A Multi-Centre, Randomized, Double Blind, Phase 2b Trial to Evaluate the Safety and Immunogenicity of Janssen Ad26COVS1 (or mRNA (Moderna mRNA-1273 or Pfizer/BNT) and Novavax NVX-CoV2373 COVID-19 Vaccines for Homologous and Heterologous Boosting in Adolescents and Adults Aged 12 to 64 Years With and Without HIV Infection in 3 African Countries Kenya, Democratic Republic of Congo, and Rwanda.
Phase: PHASE2
Conditions: COVID -19, SARS CoV 2 Infection
Sponsor: Victoria Biomedical Research Institute

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A Multi-Centre, Randomized, Double Blind, Phase 2b Trial to Evaluate the Safety 
and Immunogenicity of Janssen Ad26COVS1 (or mRNA (Moderna mRNA-1273 or 
Pfizer/BNT) and Novavax NVX-CoV2373 COVID-19 vaccines for Homologous and 
Heterologous Boosting in Adolescents and Adults Aged 12 to 64 Years with and 
without HIV infection in 3 African Countries (Kenya, Democratic Republic of 
Congo, and Rwanda). 
 
Protocol Identification Number: VIBRI COVID-19-001/2021 (Amendment # 2) 
 
Study Principal Investigators:  
Lucas Otieno Tina, MD MPH, Victoria Biomedical Research Institute, Kenya 
Amos Ndhere, MD MS, Victoria Biomedical Research Institute, Kenya 
 
Collaborating Country Principal Investigators:  
Hypolite Muhindo, MD PhD, University of Kinshasa, Democratic Republic of Congo 
Vincent Mutabazi, MD MSc, Rinda Ubuzima & University of Rwanda, Rwanda 
 
Sponsor: Victoria Biomedical Research Institute 
P.O. Box 7180, Postal Code 40100, 
Kisumu, Kenya 
Tel: +254 720 597654 
Website: https://www.vibriafrica.org  
 
Funded by: Coalition for Epidemic Preparedness Innovation 
 
Protocol #: VIBRI COVID-19-001/2021, Version: 3.0 
Protocol Version Date: 16 January 2023 
 
Protocol Amendment #: 02 
Summary of Changes from Previous Version: 
Affected Section(s) Summary of Revisions Made 
Rationale 
1.1, 1.2, 1.3, 2.3, 3.1, 
4.1, 4.2, 5.0 and 6.1. 
Removed Janssen vaccine option as 
alternative booster vaccine and 
replaced with an mRNA (Moderna 
Mrna-1273 or Pfizer/BNT) vaccines 
for adolescents).  
There is currently no information on safety and immunogenicity 
of the Janssen Covid-19 vaccine in adolescent/paediatric 
populations. As a result, the recommendation for use of the 
Janssen Covid-19 vaccine for primary or booster vaccination in 
adolescents/paediatric populations has not yet been made. 
Therefore, it’s evaluation for booster vaccination in this study has 
been substituted with Pfizer or Moderna Covid-19 vaccines. 
 
Adolescent booster vaccination will 
be ≥5 months with no upper limit 
This has been updated as per current US CDC and US FDA 
recommendations on booster vaccination for 12-17 years and to 
be consistent with the real-world setting. An overall and stratified 
immune analysis will be done by boost at ≥5-12 or >12 months.  

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Table of Contents 
Statement of Compliance .......................................................................................................................................... 4 
PROTOCOL SIGNATURE PAGE .................................................................................................................................... 4 
1 Protocol Summary ...................................................................................................................................................... 5 
1.1 SCIENTIFIC ABSTRACT .......................................................................................................................................... 5 
1.2 LAY SUMMARY ..................................................................................................................................................... 8 
1.3 STUDY Schema ..................................................................................................................................................... 9 
1.4 Schedule of Events (SoE).................................................................................................................................... 11 
1.5 PROTOCOL – Key Roles ...................................................................................................................................... 14 
2 Introduction .............................................................................................................................................................. 16 
2.1 Background ........................................................................................................................................................ 16 
2.2 Study Rationale .................................................................................................................................................. 18 
2.3 Risk/Benefit Assessment.................................................................................................................................... 19 
3 Objectives and Endpoints ......................................................................................................................................... 23 
3.1 PRIMARY OBJECTIVES ........................................................................................................................................ 23 
3.1.1.    PRIMARY SAFETY OBJECTIVES ................................................................................................................. 23 
3.1.2.    PRIMARY IMMUNOGENICITY OBJECTIVE ................................................................................................ 23 
3.2 SECONDARY OBJECTIVES ............................................................................................................................... 23 
3.2.2.    SECONDARY IMMUNOGENICITY OBJECTIVES ......................................................................................... 24 
3.3 EXPLORATORY OBJECTIVES ............................................................................................................................ 24 
4 Study Design ............................................................................................................................................................. 26 
4.1 STUDY SETTING .................................................................................................................................................. 26 
4.1.1 Victoria Biomedical Research Institute, Kenya ........................................................................................... 26 
4.1.2 Rinda Ubuzima/University of Rwanda, Rwanda ......................................................................................... 27 
4.1.3 University of Kinshasa (UNIKIN), the Democratic Republic of Congo (DRC) ............................................... 28 
4.2 STUDY Design ..................................................................................................................................................... 29 
4.3 SAMPLE SIZE ...................................................................................................................................................... 34 
5 Study Population ...................................................................................................................................................... 39 
5.1 Inclusion Criteria ................................................................................................................................................ 39 
5.2 Exclusion Criteria ............................................................................................................................................... 41 
5.3 Screen Failures ................................................................................................................................................... 44 
5.4 Strategies for Recruitment and Retention ......................................................................................................... 44 
5.4.1.    Community information.......................................................................................................................... 44 
5.4.2.    Recruitment ............................................................................................................................................ 44 
6 Study PRODUCT AND ADMINISTRATION .................................................................................................................. 46 
6.1 Study Intervention(s) Administration ................................................................................................................ 46 
6.1.1 DESCRIPTION OF STUDY PRODUCTS ........................................................................................................... 46 
6.1.2 Dosing and Administration ......................................................................................................................... 47 
6.2 PACKAGING, LABELLING, STORAGE, AND HANDLING OF STUDY PRODUCTS .................................................... 47 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 49 
6.3.1 Procedures for Randomization and Stratification ...................................................................................... 49 
6.3.2.     Study Vaccination Pausing Rules ............................................................................................................ 51 
6.4 Study Intervention Compliance ......................................................................................................................... 52 
6.5 Concomitant Therapy ........................................................................................................................................ 52 
7 Participant COMPLETION AND Withdrawal .............................................................................................................. 54 

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7.1 PARTICIPANT WITHDRAWAL FROM the STUDY ................................................................................................. 54 
7.3 Lost to Follow-Up ............................................................................................................................................... 55 
8 Study Assessments and Procedures ......................................................................................................................... 57 
8.1 informed consent, recruitment, screening nd other study procedures ............................................................ 57 
8.2 Standard of care study procedures.................................................................................................................... 58 
8.3 Laboratory procedures and evaluation ............................................................................................................. 59 
8.3.1 Clinical Laboratory Evaluations ................................................................................................................... 59 
8.3.2 Specimen Preparation, Handling and Storage ............................................................................................ 59 
8.3.3 Specimen Shipment .................................................................................................................................... 59 
8.4 Scheduled study visits ........................................................................................................................................ 60 
8.5 Unscheduled visits ............................................................................................................................................. 60 
8.6 SAFETY and other assessments ......................................................................................................................... 60 
8.6.1 Adverse Events and Serious Adverse Events - Definition and classification ............................................... 60 
8.6.2 ADVERSE EVENTS REPORTING .................................................................................................................... 65 
8.6.2 Reporting of Pregnancy .............................................................................................................................. 69 
8.6.5 Unanticipated Problems Requiring ETHICS Committee reporting .............................................................. 69 
9 Statistical Considerations ......................................................................................................................................... 71 
9.1 Statistical Hypotheses ........................................................................................................................................ 71 
9.2 Statistical Analyses............................................................................................................................................. 72 
10 Supporting Documentation and Operational Considerations ................................................................................ 75 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 75 
10.1.1 Kenya Ethics and Regulatory Approval ..................................................................................................... 75 
10.1.2 Rwanda Ethics and Regulatory Approval .................................................................................................. 76 
10.1.3 Democratic Republic of Congo Ethics and Regulatory Approval .............................................................. 76 
10.2 PROTOCOL AMENDMENTS .............................................................................................................................. 77 
10.3 REPORTING REQUIREMENTS ........................................................................................................................... 77 
10.3.1 Continuing Review Reporting ................................................................................................................... 77 
10.3.2 Protocol Deviation Reporting ................................................................................................................... 78 
10.3.3 Reporting of Inspections or Audits ........................................................................................................... 78 
10.4 Informed Consent Process ............................................................................................................................... 78 
10.4.1 Consent/assent and Other Informational Documents ............................................................................. 78 
10.5 Confidentiality and Privacy .............................................................................................................................. 79 
10.6 Future Use of Stored Specimens and Data ...................................................................................................... 79 
10.7 Key Roles and Study Governance .................................................................................................................... 80 
10.8 Safety Oversight ............................................................................................................................................... 80 
10.9 Clinical Monitoring ........................................................................................................................................... 80 
10.10 Quality Assurance and Quality Control .......................................................................................................... 81 
10.11 Data Handling and Record Keeping ............................................................................................................... 82 
10.11.1 Data Collection and Management Responsibilities ................................................................................ 82 
10.11.2 STUDY RECORDS RETENTION AND DISPOSAL ......................................................................................... 83 
10.12 Conflict of Interest Policy ............................................................................................................................... 84 
10.13 Additional Considerations ............................................................................................................................. 84 
10.13.1 EXPECTED APPLICATION OF THE RESULTS .............................................................................................. 84 
10.13.2 Publication and Data Sharing Policy ....................................................................................................... 84 
11 Abbreviations .......................................................................................................................................................... 85 
12 References .............................................................................................................................................................. 87 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Council on Harmonization Good Clinical 
Practice (ICH GCP), applicable local regulatory authority guidelines. The Principal Investigator will assure 
that no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and documented approval from the Ethics Review Committee (ERC), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRC for review and approval. Approval of both the protocol and the consent form(s) must 
be obtained before any participant is consented. Any amendment to the protocol will require review and 
approval by the Ethics Review Committee (ERC) before the changes are implemented to the study. All 
changes to the consent form(s) will be ERC approved; a determination will be made regarding whether a 
new consent needs to be obtained from participants who provided consent, using a previously approved 
consent form. 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and ICH-GCP (E6) guidelines. 
 
 
                      
Signature: 
 
 
 
 
 
Date: 
 
Dr. Lucas Otieno Tina, MD, MPH 
 
 
 
 
16 January 2023 
Principal Investigator 
 
 
Signature:  
 
 
 
 
 
 
 
Date: 
 
Dr. Amos Ndhere, MD, MS 
 
 
 
 
 
16 January 2023 
Principal Investigator 

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1 PROTOCOL SUMMARY 
1.1 SCIENTIFIC ABSTRACT 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in the 
human population in Wuhan City, Hubei Province, China in December 2019. As of Jan 2022, there are over 
328 million SARS-CoV-2 case worldwide and over 5.54 million deaths as a result of infection with SARS-
CoV-2 (COVID-19). According to WHO Situation Report on 17 January 2022, Africa has 7 million confirmed 
cases with over 160, 804 deaths. The COVID-19 pandemic has caused global suffering, mortality, and 
severe economic pressures. There is thus a continued urgent global need to develop effective and safe 
vaccines and drugs to make them available at scale and equitably across all countries including in Africa.  
Despite the rapid successes in vaccine development and issuance of WHO Emergency Use Listings (EUL), 
the WHO SAGE Interim Reports and FDA Emergency Use Authorization (EUA) for COVID-19 vaccine 
evaluations have reported limitations on safety and efficacy data in certain populations including children 
and adolescents, pregnant women, and immunocompromised individuals such as those with HIV/AIDS 
who are at higher risk of severe COVID-19 disease. Africa is especially vulnerable in this respect given the 
high prevalence of HIV/AIDS in countries such as Kenya where the prevalence is over 20% in some places.  
The risk of recurring new waves of COVID-19 cases caused by Variants of Concern (VOC) exacerbate global 
public health crisis. A weak immune response to either single or two doses of primary vaccination against 
SARS-CoV-2 has been observed in immunocompromised population. Emerging data from observational 
studies consistently show waning immunity to primary vaccination for SARS-CoV-2 mutants, and a decline 
in vaccine effectiveness against SARS-CoV-2 infection and COVID-19 with time since primary vaccinations.  
These factors have led to consideration of the potential need for, and optimal timing of, booster doses for 
vaccinated populations. However, vaccine inequality, lack of availability of the same vaccine product used 
for primary vaccinations and unpredictable vaccine supply remain a challenge in LMIC. Consideration of 
heterologous COVID-19 vaccine to allow interchangeability (mix and match) use of vaccine products 
available in LMIC would therefore allow for programmatic flexibility. 
Based on a recent systematic review and meta-regression analysis, across the four WHO EUL COVID-19 
vaccines with the most data (i.e., BNT162b2, mRNA 1273, Ad26.COV2.S and ChAdOx1-S [recombinant] 
vaccine), vaccine effectiveness against severe COVID-19 decreased by about 8% (95% confidence interval 
(CI): 4-15%) over a period of 6 months in all age groups.  In adults above 50 years, vaccine effectiveness 
against severe disease decreased by about 10% (95% CI: 6 – 15%) over the same period.  Vaccine 
effectiveness against symptomatic disease decreased by 32% (95% CI: 11 – 69%) for those above 50 years 
of age. For some inactivated vaccines (CoronaVac and COVID-19 vaccine BIBP), WHO has already issued 
the recommendation for the administration of an additional dose to those aged 60 years or older as part 
of the primary series to make initial immunity more robust. 
The FDA issued a EUA for the Janssen Ad26.COV.S1 COVID-19 vaccine for active immunization to prevent 
COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. In September 2021, both the 
single dose and 2 dose Janssen COVID-19 vaccine regimens demonstrated high efficacy (79% protection 

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(CI, 77%-80%) for COVID-19-related infections and 81 percent (CI, 79%-84%) for COVID-19-related 
hospitalizations. vs 94% (CI, 58%-100%) protection against symptomatic COVID-19 in the U.S. respectively. 
Furthermore, the safety profile of the vaccine remained consistent and generally well-tolerated in the 2 
regimens. Finally, when a booster of the Janssen COVID-19 vaccine given 6 months after the single shot, 
antibody levels increased nine-fold one week after the booster and continued to climb to 12-fold higher 
four weeks after the booster. 
On June 14, 2021, Novavax reported the results of its PREVENT-19 pivotal Phase 3 trial of the NVX-
CoV2373. The results showed an overall vaccine efficacy of 90.4% (95% CI: 82.9 – 94.6) in the US and 
Mexico. Sequenced data showed a vaccine efficacy was 93.2% (95% CI: 83.9 – 97.1) against Variants of 
Concern and Variants of Interest which represented 82% of cases. Studies of NVX-CoV2373 with Matrix-
M adjuvant have demonstrated an acceptable safety and reactogenicity profile in adults ≥18 years of age. 
On December 20, 2021, the WHO issued interim recommendations and authorized under its emergency 
use listing (EUL) procedure, the NVX-CoV2373 COVID-19 vaccine developed by Novavax and Serum 
Institute of India.  
The pivotal phase 3 registration trial of the Moderna mRNA-1273 COVID-19 vaccine was conducted in the 
United States of America and involved about 30 000 participants aged 18 years or older with no known 
history of SARS-CoV-2 infection. Efficacy was evaluated for those subjects who received the second dose 
21-42 days after the first dose. Vaccine efficacy (VE) was estimated as 94.1% (95% confidence interval (CI) 
89.3–96.8%). In the phase 3 trial, the safety data supported a favorable safety profile. Reactogenicity 
symptoms, defined as solicited local injection site or systemic reactions during the seven days after 
vaccination, were frequent, mostly mild to moderate and short-lived after dosing for both adult age 
groups. The vaccine’s AE profile did not suggest any specific safety concerns (WHO SAGE, 2021). The US 
CDC and FDA recommend that adolescents age 12 to 17 years old can receive a 3rd primary series at least 
4 weeks after the 2nd dose and 4th booster shot at least 2 months after their last dose (CDC 2022). 
The phase 2/3 pivotal registration trial of the BNT162b2 (Pfizer-BioNTech) vaccine was conducted at sites 
in six countries (Argentina, Brazil, Germany, South Africa, Turkey and the USA) and involved about 43 000 
participants aged 16 to 85 years. The estimated vaccine efficacy (VE) was 94.6% (95% credibility interval 
(CI) 89.9–97.3%). Reactogenicity and adverse events associated with the vaccine were generally milder 
and less frequent in the older group (≥55 years of age) than the younger group (18–55 years of age) and 
tended to increase after the second dose. Reactogenicity was mostly mild to moderate and short-lived for 
both adult age groups (WHO SAGE, 2021). The WHO SAGE approved BNT162b2 (Pfizer-BioNTech) vaccines 
for children aged 6 months and older, having met the necessary criteria for safety and efficacy for 
administration (WHO SAGE, 2022). On 5th January 2022, the US CDC endorsed the Advisory Committee on 
Immunization Practices’ (ACIP) recommendation to expand eligibility of booster doses to those 12 to 15 
years old. CDC recommended that adolescents age 12 to 17 years old should receive a booster shot 5 
months after their initial Pfizer-BioNTech vaccination series. ACIP reviewed the available safety data 
following the administration of over 25 million vaccine doses in adolescents; COVID-19 vaccines are safe 
and effective (CDC 2022). 

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The FDA and WHO have both recommended continued evaluation of vaccine effectiveness following 
issuance of a EUA and/or licensure which is critical to address the existing uncertainties, with high urgency 
to understand homologous and heterologous boosting, both for improved coverage of variants of concern 
and due to limitations of global vaccine availability. The VIBRI Consortium proposes to carry out a Multi-
Centre Phase 2b RCT to evaluate the Safety and Immunogenicity of the Janssen Ad26COVS1, the Novavax 
NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines used as homologous and 
heterologous boost strategies among HIV positive adolescents and adults with a small control arm of HIV 
(-) participants. The trial will enroll up to 300 HIV (+) adolescents 12 to 17 years and about 1,650 adults 
aged 18 to 64 years (of which 1350 will be HIV (+) and 300 HIV (-), who have completed a primary series 
with a homologous vaccine series based on any one vaccine platform of a) mRNA (Moderna or Pfizer), b) 
adenovirus 26 (J&J) or c) inactivated (Sinopharm or Sinovac).  These three have been the main vaccine 
platforms introduced across the three participating countries (Kenya, Democratic Republic of Congo and 
Rwanda) as of the current protocol. Participants must have completed the primary series at least 3 months 
prior to enrollment.  In Stage 1, the booster vaccines will be evaluated in adult participants 18-64 years 
while in Stage 2, the booster vaccines will be assessed in adolescents 12-17 years of age. 
Given the difference in vaccine rollout between countries, the timing of enrollment within each country 
is expected to stagger.  All adult participants will be randomized 1:1 within their primary vaccine platform 
to receive either a single dose of Janssen Ad26COVS1 vaccine or Novavax NVX-CoV2373 COVID-19 vaccine 
between 5 and 7 months from completion of their primary series. All adolescent participants will be 
randomized 1:1 within their primary vaccine platform to receive either a single dose of Novavax NVX-
CoV2373 COVID-19 vaccine or an mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccine ≥5 months after 
the primary series for adolescent participants. The booster vaccination interval for adolescents is 
consistent with new guidance from the US CDC/FDA and is reflective of real-world settings 
implementation of country MOH COVID-19 vaccination programs.  Due to the uncertainty of vaccine 
supply and to allow for adequate capture of participants, the pre-booster vaccination enrollment period 
may vary anywhere from -85 days to 0 days till the time of boost (Day 0).  
 

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1.2 LAY SUMMARY 
 
The Coronavirus (COVID-19 disease) is a worldwide illness that emerged in the human population in 
Wuhan City, Hubei Province, China in December 2019. As of Jan 2022, there are over 328 million SARS-
CoV-2 case worldwide and over 5.54 million deaths as a result of infection with SARS-CoV-2 (COVID-19). 
According to WHO Situation report obtained 17 January 2022, Africa has 7 million confirmed cases with 
over 160, 804 deaths. The COVID-19 pandemic has caused global suffering, mortality, and severe 
economic pressures. There is therefore a continued urgent global need to develop effective and safe 
vaccines and drugs to make them available at scale and equitably across all countries including in Africa.  
Despite the rapid successes in vaccine development, the WHO reports, and US Food and Drug 
Administration (FDA) reports written after assessing the COVID-19 vaccines for approval for Emergency 
Use, have shown that the COVID-19 vaccines require additional information which was not available from 
the big vaccine studies. For example, information on safety and how the primary and booster vaccines 
work in certain populations such as children and adolescents less than 18 years of age, pregnant women, 
and immunocompromised individuals like people with HIV/AIDS who are at higher risk of severe COVID-
19 disease is required. Africa is especially at risk given the high number of HIV/AIDS patients in countries 
like Kenya where some places the rate of HIV infection is over 20% like in western Kenya.  
Emerging new COVID-19 variants of concern have led to new waves of COVID-19 cases worldwide and 
caused public health problems. Some studies suggest that some individuals, especially those with 
immunosuppression who received either a single dose or two doses of primary vaccination against COVID-
19 developed only a weak immune response to the disease. Other studies have shown reducing immunity 
to primary vaccination against new cases of COVID-19 disease, and a declining vaccine effectiveness 
against COVID-19 from about 6 months after primary vaccinations. These factors have led to consideration 
of the need for booster doses for COVID-19 vaccinated populations.  
A few studies have shown that some of the WHO approved COVID-19 vaccine are more effective when a 
mix and match primary and boosting schedules is used by reduction in the number of severe COVID-19 
disease and hospital admissions. With emerging COVID-19 variants, vaccine constraints, and the need to 
achieve a broad immune response based on mix and match boosting strategies are currently being 
studied.  A need for additional studies to assess how effective the vaccines in the context of heterologous 
boost in immunocompromised populations continue to be existing gaps in medical information.  Because 
of limited supply of vaccines, lack of availability of the same vaccine product used for primary vaccinations 
and unpredictable vaccine supply in Low- and Middle-Income Countries (LMIC), use of COVID-19 vaccines 
to allow exchanged (mix and match) use of vaccines available in these countries would therefore address 
these challenges and allow flexibility within Ministry of Health vaccination programs. 
The VIBRI Consortium which brings together researchers from Kenya, Rwanda and the Democratic 
Republic of Congo plan to conduct a Phase 2 vaccine study in these three countries to assess safety, mix 
and match booster vaccination schedule, how long the immune responses last after the booster and 
monitoring for new COVID-19 cases after vaccination.   
 

