witness’ signature:  _____________________________________ Date _____________ 
Witness’ name:       _____________________________________ Time ______________ 
I (KEMRI person taking consent) certify that I have followed the SOP for this study and have explained 
the study information to the study participant named above, and that he/she has understood the nature 
and the purpose of the study and consents to the participation in the study. He/ She has been given 
opportunity to ask questions which have been answered satisfactorily.  
Designee /Investigator’s / Signature: ------------------------------         Date: ---------------------  
Designee /Investigator’s Name: -------------------------------------- 
   Time: --------------- 
THE PARTICIPANT SHOULD BE GIVEN A SIGNED COPY AND A COPY KEPT IN FILE.  

 
 
 
 
Page 68 of 75 
 
 
Appendix 3: Non-KEMRI Investigator CVs  
 
Curriculum vitae: Katherine E. Gallagher, BA MSc PhD  
 
September 2017 
Katherine.Gallagher@lshtm.ac.uk; +44 7725 310 366 
 
Current post: Assistant Professor; Faculty of Epidemiology and Population Health, Department of 
Infectious Disease Epidemiology; London School of Hygiene and Tropical Medicine. 
 
 
Education 
 
2013-2016 
Medical Research Council (MRC) UK PhD Studentship in Vaccine Research, Clinical Research 
Department, London School of Hygiene and Tropical Medicine. 
2012-2013 
MSc Epidemiology, London School of Hygiene and Tropical Medicine (Distinction). 
2008-2011 
BA Biological Natural Sciences (Major: Pathology), University of Cambridge (2i). 
 
Prior Experience: 
 
August 2016-August 2017 
 International Study Coordinator EBOVAC1; Assistant 
Professor, Clinical Research Department; London School of 
Hygiene and Tropical Medicine. 
 
Based in London, I was the academic coordinator for the portfolio of projects funded by the EBOVAC1 grant, 
including an ongoing Phase 1 trial in Tanzania (25 adult participants) and a large Phase 2 clinical trial in Sierra 
Leone (976 adult and paediatric participants). The trials involved a candidate heterologous prime-boost 
vaccine regimen against Ebola Virus Disease (AD26.ZEBOV and MVA-BN-Filo). In addition, I was actively 
involved in the set up and site preparations in Sierra Leone for a further phase 2 trial of AD26.ZEBOV and 
MVA-BN-Filo, the rVSV vaccine and placebo (The PREVAC trial) under the same funding (EUR 58 million).    
Aside from tracking recruitment, reporting to ethics and regulatory authorities, managing Sponsor 
communications and working with the QA manager to respond to audit findings, I also input into legal 
contracts, SOPs, protocol amendments and source documents. I attended lab calls and organised the testing 
of samples for two ancillary studies in Sierra Leone investigating the prevalence of asymptomatic Ebola in 
screened participants and the effect of malaria infection on vaccine-induced immune response.  
I prepared grant proposals and budgets to: 1) extend safety follow up in Tanzania from 12 months to 5 years 
(Janssen Registry Protocol) 2) to extend immunological follow up in Sierra Leone for 4 years and enrol an 
additional 200 paediatric participants (EC IMI2 Call 8) and 3) to extend the PREVAC trial follow up for 4 years 
to extend immunological and safety data collection (EDCTP).  
 
September 2013- 2016 
MRC UK PhD Vaccine Research Studentship; Mwanza 
Intervention Trials Unit (MITU) the National Institute for 
Medical Research (NIMR), Tanzania. Supervisor: Dr Deborah 
Watson-Jones; London School of Hygiene and Tropical Medicine.            
 
2014  
Project coordinator: Case-control study to analyse the association between HPV and subsequent 
HIV acquisition (MRC PHIND funding scheme, PI Deborah Watson-Jones).  
2014-2016 
Co-investigator & project coordinator: Collating lessons learnt from HPV vaccine demonstration 
projects and national programmes in 46 low and middle-income countries (BMGF USD 
1,326,272, PI Deborah Watson-Jones). This project was requested to specifically analyse the 
value of demonstration projects in order to inform policy on whether funding for them should 
continue.  
2014-2015 
Project lead: Investigating the impact of HPV vaccine campaign activities on the provision of 
routine primary healthcare services in NW Tanzania (The Chadwick Trust fellowship & the 
LSHTM Travelling Scholarship GBP 10,000; PI K Gallagher). 
Dec’ 2014- 
Feb’ 2015  
Interim site coordinator for the EBOVAC1 Phase 1 trial of a heterologous prime-boost vaccine 
against Ebola Virus Disease. Mwanza. Initial 3 months of trial set-up due to gaps in recruitment.  
 