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1.3 STUDY SCHEMA 
 
Study Schematic Overview: Stage 1: 1,350 Adults HIV (+) Age 18-64 years old & 300 Adults HIV (-) Age 18-64 years old - stratified 2:1 by age (18-44; 45-64)  
 
 
Eligibility Determination: Screen >1,650 Subjects 
 
 
 
 
 
 
↓  
 
 
 
↓  
 
 
 
 
 
Primary Vaccination Series 
 
 
MoH Vaccinated 
 
MoH Vaccinated 
 
MoH Vaccinated 
 
 
Group 1 – mRNA Vaccine Platform 
 
Group 2 – Adenovector Vaccine Platform 
 
Group 3 – Inactivated Vaccine Platform 
 
 
 Moderna vaccine or Pfizer vaccine  
 
Janssen Ad26.COV2.S vaccine 
 
Sinopharm or Sinovac vaccine 
 
 
2 Primary Doses 
 
Single Primary dose 
 
2 Primary Doses 
 
 
Screening Window -85 to 0 (Begins ≥3 months after MoH primary series completed) – (pre baseline immunogenicity sample if >30 days out from scheduled 
booster) 
 
 
Number of Subjects: 550 
 
Number of Subjects: 550 
 
Number of Subjects: 550 
 
 
Group 1a 
Group 1b 
 
Group 2a 
Group 2b 
 
Group 3a 
Group 3b 
 
 
450 HIV (+) 
100 HIV (-) 
 
450 HIV (+) 
100 HIV (-) 
 
450 HIV (+) 
100 HIV (-) 
 
 
Single-Dose Booster Vaccination Day 0 (-30 to Day 0 for baseline sample) Booster (5-7 months following completion of primary series) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 HIV (+) 
HIV (-) 
 
 HIV (+) 
HIV (-) 
 
 HIV (+) 
HIV (-) 
 
 
Group 1a 
NVX 
Group 1a 
Ad26 
Group 1b 
NVX 
Group 1b 
Ad26 
 
Group 2a 
NVX 
Group 2a 
Ad26 
Group 2b 
NVX 
Group 2b 
Ad26 
 
Group 3a 
NVX 
Group 3a 
Ad26 
Group 3b 
NVX 
Group 3b 
Ad26 
 
 
NVX-
CoV2373 
Ad26.COV2.
S 
NVX-
CoV2373 
Ad26.COV2.S 
 
NVX-
CoV2373 
Ad26.COV2.
S 
NVX-
CoV2373 
Ad26.COV2.S 
 
NVX-
CoV2373 
Ad26.COV2.
S 
NVX-
CoV2373 
Ad26.COV2.S 
 
 
225 subjects 
225 
subjects 
50 subjects 
50 subjects 
 
225 subjects 
225 
subjects 
50 subjects 
50 subjects 
 
225 
subjects 
225 
subjects 
50 subjects 
50 subjects 
 
 
↓ 
 
 
↓ 
 
↓ 
 
 
↓ 
 
↓ 
 
 
↓ 
 
 
Day 7 Reactogenicity; all Adverse events; Subset for CMI 
 
 
 
 
 
 
↓  
 
 
 
↓  
 
 
 
 
 
Day 28 Immunogenicity (serum and mucosal); All Adverse events 
 
 
 
 
 
 
↓  
 
 
 
↓  
 
 
 
 
 
Day 85 (+/- 15) Immunogenicity (serum); TEAE+AESI+SAE 
 
 
 
 
 
 
↓  
 
 
 
↓  
 
 
 
 
 
Month 6 (+/- 15) Immunogenicity (serum); AESI+SAE 
 
 
↓ 
 
 
↓ 
 
 
 
 
 
 
↓ 
 
 
↓ 
 
 
Month 12 (+/- 15) Immunogenicity (serum); AESI+SAE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 15-18 (+/- 15) Immunogenicity (serum); AESI+SAE 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
EOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Schematic Overview Stage 2: up to 300 Adolescents HIV (+) Age 12-17 years old 
 
 
Eligibility Determination: >300 Subjects 
 
 
 
↓ 
↓ 
 
 
↓ 
 
 
 
 
Primary Vaccination Series 
 
 
MoH Vaccinated 
 
 
 
mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
 
 
 
 
2 Primary Doses 
 
 
Screening -85 to 0 (after MoH primary series completed) – (pre baseline sample if >30 days out from scheduled booster) 
 
 
Number of Subjects: 300 
 
 
 
Single-Dose Booster Vaccination Day 0 (-30 to Day 0 for baseline sample) Booster (≥5 months following completion of primary series) 
 
 
 
 
 
 
 
 
 
 
 
 
 HIV (+) 
 
 HIV (+)  
 
 
Group 1 
 
Group 2  
 
 
Novavax NVX-CoV2373 
 
mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
 
 
150 
 
150 
 
 
↓ 
 
 
↓ 
 
 
↓ 
 
 
 
Day 7 Reactogenicity; all Adverse events 
 
 
 
 
↓ 
 
 
↓ 
 
 
 
 
Day 28 Immunity (serum and mucosal); All Adverse events 
 
 
 
 
↓ 
 
 
↓ 
 
 
 
 
Day 85 (+/- 15) Immunity (serum); TEAE+AESI+SAE 
 
 
 
 
↓ 
 
 
↓ 
 
 
 
 
Month 6 (+/- 15) Immunity (serum); AESI+SAE 
 
 
↓ 
 
 
↓ 
 
 
 
 
 
 
Month 12 (+/- 15) Immunity (serum); AESI+SAE 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
 
 
a Currently MoH vaccination is only occurring with mRNA vaccines.   
 
 
 

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1.4 SCHEDULE OF EVENTS (SOE) 
 
Table 1: Study Schedule of Events 
Activity 
Screening 
Period 
Treatment Period 
Booster Vaccination & 
Follow-up Period (Days) 
Follow up Period 
(months) 
Study Day/Month 
–85 to 0 
0 
7 
28 
85 
6 
12 
15-18 
Window (days) 
7 
0 
+7 
+7 
+15 
± 15 
±15 
± 15 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
x 
Demographics 
x 
Vital Signs measurements (Temp, Heart 
Rate, Respiratory Rate & BP)g 
x 
xaxb 
x 
x 
x 
x 
x 
x 
Medical history 
x 
xa 
 
 
 
 
 
 
Physical examination 
x 
xc 
xc 
xc 
xc 
xc 
xc 
xc 
Primary vaccination series recorded for 
SARS-COV-2 
x 
 
 
 
 
 
 
 
Concomitant medications & vaccinations 
xd 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test (WOCBP) 
x 
xa 
 
 
 
 
 
 
FSH (if needed for post-menopausal status 
confirmation) 
x 
 
 
 
 
 
 
 
HIV testing (2 mL)k 
x 
HIV viral load, and/or CD4+ Cell Count (2mL) 
– for HIV (+) individuals 
x 
x 
x 
x 
CBC, ALT, AST, Creatinine (4mL) 
x 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
xa 
Randomization 
xa 
Adult Booster Vaccination (Janssen 
Ad26.COV2.S1/Novavax NVX-CoV2373) 
x 
Adolescent Booster Vaccination (Novavax 
NVX-CoV2373 or mRNA (Moderna mRNA-
1273 or Pfizer/BNT) 
 
xj 
 
 
 
 
 
 
Immediate Reactogenicityg  
xb 
Participant diary distribution (7-day diary) 
x 
Participant diary review and collectiong 
x 
SARS-CoV-2 Rapid Antigen (Nasal Swab) 
xa 
x 
x 
x 
x 
x 
x 
Nasopharyngeal sample (PCR)e 
x 
x 
x 
x 
x 
x 
Monitoring (passive surveillance) for COVID-
19-like illnessh 
 
X 
COVID-19 daily diary self-directed diary (if 
X 

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12
rapid antigen test is positive)i 
Rapid positive SARS-CoV-2 retest or PCR 
10-14 days after each (+) test 
Blood sampling for SARS-CoV-2 
immunogenicity (ELISA) – IgG (5mL) 
xf 
xa 
x 
x 
x 
x 
x 
Blood sampling for SARS-CoV-2 
neutralization antibody assay (10mL) 
xf 
xa 
x 
x 
x 
x 
x 
Mucosal Immunity (ELISA) – secretory IgAj 
xa 
x 
CMI-Subset (20 mL)j  
xa 
x 
Unsolicited AEs  
xb 
x 
x 
TEAE attributed to vaccination  
xb 
x 
x 
x 
SAEs and AESIs 
xb 
x 
x 
x 
x 
x 
x 
End of Study (EOS) form completion 
xl 
x 
Abbreviations: AE = adverse event; AESI = adverse event(s) of special interest; CD4 = cluster of 
differentiation; CMI=Cell Mediated Immunity; COVID-19 = coronavirus disease 2019; ELISA = enzyme-
linked immunosorbent assay; FDA = United States Food and Drug Administration; HIV = human 
immunodeficiency virus; hACE2 = human angiotensin-converting enzyme 2; ID = identification; IgG = 
immunoglobulin G; TEAE = treatment emergent adverse event; PCR = polymerase chain reaction; SAE = 
serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WOCBP = 
women of childbearing potential. 
a   Pre-booster vaccination 
b   30-60 min following vaccination (Prior to discharge from clinic). All Adverse Events (e.g., unsolicited, 
TEAE, SAE and AESI) will be collected from Visit 2 following randomization and booster vaccination. 
c   Symptom targeted 
d   Record concomitant medications or vaccinations received in last 30 days (inclusive of current 
medication) 
e   If SARS-CoV-2 rapid antigen test is positive for passive surveillance/unscheduled visits. In all 
participants for active surveillance from visit 3-8.  
f    If 6 month booster is planned for > 30 days after enrollment 
g   FDA toxicity grading to be applied for purposes of analysis but not clinical significance.  In the case of 
vital signs in adolescents, only temperature will have FDA toxicity scoring applied.  
h   Subjects will be instructed to report any symptoms or exposure to SARS-CoV2 and be brought in for 
an unscheduled visit for SARS-CoV-2 Ag testing as well as scheduled testing. 
i   If SARS-CoV-2 Rapid Antigen test or PCR is (+) then subjects will be provided a COVID-19 illness 
symptom diary to be completed over 10 days.  An Unscheduled visit will be performed at 10-14 days 
where SARS-CoV-2 Rapid Antigen or PCR retesting will be performed and diary reviewed.  If subject 
remain symptomatic then another diary will be dispensed.  If subjects remain symptomatic OR have a 
positive SARS-COV-2 rapid antigen test or PCR then they will return in another 10 days (unscheduled 
visit).  Subject will continue to be followed until SARS-CoV-2 test is negative and subject is 
asymptomatic. 

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13
J   Adults participants in Kenya only. No more than 60 HIV (+) and 30 HIV (-) participants within each 
primary vaccine platform will contribute to CMI testing based on subjects agreeing at the time of 
consent (opting in). 
K HIV testing may be repeated at subsequent visits if clinically indicated but repeat not required per 
protocol. 
l Adolescent follow-up period will be up to 12 months post booster vaccination.  
j Monovalent or bivalent vaccines depending on MOH availability and supply. 
 

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1.5 PROTOCOL – KEY ROLES 
 
KEY ROLES 
Principal Investigator  
Dr. Lucas Otieno Tina, MBChB MSc. DLSHTM  
Director and Principal Investigator,  
Victoria Biomedical Research Institute, 
P.O. Box 7180-40100, Kisumu, Kenya 
Phone: + 254 720 597654 
Email: ltina@vibriafrica.org  
Principal Investigator 
Dr. Amos Ndhere, MBChB MS, 
Director and Principal Investigator,  
Victoria Biomedical Research Institute, 
P.O. Box 7180-40100, Kisumu, Kenya 
Phone: + 254 729 006300 
Email: andhere@vibriafrica.org  
Country Principal Investigator – 
Democratic Republic of Congo 
(DRC) 
Hypolite Muhindo, MD PhD,  
Principal Investigator, 
Department of Tropical Medicine, Faculty of Medicine, University of 
Kinshasa, Kinshasa, Democratic Republic of Congo (DRC) 
Email: hypolite.muhindo@unikin.ac.cd 
Country Principal Investigator - 
Rwanda 
Vincent Mutabazi, MD MSc,  
Principal Investigator, 
Rinda Ubuzima & University of Rwanda 
Email: mutabazivincent@gmail.com  
Sub-Investigators 
Dr. Walter Otieno, MBChB MMED, PhD,  
Victoria Biomedical Research Institute, 
P.O. Box 7180-40100, Kisumu, Kenya 
Dr. Dismas Oketch, MBChB MSc. Clinical Trials,  
Victoria Biomedical Research Institute, 
P.O. Box 7180-40100, Kisumu, Kenya 
Prof. Dr Junior Matangila Rika, MD MSc PhD 
Department of Tropical Medicine, Faculty of Medicine, University of 
Kinshasa, Kinshasa, Democratic Republic of Congo (DRC) 
Prof. Dr Vivi Maketa, MD PhD 
Department of Tropical Medicine, Faculty of Medicine, University of 
Kinshasa, Kinshasa, Democratic Republic of Congo (DRC) 
Prof. Dr. Patrick Mitashi, MD, PhD,  
Department of Tropical Medicine, Faculty of Medicine, University of 
Kinshasa, Kinshasa, Democratic Republic of Congo (DRC) 
Jean Claude Sumanyi,  
Rinda Ubuzima, CMHS/KG 11. Avenue 47 Remera Campus, PO. Box 
4560 Kigali-Rwanda 

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15
MD, Dr Muhoza Joel, MD 
Rinda Ubuzima, CMHS/KG 11. Avenue 47 Remera Campus, PO. Box 
4560 Kigali-Rwanda 
RBC:  TBD University of Rwanda: TBD, National Laboratory: TBD  
Rinda Ubuzima, CMHS/KG 11. Avenue 47 Remera Campus, PO. Box 
4560 Kigali-Rwanda 
Contact Person – Rinda 
Ubuzima, Rwanda 
Contact Person-RU Umulisa Marie Michele, MScs Oversight of field 
activities and Sub-Investigator, CMHS/KG 11. Avenue 47 Remera 
Campus, PO. Box 4560 Kigali-Rwanda Tel number: + 250 788302073/ 
+ 250 788439009  
Scientific Consultant 
Cheryl Keech, MD, PhD 
Infectious Disease Physician, 
Seattle, WA, USA 
Sponsor 
Dr. Lucas Otieno Tina, MBChB MSc. DLSHTM  
Director and Principal Investigator,  
Victoria Biomedical Research Institute, 
P.O. Box 7180-40100, Kisumu, Kenya 
Phone: + 254 720 597654 
Email: ltina@vibriafrica.org 
Sub-Grantee - CRO 
Victorine Adhiambo Owira, BA MPH 
Director Clinical Operations 
Africa Clinical Research Management Ltd (ACE Research), 
P.O. Box 3897-40100, 
Kisumu, Kenya  
Email: vowira@aceresearchafrica.com  
Funder 
Coalition for Epidemic Preparedness Innovations (CEPI)  
Marcus Thranes gate 2, 0473  
Oslo, Norway  
Data Management 
Jim Choi,  
Vice President of Business Development 
12410 Milestone Center Drive, Suite 600, Germantown, MD 20876 
+1.206.719.3645 Mobile  
Email: jim@crscube.io  
Immunology Laboratory  
CEPI Clinical Lab Network – ICDDR Bangladesh 
 
Dr. Lucas Otieno Tina and Dr. Amos Ndhere as Principal Investigators at Victoria Biomedical Research 
Institute will be the study sponsors and will be responsible for the overall conduct of the trial, 
administrative actions between the VIBRI Consortium members, and oversight of study activities. They 
both led the development of the study protocol and will lead the statistical analysis and writing of the 
scientific report(s). All Clinical Investigators listed above will be responsible for the clinical conduct of the 
trial, the care provided to patients, oversight of field activities, and will contribute to the statistical analysis 
and writing of scientific report(s). See Appendix I for detailed roles and responsibilities for this study. 

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2 INTRODUCTION 
2.1 BACKGROUND 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in the 
human population in Wuhan City, Hubei Province, China in December 2019. As of Jan 2022, there are over 
328 million SARS-CoV-2 case worldwide and over 5.54 million deaths as a result of infection with SARS-
CoV-2 (COVID-19). According to WHO Situation report obtained 17 January 2022, Africa has 7 million 
confirmed cases with over 160, 804 deaths (1). The COVID-19 pandemic has caused global suffering, 
mortality, and severe economic pressures (2). There is therefore a continued urgent global need to 
develop effective and safe vaccines and drugs to make them available at scale and equitably across all 
countries including in Africa.  
Despite the rapid successes in vaccine development, the WHO SAGE interim reports and FDA Emergency 
Use Authorization (EUA) for COVID-19 vaccine evaluations (3) have reported limitations on safety and 
efficacy data in certain populations including children and adolescents less than 18 years of age, pregnant 
women, and immunocompromised individuals such as those with HIV/AIDS who are at higher risk of 
severe COVID-19 disease. Africa is especially vulnerable in this respect given the high prevalence of 
HIV/AIDS in countries such as Kenya where the prevalence is over 20% in some places (4). In Kigali-Rwanda 
the prevalence estimate was 6% (5) and in the greater Kinshasa-DRC, prevalence was 11% (6). 
The risk of recurring new waves of COVID-19 cases caused by Variants of Concerns (VOC) exacerbate 
global public health crisis. A weak immune response to either single or two doses of primary vaccination 
against SARS-CoV-2 has been observed in immunocompromised population (7). Emerging data from 
observational studies consistently show waning immunity to primary vaccination or SARS-CoV-2 mutants, 
and a decline in vaccine effectiveness against SARS-CoV2 infection and COVID-19 with time since primary 
vaccinations (8). These factors have led to consideration of the potential need for, and optimal timing of, 
booster doses for vaccinated populations (9). However, vaccine inequality, lack of availability of the same 
vaccine product used for primary vaccinations and unpredictable vaccine supply remain a challenge in 
LMIC. Consideration of heterologous COVID-19 vaccine to allow interchangeability (mix and match) use 
of vaccine products available in LMIC would therefore allow for programmatic flexibility. 
Based on a recent systematic review and meta-regression analysis, across the four WHO EUL COVID-19 
vaccines with the most data (i.e., BNT162b2, mRNA 1273, Ad26.COV2.S and ChAdOx1-S [recombinant] 
vaccine), vaccine effectiveness against severe COVID-19 decreased by about 8% (95% confidence interval 
(CI): 4-15%) over a period of 6 months in all age groups.  In adults above 50 years, vaccine effectiveness 
against severe disease decreased by about 10% (95% CI: 6 – 15%) over the same period.  Vaccine 
effectiveness against symptomatic disease decreased by 32% (95% CI: 11 – 69%) for those above 50 years 
of age. For some inactivated vaccines, WHO has already issued the recommendation for the 
administration of an additional dose to those aged 60 years or older as part of the primary series to make 
initial immunity more robust (10).  

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The FDA issued a EUA for the Janssen Ad26.COV.S1 COVID-19 vaccine for active immunization to prevent 
COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older (11). In September 2021, both 
the single dose and 2 dose Janssen COVID-19 vaccine regimens demonstrated high efficacy (79% 
protection (CI, 77%-80%) for COVID-19-related infections and 81 percent (CI, 79%-84%) for COVID-19-
related hospitalizations. vs 94% (CI, 58%-100%) protection against symptomatic COVID-19 in the U.S. 
respectively. Furthermore, the safety profile of the vaccine remained consistent and generally well-
tolerated in the 2 regimens. Finally, when a booster of the Janssen COVID-19 vaccine given 6 months after 
the single shot, antibody levels increased nine-fold one week after the booster and continued to climb to 
12-fold higher four weeks after the booster (12). 
On June 14, 2021, Novavax reported the results of its PREVENT-19 pivotal Phase 3 trial of the NVX-
CoV2373. The results showed an overall vaccine efficacy of 90.4% (95% CI: 82.9 – 94.6) in the US and 
Mexico. Sequenced data showed a vaccine efficacy was 93.2% (95% CI: 83.9 – 97.1) against Variants of 
Concern and Variants of Interest which represented 82% of cases (13). Studies of NVX-CoV2373 with 
Matrix-M adjuvant have demonstrated an acceptable safety and reactogenicity profile in adults ≥18 years 
of age. On December 20, 2021, the European Medicines Agency issued its authorization (14), the WHO 
issued interim recommendations and authorized under its emergency use listing (EUL) procedure for the 
Novavax NVX-CoV2373 COVID-19 vaccine (15).  
The FDA and WHO have both recommended continued evaluation of vaccine effectiveness following 
issuance of a EUA and/or licensure which is critical to address the existing uncertainties, with high urgency 
to understand homologous and heterologous boosting, both for improved coverage of variants of concern 
and due to limitations of global vaccine availability. The VIBRI Consortium proposes to carry out a Multi-
Centre Phase 2b RCT to evaluate the Safety and Immunogenicity of the Janssen Ad26COVS1 and the 
Novavax NVX-CoV2373 used as homologous and heterologous boost strategies among HIV positive 
adolescents and adults with a small control arm of HIV (-) participants. The trial will enroll adolescents and 
adults aged 12 to 64 years, who have completed a primary series with a homologous vaccine series based 
on any one platform of a) mRNA (Moderna or Pfizer), b) adenovirus 26 (J&J) or c) inactivated (Sinopharm 
or Sinovac).  These three have been the main vaccine platforms introduced across the three participating 
countries (Kenya, Democratic Republic of Congo and Rwanda) as of the current protocol. Participants must 
have completed the primary series at least 3 months prior to enrollment. Given the difference in vaccine 
rollout between countries, the timing of enrollment within each country is expected to stagger.  
This study will be a multi-centre, randomized, double-blind, phase 2b trial to assess the safety, and 
immunogenicity of Janssen Ad.26COV2.S1 and Novavax NVX-CoV2373 booster vaccines in adults 18-64 
years of age and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT)) vaccine in 
adolescents 12-17 years of age.  Adolescent enrollment will be staggered to allow for an initial safety 
assessment in a sub-set of 300 HIV (+) adults before enrollment. The safety of the booster vaccines will 
be evaluated by the Data Safety Monitoring Board (DSMB) in the first 300 HIV (+) adult participants 18-64 
years through day 28 (Visit 4).  Once the DMSB provides their assessment of an acceptable safety in this 
subset of adult subjects, then adolescents may begin enrollment.   

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Using a block randomization approach based on primary vaccine platform, approximately equal number 
of adult participants from each primary platform (mRNA, Adeno26, inactivated) will be enrolled to achieve 
a total of 1,350 HIV (+) participants (n~ 450/primary platform) and 300 HIV (-) participants (n~ 100/primary 
platform).  Adults will be stratified 2:1 by age (18-44; 45-64) within each primary platform with a goal of 
2:1:1 distribution of all adults across Kenya, Democratic Republic of Congo (DRC) and Rwanda. However, 
adjustments for country level enrollment may be needed to achieve the age strata and the primary 
vaccine series distribution and study enrollment target.  
As adolescents may not have received similar vaccine distribution as adults.  Therefore, a minimum 
number of 150 adolescents across at least one (1) primary platform will be enrolled and a maximum of 
300 subjects could be enrolled. The primary vaccine group for the adolescent cohort at this point in the 3 
countries is the mRNA Platform, specifically Pfizer vaccine and therefore at least 150 enrolled subjects are 
possible.  
2.2 STUDY RATIONALE 
 
As of Jan 2022, there are over 328 million SARS-CoV-2 case worldwide and over 5.54 million deaths as a 
result of infection with SARS-CoV-2 (COVID-19). According to WHO Situation report obtained 17 January 
2022, Africa has 7 million confirmed cases with over 160, 804 deaths. The COVID-19 pandemic has caused 
global suffering, mortality, and severe economic pressures.  
 
The FDA and WHO have both recommended that continued evaluation of vaccine effectiveness following 
issuance of Emergency Use Authorization (EUA) and/or licensure and WHO listing of COVID-19 vaccines. 
This is critical to address the data gaps that exist despite the rapid successes in vaccine development. 
WHO SAGE Interim Reports and FDA EUA for COVID-19 vaccines so far evaluated have stated there is 
limited safety and efficacy data in special populations such as children and adolescents less than 18 years 
of age, pregnant women, and immunocompromised individuals including People Living With HIV/AIDS 
(PLWHA) who have been shown to be at higher risk of severe COVID-19 disease. Africa is especially 
vulnerable in this respect given the high prevalence of HIV/AIDS in countries such as Kenya where the 
prevalence is more than 20% in certain regions (KENPHIA) 2018). In Kigali, Rwanda the prevalence 
estimate was 6% (UNAIDS 2017) and in the greater Kinshasa-DRC, prevalence was 11% (Pour M, et al. 
2020). 
 
The risk of recurring new waves of COVID-19 cases caused by Variants of Concerns (VOC) exacerbate 
global public health crisis. A weak immune response to either single or two doses of primary vaccination 
against SARS-CoV-2 has been observed in immunocompromised population. Emerging data from 
observational studies consistently show waning immunity to primary vaccination or SARS-CoV-2 mutants, 
and a decline in vaccine effectiveness against SARS-CoV2 infection and COVID-19 with time since primary 
vaccinations. These factors have led to consideration of the potential need for, and optimal timing of, 
booster doses for vaccinated populations. Vaccine inequality, lack of availability of the same vaccine 
product used for primary vaccinations and unpredictable vaccine supply remain a challenge in LMIC. 

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Consideration of heterologous COVID-19 vaccine to allow interchangeability (mix and match) use of 
vaccine products available in LMIC would therefore allow for programmatic flexibility. 
The FDA and WHO have both recommended continued evaluation of vaccine effectiveness following 
issuance of a EUA and/or licensure which is critical to address the existing uncertainties, with high urgency 
to understand homologous and heterologous boosting, both for improved coverage of variants of concern 
and due to limitations of global vaccine availability. The VIBRI Consortium proposes to carry out a Multi-
Centre Phase 2b RCT to evaluate the Safety and Immunogenicity of the Janssen Ad26COVS1 and the 
Novavax NVX-CoV2373 used as homologous and heterologous boost strategies among HIV positive 
adolescents and adults with a small control arm of HIV (-) participants. The trial will enroll adolescents and 
adults aged 12 to 64 years, who have completed a primary series with a homologous vaccine series based 
on any one vaccine platform of a) mRNA (Moderna or Pfizer), b) adenovirus 26 (J&J) or c) inactivated 
(Sinopharm or Sinovac).  These three have been the main vaccine platforms introduced across the three 
participating countries (Kenya, Democratic Republic of Congo and Rwanda) as of the current protocol. 
Participants must have completed the primary series at least 3 months prior to enrollment. The study has 
been justified based on the WHO Strategic Advisory Group of Experts (SAGE). Beyond that, the issues of 
homologous and heterologous vaccinations are known to influence booster vaccine choice. It is therefore 
important to understand the  mix and match  aspect of booster vaccination in order to generate data that 
could be used to inform policy in these countries. In addition, to address expanded access and equitable 
COVID-19 and disruption in vaccine supplies, it’s important for African countries to evaluate different 
COVID-19 boosting regimens as a strategy to ensure sustainability of its COVID-19 vaccination programs.  
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
 
The following potential risks will be monitored during the study and are specified below: 
 
2.3.1.1 Risks Related to Vaccination 
 
Several clinical studies of the Janssen COVID-19 vaccine have been conducted in more than 70,000 adult 
participants worldwide. On 2nd April 2021, Janssen started enrolling adolescents 12-17 years into a new 
adolescent clinical study. The Novavax COVID-19 vaccine has been evaluated in several clinical studies in 
adults with more than 50,000 participants taking part. 
 
In general, intramuscular (IM) injection may cause local itching, warmth, pain, tenderness, erythema, 
swelling, arm discomfort or bruising of the skin at vaccine injection sites. In addition, participants may 
experience headache, chills, joint pain, muscle pain, tiredness, generally not feeling well, nausea and 
fever have been seen with these study vaccines. These reactions usually start within 1 to 2 days after the 
injection and most of the reactions get better within 1 to 3 days.    
 

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More detailed relevant information about potential risks are provided in the Investigator’s Brochures for 
the Janssen Ad26COVS1 and Novavax NVX-CoV2373 vaccines.  
 
2.3.1.2 Risks of accidental disclosure of Personal Health Information (PHI) 
 
In order to ensure that all information collected on study volunteers is kept confidential, the following 
safeguards will be applied: Access to study files and personal information will be limited to study 
personnel, ethics committees, regulatory authorities, the sponsor and sponsor representatives. Study 
information will be kept in locked rooms at the site when not in use. All information or samples that leave 
the study sites will be labeled with a unique study identification number and have no personal identifying 
information (PII). Any link between individual study identification number and an individual’s PII (e.g., an 
individual’s study file and associated documents) will be maintained at the study sites in accordance with 
site SOPs to maintain each individual’s confidentiality. 
 
There may be additional risks associated with disclosure of participants’ COVID-19 and HIV status as well 
as disclosure of any abnormal lab tests found during screening, and careful measures will be taken to 
ensure confidentiality is maintained. Participants who are tested will undergo pre- and post-test 
counseling in accordance with respective National Guidelines.  Standard pre-testing and post-testing 
counseling and linking to care will be followed. In the event that a participant is diagnosed with SARS-CoV-
2 infection, the testing laboratory will report the result to the respective National Ministry of Health as 
per the guidelines on COVID-19. To the greatest extent possible, abnormal tests will be communicated to 
participants and screen failures in simplified language and referrals made to health care provider as 
appropriate. 
  
2.3.1.3 Risk of Injury as a result of participation in the study 
If a participant is injured as a direct result of participation in this study, the medical care will be provided 
by the study team at the respective study sites or will be referred appropriately to a hospital or health 
care provider, and the study will pay for the expenses. The participant will be compensated using the 
clinical trial insurance obtained for this trial.  
 
2.3.1.4. Risk of phlebotomy and mucosal secretion sampling 
 
Venipuncture is a routine clinical procedure the medical community commonly uses to obtain blood 
samples. Immediate complications may be slight pain during the entry of the needle into the skin, very 
rarely possible dizziness, and syncope. Additionally, a hematoma may result from the venipuncture, but 
this has minimal risk. Infection of the skin/soft tissue at the puncture site, vein, or blood stream can all 
occur, though are very rare with venous blood draws. Late complications might include thrombosis of the 
vein due to trauma or infection. These complications are extremely rare. Participant monitoring, aseptic 
technique, including sterile disposable blood collection apparatus and adherence to standard medical 
precautions reduce any risk to a minimum. A credentialed phlebotomist or member of the clinical team 
experienced in venipuncture techniques will perform all venipunctures. The amount of blood to be taken 

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21 
 
for sampling will not be harmful to the participant’s health.  When appropriate for adolescents, a numbing 
cream or spray may be used to reduce discomfort.  
 
Sampling of mucosal secretions is a standard procedure and during COVID has been successfully 
completed without medical supervision.  Nasosorption™ FX·I is a nasal sampling device which uses a 
synthetic absorptive matrix (SAM™) swab to gently absorb mucosal lining fluid from the mucosa within 
the nose.  It is designed for targeted sampling with minimal patient discomfort.  The device will be shown 
to participants and the procedure explained before sampling is performed.  Inspection of the nasal cavity 
to confirm no obstruction, ulcers or masses are present.  Sampling may cause sneezing, rarely irritation 
and 
very 
rarely 
nose 
bleeds.    
 
2.3.1.5 Unknown Risks 
There may be other risks that are not known. If any significant new risks are identified, the Principal 
Investigator and participants (parents/guardians) will be informed. 
2.3.2 KNOWN POTENTIAL BENEFITS 
All volunteers for this study will receive the following benefits for their participation: 
• 
All volunteers will undergo a medical examination at screening free of charge. All volunteers, 
whether accepted for enrolment into the trial or not will benefit from this free health check-up. 
The results of all tests will be communicated to all volunteers. Where illnesses are newly- 
diagnosed, a referral to an appropriate health provider will be made for the volunteer. 
• 
For the duration of their participation in the trial, study participants will receive health care for 
acute conditions. In case of chronic conditions, participant will be referred to appropriate health 
providers. 
• 
All volunteers in the study will receive a SARS-CoV-2 vaccine booster that have been shown to 
protect against severe SARS-CoV-2.   
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
 Based on the available data and proposed safety measures, the overall benefit/risk assessment for this 
clinical study is considered acceptable for the following reasons: 
• 
To date, safety data from the COVID-19 vaccine studies have shown a favorable safety profile.  
There are ongoing trials and long-term safety follow up after issuance of EUA that will add to the 
evidence of safety of the study vaccines during the course of the study.  Any new safety 
information on either vaccine used in the study will be provided to all participants in 
appropriate level of understanding to ensure informed consent remains in place.  
• 
The study provides for pausing rules based predefine safety outcomes that will result in pausing 
of further vaccination if predefined conditions occur, preventing exposure of new participants to 
study intervention until a DSMB evaluates all safety data. 

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• 
Enrollment of participants will be determined by the study investigators where only participants 
who meet eligibility Criteria will be considered for enrollment.  
• 
Safety measures have been included in the protocol to minimize the potential risk to 
participants, including the following: 
a. Post vaccination observation to monitor reactogenicity at the study site for 30-60 
minutes  
b. Clinical (physical examinations +/- vital sign measurements) will be performed during 
study visits based on medical need.  
c. As part of safety follow up, the study team will assess adverse events (Solicited Adverse 
Events, Unsolicited Adverse Events, Treatment Emergent Adverse Events (TEAE), Serious 
Adverse Events (SAE), and AESI) through various timeframes. 
• 
Monitoring for breakthrough COVID-19 cases (along with symptoms and severity scoring) will 
occur throughout the duration of the study.  
• 
During the study, participants will be monitored for acute illnesses and managed in accordance 
with country specific standard of care. 

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3 OBJECTIVES AND ENDPOINTS 
3.1 PRIMARY OBJECTIVES 
3.1.1.    PRIMARY SAFETY OBJECTIVES 
  
Objectives 
Endpoints 
To evaluate reactogenicity (solicited adverse 
events (AEs) Ad26.COV2S1 and NVX-CoV2373 
for adults or for adults or NVX-CoV2373 vs 
mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
vaccine for adolescents following boosting.   
Occurrence of solicited AEs (local and systemic) 
reactogenicity events through 7 days following boosting 
vaccination.  Analysis to include by HIV status, age 
group, booster treatment group, homologous and 
heterologous vaccination series (primary platform + 
boosted vaccine).  
To evaluate Serious Adverse Events related to 
vaccination of Ad26.COV2S1 or NVX-CoV2373 
for adults or NVX-CoV2373 vs mRNA 
(Moderna mRNA-1273 or Pfizer/BNT) vaccine 
for adolescents during the entire study.  
Incidence of vaccine related Serious Adverse Events 
(SAEs) throughout the study period. Analysis to include 
by HIV status, age group, booster treatment group, 
homologous and heterologous vaccination series 
(primary platform + boosted vaccine). 
3.1.2.    PRIMARY IMMUNOGENICITY OBJECTIVE 
  
Objective 
Endpoints 
To 
evaluate 
the 
immunogenicity 
of 
Ad26.COV2S1 and NVX-CoV2373 vaccines 
for adults or NVX-CoV2373 vs mRNA 
(Moderna 
mRNA-1273 
or 
Pfizer/BNT) 
vaccine for adolescents at day 28  
 
1. SARS-CoV-2 neutralization: SARS-CoV-2 neutralizing 
titers in serum measured by a virus neutralization assay 
(VNA) using pseudovirion expressing S protein 
(standardized to 50% neutralization with 95% CI).  
2. Serum IgG antibodies to SARS-CoV-2 rS protein 
measured by enzyme-linked immunosorbent assay 
(ELISA) using geometric mean titers (GMT with 95% CI).  
3. Geometric mean fold ratio over baseline (IgG and VNA). 
Analysis to include by HIV status, age group and booster 
treatment group (Ad26.COV2S1 or NVX-CoV2373) or mRNA 
(Moderna mRNA-1273 or Pfizer/BNT) vaccine 
3.2 SECONDARY OBJECTIVES 
3.2.1.    SECONDARY SAFETY OBJECTIVES 
 
Objectives  
Endpoints 
To evaluate all unsolicited AEs post-
vaccination through 28 days and 
Treatment Emergent Adverse Events 
(TEAEs) through day 85 in all participants. 
Incidence of unsolicited AEs and TEAEs by MedDRA coding 
(high ordered term and preferred term), severity and 
relatedness.  Analysis to include by HIV status, age group, 
booster treatment group, homologous and heterologous 
vaccination series (primary platform + boosted vaccine). 

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To evaluate safety in terms of Adverse 
Events of Special Interest (AESIs) 
following vaccination, for all participants 
through end of study.  
Incidence of AESIs for all participants following vaccination 
through the EOS. Analysis to include by HIV status, age group, 
booster treatment group, and primary vaccination 
platform/series. AESI will be assessed as Potential Immune 
Mediated Medical Conditions (PIMMC) or events deemed of 
special interest by COVID-19 disease.  
To describe Serious Adverse Events 
(SAEs) through end of study in all 
participants. 
Analysis to include by HIV status, age group, booster 
treatment group, and primary vaccination platform/series.  
 
3.2.2.    SECONDARY IMMUNOGENICITY OBJECTIVES 
 
Objectives  
Endpoints 
To compare the immunogenicity of 
heterologous boost in participants at Day 
28 (IgG ELISA and neutralization) 
Means and 95% CI for VNA, GMT, geometric mean fold rise 
(GMFR) from baseline to Day 28.   Analysis to include by 
HIV status, age group, treatment group, adolescents 
boosted at ≥5-12 or >12 months and primary vaccination 
series/platform.   
To compare the durability of response 
through end of study (IgG ELISA and 
neutralization) 
Mean and 95% CI for VNA, GMT, geometric mean fold rise 
(GMFR) at each study visit.  Analysis to include by HIV 
status, age group, treatment group, adolescents boosted at 
≥5-12 or >12 months and primary vaccination 
series/platform.  
To evaluate mucosal immunogenicity of 
homologous and heterologous boost in 
participants at Day 28 (S-IgA ELISA).  
Mucosal secretory (S-IgA) to SARS-CoV-2 rS protein 
measured by enzyme-linked immunosorbent assay (ELISA) 
using geometric mean titers (GMT) and GMFR at Day 28. 
Analysis to include by HIV status, age group, treatment 
group, and primary vaccination series/platform.  
 
3.3 EXPLORATORY OBJECTIVES 
 
Objectives 
Endpoints 
To evaluate the occurrence SARS-CoV-2 
infection and level of severity in 
participants  
Incidence of rapid antigen and virologically confirmed 
SARS-CoV-2 starting at Day 28 through EOS in all 
participants, by subject reported symptomatology, duration 
and severity.   Classification as asymptomatic, mild, 
moderate or severe along with analysis of symptomatology 
(type/duration) and time to symptom resolution and time 
to negative rapid Ag test will be derived.   Analysis to 
include HIV status, age group, booster treatment group, 
and vaccination platform/series. 
To evaluate the occurrence SARS-CoV-2 
infection variants of concern in all 
participants with moderate to severe 
disease following booster vaccination.   
Incidence of virologically confirmed SARS-CoV-2 variants of 
concern (e.g., B.1.351, B.1.1.7, B.1.617, B.1.1.529, or others 
to be identified as the pandemic evolves)-COVID-19, 
starting at Day 28 through EOS in participants who develop 

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moderate or severe COVID-19 disease.   Analysis to include 
HIV status, age group, booster treatment group, 
vaccination platform/series and SARS-CoV-2 severity grade.  
To evaluate the Cell Mediated Immune 
response of Ad26.COV2S1 and NVX-
CoV2373 vaccines in adults HIV (+) and HIV 
(-) participants  
SARS-CoV-2 Cell Mediated Immunity in Peripheral 
Mononuclear Cells (PBMCs) as measured by ELISPOT at 
baseline and on Day 7 following boost. Analysis to include 
boost treatment group and primary vaccination 
platform/series.   
To identify a threshold of immune 
protection for HIV (+) and HIV (-) 
participants to prevent SARS-CoV-2 
infection following booster vaccination.  
Analysis of breakthrough cases with GMT and VNA levels to 
determine a potential threshold of protection (through 
EOS).  
To assess if changes in control of HIV 
infection (by viral loads and CD4 counts) 
has an effect on immune responses or 
breakthrough SARS-CoV-2 infection 
rates/severity during the trial  
Assessment of changes in HIV viral loads and CD4 counts 
during long term immune durability within HIV subjects (by 
booster and by primary vaccination platform). 
 
 
 

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4 STUDY DESIGN 
4.1 STUDY SETTING 
4.1.1 VICTORIA BIOMEDICAL RESEARCH INSTITUTE, KENYA 
 
Victoria Biomedical Research Institute (VIBRI) is a non-profit organization based in Kenya providing 
pharmaceutical, academic research, and non-profit organizations with a network of clinical sites and 
expertise focusing on accelerating transformative therapeutics, vaccines, and devices research for major 
global health diseases in Africa. VIBRI is located at the Kisumu County Referral Hospital in Kisumu County, 
western Kenya (see Figure 1 below).   
 
Figure 1: Map of Kenya showing Kisumu County. 
 
VIBRI was established to conduct biomedical research including clinical trials, bioequivalence studies, 
basic science research studies, epidemiology and population health studies, implementation science 
studies, build a strong foundation in data science, conduct training and capacity building on clinical 
research in Kenya. VIBRI has experienced and accomplished clinical research scientists who have designed 

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and conducted GCP compliant phase 1b to phase IV paediatric and adult clinical trials on vaccines and 
drugs for different indications including malaria, HIV, tuberculosis, diarrhea, sickle cell disease, ebola, 
pneumonia, polio among many others. The VIBRI Clinical Trials site will conduct trial activities out of the 
Kisumu County Referral Hospital and surrounding health facilities. The staff and infrastructure can serve 
several satellite sites for reaching high-risk populations from Kisumu City. All members of the clinical trial 
team are trained in GCP and Human Participants Protection. The research team has a close affiliation with 
the Kenya Ministry of Health at the county and national levels and with the personnel working in the 
Ministry of Health facilities within the study area. Trained VIBRI staff and Ministry of Health Community 
Health Workers will assist with study activities conducted in the field and in satellite facilities. 
 
Kisumu County is one of 47 counties in the Republic of Kenya. Its headquarters is Kisumu City which is the 
third largest city in Kenya. It has a population of 1,155,574 (Kenya National Bureau of Statistics, 2019). 
The land area of Kisumu County totals 2085.9 km2. The county has a shoreline on Lake Victoria, occupying 
northern, western and a part of the southern shores of the Winam Gulf. The city of Kisumu has historically 
functioned as a major center of Western Kenya commerce. Health in Kisumu County is provided by several 
institutions that are either private or government funded. There is one teaching and referral hospital, 5 
County referral hospitals, 14 sub-county hospitals, 74 dispensaries and 18 health centres in the county.  
4.1.2 RINDA UBUZIMA/UNIVERSITY OF RWANDA, RWANDA 
 
In Rwanda, the study will be carried out by Rinda Ubuzima, a Non-Governmental Organization which is 
housed within the University of Rwanda. Rinda Ubuzima is the continuation of the former Project 
Ubuzima; an International Non-Governmental Organization founded in 2004 in Amsterdam by members 
of Management Team of the International Antiviral Therapy Evaluation Center (IATEC). Rinda Ubuzima 
has more than 15 years of experience in the field of clinical trials marked by intensive capacity building 
and acquisition of clinic and laboratory equipment. Rinda Ubuzima is operating Clinical Trials and 
Laboratory Research in Kigali and has successfully implemented various studies, focusing on HIV, 
Reproductive Health and Malaria. In addition to the clinical trial activities, Rinda Ubuzima has extended 
its area of expertise to include conducting and implementing community engagement and outreach 
activities as well as social science.  
   
To achieve its mission, Rinda Ubuzima has fixed itself the following objectives: 
• 
To collaborate with researchers from all over the world (Africa, Europe, Asia, North and South 
America) to support medical research in Rwanda. 
• 
To conduct/implement the clinical trials and other studies to move medicine forward, through 
medical and global health research. 
• 
To contribute to capacity building in clinical trials and social sciences activities.  
• 
To conduct health promotion activities through community engagement and outreach, respecting 
the GPP (Good Participatory Practice). 
• 
To closely collaborate with University of Rwanda in implementing public health issues. 
• 
To closely collaborate with Rwanda Ministry of Health in clinical trials issues. 
 

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Rwanda is a small mountainous and land locked country of 26,338 square kilometers and lying just south 
of the equator with an average elevation of 1,700 meters. Approximately 76 percent of the land is fit for 
cultivation. Rwanda’s population is growing rapidly with implication on the demographic situation. The 
most recent population census conducted in 2012 estimated the population to be around 10.5 million 
people and the population density is the highest in Sub-Saharan Africa (416 inhabitants per square 
kilometer). The population is essentially young, with 52 percent of all Rwandans under the age of 20. In 
terms of gender, the 2012 census shows females to be in the majority (52 percent) of the population 
(NISR, 2012). The illiteracy rate declined from 34 percent to 15.5 percent among women and from 24 
percent to 10.3 percent among men between 2005 and 2010 (DHS 2005 and 2010).  
 
In the last 20 years, the Government of Rwanda (GoR) successfully designed and implemented a broad 
set of policies and programs of economic reform and decentralization to enhance local capacity. Rwanda 
is committed to the international and regional agreements for which it is a signatory such as the SDGs. 
Efforts have been made to develop the service sector and stimulate investment in the industrial sector; 
however, the Rwandan economy remains dominated by agriculture. The health sector has a crucial role 
to play in the achievement of the national mid-term Economic Development and Poverty Reduction 
Strategy (EDPRS 2) goal of 11.5% economic growth rate. Continuous progress in the coverage and quality 
of promotive, preventive, curative and rehabilitative health interventions and in the health seeking 
behavior of the population ensure improvements in the health status and productivity of the Rwandan 
population. Availability of high-quality health services, as an important element of the service sector, 
contributes to the generation of collective wealth and is crucial to attracting investors and tourists. 
4.1.3 UNIVERSITY OF KINSHASA (UNIKIN), THE DEMOCRATIC REPUBLIC OF CONGO (DRC) 
 
In the DRC, the study will be carried out by the Department of Tropical Medicine, Faculty of Medicine at 
the University of Kinshasa (UNIKIN). This department has three missions:  training of doctors in the field 
of infectious and parasitic diseases, research and services in the community (health care). The department 
of tropical medicine collaborates with several disease control programs of the Ministry of Health and the 
National Biomedical Research Institute. As such, these members participate as experts in several health 
projects. Department staff play an important role in changing health policies and generating evidence for 
the Ministry of Health. The Ministry of Health through the General Secretary of Health recommends every 
two years about twenty doctors for specialization training in the field of tropical medicine. The members 
of the Department are skilled in design and implementation of studies in the remote areas in the DRC, 
where the conditions are challenging. The Department of Tropical Medicine has a clinical research unit 
which has conducted, with the support of some international organizations (DGD, EDCTP, FIND, VLIR, IMI, 
etc.) several research studies on malaria, human African trypanosomiasis, schistosomiasis, cervical cancer, 
Ebola viral disease, etc. The clinical research unit was strengthened by a long-lasting and fruitful 
collaboration with the Global Health Institute of the University of Antwerp. 
 