Publications 

 
 
 
 
Page 69 of 75 
 
 
 
1) The associations between human papillomavirus prevalence, persistence or clearance and 
subsequent HIV acquisition in Tanzanian and Ugandan women: a nested case-control study. 
Gallagher K.E., Baisley K., Hayes R., Kapiga S., Vandepitte J., Grosskurth H., Vallely A., Kamali A., De 
Sanjose S., Changalucha J., Watson-Jones D. Journal of Infectious Disease 2016; first published online 
March 6, 2016. 
2) Social mobilization, acceptability, and consent procedures for human papillomavirus vaccination in 
low- and middle-income countries. Severin Kabakama1, Katherine E Gallagher1,2,*, Natasha Howard3, 
Sandra Mounier-Jack3, Helen ED Burchett3, Ulla K Griffiths3, Marta Feletto4, D Scott LaMontagne4, Deborah 
Watson-Jones1. BMC Public Health 2016, 16:834.  
3) Lessons learnt from human papillomavirus vaccine delivery in low and middle-income countries. 
Gallagher K.E., Griffiths U.K., Burchett H., Howard N., Kabakama S., Mounier-Jack S., LaMontagne D.S., 
Watson-Jones D. PloS one. 2017;12(6):e0177773. doi: 10.1371/journal.pone.0177773. 
4) The impact of HPV vaccination campaign activities on routine primary healthcare services in 
Kilimanjaro region, Tanzania. KE Gallagher, T. Erio, K Baisley, S Lees, D Watson-Jones. (Accepted; 
BMC Health Services Research) 
5) Human papillomavirus (HPV) vaccine coverage achievements in low- and middle-income countries 
2007-2016 Gallagher K.E., Griffiths U.K., Burchett H., Howard N., Kabakama S., Mounier-Jack S., 
LaMontagne D.S., Watson-Jones D. (Accepted, Journal of Papillomavirus research) 
6) Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic 
review. K. E. Gallagher, E. Kadokura, L. O. Eckert, S. Miyake, S. Mounier-Jack, M. Aldea, D. A. Ross, D. 
Watson-Jones. BMC public health 2016, 16(1):172 
7) The status of HPV vaccination programs in low and lower middle income countries. LaMontagne DS, 
Bloem PJN, Brotherton JML, Gallagher KE, Badiane O, Ndiaye C. Progress in HPV vaccination in low- and 
lower-middle-income countries. International Journal of Gynecology & Obstetrics. 2017;138:7-14. doi: 
10.1002/ijgo.12186. 
8) The value of demonstration projects for new interventions: the case of human papillomavirus 
vaccine introduction in low-income and lower-middle-income countries. Howard N, Mounier-Jack S, 
Gallagher KE, et al. Human vaccines & immunotherapeutics 2016:1-3. 
9) What works for human papillomavirus vaccine introduction in low and middle-income 
countries? Howard N, Gallagher KE, Mounier-Jack S, Burchett HED, Kabakama S, LaMontagne DS, 
et al. Papillomavirus Research. 2017;4:22-5. doi: http://dx.doi.org/10.1016/j.pvr.2017.06.003. 