The Democratic Republic of Congo (DRC) is the largest country in Sub-Saharan Africa.  After more than 
three decades, the Democratic Republic of the Congo (DRC) adopted a Constitution that enshrined a highly 
decentralized state. Parliaments and governments were established at the provincial level and at the 

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national level. These political changes came at a time of considerable progress in terms of economic 
growth and macroeconomic stability. Between 2008 and 2012, gross domestic product (GDP) grew at an 
average rate of 6.1% per year. After the global economic crisis of 2009, the DRC achieved growth rates 
that were consistently higher than the average for sub-Saharan Africa. Investments in the extractive 
industries and the effects of dynamic growth in agriculture, construction and trade resulted in economic 
growth of 7.2% in 2010 and again in 2012. Structural reforms that enabled the country to attract more 
foreign capital contributed to a new dynamism in the Congolese economy. The cancellation of 90% of the 
external debt in 2010 as part of the Heavily Indebted Poor Countries initiative expanded fiscal space and 
gave the State more means to carry out its policy of reconstruction. 
 
The health system of the DRC is organized in three levels. At the implementation level there are 516 health 
districts, where a district team manages a network of health centres and a district hospital. Districts 
typically cover a population of 100 000 to 200 000. The intermediate level, responsible for technical and 
logistic support, is managed by provincial health departments, the number of which has recently increased 
from 11 to 26. The central level has a normative role. The process of revitalizing the health sector in the 
DRC started in 2005 with the adoption of the Health System Strengthening Strategy (HSSS). The strategy 
was developed by key national actors following extensive discussions and analyses of the history and 
political economy of the health sector and the health status of the population. It provides a framework 
for reforms to overcome inefficiencies in the sector and the marginalization of national policy-making in 
a context of dependency on external aid. This study will be conducted in Kinshasa, the capital city. 
Depending on the recruitment speed, the UNIKIN team may extend recruitment in Haut-Katanga, Nord-
Kivu and Tshuapa provinces. 
4.2 STUDY DESIGN 
 
This will be a Multi-Centre, Multi-Stage, Randomized, Double Blind, Phase 2b Trial to Evaluate the Safety 
and Immunogenicity of Janssen Ad26COVS1 and Novavax NVX-CoV2373 COVID-19 vaccines for adults or 
NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents administered as 
homologous and heterologous Boost Regimens in Adolescents (12-17 years) with HIV and in Adults (18- 
64 Years) with/without HIV infection in 3 African Countries (Kenya, Democratic Republic of Congo and 
Rwanda).  Adolescent enrollment will be staggered to allow for an initial safety assessment in a subset of 
the first 300 HIV (+) adults before enrollment. The safety of the booster vaccines will be evaluated by the 
Data Safety Monitoring Board (DSMB) in the first 300 HIV (+) adult participants 18-64 years through day 
28 (Visit 4).  Once the DMSB provides their assessment of an acceptable safety profile in those adult 
subjects, then adolescents may begin enrollment.  The overall study design is depicted in Table 2. 
 
 
 
 
 
 
 
 

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Table 2: Study Design-Homologous and Heterologous Prime-Boost Vaccination Adult Groups 
Vaccine Platform for Primary Series 
HIV (+) adults 
(age 18-64) 
HIV (-) Adults 
(age 18-64) 
Booster vaccination (5-7 
months) 1:1* 
mRNA (Moderna mRNA-1273 or 
Pfizer/BNT)  
450 
100 
Janssen Ad26COVS1 
Novavax NVX-CoV2373 
Adenovector 26 (Janssen Ad26COVS1)  
450 
100 
Janssen Ad26COVS1 
Novavax NVX-CoV2373 
Inactivated whole virus (Sinopharm-BIBP 
or Sinovac) 
450 
100 
Janssen Ad26COVS1 
Novavax 
NVX-CoV2373 
Total 
1,350 
300 
Maximum 1,650 
 
Table 3: Study Design-Homologous and Heterologous Prime-Boost Vaccination Adolescent Groups 
Vaccine Platform for Primary Series 
HIV (+) adolescents (age 12-17) 
Booster vaccination (≥5 
months) 1:1 
 
mRNA (Moderna mRNA-1273 or Pfizer/BNT)  
150  
Novavax NVX-CoV2373 
150  
Moderna mRNA-1273 or 
Pfizer/BNT** 
Total 
Maximum 300 
Maximum 300 
 
*Booster vaccination for adolescents will be ≥5 months after the last primary vaccination series consistent 
with US CDC and FDA recommendations.  
** Monovalent or bivalent vaccines depending on MOH availability and supply. 
Using a block randomization approach based on primary vaccine platform, approximately equal number 
of participants from each primary platform (mRNA, Adeno26, inactivated) will be enrolled.  Among HIV 
(+) participants, randomization will occur across 3 primary vaccine platforms with approximately 450 
adults/platform (expected 2:1 distribution of ages 18-44:45-64).  In addition, a group of 300 HIV (-) adult 
participants (aged 18-64) will be enrolled who have received a homologous primary series from one of 
the three platforms (~100/primary platform).  All adult participants will be randomized 1:1 within their 
primary vaccine platform to receive a single dose of either Janssen Ad26COVS1 vaccine or Novavax NVX-
CoV2373 COVID-19 vaccine between 5 and 7 months from completion of their primary series. All 
adolescent participants will be randomized 1:1 to receive either Novavax NVX-CoV2373 or mRNA 
(Moderna mRNA-1273 or Pfizer/BNT) vaccines ≥5 months after the primary series as shown in (Table 3). 
The ≥5 months adolescent booster vaccination interval is consistent with new guidance from the US CDC 
and FDA (16, 17, 18) and is more reflective of real-world settings implementation of country MOH COVID-
19 vaccination programs.  Due to the uncertainty of vaccine supply and to allow for adequate capture of 
participants, the pre- booster vaccination enrollment period will vary anywhere from -85 days to 0 days 
at the time of boost.  Adults will be stratified 2:1 by age (18-44; 45-64) within each primary platform with 

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a goal of 2:1:1 distribution of adults from Kenya, DRC and Rwanda. However, adjustments for country 
level enrollment may be needed to achieve the age strata and the primary vaccine series distribution and 
study enrollment target.  
As adolescents may not have received similar vaccine distribution as adults, a maximum of 300 across the 
primary platforms and a minimum of 150 adolescents across one (1) primary platform may be enrolled. 
The primary vaccine group for the adolescent cohort at this point in the 3 countries is the mRNA Platform, 
specifically Pfizer/BNT vaccine.    
Due to the uncertainty of vaccine supply and to allow for adequate capture of participants, the pre-
booster vaccination enrollment period may vary anywhere from -85 days to 0 days from the time of boost 
(Day 0) with the adolescent booster delivered between 5- and 12-months following completion of the 
adolescent primary series.  
There will be 3 interim analysis time points by primary vaccine platform: a) 28 days following booster 
vaccination of adults/adolescent (safety and immunogenicity); b) 6 months after adult/adolescent boost 
vaccinations; c) 12 months after boost vaccination for all subjects (safety, immunogenicity and SARS-CoV-
2 breakthrough infections).  The interim analyses will be at the treatment level only and blinding will 
remain at the individual level, site level and for all operational teams and sponsor.  The final database lock 
and analysis will occur after adult participants have completed the long term follow up (15-18 months) 
and 12 months for adolescent participants.  Both Sponsor and DSMB will have interim analyses available 
for decision making.  
 
As immunologic durability in HIV (+) participants is relatively unknown, should the loss of immunity be 
observed at 6 months (significant reduction in GMT among HIV (+) participants compared to HIV (-) 
participants over the same time period), or if efficacy of SARS-CoV-2 vaccination appears to demonstrate 
waning after 12 months (accrual of breakthrough moderate and severe cases by review of DSMB), or new 
data emerges that vaccine boosting is not sustained over time then participants may be re-boosted with 
the same vaccine used for the initial boost.  Alternatively, the study may be terminated early to allow re-
boosting to occur under national guidelines with appropriate vaccines indicated.  This determination will 
be made by the DSMB based on ongoing reviews following interim analyses with quarterly meetings after 
all participants have enrolled to provide adequate oversight of safety and provide guidance on needs to 
implement an alternative boosting vaccination strategy. 
 
At the time of enrollment, participants will provide a blood sample for immunity.    If enrollment occurs 
greater than 30 days prior to randomization, then participants will provide an additional sample on the 
day of randomization/booster vaccination (prior to receiving the vaccine).  The serum sample provided at 
-30 to 0 days relative to the booster vaccination will be considered the baseline sample.  Participants will 
be followed for reactogenicity through 7 days following booster vaccine and for unsolicited Adverse 
Events through 28 days following booster vaccine.  Participants will continue to be followed for any 
Treatment Emergent Adverse Events (TEAE) through day 85, AESI and any SAE or COVID disease 
occurrence through EOS.  Serum samples for immunogenicity testing (IgG ELISA and neutralization) will 
be taken at time of enrollment (unless as noted above), days -30 to 0 Days (relative to vaccination) and 

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28D, 85D, 6M, 12M and 15-18M following booster vaccination.  All adults will contribute 2 samples for 
mucosal immunity taken with a leukosorb nasal swabs at baseline (Visit 2) and Day 28 (Visit 4) following 
booster vaccination. 
 
Samples for Cellular Mediated Immune (CMI) response will be taken in a subset of adult participants, 
located at the Kisumu site in Kenya.  No more than 60 HIV (+) and 30 HIV (-) participants within each 
primary vaccine platform will contribute to CMI testing based on subjects agreeing at the time of consent 
(opting in).  As it may not be possible to achieve equal distribution across primary vaccination platforms 
or consenting by subjects, this is the maximum planned and stratification will be performed for balance 
between the booster vaccine arms within the platforms.  Samples will be taken at baseline (V2) and again 
at Day 7 (V3) following booster vaccination.   
 
SARS-CoV-2 symptom and exposure inquiries will be performed every month by field staff or via electronic 
media as well as at each visit.  In addition, participants are encouraged notify staff if symptoms consistent 
with SARS-CoV-2 are evident or known exposure has occurred and they will be organized to be seen in an 
unscheduled visit.  Participants will provide a nasal sample test using a Rapid Antigen Test or PCR.  If a 
rapid Ag test is (+), then this will be confirmed by a nasopharyngeal RT-PCR test.  Any positive Rapid 
Antigen test will result in daily self-monitoring of symptoms over a 10-day period using a diary (self-
evaluation symptom scoring tool) with each confirmed case receiving a final classification of 
asymptomatic, mildly symptomatic, moderately symptomatic or severely symptomatic by modified WHO 
classifications (Table 4).  In addition, participants will return for a SARS-COV-2 antigen test after 10 days.  
If the rapid antigen test is positive, then subjects will again provide a nasopharyngeal sample for RT-PCR.  
Subjects will continue to return to the clinic every 10 days for retesting until negative.  In addition, subjects 
will continue with daily monitoring of symptoms with a self-directed diary until symptom free.  Anytime 
exposure or COVID-19 symptoms occur this testing algorithm will be followed.  A reinfection is classified 
once at least one test following primary infection has been negative.  All subjects with a positive RT-PCR 
test result depending on the CT value will be considered for possible sequencing to determine SARS-CoV-
2 variants of concern (VoC) .   Length of time of positivity will be reported descriptively given the resample 
timing.  Highest level of SARS-CoV-2 severity will be applied for each participant.    
 
Table 4: WHO COVID-19 Case Definitions for Severity 
COVID-19 Severity 
Definitions  
Virologically 
Confirmed SARS-CoV-
2  
All SARS-COV-2 asymptomatic and symptomatic cases confirmed by Rapid Ag 
testing beginning 28 days following boost until end of study. 
Asymptomatic and 
virologically 
confirmed 
Positive by Rapid Ag test but without sufficient symptoms at presentation or 
during symptom monitoring phase to be classified by symptomatic.  
Mildly Symptomatic 
and Virologically 
confirmed 
≥ 1 of: 
• 
Fever (defined by subjective or objective measure, regardless of use of anti-
pyretic medications) OR 
• 
New onset cough OR 
• 
≥ 2 COVID-19 respiratory/non-respiratory symptoms  

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      AND 
• 
Does not meet criteria for moderate or severe 
Moderately 
Symptomatic and 
Virologically 
confirmed 
≥ 1 of: 
 
• 
Fever (defined by subjective or objective measure, regardless of use of anti-
pyretic medications) + any 2 COVID-19 symptoms for ≥ 3 days OR 
• 
High fever (≥ 38.4°C) for ≥ 3 days (need not be contiguous days) without 
other cause documented OR 
• 
Any evidence of significant LRTI: 
−   Shortness of breath (or breathlessness or difficulty breathing) with or without 
exertion (greater than baseline) 
−   Tachypnea: >20 breaths per minute at rest 
−   SpO2: < 95% on room air 
−   Abnormal chest x-ray or chest CT consistent with pneumonia or LRTI 
−   Adventitious sounds on lung auscultation (e.g., crackles/rales, wheeze, 
rhonchi, pleural rub, stridor) 
      AND 
• 
Does not meet criteria for severe disease 
Severely 
Symptomatic and 
Virologically 
confirmed 
≥ 1 of: 
 
• 
Tachypnea: ≥ 30 breaths per minute at rest OR 
• 
Resting heart rate ≥ 125 beats per minute OR 
• 
SpO2: ≤ 93% on room air or PAO2/FiO2 < 300 OR 
• 
High flow oxygen therapy or NIV/NIPPV (e.g., CPAP or BiPAP) OR 
• 
Requirement for vasopressors, systemic high dose corticosteroids, 
hemodialysis or extracorporeal blood circuitry support for renal/hepatic 
malfunction OR 
• 
One or more major organ system dysfunction or failure (e.g., 
cardiac/circulatory, pulmonary, renal, hepatic, and/or neurological, to be 
defined by diagnostic testing/clinical syndrome/interventions), including any 
of the following: 
− ARDS 
− Acute renal failure 
− Acute hepatic failure 
− Acute right or left hear failure 
− Septic or cardiogenic shock (with shock defined as SBP < 90 mmHg OR 
DBP < 60 mm Hg) 
− Acute stroke (ischemic or hemorrhagic) 
− Acute thrombotic event:  AMI, DVT, PE 
− Other organ dysfunction as outlined by Safety Platform for Emergency 
vACcines (SPEAC)for Covid-19 complications 
Abbreviations: AMI = acute myocardial infarction; ARDS = acute respiratory distress syndrome; BiPAP = bi-
level positive airway pressure; COVID-19 = coronavirus disease 2019; CPAP = continuous positive air 
pressure; CT = computed tomography; DBP = diastolic blood pressure; DVT = deep vein thrombosis; FiO2 = 
fraction of inspired oxygen; ICU = intensive care unit; LRTI = lower respiratory tract infection; NIV = non-
invasive ventilation; NIPPV = non-invasive positive pressure ventilation; PAO2 = partial pressure of oxygen 
in the alveolus; PE = pulmonary embolism; SBP = systolic blood pressure; SpO2 = oxygen saturation 

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4.3 SAMPLE SIZE 
The sample size is estimated to be adequate based on boosting data available for both vaccines if a similar 
response is observed in HIV (-) participants.  The HIV (-) control has been incorporated into the study 
design to allow for monitoring of both immunity and safety in an immunocompetent population to 
observe for similar magnitude in responses over time (descriptive). The sample size is based on 
calculations to achieve testing at Day 28 of significance over baseline and comparison of assessments 
between the 2 vaccine treatment arms in HIV (+) adults at the level of primary vaccine platform.   
  
We compute the booster vaccine trial sample size based on the following primary objectives: 
1. To evaluate reactogenicity (solicited adverse events (AEs) Ad26.COV2S1 and NVX-CoV2373 for 
adults or NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents 
following boosting.   
2. To evaluate Serious Adverse events related to vaccination of Ad26.COV2S1 vs NVX-CoV2373 for 
adults or NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents 
during the entire study. 
3. To evaluate the immunogenicity of Ad26.COV2S1 and NVX-CoV2373 vaccines for adults or NVX-
CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents at day 28  
 
As the study seeks to compare reactogenicity and immunogenicity outcomes between HIV+ and HIV- 
participants as well as between the two vaccine treatment arms (Ad26.COV2S1 vs NVX-CoV2373 for adults 
and NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents, we calculate 
the sample size under the following scenarios. 
 
Scenario 1: Evaluating sample size that would detect a difference in (Serious) Adverse Events (AEs) and 
mean IgG between HIV+ and HIV- participants. 
 
In evaluating significance of solicited and serious adverse events in HIV+ participants, analysis will 
compare the incidence in HIV+ participants with that observed in HIV- participants. Under this scenario, 
the expected ratio of HIV+ to HIV- participants is 4.5:1. Therefore for sample size computation, we use the 
formula in Wittes (2002) which takes into account the imbalance of participants between groups, i.e.:  
 
𝑛𝐻𝐼𝑉−= (
𝑘+1
𝑘) × (
𝑝̅×(1−𝑝̅)× (𝑧𝛽−𝑧1−𝛼
2
)
2
(𝑝1−𝑝2)2
)                                                                          (1) 
Where: 
𝑛𝐻𝐼𝑉− = sample size for HIV- participants (smaller group) 
k = ratio of sample size in HIV+ to HIV- groups 
𝑝1 −𝑝2 = clinical difference in proportions of AEs (𝑝1 and 𝑝2 are proportions of AEs in HIV+ and HIV- 
participants. 
𝑧𝛽 = corresponds to a power of either 80% or 90% 
𝑧1−𝛼/2 = corresponds to two-tailed significance level 

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NOTE: In evaluating sample size that would be sufficient to answer objective 3, 𝑝̅ × (1 −𝑝̅) is replaced by 
the variance of the expected mean difference in the two groups, and 𝑝1 −𝑝2 is replaced by the difference 
in two group means. 
 
We examined the literature to determine the expected proportion of adverse events in HIV+ population. 
A recent meta-analysis by McDonald (2021) evaluated the difference in AEs between vaccinated 
individuals and various control groups.  The authors found the percentage of solicited adverse events to 
be 60% and grade 3 (equivalent to serious) AEs to be up to 11% in healthy participants1. In addition, the 
mean logarithm of IgG in each study was found to at least ~ 1000 in equivalent vaccine arms. We therefore 
adopt a conservative approach, in which we assume that the expected percentage of (i) adverse events 
would be 60%, (ii) serious adverse events would be 10%, and (iii) the expected mean logarithm of IgG 
would be at least 1000 in HIV+ participants. We apply these estimates to the defined sample size formula 
for 80% and 90% power, while varying the detectable difference for the three primary objectives 
respectively. The findings are presented in Figure 2. At a power of 80% and 5% significance level: 
• 
Under objective 1, a sample size of 1980 would be sufficient to detect a risk ratio of 1.20 in 
solicited AEs in HIV+ participants (compared to HIV- participants).  
• 
Under objective 2, a sample size of 1958 would be sufficient to detect a risk ratio of 1.80 in serious 
AEs in HIV+ participants (compared to HIV- participants).  
• 
Under objective 3, a sample size of 1980 would be sufficient to detect a mean difference of 80 in 
logarithm of IgG in HIV+ participants (compared to HIV- participants).  
 
 
1Another study conducted by  Wu 2021 found AEs to be about 10% in vaccinated HIV+ participants. 

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Figure 2: Sample sizes for determining differences in reactogenicity and immunogenicity outcomes 
between HIV+ and HIV- participants. 
 
Feasible assumptions to support an approximate sample size of 1950: 
- 
Expected incidence of solicited and serious adverse events (AEs) in HIV+ would be approximately 
60% and 10% respectively. 
- 
Expected mean logarithm of IgG would be at least 1000 (with a standard deviation of 500). 
- 
Expected detectable risk ratio in solicited and serious AEs in HIV+ participants (versus HIV- 
participants) would be about 1.2 and 1.8 respectively.  
- 
We expect little to no variation in AEs across the sites, hence no need to adjust the sample size 
by a design effect. 
 
Scenario 2: Comparison of Ad26COVS1 (mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines and NVX-
CoV2373 vaccine treatment arms in HIV+ participants 
As the analysis will compare the two vaccine treatment arms (Ad26COVS1 and NVX-CoV2373) in adults, 
and NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents, we evaluate 
the detectable risk ratios that would be considered plausible. We applied the same formula as scenario 1, 
and to achieve a ratio of 1:1 participant distribution between the two arms we set k = 1. We also adopt a 
conservative approach, in which we assume that the expected percentage of (i) adverse events would be 
60%, (ii) serious adverse events would be 10%, and (iii) the expected mean logarithm of IgG would be at 
least 1000 in participants who would be allocated NVX-CoV2373 booster vaccine. We apply these 
estimates to the defined sample size formula for 80% and 90% power, while varying the detectable 

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difference for the three primary objectives respectively. The findings are presented in Figure 3. At a power 
of 80% and 5% significance level: 
• 
Under objective 1, a sample size of 1938 would be sufficient to detect a risk ratio of 1.12 in 
solicited AEs in HIV+ participants (compared to HIV- participants).  
• 
Under objective 2, a sample size of 1938 would be sufficient to detect a risk ratio of 1.53 in serious 
AEs in HIV+ participants (compared to HIV- participants).  
• 
Under objective 3, a sample size of 2052 would be sufficient to detect a mean difference of 60 in 
logarithm of IgG in HIV+ participants (compared to HIV- participants).  
 
 
Figure 3: Sample sizes for determining differences in reactogenicity and immunogenicity outcomes 
between Ad26COVS1 and NVX-CoV2373 vaccine arms. 
 
Feasible assumptions to support an approximate sample size of 1950 in comparing Ad26COVS1 versus 
NVX-CoV2373 in adults and NVX-CoV2373 mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for 
adolescents: 
• 
Expected incidence of solicited and serious adverse events (AEs) in NVX-CoV2373 vaccine arm 
would be approximately 60% and 10% respectively. 
• 
Expected mean logarithm of IgG would be at least 1000 (with a standard deviation of 500) in NVX-
CoV2373 arm. 
• 
Expected detectable risk ratio in solicited and serious AEs in NVX-CoV2373 arm (versus 
Ad26COVS1 arm) and NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for 
adolescents would be about 1.1 and 1.5 respectively.  

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• 
We expect little to no variation in AEs across the sites, hence no need to adjust the sample size 
by a design effect. 
 
Conclusion 
In our sample size computation, we conclude that a sample size of 1950 (n=1350 adults for HIV+ and 
n=300 for HIV- and 300 HIV positive adolescents) would be sufficient to evaluate the three primary 
objectives on reactogenicity and immunogenicity with sufficient power of at least 80% and 5% significance 
level between (i) HIV+ and HIV- participants and (ii) Ad26COVS1 and NVX-CoV2373 vaccine treatment 
arms. In the two scenarios, the derived assumptions commonly apply. 
 