 
 
 
 
Page 70 of 75 
 
 
CV: Professor David Goldblatt 
Date of birth: 16 March 1960 
Nationality: Irish 
Education 
MB, CH, B (University of Cape Town) 1983 
MRCP (UK) 1986 
PhD (Immunology, University of London) 1991 
Current position  
Professor of Vaccinology and Immunology 
ICH Infect, Imm, Infla. & Physio Med 
UCL GOS Institute of Child Health 
30 Guilford Street, London WC1N 1EH, UK 
Recent Publications 
Pneumococcal conjugate vaccine given shortly after birth stimulates effective antibody concentrations and 
primes immunological memory for sustained infant protection. Scott JA, Ojal J, Ashton L, Muhoro A, Burbidge 
P, Goldblatt D. Clinical infectious diseases : an official publication of the Infectious Diseases Society of 
America. 2011;53(7):663-70. Epub 2011/08/26. doi: 10.1093/cid/cir444. PubMed PMID: 21865175; PubMed 
Central PMCID: PMCPMC3166350. 
 
Immunogenicity of a reduced schedule of pneumococcal conjugate vaccine in healthy infants and correlates of 
protection for serotype 6B in the United Kingdom. Goldblatt D, Southern J, Ashton L, Andrews N, Woodgate 
S, Burbidge P, et al. The Pediatric infectious disease journal. 2010;29(5):401-5. Epub 2009/12/17. doi: 
10.1097/INF.0b013e3181c67f04. PubMed PMID: 20010312. 
 
Dosing Schedules for Pneumococcal Conjugate Vaccine: Considerations for Policy Makers. Whitney CG, 
Goldblatt D, O’Brien KL. The Pediatric infectious disease journal. 2014;33(Suppl 2 Optimum Dosing of 
Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different 
Schedules):S172-S81. doi: 10.1097/INF.0000000000000076. PubMed PMID: PMC3940379. 
 
Colonisation endpoints in Streptococcus pneumoniae vaccine trials. Auranen K, Rinta-Kokko H, Goldblatt D, 
Nohynek H, O'Brien KL, Satzke C, et al. Vaccine. 2013;32(1):153-8. Epub 2013/09/11. doi: 
10.1016/j.vaccine.2013.08.061. PubMed PMID: 24016803. 
 
Comparative immunogenicity of 7 and 13-valent pneumococcal conjugate vaccines and the development of 
functional antibodies to cross-reactive serotypes. Grant, L. R., O'Brien, S. E., Burbidge, P., Haston, M., Zancolli, 
M., Cowell, L., . . . Goldblatt, D. PLoS One, 2013, 8(9), e74906. doi:10.1371/journal.pone.0074906 
 
Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) 
determined during an efficacy trial in The Gambia. Saaka M, Okoko BJ, Kohberger RC, Jaffar S, Enwere G, Biney 
EE, Oluwalana C, Vaughan A, Zaman SM, Asthon L, Goldblatt D, Greenwood BM, Cutts FT, Adegbola RA. 
Vaccine. 2008 Jul 4;26(29-30):3719-26. 
 
Bacteria, polysaccharides, vaccines and boosting: measuring and maintaining population immunity. Goldblatt 
D. Arch Dis Child. 2008 Aug;93(8):646-7. 
 
Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, 
Neisseria meningitidis and Streptococcus pneumoniae. Trotter CL, McVernon J, Ramsay ME, Whitney CG, 
Mulholland EK, Goldblatt D, Hombach J, Kieny MP; SAGE subgroup. Vaccine. 2008 Aug 18;26(35):4434-45. 
 
Natural human antibodies to pneumococcus have distinctive molecular characteristics and protect against 
pneumococcal disease. Baxendale HE, Johnson M, Stephens RC, Yuste J, Klein N, Brown JS, Goldblatt D. Clin Exp 
Immunol. 2008 Jan;151(1):51-60.  

 
 
 
 
Page 71 of 75 
 
 
PERSONAL HISTORY - Peter George SMITH 
 
ACADEMIC QUALIFICATIONS 
Qualification 
Discipline 
Institution 
Dates 
B.Sc. (1st class) 
Applied Mathematics 
Northampton College of Advanced 
Technology (now City University) 
1959-63 
 
D.Sc. 
Medical Statistics 
City University 
1983 
HonMFPH 
 
Faculty of Public Health (Hon. Member) 
1992- 
FMedSci 
 
Academy of Medical Sciences (Fellow) 
1999- 
 
HONOURS 
CBE 
For services to the Spongiform Encephalopathy Advisory 
Committee and to Tropical Disease Research 
2001 
Donald Reid Medal 
For distinguished contributions to epidemiology 
2003 
Ronald Ross Medal 
For outstanding contributions to research in tropical public health 
2016 
 
CURRENT POSITION 
Professor of Tropical Epidemiology 
London School of Hygiene and 
Tropical Medicine, UK. 
1989-
present 
 
CURRENT MEMBERSHIP OF SOME RELEVANT COMMITTEES 
 
Member of Independent Data Monitoring Committee, for Sanofi-Pasteur clinical trials of 
dengue vaccines. 
2008-present 
Chair of Scientific Review Board and Member of Governance Council of the INDEPTH 
Effectiveness and Safety Studies of Anti-malarials in Africa (INESS). 
2009-present 
Chair of the Programme Board for Global Health and Vaccination Research (GLOBVAC) 
of the Research Council of Norway. 
2011-present 
Member of Global Burden of Disease Independent Advisory Committee. 
2013-present 
Member of WHO Product Development for Vaccines Advisory Committee (PD-VAC). 
2014-present 
Member of DFID/MRC/Wellcome Trust Global Health Trials Funding Committee. 
2014-present 
Member of Technical Advisory Group (TAG) for BMGF-supported Indian Platform for 
Research Excellence Related to National Aims (PRERNA) (comprising The Society for 
Applied Studies (New Delhi), Christian Medical College (Vellore), and KEM Hospital 
Research Centre (Pune)). 
2015-present 
Therapeutic Expert (Vaccines) to Wellcome Trust Independent Review Panel for 
ClincalStudyDataRequest.com 
2015-present 
Member of WHO Respiratory Syncytial Virus (RSV) Vaccine Technical Advisory Group 
2015-present 
Member of Scientific Advisory Committee (SAC) of the Coalition for Epidemic 
Preparedness Innovations (CEPI) 
2016-present 
Member of Advisory Group to the WHO Global Respiratory Syncytial Virus (RSV) 
Surveillance Pilot 
2016-present 
Member of Scientific Advisory Committee of European and Developing Countries Clinical 
Trials Partnership (EDCTP). 
2017-present 
Member of World Bank and CEP International Task Force on Strengthening Country 
Capacity for Vaccines Research and Development 
2017-present 

 
 
 
 
Page 72 of 75 
 
 
 
PUBLICATIONS 
 
Over 350 scientific publications including relevant publications below: 
 