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5 STUDY POPULATION 
The target population for this Phase 2b study is HIV+ adolescents ≥ 12 to 17 years and HIV (+) and HIV (-) 
adults aged ≥ 18 to 64 years. Participants will be screened for eligibility criteria at the time of inclusion 
and may be enrolled anytime from 3months of completing their primary homologous vaccination series.  
Randomization will occur on day of vaccination and be 5-7 months following completion of the primary 
series for adult participants and ≥5 months after the primary series for adolescent participants consistent 
with US CDC and FDA recommendations and real-world setting.  Randomization will be 1:1 to either the 
Janssen vaccine or Novavax vaccine within each primary vaccine platform for adult participants and 
Novavax or Pfizer/Moderna vaccine for adolescents.  The duration of each adult participant’s participation 
in the trial will be approximately 15-18 months depending on time of enrollment relative to boosting 
(subjects will be followed through for at least 15 mo post boost) and 12 months follow up for adolescents. 
Adherence to inclusion and exclusion criteria is essential to ensure safety to participants and precise 
comparison of groups. Waivers on inclusion and exclusion criteria are not allowed because they could 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety.  
5.1 INCLUSION CRITERIA 
 
To be eligible for the study, each HIV (+) participants must satisfy all of the following criteria: 
1. Adolescent male or female aged ≥ 12 to 17 years at screening and adult male or female aged ≥ 18 to 
64 years at screening (inclusive). 
2. Written informed consent (and assent if adolescent), after review of the consent form and having 
adequate opportunity to discuss the study with an investigator or a qualified designee. For 
participants who cannot read or write, the consent must be witnessed by a literate third party not 
involved in study conduct.  
3. Comply with study procedures, including potential home visits for COVID-19 follow-up. 
4. Has completed a primary homologous vaccination series at least 3 months prior to enrollment.  
Vaccinations allowed include:  
a) mRNA (Moderna mRNA-1273 or Pfizer/BNT) – primary series is 2 doses  
b) Adenovector 26 (Janssen Ad26COVS1) – primary series is 1 dose;  
c) Inactivated whole virus (Sinopharm-BIBP or Sinovac) – primary series is 2 doses;  
5. Female participants of childbearing potential (defined as any female who has experienced menarche 
and who is NOT surgically sterile [i.e, hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months or 
documented plasma follicle-stimulating hormone level ≥40 mIU/mL]) must agree  to consistently use 

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an effective method of contraception from enrolment and agree to continue adequate 
contraception until 12 weeks after vaccination: 
a. Condoms (male or female) 
b. Diaphragm with spermicide 
c. Cervical cap with spermicide 
d. Intrauterine device 
e. Oral or patch contraceptives 
f. Hormonal Contraceptives implants or injection e.g., Norplant®, Depo-Provera®. 
g. Abstinence, as a form of contraception, is acceptable if in line with the participant’s lifestyle. 
 
NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. These procedures and laboratory test results 
must be confirmed by physical examination, by participant recall of specific date and hospital/facility of 
procedure, or by medical documentation of said procedure. 
6. Medically stable at screening, as determined by the investigator (based on review of health status, 
vital signs, medical history, and targeted physical examination). Acceptable Vital signs as determined 
by the Principal Investigator or designee. 
7. Receiving highly active antiretroviral therapy (HAART) and using the same regimen the past 8 weeks 
before screening.  Changes in antiretroviral dosage within 8 weeks prior to entering the study are 
permitted. In addition, the exchange of pharmacological formulation (e.g., the conventional 
formulation for combination formulations) is allowed.  If regimen has changed then the participant 
can be reconsidered for inclusion once the 8 weeks has passed.  
 
8. An HIV-1 viral load < 1000 copies/mL and/or CD4 Count ≥ 200 cells/mm3 within 3 months before 
randomization. May be taken during screening or utilize medical testing from clinic.  
9. Documentation of HIV positivity by HIV rapid test or assay as per the Ministry of Health guidelines in 
the respective countries. 
Each HIV (-) participant must meet all the following criteria to be enrolled in this study: 
1. Male or female aged ≥ 18 to 64 years at screening, inclusive. 
2. Willing and able to give informed consent prior to study enrolment and comply with study 
procedures, including potential home visits for COVID-19 follow-up. 
3. Has completed a primary homologous vaccination series at least 3 months prior to enrollment.  
Vaccinations allowed include:  
a. mRNA (Moderna mRNA-1273 or Pfizer/BNT) – primary series is 2 doses  
b. Adenovector 26 (Janssen Ad26COVS1) – primary series is 1 dose;  
c. Inactivated whole virus (Sinopharm-BIBP or Sinovac) – primary series is 2 doses;  

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4. Female participants of childbearing potential (defined as any female who has experienced menarche 
and who is NOT surgically sterile [i.e, hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months or 
documented plasma follicle-stimulating hormone level ≥40 mIU/mL]) must agree to abstain from 
enrolment and through 3 months after the last vaccination OR agree to consistently use an effective 
method of contraception from enrolment and through 3 months after the last vaccination: 
a. Condoms (male or female) 
b. Diaphragm with spermicide 
c. Cervical cap with spermicide 
d. Intrauterine device 
e. Oral or patch contraceptives 
f. Hormonal Contraceptives implants or injection e.g., Norplant®, Depo-Provera®. 
g. Abstinence, as a form of contraception, is acceptable if in line with the participant’s lifestyle. 
 
NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. These procedures and laboratory test results 
must be confirmed by physical examination, by participant recall of specific date and hospital/facility of 
procedure, or by medical documentation of said procedure. 
5. Medically stable at screening, as determined by the investigator (based on review of health status, 
vital signs, medical history, and targeted physical examination). Acceptable vital signs by PI.  
6. Documentation of negative HIV rapid test (or assay) as per the Ministry of Health guidelines in the 
respective countries.  
5.2 EXCLUSION CRITERIA 
Participants with any of the following criteria will be excluded: 
1. Use of a heterologous COVID-19 primary series at the platform level (mRNA, Adenovector and 
inactivated vaccine). 
2. Use of an extended primary vaccination series or prior booster with any SARS-COV2 vaccine.  
3. Any subject with prior Adverse Events of Special Interest Relevant to COVID-19 (see table 6). 
4.  Unstable or Severe Chronic disease inclusive of: 
a. Hypertension (elevated blood pressure [SBP>180mmHg or DBP>110mmHg]).  Note that 
participants can be retested once after resting or return on another day for retesting.  
Participants may also have anti-hypertensive medication adjusted and may be reassessed after 
at least 2 weeks. 
 

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b. Congestive heart failure (CHF) stage 3 or greater or diagnosed cardiovascular disease that is not 
controlled using medication in the past 6 months. 
 
c. Chronic obstructive pulmonary disease (COPD) with a history of an acute exacerbations 
repeated in the past 2 years. Note: If participant has been stable the last 6 months and are not 
Gold stage 3 or greater, they may be included. 
 
d. Asthma stage 4 and/or unstable cases with asthma therapy adjustments in the past that 2 
months. 
 
e. Type 1 or any type 2 diabetes (adult onset) of severe grade by history/medical review or with an 
HbA1c > 8.5 in the last 6 months.   
 
f. Chronic kidney disease requiring dialysis or GFR <30 (may use associated creatinine based on 
age and gender).  
 
g. Chronic hepatic disease with evidence of hepatic compromise by history/medical review. 
Includes known Hepatitis B or C.  
h) Chronic or serious neurological diseases (e.g.  cerebrovascular disease (including transient 
ischemic attacks), autoimmune disorders, neurologic deterioration (including dementia), Guillain 
Barre syndrome).  
i) 
Any ongoing, symptomatic acute illness requiring medical or surgical care or chronic illness of 
severe grade or that is not stable over the past 6 months (at the discretion of the investigator).  
j) HIV Stage III/IV  
5. Cognitive impairment – congenital or acquired  
 
6. A child in care i.e., a child who is in the custody, care or guardianship of a director or a director of 
adoption.  
 
7. Participation in research involving an investigational product (drug/biologic/device) within 30 days 
prior to first study vaccination and planned participation during this study. Exception is if participant 
in a follow up safety phase and the investigation product has been given > 6 months previously.   
 
8. Prior receipt of an Ebola vaccine i.e., Ad26.ZEBOV/MVA-BN-Filo vaccines. 
 
9. Received any other vaccine within 4 weeks prior to first study vaccination or planned vaccination 
within 4 weeks after study vaccination (including mass vaccination campaigns).  Participants may be 
revaluated after the window has passed.  
 

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10. Any autoimmune or immunodeficiency disease/condition (iatrogenic or congenital), excluding HIV. 
Note: Stable endocrine disorders that have a confirmed autoimmune etiology (e.g., thyroid, 
pancreatic), including stable diabetes are allowed. 
 
11. Chronic administration (>14 continuous days) of immunosuppressant, systemic glucocorticosteroids, 
or other immune-modifying drugs within 60 days prior to first study vaccination, excluding HAART. 
Note: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 10 mg of 
prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be 
permitted. 
 
12. Received immunoglobulin, blood-derived products, or other immunosuppressant drugs within 90 
days prior to first study vaccination, excluding HAART. 
 
13. Known disturbance of coagulation (iatrogenic or congenital). Note: The use of low-dose aspirin (≤ 
325 mg/day) as prophylaxis is acceptable in dosages consistent with local standards of care, but the 
use of other platelet aggregation inhibitors, thrombin inhibitors, Factor Xa inhibitors, or warfarin 
derivatives is exclusionary, regardless of bleeding history, because these imply treatment or 
prophylaxis of known cardiac or vascular disease. 
 
14. Any disease or disorder that would indicate a life expectancy less than 3 years such as active cancer. 
 
15. Any known allergies to products contained in the investigational product or latex allergy or any 
history of anaphylaxis in relation to any previous vaccination. 
 
16. Women who are breastfeeding or who are pregnant at the time of screening or plan to become 
pregnant within the first 12 months of the study. 
 
17. A serious adverse event that occurs between screening and randomization.  Subjects will not be 
allowed to be randomized. 
 
18. History of alcohol abuse or drug addiction within 2 years prior to the first study vaccination. 
 
19. Any condition (other than HIV) that, in the opinion of the investigator, would pose a health risk to 
the participant if enrolled (including neurologic or psychiatric conditions deemed likely to impair the 
quality of safety reporting). 
 
20. Study team member or first-degree relative of any study team member (inclusive of sponsor, and 
site personnel involved in the study). 
 
Temporary exclusions:  
 

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21. Acute respiratory and/or non-respiratory illness or documented temperature of > 38°C in the past 
24 hours. Note: Participant may be re-evaluated after symptoms have resolved for at least 3 days.  
 
22. Positive RT-PCR SARS-CoV-2 test during screening or at time of randomization. Subject must be 
SARS-COV-2 symptom free and have a negative test prior to randomization.  
 
23. Documented severe SARS-CoV-2 infection in the last 3 months.  May be rescreened when this period 
has passed.  
5.3 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but during the 
screening process meet an exclusion criterion or fail to meet an inclusion criteria.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE) that occurred during the screening period. Individuals who 
do not meet the criteria for participation in this trial (screen failure) may be rescreened once as 
appropriately noted in the exclusion criteria.  Rescreened participants should be assigned the same 
participant number as for the initial screening.  Screening will remain open until the randomization 
assignments are fulfilled.  It is possible participants may be screened and are eligible but are not 
randomized to the study due to either temporary waiting periods or excess number of participants that 
qualify for randomization.  
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
5.4.1.    COMMUNITY INFORMATION 
  
The community in which the study will take place will be informed about the nature and design of the 
study. Community leaders (including chiefs, local village elders, and opinion leaders as applicable), 
Community Advisory Board members, local and national health authorities will be formally briefed in their 
own language on the nature and purpose of the study. They will have the opportunity to ask questions of 
the PI or his designees. 
5.4.2.    RECRUITMENT 
  
Participants will be recruited with methods that are in accordance with ICH-GCP standards, other policies 
and regulations of the governments of Kenya, Rwanda and the Democratic Republic of Congo. 
Recruitment activities will be implemented in coordination with Ministry of Health (MoH), community, 
civil society, and other stakeholders to address and meet local needs and expectations, and to achieve 
community support. Adolescents 12-17 years and adults 18-64 years will be identified and recruited from 
the HIV patient cohorts in the health facilities and for the HIV negative adults, from the households in the 
surrounding communities at the respective study sites. Depending on the site practice, potential 

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participants identified from within these locations will be approached at the clinic or in the community 
using a recruitment script depending on site practice by study staff delegated to carry out recruitment. 
Informed consent and assent will be administered in accordance with the protocol, ICH-GCP guidelines 
and country guidelines. Language and illiteracy will not be impediments in the recruitment process, all 
briefings and explanations will be in the understandable language of the participant. It is expected that 
not more than 2,400 HIV (+) participants will be screened to identify 1,650 to randomize (30% failure rate).  
The failure rate for HIV (-) participants is expected to be about 25%.   
  
Community engagement will be conducted to identify community organizations in each sector that may 
potentially serve as recruitment and referral sites. Community support of the study will be sought through 
community engagement activities including ongoing communication with community leaders, established 
community groups, local Ministry of Health leadership, and where applicable involvement of the local 
Community Advisory Board (CAB) or equivalent. Community Health Workers will also assist with 
community sensitization and mobilization. Another community engagement strategy will be through use 
of small group or informal gatherings. These will involve fewer people and may target less represented 
group of people within the larger community e.g., adolescents and young women. 
  
Study staff may also recruit study participants through HIV care and treatment clinics, and outpatient 
hospital clinics.  Prior to recruiting from a facility or clinic, the study team will engage the MoH leadership 
of the facility (with the permission of the MOH leadership) and will sensitize MoH Staff at the facility about 
the study. 
 
Once potential participants have been identified by study staff, they will be given a brief overview of the 
study, and those who are interested in participating in the study will be referred to study staff at the 
respective Clinical Research Centers for further briefing. If participants remain interested, they will engage 
in the informed consent process and then formal screening will begin.  

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6 STUDY PRODUCT AND ADMINISTRATION  
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
Trial intervention is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a trial participant according to the trial protocol. 
Details of dosage, preparation, handling, storage, labelling, etc will be provided in the study pharmacy 
manual. 
6.1.1 DESCRIPTION OF STUDY PRODUCTS  
6.1.1.1.    JANSSEN AD26COVS1 (COVID-19) VACCINE 
  
Janssen Ad26COVS1 is formulated to contain: recombinant, replication-incompetent adenovirus type 26 
expressing the SARS-CoV-2 spike protein, citric acid monohydrate, trisodium citrate dihydrate, ethanol, 2-
hydroxypropyl-β-cyclodextrin (HBCD), polysorbate-80, sodium chloride. Janssen Ad26COVS1 vaccine 
components are provided in multi-dose vials at a concentration of 1×1011 vp/mL, with an extractable 
volume of 0.5 mL, and dosed at 5×1010 vp.  A multi-dose vial may be used on more than one occasion 
within a single clinic day.  
6.1.1.2. NOVAVAX NVX-COV2373 (COVID-19) VACCINE 
  
Novavax NVX-CoV2373 vaccine is a recombinant SARS-CoV-2 nanoparticle vaccine composed of trimeric 
full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. The vaccine components are 
provided in multi-dose vials. The dose level will be 5 μg SARS-CoV-2 rS with 50 μg Matrix-M1 adjuvant 
(mixed in clinic or previously co-formulated).  A multi-dose vial may be used on more than one occasion 
within a single clinic day, not to exceed 6 hrs. from first use (based on WHO multidose open vial policy).  
 
6.1.1.3. MRNA (MODERNA MRNA-1273 OR PFIZER/BNT) VACCINES 
  
The Pfizer–BioNTech COVID-19 vaccine, BNT162b2, is an mRNA vaccine encoding a P2 mutant spike 
protein (PS 2) and formulated as an RNA–lipid nanoparticle of nucleoside-modified mRNA (modRNA). 
BNT162b2 elicits a blunted innate immune sensor activating capacity and thus augments antigen 
expression. Encapsulation into LNPs allows transfection of the mRNA into host cells after intramuscular 
(IM) injection. During mixing of the RNA and the dissolved lipids, the lipids form the nanoparticles 
encapsulating the RNA. After injection, the LNPs are taken up by the cells, and the RNA is released into 
the cytosol, where it is translated into the encoded viral protein. The mRNA is rapidly degraded 
intracellularly, while the resulting peptides are presented at the cell surface, triggering a specific humoral 
T-cell-mediated immune response with activity against the spike protein 
 
Moderna’s mRNA-1273 COVID-19 vaccine is an LNP-encapsulated mRNA vaccine expressing the prefusion-
stabilized spike glycoprotein. The vaccine contains a synthetic mRNA (single-stranded, 5'-capped) 

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encoding the prefusion-stabilized spike glycoprotein (S) of SARS-CoV-2 virus. The vaccine also contains the 
following ingredients: lipids (SM-102, 1,2-dimyristoyl-rac-glycero-3- methoxy polyethylene glycol-2000 
(PEG2000-DMG), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), tromethamine, 
tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose. The Moderna COVID-19 vaccine 
is supplied as a frozen suspension, at between -250C and -150C, in a multidose vial containing 10 doses. 
The vaccine is a white to off-white, sterile, preservative-free frozen suspension for intramuscular injection. 
The vaccine must be thawed prior to administration. After thawing, a maximum of 10 doses (0.5 ml each) 
can be withdrawn from each vial. Vials can be stored refrigerated at 2–8°C for up to 30 days prior to first 
use. Unopened vials may be stored at 8–25°C for up to 12 hours. After the first dose has been withdrawn, 
the vial should be held at 2–25°C and discarded after 6 hours. 
6.1.2 DOSING AND ADMINISTRATION 
 
Date and time of study vaccine administration, and arm of injection must be captured in the source 
documents and the eCRF. Vaccine doses will be prepared in a clinical pharmacy under aseptic conditions. 
Detailed instructions for the preparation, storage and handling of study vaccine will be provided in a 
Pharmacy Manual.   
 
Adult study participants will be randomized to receive either a single dose of Janssen Ad26COVS1 or 
Novavax NVX-CoV2373 vaccine at day 0. Adolescent study participants will be randomized to receive 
either a single dose of Novavax NVX-CoV2373 or mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines at 
day 0. Study vaccine will be administered by IM injection (0.5 ml) into the deltoid muscle, preferably of 
the non-dominant arm. If an injection cannot be given in the deltoids due to a medical or other 
contraindication (for example, tattooed upper arms rendering it difficult to assess site reactogenicity), use 
alternative locations will be considered. In all circumstances, IM injections in other locations than the 
upper arm are not considered protocol deviations. The location of injection will be documented in the 
source documents and the eCRF. All vaccinations will be administered on an outpatient basis by 
designated site personnel in a way to maintain the blind. The unblinded pharmacist or assigned site 
personnel involved in study drug preparation or management will not otherwise be involved in the study 
procedures or clinical observation of participants. 
 
6.2 PACKAGING, LABELLING, STORAGE, AND HANDLING OF STUDY PRODUCTS 
 
Each study intervention (vial) and each box will bear a fixed label containing the dose number. All will be 
labeled in accordance with regulatory authority requirements. 
 
All investigational products must be stored according to the label instructions in a secure room with 
restricted access by authorized study personnel only. Each site will be required to keep a temperature log 
to establish a record of compliance with storage conditions. 
 

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Janssen Ad26COVS1 vaccine components are provided in multi-dose vials at a concentration of 1×1011 
vp/mL, with an extractable volume of 0.5 mL, and dosed at 5×1010 vp. The product will be stored 
unpunctured at 2°C to 8°C (36°F to 46°F) and will be protected from light. After the first dose has been 
withdrawn, the vial should be held between at 2°C to 8°C for up to 6 hours in compliance with WHO 
Multidose open vial policy. Any remaining dose of opened vial must be discarded after 6 hours or at the 
end of the immunization session, whichever comes first. 
 
The Novavax NVX-CoV2373 SARS-CoV-2 rS vaccine with Matrix-M1 adjuvant is stored and stable at 2°- 
8°C. After the first dose has been withdrawn, the vial should be held between at 2°C to 8°C for up to 6 
hours in compliance with WHO Multidose open vial policy. Any remaining dose of opened vial must be 
discarded after 6 hours or at the end of the immunization session, whichever comes first.  
 
The Pfizer/BNT) vaccine are provided in multidose vials at a concentration. Unpunctured vaccine vials may 
be stored in ultra-cold freezer between -90°C and -60°C until the expiration date or may be stored in the 
refrigerator between 2°C and 8°C (36°F and 46°F) for up to 10 weeks. Vaccine vials should be store upright 
in the tray or box protected from light. Punctured vials after withdrawal of the first dose may be stored 
between 2°C and 25°C for up to 12 hours in compliance with WHO Multidose open vial policy. All 
remaining vaccine vials must be discarded after 12 hours or at the end of the immunization session, 
whichever comes first. 
 
Moderna mRNA-1273 vaccine vials may be stored unpunctured in the freezer at -50°C to -15°C until the 
expiration date or in the refrigerator between 2°C and 8°C for up to 30 days. Store vials upright in the tray 
or box, protected from light. Punctured vaccine vials after withdrawal of the first dose should be stored 
between 2°C and 25°C for a maximum of 8 hours in accordance with WHO multidose open vial policy. 
Discard vial and any remaining vaccine after 12 hours (8 hours for Bivalent Pink capped yellow-bordered 
vial) at the end of immunization session.  
 
If study vaccine is exposed to temperatures outside the specified temperature range, the affected 
vaccines will be quarantined, and all relevant data will be sent to the sponsor to determine if the affected 
supplies can be used or will be replaced. Vials will be used for multiple participants per day but at the end 
of the expiry time any unused product from an opened vial will be retained for disposal and not used 
further.  Both used and unused vaccine vials and syringes will be stored at the site and made available to 
the unblinded monitor for verification before destruction/return to sponsor. Additional information will 
be provided in investigational brochures and pharmacy manual.   
 
The investigator at each site is responsible for ensuring that all study vaccine received at the site is 
inventoried and accounted for throughout the study. The actual study vaccine administered to the 
participant must be documented on the vaccine accountability form or within the IVRS or IWRS system 
that can track study vial used. All study vaccine will be stored and disposed of according to the sponsor’s 
instructions. Study-site personnel must not combine contents of the study vaccine containers. 
 

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Study vaccine must be handled in accordance with the protocol and the container label and must be 
stored at the study site in a limited-access area.  
 
Unused study vaccine must be available for verification by the sponsor’s unblinded site monitor during 
on-site monitoring visits. The local destruction or return to the sponsor of unused study vaccine will be 
documented on the vaccine accountability form. When the study site is an authorized destruction unit or 
has access to authorized destruction unit and study vaccine supplies are destroyed on-site/in-country, this 
must also be documented on the vaccine destruction form. Potentially hazardous materials containing 
hazardous liquids, such as needles should be disposed of immediately in a safe manner and therefore will 
not be retained for vaccine accountability purposes. The vaccine syringes will be retained and stored after 
vaccine administration for purposes of accountability by the pharmacy (unblinded) study monitor.  
  
Study vaccine should be administered under the supervision of a qualified member of the study-site 
personnel or pharmacist trained to perform vaccinations. Study vaccine will be administered only to study 
participants.  The investigator agrees neither to dispense the study vaccine from, nor store it at, any site 
other than the study sites agreed upon with the sponsor. 
  
The investigator (or designee) will maintain accurate records of receipt of all investigational product, 
including dates of receipt and documentation of cold chain requirements. At the completion of the study, 
and to satisfy regulatory requirements regarding investigational product accountability, all investigational 
products will be reconciled and retained or destroyed according to applicable regulations. No 
investigational product will be destroyed until authorized in writing by the sponsor. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
6.3.1 PROCEDURES FOR RANDOMIZATION AND STRATIFICATION 
  
Treatment assignment will be based on a computer-generated randomization schedule will be prepared 
by the Sponsor statistician. Adult participants will be randomly assigned in a blinded manner using a 
centralized Interactive Response Technology (IRT/IWRS) in a 1:1 ratio to receive either the Novavax NVX-
CoV2373 or Janssen Ad26COVS1 vaccine within primary treatment platform and by strata of age and HIV 
status within country. Adolescent participants will be randomized in 1:1 ration to receive either Novavax 
NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines. 
 
The randomization of adult participants will be balanced by using randomly permuted blocks and will be 
stratified by: HIV (+) adults age group (18-45, 46-64 with a 2:1 ratio) within each primary platform with 
equal representation of the 3 primary platforms.  All 3 countries will participate in adult recruitment with 
a goal of 2:1:1 contribution of participants from Kenya, DRC and Rwanda. However, adjustments for 
country level enrollment may be needed to achieve the age strata and the primary vaccine series 
distribution and study enrollment target. In addition, a group of 300 HIV (-) adult participants (aged 18-
64) will be enrolled who have received a homologous primary series from one of the three platforms 
(~100/primary platform), with a goal of similar ratio of country recruitment.  

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As adolescents may not have received similar vaccine distribution as adults, stratification will not occur 
and representation by country and primary vaccine platform is more uncertain.  Therefore, a maximum 
of 300 adolescents for the mRNA primary platform will be planned.  However, adolescent immunogenicity 
data will be analysed both overall and also considering the time of boost (≥5-12 or >12 months) post 
primary vaccination. Unequal distribution of primary vaccine platform for adolescents between 
participating countries is expected.   
  
The IRT/IWRS will assign a unique intervention code, which will dictate the intervention assignment for 
the participant. The requestor must use his or her own user identification and personal identification 
number when contacting the IRT/IWRS and will then give the relevant participant details of treatment 
assignment to uniquely identify the participant. Information regarding the IRT/IWRS procedure will be 
provided to the sites.   
 
A subset of HIV (+) (maximum of 60/primary vaccine platform) and HIV (-) (maximum of 30/primary 
vaccine platform) adult participants from the Kenya site will contribute to CMI subset based on consenting 
(opt in) and will be stratified between the arms in each vaccine platform.   This subset will only involve 
HIV (+) and HIV (-) adult participants aged 18-64 because of the required blood volumes and will only be 
conducted in Kenya to ensure standardization of the procedures for PBMC processing, operational 
efficiency, and experience of the immunology lab.  
6.3.1.1 BLINDING PROCEDURES 
  
This is a double blinded study. The unblinded site personnel will manage study vaccine logistics, 
preparation, dispensing and administration so as to maintain the blind from the remainder of the site 
personnel and participants. The unblinded site personnel will not be involved in study-related 
assessments or have participant contact for data collection following study vaccine administration. 
  
Randomization codes will be maintained within the IRT/IWRS, which has the functionality to allow the 
investigator to break the blind for an individual participant. Data that may potentially unblind the study 
vaccine assignment (e.g., immunogenicity data, study vaccine accountability data, study vaccine 
allocation, or specific laboratory data) will be handled with special care to ensure that the integrity of the 
blind is maintained at the participant level and the potential for bias is minimized. This can include making 
special provisions, such as segregating the data in question from view by the investigators, sponsor, 
clinical team, or others as appropriate until the time of database lock and unblinding. 
 
 Vaccines will be handled to maintain the study vaccine in a blinded manner by the unblinded drug 
accountability team.  This many include providing a masked syringe to the blinded vaccine administrator 
or using an unblinded drug accountability team member who performs the injection and then hands the 
participant over to the blinded team for further evaluation.  In either case the vaccinator is a trained and 
qualified study nurse, medical doctor, otherwise qualified Health Care Professional who will perform the 
injection. 

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6.3.1.2 BREAKING THE BLIND 
 A participant’s study vaccine assignment will not be broken until the end of the study unless medical 
treatment of the participant depends on knowing the study vaccine the participant received. In the 
event that the blind needs to be broken because of a medical emergency, the investigator may unblind 
an individual participant’s study vaccine allocation. Whenever possible, the investigator should contact 
the medical monitor to discuss the medical emergency and the reason for revealing the actual study 
vaccine received by that participant. If the investigator cannot contact the medical monitor in a timely 
manner the blind may be broken by the investigator. The medical monitor should be contacted as soon 
as feasible after the unblinding. The study vaccine assignment will be unblinded through IRT/IWRS. 
Reasons for study vaccine unblinding must be clearly explained and justified in the eCRF. The date on 
which the code was broken together with the identity of the person responsible must also be 
documented. The blind may also be broken in the event of a Suspected Unexpected Serious Adverse 
Reaction (SUSAR) to determine regulatory reporting. In addition to the aforementioned situations where 
the blind may be broken, the data will also be unblinded to a statistical team at specified time points for 
planned interim analyses prior to study completion. All data will be analyzed separately from the point 
of unblinding for safety, immunogenicity and efficacy, as described in the Statistical Analysis Plan. 
  
In the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, and 
reason for the unblinding must be documented in the IRT/IWRS and in the source document. The 
documentation received from the IRT/IWRS indicating the code break must be retained with the 
participant’s source documents in a secure manner. Participants who have had their intervention 
assignment unblinded should continue to return for scheduled safety evaluations at a minimum.  They 
may also contribute to immune sampling, but their data will be handled in the appropriate manner as 
outlined in the Statistical Analysis Plan. All data will be analyzed for safety, immunogenicity, and efficacy 
as described in the Statistical Analysis Plan for both interim and final analyses.  The Statistical analysis plan 
will be approved prior to the first interim analysis.  
6.3.2.     STUDY VACCINATION PAUSING RULES 
 
Adverse events that may lead to the study vaccination pausing rules are described below and will be 
assessed by the DSMB to confirm that the study pause is warranted. 
 
The occurrence of any of the following events will lead to a pause in further study vaccination and a 
review by the DSMB: 
 
• 
Death of a participant, considered related to study vaccine or if the causal relationship to the 
study vaccine cannot be excluded, OR 
• 
One or more participants experience an SAE that is determined to be related to study vaccine or 
by causal relationship to the study vaccine cannot be excluded, OR 
• 
Multiple grade 3 reactogenicity events following booster vaccination that exceed that specified 
in the product investigator brochure or >10% grade 3 (whichever is higher) for any 
reactogenicity events by primary vaccine platform OR  

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• 
If a PI, Safety Monitor or Sponsor requests the DSMB to convene because of concerns about 
safety in the study 
To enable prompt response to a situation that could trigger pausing rules, the investigator should notify 
the sponsor’s medical monitor, immediately and no later than 24 hours after becoming aware of any 
death or a potentially related SAE AND update the eCRF with relevant information on the same day the 
SAE information is collected. Based on the pausing criteria, the sponsor’s medical monitor or designee, 
then decides whether a study pause is warranted and informs the DSMB of the decision. In the case of 
the grade 3 reactogenicity events the safety/medical monitor will be informed/monitor for pause criteria 
being met.  The sponsor’s medical monitor or designee or the investigator(s) (upon consultation with the 
sponsor’s medical monitor or designee) may initiate DSMB review for any single event or combination of 
multiple events which, in their professional opinion, could jeopardize the safety of the participants or the 
reliability of the data.  All sites will be notified immediately in the event of a study pause. If vaccination is 
still ongoing, it will be paused and visit schedules will be adjusted so as not to induce protocol violations.  
The coordinator of the DSMB is responsible for notifying DSMB members and coordination of a DSMB 
meeting in the event of a study pause. Resumption of vaccinations will start only upon receipt of written 
recommendations by the DSMB. The clinical site(s) will be allowed to resume vaccination activities upon 
receipt of a written notification from the sponsor. The formal recommendation from the DSMB will be 
forwarded by the investigator to the ERC/IRB and by the sponsor to the relevant health authorities, 
according to local standards and regulations. Vaccinations for the study may be suspended for safety 
concerns other than those described above, or after review during standard DSMB meeting if participant 
safety may be threatened. 
  
In addition, the DSMB will meet quarterly after enrollment is completed to review unblinded safety data 
including breakthrough confirmed SARS-CoV2 cases.  They may also be asked to include in their review 
any available immunogenicity data following interim database locks should there be concerns of waning 
immunity relative to breakthrough cases or to ongoing new data generated in the field of COVID-19.  The 
DSMB may recommend modifications to the protocol or stopping of the study early.  The sponsor has the 
final authority to accept the DSMB recommendations. Details of the DSMB functioning are described in 
the DSMB Charter. 
6.4 STUDY INTERVENTION COMPLIANCE 
All doses of the study vaccine should be administered at the site under direct observation by delegated 
qualified study personnel. Details of vaccine administration will be recorded in the source document and 
eCRF. The location (i.e., right or left arm), date, and timing of all doses of study vaccine will be recorded 
in the participants’ source document and eCRF. If a participant is not administered study vaccine, the 
reason for the missed dose will be recorded. 
6.5 CONCOMITANT THERAPY 
Concomitant medications, treatments and procedures will be recorded on the source document and 
documentation in the eCRF of ongoing concomitant medication(s) will be limited to specific categories of 
medication(s) being taken due to chronic conditions or associated with adverse events being collected. Of 

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note, given the population being studied, all HAART will be recorded at each visit for HIV + participants 
and changes in HAART therapy during the trial be documented.  Adverse events being collected on a given 
visit will have associated medications recorded.  Administration of all vaccines during trial participation 
will be recorded in the source document and eCRF.  Prescription and over the counter (OTC) drugs, as well 
as herbals, vitamins, and supplements, will be included as designated according to the adverse event 
monitoring schedule. 
  
Antipyretics may be recommended post-vaccination for symptom relief as needed. During the study, the 
use of investigational vaccines other than the study vaccine is not allowed.   Treatment with investigational 
COVID-19 drugs after diagnosis of a COVID-19 case is allowed during the follow-up period and needs to 
be recorded in the COVID-19-episode description. 
  
Licensed vaccines can be given at least 28 days before or at least 28 days after a study vaccination.  
Exceptions are when medically needed (e.g., yellow fever, rabies, tetanus), it must take priority over the 
study vaccine windows and should be documented in the source document and eCRF.  Participants should 
not receive additional COVID-19 vaccines once they are enrolled in the trial because it would impact the 
scientific validity of the study. However, participants are at liberty to voluntarily decide whether or not 
they would like to receive any licensed COVID-19 vaccines and such receipt should be recorded in the 
concomitant medication/vaccination eCRF.  
  
Documentation of any prohibited therapies administered (medications/vaccinations) may result in 
removal of such subjects for specific immunogenicity analyses. Depending on the time of the occurrence, 
any participant who receives a prohibited concomitant therapy will not be included in the per protocol 
immunogenicity analyses. 
 
 

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7 PARTICIPANT COMPLETION AND WITHDRAWAL 
7.1 PARTICIPANT WITHDRAWAL FROM THE STUDY  
 A participant who returns for the concluding visit at Month 15-18 post booster is considered to have 
completed the study. 
 
• 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
• 
 Study participants who withdraw from the study i.e., “withdrawal” will not be replaced unless 
the withdrawal is prior to the booster dose of study vaccine and randomization remains open. 
• 
Study participants can withdraw consent and withdraw from the study at any time, for any 
reason, without prejudice to further treatment the participant may need to receive. All attempts 
will be done by the investigator to follow study participants who have received a dose of study 
vaccine until the end of the study. The investigator may request that the study participant 
complete safety evaluation or study procedures prior to withdrawal. 
• 
Information related to the withdrawal will be documented in the source document and eCRF. 
The Investigator will document whether the decision to withdraw a study participant from the 
study was made by the participant or by the Investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
 
o COVID-19-related AEs (specify) 
o COVID-19-related SAEs (specify) 
o Non-COVID-19-related AEs (specify) 
o Non-COVID-19-related SAEs (specify) 
o Death 
o Lost to follow-up 
o Physician decision (specify) 
o Pregnancy 
o Protocol deviation 
o Study terminated by Sponsor 
o Withdrawal of consent by participant* (specify) 
o Other (specify) 
 
*In a case where a participant is withdrawn from the study because they have withdrawn consent, 
though not mandatory, the investigator will endeavor to document the reason for withdrawal of 
consent, if specified by the participant, in the eCRF. 
 
• 
Should study participant request to be withdrawn from the study because of an AE, the 
investigator will try to obtain an agreement to follow up with the participant until the event is 
considered resolved or stable and will then complete the end of study eCRF. Study participants 

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who have been withdrawn from the study because of AEs (including SAEs) must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigators will follow 
up with participants who are withdrawn from the study as result of an SAE or AE until resolution 
of the event or until the event has subsided, stabilized, disappeared, or until the event is 
otherwise explained, or the participant is lost to follow-up. 
• 
Investigators will make an attempt to contact those participants who do not return for 
scheduled visits or follow-up.  Only after 3 unsuccessful attempts at contact can a subject be 
considered lost to follow up.  This should include one attempt by a community worker to visit 
the subject in their home (or local equivalent).  
• 
If the study participant withdraws from the study and also requests withdrawal of his/her 
consent for disclosure of future information, no further evaluations should be performed, and 
no additional data should be collected. The sponsor may retain and continue to use any data 
and samples collected before such withdrawal of consent i.e., all data collected until the date of 
withdrawal/last contact of the participant will be used for the analysis. 
• 
If a study participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records and 
comply. 
• 
The Sponsor will continue to retain and use all research results and/or data that have already 
been collected for the study evaluation, unless the participant has requested destruction of 
these samples and data. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as permitted by local regulations). 
• 
From an analysis perspective, a ‘withdrawal’ from the study refers to any participant who did 
not come back for the concluding visit/was not available for the concluding contact foreseen in 
the protocol. A study participant is considered a ‘withdrawal’ from the study when no study 
procedure has occurred, no follow-up has been performed and no further information has been 
collected for this participant from the date of withdrawal/last contact. 
• 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. Should 
pregnancy occur in the study it is advisable that the participant continue in the study to be 
monitored and a pregnancy notification form and outcome of the pregnancy and infant should 
be recorded.   
• 
 Participants who withdraw, are withdrawn or terminated from this study, or are lost to follow-
up after signing the ICF but prior to study vaccination may be replaced.  
• 
Whenever possible, it is desired that participant remain in the study to be followed for safety.  It 
is highly encouraged to allow safety follow up to be achieved for participant constraints (e.g., 
phone follow up) rather than to have a participant withdrawal from the study.  
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for at least 3 scheduled visits 
and is unable to be contacted by the study site staff. 
  

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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit as per the study 
visit window and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls, home visit if 
necessary, or local equivalent methods). These contact attempts should be documented in the 
participant's medical record or study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 

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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 INFORMED CONSENT, RECRUITMENT, SCREENING ND OTHER STUDY PROCEDURES 
 
At the beginning of the study, potential participants will be approached using a recruitment script at the 
HIV treatment, care clinics within the Hospitals, health facilities within the study areas or any site 
recruitment facility by study staff delegated to carry out recruitment activities. Prior to any volunteer 
joining the study, a briefing session with a review of inclusion and exclusion may be completed to minimize 
the number of screen failures and ensure participants have interest to participate.  The study staff will 
brief the participants and their parents/legally acceptable representatives (LAR) for those below 18 years 
(or age appropriate based on national guidelines and referenced herein as ‘below 18 years) individually 
or in small groups about the study with the aid of study briefing materials (study information leaflet) and 
may also use the informed consent document to review critical information. At the end of the briefing, 
questions will be addressed. This will enable participants and their parents/LAR to understand the purpose 
of the study as well as the study procedures. They will be given adequate time to think about participating, 
ask any questions and decide whether they want to participate or not. Thereafter, the informed consent 
review will be completed and a signature on the written informed consent document will be obtained 
from each individual who wants to participate in the study. The participant and their parents/LAR for 
those below 18 years and the study staff conducting informed consent and assent explanation will sign 
and date the consent and assent forms. The participant signature confirms that (s)he has understood the 
information. For illiterate individuals, the informed consent process will be conducted in the presence of 
an impartial witness. The participant and their parents/LAR for those below 18 years will thumb print the 
consent form and assent form and the witness will sign and date the form. Each participant’s consent and 
assent forms will be kept in their study folder and a copy will be given to the participant to take home on 
the same day. The study team will use the participant’s preferred language usually English, French, or local 
language for both consent and assent depending on the study site. In case of any amendments to the 
protocol resulting in changes in study procedures, the participant will be informed, and additional 
informed consent and assent will be obtained if necessary.  Formal screening will only commence once 
informed consent has occurred.  In accordance with Good Clinical Practice, the volunteer may terminate 
participation in the study at any time for any reason without penalty. Additionally, in the event that the 
participant is unable or unwilling to adhere to the protocol design, the investigator may terminate 
participant’s participation. 
 
Screening procedures are to be completed as shown in the Study Schedule of Events (Table 1).  
 
Screening procedures include (but are not limited to); vital signs, medical history, concomitant 
medications, demographics, physical examination, standard laboratory screening tests (Complete Blood 
Count (CBC) including Hemoglobin, White Blood Cells and, Platelets, Creatinine, ALT, AST, HIV rapid test), 
and in HIV (+) subjects: HIV viral load and CD4 count.  A urine/serum pregnancy test will be performed on 
all female participants of childbearing potential. Certain exclusions allow rescreening.  Participants 
excluded from this study because of significant abnormalities not previously known by them will be 

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referred to an appropriate health provider for evaluation and treatment. Vitals signs will be collected in 
at the time of screening, prior to and 30-60 minutes following vaccination and at any other visit if medically 
indicated and scored by FDA toxicity grading (Table 4).  For adolescents, FDA toxicity scoring will be applied 
for fever only.  Information gathered during screening (medical history, physical examination, and 
laboratory analysis) will be recorded in the Source Documents and the eCRFs. 
 
Table 4: FDA Toxicity Scoring of Vital Signs for Adults.  Adolescents to have FDA Scoring for Fever only. 
Vital Signs *  
Mild  
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Fever (°C) **  
38.0 – 38.4  
38.5 – 38.9  
39.0 – 40 
 
> 40  
Tachycardia - beats per  
minute  
101 – 115  
116 – 130  
> 130  
ER visit or hospitalization for  
arrhythmia  
Bradycardia - beats per  
minute***  
50 – 54  
45 – 49  
< 45  
ER visit or hospitalization for  
arrhythmia  
Hypertension (systolic) -  
mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or hospitalization for  
malignant hypertension  
Hypertension (diastolic) -  
mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or hospitalization for  
malignant hypertension  
Hypotension (systolic) –  
mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or hospitalization for  
hypotensive shock  
Respiratory Rate – breaths 
per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
*vital signs to be taken at rest. 
**no hot or cold beverages or smoking for at least 15 min prior to temperature reading.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterizing bradycardia among some 
healthy subject populations. 
 
The principal investigator or designee will determine the eligibility for all participants after reviewing the 
results. A study identification document (may include photograph) will be made of each participant who 
is screened. The participants will bring the study identification cards whenever they visit the research 
clinic for checkup(s).  
8.2 STANDARD OF CARE STUDY PROCEDURES 
 
For the duration of their participation in the trial, all participants will receive essential health care in 
accordance with National Ministry of Health guidelines. Treatment and care for COVID-19 will primarily 
be through respective country MoH facilities in accordance with national guidelines. However, if inpatient 
care is required and if the capacity of the MoH facilities is overwhelmed and unable to provide necessary 
care to the volunteer, the site will strive to arrange for alternative care at an appropriate faith based or 
private health facilities as deemed appropriate to the extent possible with the current COVID-19 bed 
capacities.  

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8.3 LABORATORY PROCEDURES AND EVALUATION 
 
Laboratory samples will be collected primarily at the study site as per the laboratory manual of 
procedures. During the surveillance for symptoms of COVID-19-like illness, participants will notify 
investigators about the onset of COVID-19-like symptoms, if they had known exposure to a COVID-19 
positive contact or if they had a positive COVID test from any other source. Participants will have samples 
collected in the field or be asked to visit the site for the collection of rapid antigen testing (and 
confirmatory RT-PCR by nasopharyngeal swab for any positive rapid tests).  If confirmed as positive by 
rapid Ag testing, participants will undergo a nasopharyngeal sample for RT-PCR and complete daily 
reporting of their symptoms in the paper diary through 10 days post test. Should participants have a 
positive RT-PCR test, they will undergo genomic sequencing analysis for VOC if their CT value is significant.    
 
Blood samples will be collected using kits and supplies provided and following an aseptic technique with 
minimization of discomfort.  Nasal secretory samples will be collected using Nasosorb kit. All samples 
should follow collection and processing according to the laboratory manual of procedures. All biological 
materials collected will be handled according to established SOPs for the protection of participants and 
study staff. 
8.3.1 CLINICAL LABORATORY EVALUATIONS 
 
The clinical laboratories at the sites will process the blood samples for: CBC (Hgb, WBC, PLT), creatinine, 
ALT, AST, AIC (if required by exclusion criteria), HIV rapid test, participant viral loads and CD4 cell count 
(for HIV positive participants), FSH (optional), SARS-CoV-2 Rapid Antigen, RT-PCR test and pregnancy test 
where applicable.  
8.3.2 SPECIMEN PREPARATION, HANDLING AND STORAGE 
 
Samples will be prepared, handled, and stored according to the laboratory procedures manual and site 
laboratory SOPs as applicable. All samples will be labeled with appropriate unique identifiers.  
Documentation of samples will include such information as participant ID number, date/time of collection, 
study designee, aliquot number and any other data required by testing facility (e.g., bar codes).  Samples 
being shipped to another laboratory for performance of an assay will be sent from the study site to the 
performing lab, while maintaining appropriate temperatures according to laboratory procedures manual 
and site SOPs as applicable. A chain of custody will be maintained both at the sending lab and the receiving 
lab. Local storage of specimens (e.g., serological or respiratory samples) will be at appropriate 
temperatures and according to local SOP. 
8.3.3 SPECIMEN SHIPMENT 
 
The study immunological samples will be analyzed at a laboratory within CEPI Central Lab Network at 
the International Center for Diarrhoeal Diseases Research in Bangladesh (ICDDRB), 68, Shaheed Tajuddin 
Ahmed Sarani Mohakhali, Dhaka 1212, Bangladesh. Immunological assays will include ELISA, viral 

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neutralization antibodies and Cell Mediated Immunity (CMI). The immunology test samples to be 
transported to ICDDRB will include serum for IgG ELISA, mucosal swabs for IgA ELISA, serum for Pseudo-
neutralization antibodies and peripheral blood mononuclear cells (PBMC) samples for CMI by ELISPOT.   
8.4 SCHEDULED STUDY VISITS 
All visits completed according to the Schedule of Event (SOE) as shown in Table 1 above. 
8.5 UNSCHEDULED VISITS 
 
Any participant visit to the study sites or evaluation by study staff at a health facility that takes place 
outside of the scheduled visits will be considered an unscheduled visit. Any medical issues discovered at 
an unscheduled visit will be evaluated, treated, and/or referred as appropriate and their encounter 
documented on source documents and entered into the eCRF as an unscheduled visit. Appropriate CRFs 
will be utilized as deemed necessary for any unscheduled visit.  
 