Nuffield Council on Bioethics (PGS member of Working Party) (2002).  The ethics of research related to 
healthcare in developing countries. Nuffield Council on Bioethics, London. 
Jaffar S, Leach A, Smith PG, Cutts F, Greenwood B (2003).  Effects of misclassification of causes of death on 
the power of a trial to assess the efficacy of a pneumococcal conjugate vaccine in The Gambia. Int J Epid 32, 
430-436.  
Moorthy VS, Reed Z, Smith PG (2007).  Measurement of malaria vaccine efficacy in phase III trials: report of a 
WHO consultation. Vaccine 25, 5115-5123. 
Moorthy VS, Reed Z, Smith PG (2009).  Clinical trials to estimate the efficacy of preventive interventions 
against malaria in paediatric populations: a methodological review. Malaria J 8:23. 
Moorthy VS, Reed Z, Smith PG on behalf of the WHO Malaria Vaccine Advisory Committee (MALVAC) 
(2009). MALVAC 2008: Measures of efficacy of malaria vaccines in phase 2b and phase 3 trials - scientific, 
regulatory and public health perspectives. Vaccine 27, 624-628. 
Global Advisory Committee on Vaccine Safety (PGS chair) and World Health Organization secretariat (2009).  
Global safety of vaccines: strengthening systems for monitoring, management and the role of GACVS. Expert 
Review of Vaccines 8, 705-716. 
Schmidt H, Smith PG (2009).  Ethical excellence: the 2008 Declaration of Helsinki and its potential impact on 
research in developing countries.  International Clinical Trials, Spring issue: pp74-77. 
Bentsi-Enchill AD, Schmit J, Edelmam R, Durbin A, Roehrig JT, Smith PG, Hombach J, Farrar J (2013).  Long-
term safety assessment of live attenuated tetravalent dengue vaccines: deliberations from a WHO technical 
consultation. Vaccine 31, 2603-2609. 
Feikin DR, Kagucia EW, Loo JD, Link-Gelles R, Puhan MA, Cherian T, Levine OS, Whitney CG, O’Brien KL, 
Moore MR, and the Serotype Replacement Study Group (including Smith PG). (2013). Serotype-specific 
changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction – A pooled 
analysis of multiple surveillance sites. PLoS Med. 10(9):e1001517.  
Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PEM, Rodrigues LC, Smith PG, Lipman M, 
Whiting PF, Sterne JA (2014). Protection by BCG vaccine against tuberculosis: a systematic review of 
randomized controlled trials. Clin Infect Dis 58, 470-480. 
Rid A, Saxena A, Baqui AH, Bhan A, Bines J, Bouesseau M-C, Caplan A, Colgrove J, Dhai A, Gomez-Diaz R, 
Green SK, Kang G, Lagos R, Loh P, London AJ, Mulholland K, Neels P, Pitisuttithum P, Cor Sarr S, Selgelid 
M, Sheehan M, Smith PG (2014). Placebo use in vaccine trials: Recommendations of a WHO expert panel. 
Vaccine 32, 4708-4712.  
Smith PG, Morrow RH, Ross DA [Editors] (2015).  Field trials of health interventions: a toolbox (3rd Edition). 
Oxford University Press, Oxford  
Bottomley C, Bojang A, Smith PG, Darboe O, Antonio M, Foster-Nyarko E, Kampmann B, Greenwood B, 
D'Alessandro U, Roca A (2015). The impact of childhood vaccines on bacterial carriage in the nasopharynx: a 
longitudinal study. Emerging Themes in Epidemiology  12: 1. 
Baiden R, Oduro A, Halidou T, Gyapong M, Sie A, Macete E, Abdulla S, Owusu-Agyei S, Mulokozi A, Adjei 
A, Sevene E, Compaoré G, Valea I, Osei I, Yawson A, Adjuik M, Akparibo R, Ogutu B, Upunda GL, Smith PG, 
Binka F (2015).  Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-
based combination Eurartesim® (dihydroartemisinin/piperaquine) in public health facilities in Burkina Faso, 
Mozambique, Ghana and Tanzania. Malaria J 14,160. 
Hosangadi D, Smith PG, Giersing BK (2017). Considerations for using ETEC and Shigella disease burden 
estimates to guide vaccine development strategy. Vaccine (published online) 
https://doi.org/10.1016/j.vaccine.2017.09.083. 
 
 
 
 

 
 
 
 
Page 73 of 75 
 
 
22.3.1.1.1.1 
Curriculum vitae: Dr Christian Bottomley     
 
 
   
September 2017  
 
 
Surname:  
 
Bottomley       
 
Forenames:   Herbert Christian 
                    
Current post:  
Associate Professor in Medical Statistics and Epidemiology 
 
 
 
Address:   
 
MRC Tropical Epidemiology Group 
 
 
 
Faculty of Epidemiology and Public Health, 
 
 
 
London School of Hygiene and Tropical Medicine, 
 
 
 
Keppel Street, London WC1E 7HT, UK. 
 
Telephone:   
020-7927- 2533 
 
           
Email:  
 
christian.bottomley@lshtm.ac.uk 
 
Qualifications: 
1997     BA  
 
Biology, University of Oxford: 2(i)  
2000     MA  
 
Biostatistics, University of California, Berkeley 
2001     Mres  
Modelling Biological Complexity, University College London 
2006     PhD    
Mathematical Biology, University College London 
 
Posts held: 
2000 -   2001  
Statistician, California Department of Health Services 
2005 -  2006   
Lecturer and Research Associate, University College London 
2006 -   2008   
Statistician, University College London  
2008 -   2010  
Research Fellow, LSHTM 
2010 -   2015  
Assistant Professor, LSHTM 
2015 -  
 
Associate Professor, LSHTM 
 
Current citizenship roles: 
 
  
LSHTM: 
  
- Deputy Exam Board Chair, Distance Learning Epidemiology (2016- ) 
  