In the case of SARS-CoV-2 symptoms or known exposure, subjects will be brought in for a rapid antigen 
test.  Any time a SARS-CoV-2 rapid antigen test is positive, subjects will have a nasopharyngeal swab taken 
for confirmation by RT-PCR.  Subjects will be dispensed a COVID-19 symptom diary to be completed daily 
for 10 days.  They will be scheduled for a follow up visit (unscheduled visit) between 10-14 days and will 
return their diary and get retested by SARS-CoV-2 rapid antigen.  Should symptoms still be present another 
COVID-19 symptom diary will be dispensed.  If rapid Antigen remains positive or subjects have another 
COVID-19 symptom diary dispensed, then they will be rescheduled in another 10 days for repeat 
testing/diary review.  This will occur until subjects are both symptom free as well as rapid antigen 
negative.  
8.6 SAFETY AND OTHER ASSESSMENTS 
The principal investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an adverse event (AE), treatment emergent adverse event (TEAE), adverse event 
of special interest (AESI) or serious adverse event (SAE). Each participant will be instructed to contact the 
investigator immediately should they manifest any signs or symptoms they perceive as serious.  Of note, 
participants should notify the site immediately if they record a grade 3 reactogenicity event and should 
be evaluated within 24 hrs. to confirm the severity.  
8.6.1 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS - DEFINITION AND CLASSIFICATION 
8.6.1.1  DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence following the use of a medicine product or 
intervention, whether or not considered causally related to that use.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new 
or exacerbated) temporally associated with the use of a medicinal product.  The occurrence of an adverse 
event (AE) may come to the attention of study personnel during study visits and interviews of a study 

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participant presenting for medical care, or upon review by a study monitor.  In vaccine studies, solicited 
adverse events (local and systemic) are proactively collected after vaccination (before exit from clinic) and 
daily for 7 days afterwards (see section 8.6.2.1). 
  
All AEs occurring within the 28 days following vaccination must be recorded.  All Treatment Emergent 
Adverse Events (TEAE) through 85 days are to be recorded.  Serious adverse events (SAE) and Adverse 
Events of Special Interest (AESI) are to be recorded from the time of randomization and vaccination until 
EOS as shown on Table 1: Study Schedule of Events. In the case of participants who are screened but never 
randomized, any medical event/illness will be captured as part of Medical History and stored in the screen 
failure documentation. The occurrence of an AE, TEAE, AESI or SAE may come to the attention of study 
personnel during study visits and field worker visits. Information to be collected includes event 
description, date of onset, clinician’s assessment of severity, relationship to study product, and date of 
resolution/stabilization of the event. All AEs that are required to be identified during a specific study visit 
interval will be followed to adequate resolution, until stable (which may include a new baseline status) or 
until EOS. 
 
All AEs either observed by the investigator or a member of the study team or reported by the participant 
spontaneously or in response to a direct question will be evaluated by the investigator as outlined in the 
schedule of events. The nature of each event, date and time of onset (where appropriate), outcome, 
intensity and relationship to drug administration should be established. Details of any supportive 
treatment given should be recorded on the appropriate page of the CRF. When an AE occurs, it is the 
responsibility of the investigator to review all documentation relative to the event and ensure appropriate 
detail is documented in the source documents.  
 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the 
individual signs/symptoms.  
 
 Any medical condition that is present at the time that the participant is screened will be considered as 
baseline Medical History and not reported as an AE. However, if the study participant's medical condition 
deteriorates at any time during the study, it will be recorded as an AE. 
  
Maximum severity of an AE will be documented in addition to the duration of the event. AEs characterized 
as intermittent require documentation of onset and duration of each episode. 
  
At each study visit, the investigator will inquire about the occurrence of AEs (those being monitored at 
the time) since the last visit, in accordance with the adverse events being collected at that timepoint.  Any 
interventions required to treat a disease or condition in an enrolled participant will be allowed. Treatment 
of any AE is at the sole discretion of the investigator in accordance with the local treatment guidelines 
and clinical practices. Any medication administered for the treatment of an AE should be recorded in the 
participant’s eCRF. 
 

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The PI/designee will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention in the supporting 
study documents such as the protocol and investigator brochure (IB).  Suspected Unexpected Serious 
Adverse Reactions (SUSAR) are reportable to authorities similar to SAEs.  
8.6.1.2  SEVERITY OF ADVERSE EVENT 
 
The guideline below will be used to describe severity of AEs. 
• 
Grade 1; Mild – Events require minimal or no treatment and does not interfere with the 
participant's daily activities. 
• 
Grade 2; Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• 
Grade 3; Severe – Events interrupt a participant's usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
8.6.1.3  RELATIONSHIP TO STUDY VACCINE OR PROCEDURE 
 
All adverse events (AEs) must have their relationship to study vaccine (or a procedure) assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below.  
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
8.6.1.4  DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  

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• 
a congenital anomaly/birth defect.  
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Medical or scientific judgement should be exercised 
in deciding whether reporting is appropriate in other situations. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
8.6.1.5  ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
POTENTIAL IMMUNE-MEDIATED MEDICAL CONDITIONS (PIMMC) 
PIMMC is a subset of AEs i.e., Adverse Events of Special Interest (AESI) that include autoimmune diseases 
and other inflammatory and/or neurologic disorders of interest which may or may not have an 
autoimmune etiology. AEs that need to be recorded and reported as PIMMCs include, but are not limited 
to, those listed in Table 5 below. The investigator will exercise their best medical and scientific judgment 
in deciding whether other diseases have an autoimmune origin and should refer to the investigational 
brochure. In addition, the study team will use the Brighton Collaboration Guidelines on AESI Case 
Definitions as provided in the website (https://brightoncollaboration.us/category/pubs-tools/case-
definitions/). This list is based on the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1 
and may be updated during the trial conduct. 
 
Table 5. List of Potential Immune-Mediated Medical Conditions 
Neuroinflammatory 
Disorders 
Cranial nerve disorders, including paralyses/paresis (e.g. Bell’s palsy); Optic 
neuritis; Multiple sclerosis; Transverse myelitis; Guillain-Barre syndrome, 
including Miller Fisher syndrome and other variants; Acute disseminated 
encephalomyelitis, including site specific variants (e.g. encephalitis, 
encephalomyelitis, myelitis, myeloradiculomyelitis, cerebellitis); Myasthenia 
gravis, including Lambert- Eaton myasthenic syndrome; Immune-mediated 
peripheral neuropathies and plexopathies, (including chronic inflammatory 
demyelinating 
polyneuropathy, 
multifocal 
motor 
neuropathy 
and 
polyneuropathies associated with monoclonal gammopathy); Narcolepsy 
Musculoskeletal 
Disorders 
Systemic lupus erythematosus; Scleroderma, including diffuse systemic form 
and CREST syndrome; Systemic sclerosis; Dermatomyositis; Polymyositis; 
Antisynthetase syndrome; Rheumatoid arthritis; Juvenile chronic arthritis, 
(including Still’s disease); Polymyalgia rheumatica; Spondyloarthritis, including 
ankylosing 
spondylitis, 
reactive 
arthritis 
(Reiter's 
Syndrome) 
and 
undifferentiated 
spondyloarthritis; 
Psoriatic 
arthropathy; 
Relapsing 
polychondritis; Mixed connective tissue disease 
Skin Disorders 
Psoriasis; Vitiligo; Erythema nodosum; Autoimmune bullous skin diseases 
(including pemphigus, pemphigoid and Dermatitis herpetiformis); Cutaneous 

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lupus erythematosus; Alopecia areata; Lichen planus; Sweet’s syndrome; 
Morphoea 
Liver Disorders 
Autoimmune hepatitis; Primary biliary cirrhosis; Primary sclerosing cholangitis; 
Autoimmune cholangitis 
Gastrointestinal 
Disorders 
Crohn’s disease; Ulcerative colitis; Ulcerative proctitis; Celiac disease 
Metabolic Disorders 
Autoimmune thyroiditis (including Hashimoto thyroiditis); Grave's or 
Basedow’s disease; Diabetes mellitus type I; Addison’s disease 
Vasculitides 
Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis 
and temporal arteritis; Medium sized and/or small vessels vasculitis including: 
polyarteritis nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg–Strauss syndrome (allergic granulomatous angiitis), 
Buerger’s disease (thromboangiitis obliterans), necrotizing vasculitis and anti-
neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), 
Henoch- Schonlein purpura, Behcet's syndrome, leukocytoclastic vasculitis. 
Other 
Autoimmune 
hemolytic 
anemia; 
Autoimmune 
thrombocytopenia; 
Antiphospholipid 
syndrome; 
Pernicious 
anemia; 
Autoimmune 
glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, 
membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis); Uveitis; 
Autoimmune myocarditis/cardiomyopathy; Sarcoidosis; Stevens-Johnson 
syndrome; Sjogren’s syndrome; Idiopathic pulmonary fibrosis; Goodpasture’s 
syndrome; Raynaud’s phenomenon 
COVID-19 ILLNESS 
Participants will be monitored for signs of COVID-19 compatible illness throughout the study (Day -30 to 
Day 365). If a COVID-19 event of special interest (Table 8) occurs than a COVID-19 Report Form will be 
completed and expedited safety reporting timelines (e.g., SAE) will be followed as applicable.  
 
Table 6: Adverse Events of Special Interest Relevant to COVID-19  
Body System  
Diagnosesa  
Immunologic   
Enhanced disease following immunization, cytokine release syndrome 
related to  
COVID-19b, Multisystem inflammatory syndrome in children (MIS-C)  
Respiratory  
Acute respiratory distress syndrome (ARDS)  
Cardiac  
Acute cardiac injury including:   
• 
Microangiopathy  
• 
Heart failure and cardiogenic shock  
• 
Stress cardiomyopathy  
• 
Coronary artery disease  
• 
Arrhythmia  

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• 
Myocarditis, pericarditis  
Hematologic  
Coagulation disorder  
• 
Deep vein thrombosis  
• 
Pulmonary embolus  
• 
Cerebrovascular stroke  
• 
Limb ischemia  
• 
Hemorrhagic disease  
• 
Thrombotic complications  
Renal  
Acute kidney injury   
Gastrointestinal  
Liver injury   
Neurologic  
Guillain-Barré Syndrome, anosmia, ageusia, meningoencephalitis  
Dermatologic  
Chilblain-like lesions, single organ cutaneous vasculitis, erythema 
multiforme  
 
When there is enough evidence to make any of the above diagnoses, the AE must be reported as an AESI 
and must follow reporting rules of an SAE.  
8.6.2 ADVERSE EVENTS REPORTING 
8.6.2.1 SOLICITED ADVERSE EVENTS REPORTING 
 
Participants will remain in clinic for 30-60 min and be monitored for immediate reactogenicity using the 
parameters for local and systemic reactogenicity (tables 7 and 8 below).  All participants will self-monitor 
(daily) solicited AEs for 7 days after vaccination. Solicited injection site and systemic reactions (tables 7 
and 8) will be collected with FDA toxicity scoring applied.    In the case when there are not symptoms then 
a grade of 0 will be applied.  Subjects will be counselled to seek an immediate unscheduled visit if they 
record any reactogenicity that would appear to be a grade 3 or greater. Should a solicited adverse event 
exceed the 7 day period beyond vaccination than the event will be collected as an unsolicited adverse 
event, with the start date consistent with the time of the reactogenicity reporting but with standard AE 
clinical grading applied to the Adverse event classification.  This allows the event to ensure a time to 
resolution is recorded. 
Table 7: FDA Toxicity Table (Local Reactogenicity) 
PARAMETER 
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY 
LIFE-THREATENING 
(report as SAE) 
Injection Site Pain or 
Tenderness 
 
Discomfort but does 
not limit use of limb 
Interferes with activity 
OR repeated use of 
non-narcotic pain 
relief medication.    
Prevents daily activity 
OR use of narcotic 
pain reliever 
ER visit or Hospitalized 
Injection Site 
Erythema or Redness 
Adult 
 
2.5 - 5 cm 
 
5.1 - 10 cm  
 
>10 cm  
Necrosis,  or exfoliative 
dermatitis  

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≤ 15 years of age* 
≤ 2.5 cm in diameter  
> 2.5 cm in diameter 
with <50% surface 
area of the extremity 
segment involved  
≥ 50% surface area of 
the extremity segment 
involved OR 
ulceration, infection, 
phlebitis, abscess or 
drainage   
Injection Site 
Induration or 
swelling 
 
2.5 - 5 cm AND does 
not interfere with 
normal activity 
5.1- 10 cm OR 
interferes with normal 
activity 
> 10 cm OR prevents 
daily activity 
Necrosis  
≤ 15 years of age* 
≤ 2.5 cm in diameter  
> 2.5 cm in diameter 
with <50% surface 
area of the extremity 
segment involved  
≥ 50% surface area of 
the extremity segment 
involved OR 
ulceration, infection, 
phlebitis, abscess or 
drainage   
Injection Site 
Pruritus* 
Itching localized to 
the injection site 
Itching beyond the 
injection site that is 
not generalized  
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
*DAIDS definition 
Table 8: FDA Toxicity Table (Systemic Reactogenicity) 
SYSTEMIC (GENERAL) 
MILD (GRADE 1) 
MODERATE (GRADE 
2) 
SEVERE 
(GRADE 3) 
POTENTIALLY LIFE 
THREATENING 
(GRADE 4) (report as 
SAE) 
Fever* 0C 
 
38.0-38.4 
 
38.5-38.9 
 
39.0-40.0 
 
>40 
Nausea/vomiting** 
No interference with 
activity OR 
1 – 2 episodes/24 
hours 
Some interference 
with activity OR 
> 2 episodes/24 hours 
Prevents daily activity 
OR requires 
outpatient IV 
hydration 
ER visit or 
hospitalization  
Diarrhea** 
2 – 3 loose stools  
4 – 5 loose stools  
6 or more watery 
stools OR requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference with 
activity 
Some interference 
with activity OR 
repeated use of non-
narcotic pain reliever 
> 24 hours or  
Prevents daily activity 
OR use of narcotic 
pain reliever  
ER visit or 
hospitalization 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Prevents daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Prevents daily activity 
ER visit or 
hospitalization 
*No recent hot or cold beverages or smoking 
** Assessment is in addition to baseline clinical status 
 

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Individual Paper Diary Cards will be given to trial participants for the recording of daily safety information. 
Participants will also be provided with rulers for measuring the size of injection site reactions, and 
standard digital thermometers for measuring daily temperatures. To ensure consistency of reporting, the 
study nurses and clinicians will instruct participants on how to correctly use these tools. In case of an 
illiterate participant, the study team will arrange for assistance to the participant through a family 
member. On return to clinic (day 7, Visit 3), the Investigator or an authorized designee will interview the 
participants about the information recorded in the Diary Cards and will attempt to clarify anything that is 
not clear before data entry with assignment of a final FDA toxicity grade to each event.  In the case when 
there are not symptoms then a grade of 0 will be applied.  
8.6.2.2 UNSOLICITED ADVERSE EVENT REPORTING 
 
All Adverse Events (AE) will be followed through 28 after vaccination, all Treatment Emergent Adverse 
Events (TEAE) through 85 days after vaccination and all AESI and SAEs will be followed until end of study.  
Adverse Events of Special Interest (AESIs) include COVID-19 specific complications (Table 6) and potential 
immune mediated medical conditions (PIMMC; Table 5).  Adverse Events that occur in the above 
timeframes indicated will be followed until resolution, new stable condition or study completion. Anything 
that requires treatment beyond what the study sites can provide will be referred to an appropriate 
medical facility, with appropriate study staff continue to monitor.  Outcomes of any AE reported during 
the study will be assessed as: 
• 
Recovered/resolved 
• 
Not recovered/not resolved 
• 
Recovering/resolving 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
 
Authority reporting will follow country requires for adverse events.  All sites will be notified of significant 
adverse events at the study level that require country level reporting, regardless of the country where the 
event occurred.    
8.6.2.3  SERIOUS ADVERSE EVENT AND ADVERSE EVENTS OF SPECIAL INTEREST REPORTING 
  
The investigator will promptly report all SAEs to the Sponsor and designee responsible for safety reporting 
in accordance with the procedures detailed in this protocol. The clinical trial Sponsor has a legal 
responsibility to promptly notify the country competent regulatory authority as per local regulations 
about the safety of a product under clinical investigation. VIBRI is also responsible for reporting events to 
the study’s DSMB and disseminating information to all investigators in the appropriate format for 
reporting to local Ethics Review Committees (ERC) and Regulatory Authorities (RA), as appropriate. 
Prompt notification of SAEs by the investigator to the Sponsor and designee is essential so that legal 
obligations and ethical responsibilities towards the safety of other participants are met. The purpose of 
the report is to fulfill specific regulatory and GCP requirements, regarding the product under investigation. 
Table 9 below describes the timelines for submission of SAEs and other events reports to the sponsor. 

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Suspected Unexpected Serious Adverse Reactions (SUSAR) are reportable to Ethics and Regulatory 
Authorities similar to SAEs.  
 
 
Table 9: Timeframes for Submitting Serious Adverse Events and Other Event Reports to the Sponsor and 
Regulatory Authorities 
Type of 
Event 
Initial Reports 
Emerging Relevant 
Information 
Follow-Up Report 
 
Timeframe* 
Documents 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours 
SAE report 
24 hours 
SAE report 
7 days 
SAE report 
AESI 
24 hours 
SAE report 
24 hours 
SAE report 
7 days 
SAE report 
SUSAR 
24 hours 
SAE report 
24 hours 
SAE report 
7 days 
SAE report 
Pregnancy 
24 hours 
Pregnancy 
report 
48 hours 
Pregnancy 
report 
24 hours of 
outcome 
Infant 
report 
 
Once an investigator becomes aware/confirms that a SAE has occurred in a study participant, the 
investigator (or designate) must complete the information in the SAE report as thoroughly as possible 
with all available details of the event, within 24 hours. Even if the investigator does not have all 
information regarding a SAE, the report must be completed and reported within 24 hours. Once additional 
relevant information is received, the report should be updated within 7 days of receipt of relevant 
information. The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator is required to proactively follow each participant and provide additional relevant 
information on the participant’s condition to the Sponsor and/or designee responsible for medical 
monitoring and safety reporting. 
 
Once onset of an AESI is diagnosed in a study participant, the investigator (or designate) must complete 
the information on the AESI report within 24 hours after awareness of the diagnosis. AESI will be reported 
within 24 hours.  Updates to reported AESIs will follow SAE reporting criteria.  
 
An SUSAR that occurs in the trial requires reporting to each investigator who will then file it within the 
Investigator Study File and will notify the IRB/IEC and the country regulatory authority within 7 calendar 
days.  
 
The Sponsor may request that the investigator performs or arranges the conduct of additional clinical 
examinations/tests and/or evaluations, within the limits of available care, to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a participant dies 
during participation in the study or during a recognized follow-up period, the DSMB, Sponsor, and IRB will 
be provided with any available post-mortem findings. 
 
Annual safety reporting (or more frequent if required) will be provided to ethics and regulatory authorities 
per requirements. 

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8.6.2  REPORTING OF PREGNANCY 
  
Pregnant women are not eligible to participate in the study and females of childbearing potential must 
agree to use an effective contraceptive method during a period starting 4 weeks prior to through 12 weeks 
following vaccination. However, a participant could potentially become pregnant during her participation. 
If a pregnancy occurs during study participation: 
• 
When pregnancy exposure is reported following booster vaccination, the investigator should 
promptly inform the Sponsor and will record pregnancy information together with the 
contraceptive method on the appropriate form and submit to the safety database and per ethics 
and regulatory authorities within the designated regulatory reporting period. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE.  
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• 
The participant will be followed through delivery/termination of pregnancy with information on 
the participant and the neonate. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
The investigator, or his designee, will record pregnancy information on the Pregnancy Notification Report 
Form and submit it to the respective ethics committees and country regulatory authorities.  The Sponsor 
will review all pregnancy reports as will the medical monitor.  Follow up reports regarding the outcome 
of the pregnancy will be submitted once obtained. 
8.6.3.3  REPORTING EVENTS TO PARTICIPANTS 
 
When new pertinent information becomes available, informed consent will be updated and participants 
reconsented.  
8.6.5 UNANTICIPATED PROBLEMS REQUIRING ETHICS COMMITTEE REPORTING 
8.6.5.1  DEFINITION OF UNANTICIPATED PROBLEMS (UP) AND REPORTING 
 
The unanticipated problems involving risks to participants or others include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the ERC-approved research protocol and 

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informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
Unanticipated problems include problems that are not specifically described in the protocol that affect 
subjects or personnel involved in trial conduct.  Events that are identified as significant protocol deviations 
or safety issues will be assessed by investigators and with sponsor oversight for appropriate ethics 
committee reporting on a routine basis and as per ethics requirements within each country.  The 
seriousness of the event will be included and if additional important data become available at a later date 
then ethics committees will be updated accordingly. For example, misplacing a participant’s study records 
containing identifiable private information results in the risk of breach of confidentiality. Another example 
would be administering the wrong agent to a participant at one-time point in a series of vaccinations. 
Risks to others must also be reported. Appropriate supporting documents should be submitted with the 
unanticipated problem report. 
 
All non-serious unanticipated problems (events not involving risk to participants or others) will be 
reported in the continuing review report to the respective ethics committees for the study sites as per 
regulatory requirements.  
 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
The null and alternative hypothesis for the primary endpoints: 
 
H0 (Safety): There is no expected difference in % solicited adverse events (AEs) across the three vaccine 
platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-
CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents. 
H1 (Safety): There is an expected difference in % solicited adverse events (AEs) across the three vaccine 
platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-
CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents. 
 
H0 (Safety): There is no expected difference in SAE rate attributed to vaccine across the three vaccine 
platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-
CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents. 
H1 (Safety): There is an expected difference in SAE rate attributed to vaccine across the three vaccine 
platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-
CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents. 
 
H0 (Immune Response IgG): Among participants with HIV infection there is no expected difference in the 
GMT or GMFR response by ELISA between the 2 vaccine treatment groups at Day 28 for any one 
platform or across all platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and 
Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents.   
H1 (Immune Response IgG): Among participants with HIV infection there is an expected difference in the 
GMT or GMFR response by ELISA between the 2 vaccine treatment groups at Day 28 for any one 
platform or across all platforms after boosting with either Ad26.COV2S1 vs NVX-CoV2373 for adults and 
Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines for adolescents.   
 
H0 (Immune Response Neutralization): Among participants with HIV infection there is no expected 
difference in the neutralization titre response (absolute or GMFR) between the 2 vaccine treatment 
groups at Day 28 for any one platform or across all platforms after boosting with either Ad26.COV2S1vs 
NVX-CoV2373 for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
vaccines for adolescents.  
H1 (Immune Response Neutralization): Among participants with HIV infection there is an expected 
difference in the GMT response by neutralization titre response (absolute or GMFR) between the 2 
vaccine treatment groups at Day 28 for any one platform or across all platforms after boosting with 
either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-
1273 or Pfizer/BNT) vaccines for adolescents.  
 
H0 (Immune Responses compared to immune competent): Among participants with HIV infection there 
is an expected lower immune response over time (IgG ELISA and neutralization titres) when compared 

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to HIV (-) participants for any one platform or across all platforms after boosting with 
either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-
1273 or Pfizer/BNT) vaccines for adolescents.   
H1 (Immune Responses compared to immune competent): Among participants with HIV infection there 
is not an expected lower immune response over time (IgG ELISA and neutralization titres) when 
compared to HIV (-) participants for any one platform or across all platforms after boosting with 
either Ad26.COV2S1 vs NVX-CoV2373 for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-
1273 or Pfizer/BNT) vaccines for adolescents.    
 