- Research Degree Coordinator, Dept Infectious Disease Epidemiology (2014-2017) 
  
- Course Organiser, Design and Analysis of Epidemiological Studies 
  
- PhD Supervision: 1 completed, 2 ongoing 
  
- Seminar Organizer, Dept Infectious Disease Epidemiology (2009 - ) 
  
- Coordinator of MRC TEG fellowship scheme (2009-2013) 
 
  
External: 
- Associate Editor, Tropical Medicine and International Health 
- Guest Editor, PLoS Neglected Tropical Diseases  
- Reviewer, Lancet Global Health, Journal of the Royal Society Interface, Trends in   
  Parasitology, PLoS One, American Journal of Epidemiology, International  
  Journal  of Parasitology, American Journal of Tropical Medicine & Hygiene,             
  Parasitology, European Child & Adolescent Psychiatry,  
  Mathematical Biosciences, Vaccine 
- Steering committee membership: Valuing active life in dementia (2015- );  
10 Top TipsTrial (2012-2013); A web-based intervention for heart disease 
management (2007-2009) 
- Data Safety & Monitoring committee membership:  A randomized, controlled, 
  doubleblind, phase 3 trial to evaluate the effects of maternal or neonatal    

 
 
 
 
Page 74 of 75 
 
 
  pneumococcal conjugate vaccination on pneumococcal carriage in infants up to 
  nine months of age – The PROPEL Trial (2016-) 
- Fellow of the Royal Statistical Society (2006- ) 
 
 
Recent research funding 
 
2017 - 2021 
Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis and 
Death: a Phase III Double-Blind Randomized Clinical Trial. Funding: Medical 
Research Council UK Grant amount: £2.2m. Role in the project: co-
investigator. 
 
2013 - 2018 
Epidemiological & statistical research on health problems of developing 
countries:  MRC Tropical Epidemiology Group. Funding: Medical Research 
Council UK Grant amount: £3,913,897. Role in the project: named 
collaborator 
 
2015 - 2017 
Neglected Tropical Diseases Modelling Consortium Workpackage: Reaching 
the 2020 goals for human onchocerciasis. Funding: Bill and Melinda Gates 
Foundation. Grant amount: £403,890. Role in the project: named collaborator 
 
2015 - 2016 
NTD-Support Centre. Funding: Bill and Melinda Gates Foundation. Grant 
amount: $428, 519. Role in the project: trial statistician  
 
2011 - 2014:  Reduction of early mortality among HIV-infected subjects starting antiretroviral 
therapy: a randomised trial (The REMSTART trial). Funding: EDCTP. Grant 
amount:  ~ €4m. Role in the project: named co-investigator 
 
 
 
 

 
 
 
 
Page 75 of 75 
 
 
Fredrick N Were, MBCHB, MMED, FNIC, PHD, EBS 
 
Current positions:  
Professor of Pediatrics & Dean School of Medicine, University of Nairobi;  
Chair of the Kenyan National Immunisations Technical Advisory Group (KENITAG); 
Chief Researcher, Kenya Paediatric Research Consortium. 
 
Address:  
Upper Hill Med Centre. 1st floor 
Ralph Bunche Road 
Box 20956-00200 Nairobi 
Recent publications:  
 
Building Learning Health Systems to Accelerate Research and Improve Outcomes of Clinical Care in Low- and 
Middle-Income Countries. English M, Irimu G, Agweyu A, Gathara D, Oliwa J, Ayieko P, Were F, et al. (2016) 
PLoS Med 13(4): e1001991. 
doi:10.1371/journal.pmed.1001991 
 
Characteristics of admissions and variations in the use of basic investigations, treatments and outcomes in 
Kenyan hospitals within a new Clinical Information Network Ayieko P, Ogero M, Makone B, Julius T, Mbevi G, 
Nyachiro W, Were F. et al. Vol. 101. 2015. 
 
Delivery outcomes and patterns of morbidity and mortality for neonatal admissions in five  Kenyan hospitals. 
Jalemba Aluvaala, Dorothy Okello, Gatwiri Murithi, Leah Wafula, Lordin Wanjala, Newton Isika, Aggrey 
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