H0 (SARS-CoV-2 breakthrough infections): There is no expected difference in breakthrough SARS-COV2 
infections (AEs) after boosting with either Ad26.COV2S1 vs NVX-CoV2373 (across primary vaccine 
platforms) and for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
vaccines for adolescents. 
H1 (SARS-CoV-2 breakthrough infections): There is an expected difference in breakthrough SARS-COV2 
infections (AEs) after boosting with either Ad26.COV2S1 vs NVX-CoV2373 (across primary vaccine 
platforms) and for adults and Novavax NVX-CoV2373 vs mRNA (Moderna mRNA-1273 or Pfizer/BNT) 
vaccines for adolescents. 
 
Sequentially rejective procedures will be used within secondary objectives and will be ordered in the 
Statistical Analysis Plan in the following general hierarchy.  Within each of the general hierarchy 
endpoints will be tested by order according to their relative importance. Within an objective, if more 
than one endpoint is included, a Holm procedure (also known as a stepdown Bonferroni procedure) will 
be used to account for multiple testing. The importance order for secondary objectives and Holm 
procedure will be described in the statistical analysis plan (SAP). Further details of the planned statistical 
analyses, methods, and data conventions will be described in the SAP. 
9.2 STATISTICAL ANALYSES 
The statistical analysis will be conducted following the principles as specified in the International 
Conference on Harmonization (ICH) Topic E9 (ICH, 1998). There will be 3 interim analyses with database 
freeze and a final statistical analysis performed after database lock.  
All data will be collected and verified prior to analysis. Detailed statistical procedures, listings, table shells, 
and figures will be provided in a statistical analysis plan (SAP). The SAP will be finalized before study 
temporary database lock for interim analysis and will be signed off by the Sponsor prior to conducting any 
analyses.  
The following key statistical components and a detailed description will be documented in the SAP: 
• 
Primary and secondary endpoints and how they will be measured 
• 
Statistical methods and tests that will be used to analyze the endpoints 

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• 
Strategy that will be used if the statistical test assumptions are not satisfied e.g., log 
transformation of IgG titres to render normality assumptions. 
• 
Indication of whether the comparisons will be using one-tailed or two-tailed tests (with 
justification of the choice) and the level of significance to be used  
• 
Identification of whether any adjustments to the significance level or the overall p-value will be 
made to account for any planned or unplanned subgroup analyses or multiple testing. 
• 
Specification of potential adjusted analyses and a statement with which covariates or factors 
will be included. This will include comparison between the 2 booster vaccines and interaction 
with HIV status  
• 
Planned exploratory analyses and justification of their importance 
The number of participants enrolled, randomized, vaccinated, completed, or withdrawn will be 
summarized. Reasons for withdrawal, when known, will be provided. Demographic data will be 
summarized by descriptive statistics and will include total number of observations (n), mean, standard 
deviation (SD) or median and interquartile range as appropriate for continuous variables, and number and 
percentages for dichotomous variables. 
The safety analysis set will consist of all randomized participants who receive study vaccine and have any 
safety data available. Participants will be classified according to the actual vaccine received. Safety will 
include a) reactogenicity (solicited) daily for 7 days following vaccination; b) adverse events (unsolicited) 
through 28 days following vaccination; c) TEAE through 84 days following vaccination and c) AESI and SAEs 
through end of study.  
The intent-to-treat analysis set will consist of all randomized participants. Participants will be classified 
according to study group. Participant’s disposition, demographics, and medical history will be summarized 
on the analysis set. 
The immunogenicity analysis set will consist of all participants in the intent-to-treat analysis set who 
receive study vaccine, have a baseline and at least 1 post-vaccination sample for which valid results were 
reported for the test being analysed, and did not receive any COVID-19 vaccine or monoclonal antibody 
outside of the study. Participants will be classified as randomized.  
Statistical analysis will be performed using STATA version 16 or later and R software. Continuous variables 
will be summarized using the mean and standard deviation or median or median and interquartile range 
as appropriate. Categorical variables will be summarized using frequency counts and percentages, as well 
as 2-sided 95% confidence interval (CI) for proportions computed using the Clopper-Pearson method tests 
of associations using a Chi-square or the Fishers exact test as appropriate.  
Immunogenicity endpoints (GMT, GMFR) will be summarized by age groups (12-17, 18-44, 45-64) and 
across age groups, by country (within age groups), by primary platform and by boosting vaccine.   
Additional descriptive analysis by CD4 counts and key co-morbid health diagnoses will be performed to 

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assess if any participant who progresses to a more severe immunocompromised status has reduced 
immunity compared to counterparts.  Reporting will be at country level and in aggregate. Serum and 
mucosal immunogenicity endpoints will be summarized by treatment group at each time point collected, 
relative to baseline and relative to pre-boost values and will include the GMTs with 95% CIs and GMFRs 
with 95% CIs. Similar reporting will occur for neutralization results using pseudo neutralization readouts.  
All assays will be standardized using WHO (or similar) standards.  For immunogenicity analysis, it is 
assumed that the natural log of the data is normally distributed. All statistical tests will be 2-sided at 
5% significance level. 
The SARS-CoV-2 breakthrough disease analysis set will consist of all participants in the intent-to-treat 
analysis who received at least one dose of study vaccine and contributed data on SARS-CoV-2 symptoms 
following Day 28. The analysis will report out SARS-CoV2 cases a) by booster vaccine (all cases);  b) by 
primary platform series (all cases); c) by booster within primary platform series (all cases); d) by severity 
(mild, moderate, severe) (both by vaccine booster and by primary platform series for each vaccine 
booster); e) divergence of Kaplan Meier (KM) estimates for SARS-CoV-2 severe cases (including death); f) 
by VOC in moderate and severe cases by vaccine booster and by primary vaccine platform.   The vaccine 
efficacy post booster will be compared between the two arms as an exploratory objective as the study is 
not powered to test these strategies.  The SARS-CoV-2 event rates (and severity) will continue to be 
collected through end of study and descriptive analyses will be reported (including KM curves). 
A longitudinal analysis of safety and immunogenicity will be conducted at different timepoints during the 
study including from baseline, D28, D85, 6mo, 12mo to end of the study.   
Interim analyses 
There will be 3 interim analysis time points by vaccine platform: a) 28 days following booster vaccination 
in adults/adolescents (safety and immunogenicity); b) 6 months after adult/adolescent booster 
vaccination; c) 12 months after booster vaccination for all subjects (safety, immunogenicity and SARS-
CoV-2 breakthrough infections).  The interim analyses will be at the treatment level only and blinding will 
remain at the individual level, site level and for all operational teams and sponsor.  The final database lock 
and analysis will occur after all adult participants have completed the long term follow up (15-18 months) 
and adolescents have completed 12 months of follow up.  Both sponsor and DSMB will have interim 
analyses available for decision making.  

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
The conduct of this study will be consistent with the standards established by the Declaration of Helsinki 
and compliant with the ICH guidelines for GCP as well as with all local ERC/IRB requirements and/or 
national regulations and directives.  
  
Before the inclusion of the first participant, this protocol, the informed consent form (ICF), and other 
written information to be provided to participants will be approved by, and/or receive favorable opinion 
from, the appropriate ERCs or IRBs. In accordance with Good Clinical Practice (GCP) and local regulations, 
each Investigator and/or the Sponsor are responsible for obtaining this approval and/or favorable opinion 
before the start of the study. If the protocol is subsequently amended, approval will be re-obtained for 
each substantial amendment from the relevant ERC/IRB depending on the nature of the amendment. 
Copies of these approvals, along with information on the type, version number, and date of document, 
and the date of approval, will be forwarded by the Investigator to the Sponsor. 
 
According to the WHO, National Regulatory Authorities and National Ethics Committees from across Africa 
agreed to combine their expertise to expedite clinical trial review and approvals for new multinational 
preventive, diagnostic and therapeutic interventions to the COVID-19 pandemic. However, joint reviews 
are based on voluntary cooperation between the national regulatory authorities and ethics committees. 
Each country is solely responsible for granting regulatory approval. The agreement was reached during a 
virtual meeting convened by the World Health Organization (WHO) on 1 April 2020 under the platform of 
the African Vaccines Regulatory Forum (AVAREF), one of the Continental Technical Committees of the 
African Medicines Regulatory Harmonization Initiative. 
10.1.1 KENYA ETHICS AND REGULATORY APPROVAL 
 
The Key ethics and regulatory bodies mandated to regulate medical research including clinical trials in 
Kenya are the National Commission for Science, Technology and Innovation (NACOSTI) and the Kenya 
Pharmacy and Poisons Board (KPPB). NACOSTI gives accreditation to Ethics Review Committees including 
the Amref Scientific and Ethics Review Committee (ESRC). Before commencement of the study, the 
protocol, the informed consent form (ICF), participant recruitment procedures, and any other written 
information to be provided to participants must be approved by, and/or receive favorable opinion from, 
the Amref ESRC and the Kenya Pharmacy and Poisons Board, Expert Committee on Clinical Trials. In 
accordance with Good Clinical Practice (GCP) and local regulations, the Principal Investigator and/or the 
Sponsor will be responsible for obtaining ethical and regulatory approval and/or favorable opinion before 
the start of the study. If the protocol is subsequently amended, approval must be obtained for each 
amendment. All amendments (e.g., those that affect the conduct of the study or the safety of participants) 
require Amref ESRC approval, and must also be forwarded to regulatory authority i.e., the Kenya 
Pharmacy and Poisons Board. In Kenya, ethical approval is required prior to approval from the regulatory 

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authorities. The ethical approval process at Amref ESRC will occur in parallel with the Kenya Pharmacy 
and Poisons Board which takes about 1 month. Before the investigational product can be shipped to the 
investigational site, the pharmacy and poisons board issues a permit after approval of the protocol and 
study documents. Please note that for Covid-19 protocols, the review process will be expedited. Approval 
will also be sought in parallel from the County Ministry of Health and this takes a few days. The Amref 
ESRC and KPPB charge a standard fee for their review and approvals. 
10.1.2 RWANDA ETHICS AND REGULATORY APPROVAL 
 
The key ethics and regulatory bodies mandated to regulate medical research including Clinical Trials in 
Rwanda are the Rwanda National Ethics committee (RNEC) which takes control on ethical aspects of 
research projects intended to be conducted on human participants, the National Health Research 
Committee (NHRC) which aligns the research intended to be conducted in the country with the national 
health research agenda. The Rwanda Food and Drug Administration (RFDA) is the National Medicine 
Regulatory Authority that provides regulatory approvals for clinical trials. The first step involves 
submission to the Rwanda Biomedical Center (RBC) for the protocol and investigator brochure (IB). 
Approval takes/feedback takes about 5 days after which submission is made to the National Health 
Research Committee (NHRC) for the protocol and IB. The NHRC approval takes 2-4 weeks. This is followed 
by submission to the RNEC which meets monthly. Comments on the application are sent out within 2 
weeks of after the RNEC meeting. It takes about 2 months to obtain approvals at this level. After RNEC 
approval, submission is made to the RFDA, and approval is obtained within 60 days. The RNEC and RFDA 
charge a standard fee for their review and approvals. 
10.1.3 DEMOCRATIC REPUBLIC OF CONGO ETHICS AND REGULATORY APPROVAL 
 
The Directorate of Pharmacy and Medicine (Direction de la Pharmacie et du Medicament (DPM) of the 
Ministry of Health (Ministèere de la Santée) is the regulatory authority responsible for allowing clinical 
trials, as well as authorizing and controlling drug imports and exports, in the Democratic Republic of the 
Congo (DRC). In addition, an ethics committee (EC) must review the scientific validity and ethical 
acceptability of any research proposal involving human participants. 
 
The DPM is comprised of six (6) divisions including the Drug Management Division; the Pharmacy Division; 
the Division of Narcotic, Psychotropic and Dangerous Substances; the Division of Veterinary, Plant 
Protection, Cosmetic, and Dietary Products; the Division of Insurance and Quality Control of Medicines; 
and the Division for the Promotion of Medicinal Plants. The Pharmacy Division of the DPM is in charge of 
pharmaceutical inspection and legislation. The Pharmacy Division includes two 2 offices: inspection and 
control of pharmacy practice, and legislation, statistics, and archives. Pharmaceutical inspection focuses 
on best practices, including Good Manufacturing Practices (GMP) for manufacturing laboratories and drug 
production units, and Good Clinical Practices (GCP) for developing and conducting clinical trials for new 
drugs. The Pharmacy Division’s clinical trial responsibilities are carried out in collaboration with the 
National Ethics Committee (EC), the National Committee of Health Ethics (Comité National d'Éthique de 
la Santé (CNES)). CNES activities include regulatory follow up and inspecting clinical trial sites. The National 

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Ethics Committee must approve the protocol, budget and investigator brochure. They meet monthly and 
it takes about 4 weeks to get approval. The EC approval is a precondition for RA review. The RA review 
takes about 1 week to get approval in the context of COVID-19. 
 
The DPM’s Division of Insurance and Quality Control of Medicines is responsible for pharmacovigilance 
and has four offices. The DRC’s National System of Pharmacovigilance, implemented by the DPM, aims to 
identify as early as possible all the adverse effects of health products, especially those that are serious 
and unexpected. It includes the DPM’s National Pharmacovigilance Commission, which evaluates the risks 
incurred by participants in a clinical trial and advises the DPM on the trial’s continuation or 
discontinuation. In addition, the National Pharmacovigilance Center, established within the University of 
Kinshasa’s Unit of Clinical Pharmacology and Pharmacovigilance, is responsible for collecting information 
from manufacturers, health professionals, and other individuals on the adverse effects of health products; 
establishing accountability; and assessing the relative risk. For their review and approvals, the EC charges 
a fee of 2% of non-investment costs calculated from the study budget and RA charges a standard annual 
fee for none registered product applications and a very minimal fee for trials based on registered products. 
10.2 PROTOCOL AMENDMENTS 
  
Any amendments to this protocol must be discussed and approved by the Sponsor. If agreement is 
reached concerning the need for an amendment, it will be produced in writing by the Sponsor, and the 
amended version of the protocol will replace the earlier version. 
  
All substantial amendments (e.g., those that affect the conduct of the study or the safety of participants) 
require Ethics Review Committee (ERC/IRB) approval and must also be forwarded to regulatory 
authorities. An administrative amendment to a protocol is one that modifies some administrative, 
logistical, or other aspect of the study but does not affect its scientific quality or have an impact on 
the participants’ safety. The ERCs/IRBs need only to be notified about administrative changes. The 
Investigator is responsible for ensuring that changes to an approved study, during the period for which 
ERC approval has already been given, are not initiated without ERC review and approval, except to 
eliminate apparent immediate hazards to participants. 
10.3 REPORTING REQUIREMENTS 
10.3.1 CONTINUING REVIEW REPORTING 
 
The PI or designee will be responsible for submitting the required continuing review report and supporting 
documentation to the respective study site’s ERC and regulatory authorities, allowing sufficient time for 
review and continuation determination prior to the established continuing review date. 
 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a trial intervention under clinical investigation. The Sponsor will comply with 

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country-specific regulatory requirements relating to safety reporting to the regulatory authority, ERC and 
investigators. 
10.3.2 PROTOCOL DEVIATION REPORTING 
 
A protocol deviation is any change, divergence, or departure from the study design or procedures defined 
in the protocol. A major deviation is a non-compliance that significantly affects the participant’s rights, 
safety, or well-being and/or the completeness, accuracy, and integrity of the study data. A major deviation 
can include nonadherence to regulatory authority including ICH E6(R2) guidelines. 
 
Major protocol deviations will be reported by email and/or phone to the respective ERC/IRB and 
regulatory authority according to respective country guidelines. All deviations will be summarized in the 
continuing review reports that are submitted. A copy of continuing review report will be provided to the 
Sponsor for acknowledgment. The Principal Investigator or designee is responsible reporting the major 
and minor deviations to the Sponsor and the ERCs appropriately. 
 
Sponsor and study sites will conduct regular Protocol deviation review meetings during the study with 
final classification agreed upon.  
 
Any suspensions (to include continuing review lapses), clinical holds (voluntary or involuntary), or 
terminations of this research by an ERC, the institution, the Sponsor, or regulatory agencies will be 
promptly reported to the Sponsor, ERC and authorities. 
10.3.3 REPORTING OF INSPECTIONS OR AUDITS 
 
Knowledge of any pending compliance inspections/visits by a government agency concerning clinical 
investigation or research, the issuance of Inspection Reports, warning letters or actions taken by any 
Regulatory Agencies including legal or medical actions and any instances of serious or continuing 
noncompliance with the regulations or requirements will be reported immediately to the ERC and Sponsor 
by phone, email or facsimile. 
10.4 INFORMED CONSENT PROCESS 
 
Consent forms describing in detail the study agent, study procedures, and risks and benefits are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study products. 
10.4.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS  
 
Consent forms describing in detail the study agent, study procedures, and risks and benefits are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study products. 

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Test of Understanding (TOU) 
The TOU is a short assessment of the participants or parent/guardian of the potential participant’s 
understanding of key aspects of the study. The test will help the study staff to determine how well the 
participant or parent/guardian understands the study and their requirements for participation in the 
study. The participant or parent/guardian must pass the TOU, indicating that he or she understands the 
purpose of, and procedures required for the study, after reading the informed consent and after the 
investigator or designee has provided detailed information on the study and has answered the questions 
of participant or the parent/guardian. The participant or parent/guardian must subsequently sign the ICF, 
indicating that he or she is willing to allow their child to participate in the study. If a participant or a 
parent/guardian fails to achieve the passing score on an attempt, further information and counselling will 
be provided to the participant or parent/guardian by a study team member. The participant or 
parent/guardian is allowed to retake the test twice to achieve the passing score (≥90%) required for 
participation of their child in the study. If the participant or parent/guardian fails to achieve the passing 
score on the third attempt they will not be able to re-take the test again, and their child will not be allowed 
to participate in the study. Any participant or parent/guardian of a potential participant not capable of 
understanding the key aspects of the study, and their requirements for participation, should not be 
allowed to enroll in the study. 
10.5 CONFIDENTIALITY AND PRIVACY 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
Sponsor(s). This confidentiality is extended to cover testing of biological samples in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the Sponsor. The study 
monitor, other authorized representatives of the Sponsor, ERCs/IRBs and regulatory agencies may inspect 
all documents and records required to be maintained by the investigator. 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location. 
10.6 FUTURE USE OF STORED SPECIMENS AND DATA 
 
Left over biological samples and use of data, any unused part of the serum or other biological samples 
collected for this study may be retained in long-term storage to support answers to regulatory questions 
related to the product’s licensure and the potential revalidation of the study results. After the end of the 
trial, any unused part of the serum or respiratory samples will be securely stored at the VIBRI, CEPI CL Lab 
Network or Contract Research Organization (CRO) up to 10 years. These samples are being retained in 
long-term storage to support answers to regulatory questions related to the product’s licensure and the 
potential revalidation of the trial results. Participants will be asked to consent for the future use of these 
specimens beyond the scope of the testing outlined in this protocol, but consent for future use will not 

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be required for participation in this study. Participants will be asked to indicate in the ICF whether they 
will permit the future use of any unused stored serum samples for other tests not related to trial 
objectives. If they refuse permission, the samples will not be used for any testing other than that directly 
related to this trial. If they agree to this use, they will not be paid for giving permission. Anonymity of 
samples will be ensured. The aim of any possible future research is unknown today and may not be related 
to this particular study. It may be to improve the knowledge of vaccines and their mechanism of action, 
the knowledge of infectious diseases, or to improve existing tests or develop new tests to assess vaccines, 
or to help identify new vaccine targets or biomarkers that predict participant response to the vaccine. 
Such research may also include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. Genetics are not evaluated in this study. 
10.7 KEY ROLES AND STUDY GOVERNANCE 
 
The study will have a Joint Steering Committee (JSC) composed of representative of the funding agency 
and the sponsor. The JSC will monitor progress of the study.  The protocol implementation will be 
overseen by Trial Management Committee (TMC) composed of the Study Chairman, Site Study 
Coordinators, Project Managers, Data Managers, Laboratory Leads. The TMC will oversee implementation 
of the protocol. Data and Safety Monitoring Board (DSMB) will be responsible for safeguarding the 
interests of the trial participants and to monitor the data collected in the trial. Specific roles and 
responsibilities of the DSMB will be outlined in the DSMB Charter.  The sponsor and principal investigator 
will agree, in writing prior to the start of the study, to the charter of the DSMB. The DSMB will conduct 
meetings on a quarterly basis but could also have ad hoc meetings.  
10.8 SAFETY OVERSIGHT 
 
The Medical Monitor or their approved alternate are required to review all unanticipated problems 
involving risks to participants or others, and serious adverse event (SAE) reports, in a timely manner as 
described in the safety monitoring plan.  Scheduled reviews with the sponsor’s medical representative 
will occur. The Medical monitor is responsible for observing for study pauses and will declare when a study 
pause rule has been met.  They are responsible for ensuring needed safety evaluations are available to 
the DSMB.  The medical monitor must complete a review of the final assessment of any AE related to IP 
and provide summary assessments to the sponsor on pre-arranged frequency as outlined in the safety 
monitoring plan.   Medical monitors have the authority to pause enrollment or vaccination, trigger further 
investigation at a site or take additional steps necessary to protect the safety and well-being of research 
participants.  
10.9 CLINICAL MONITORING 
 

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Appropriate training of the protocol and all associated activities (e.g. data entry, data cleaning, pharmacy 
procedures, laboratory procedures, documentation practices, etc). is the responsibility of the sponsor and 
any designee. Site clinical monitoring will be conducted to ensure that the rights and well-being of human 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and that 
the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, 
and with applicable regulatory requirement(s). A separate clinical monitoring plan (CMP) will be prepared 
by the CRO for the study. The primary objectives of the monitors during the on-site and remote visits will 
be to ensure the study is being conducted according to the protocol, SOPs are adhered to, the site is 
following GCP, all regulatory requirements are being met and appropriately documented.  Monitors will 
assess the overall quality and completeness of the data, examine source documents, interview 
investigators and coordinators, and confirm that the clinical centre has complied with the requirements 
of the protocol. The monitors will verify that all consents have been obtained and adverse events were 
documented in the correct format and are consistent with protocol definition. 
 
The monitors will review the source documents as needed, to determine whether the data reported in 
the electronic case report forms are complete and accurate. Monitoring will involve periodic independent 
review of core trial processes and documents. Monitoring will be intended to preserve the integrity of the 
trial by independently verifying a variety of processes and prompting corrective action if necessary. In 
case of an audit, the processes reviewed will relate to participant enrolment, consent, eligibility, and 
allocation to study groups; adherence to trial interventions and policies to protect participants, including 
reporting of harms and completeness, accuracy, and timeliness of data collection. In addition, 
monitoring will verify adherence to applicable policies such as the International Conference on 
Harmonisation Good Clinical Practice and regulatory agency guidelines.  
 
In this study, the ethics review committees, regulatory authorities and the sponsor may conduct 
auditing of source documents at any of the enrolling sites. 
10.10 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study sites have SOPs in place for quality management to ensure compliance with ICH-GCP, the 
protocol, ethical standards, and regulatory requirements. Having the highest quality data and studies are 
essential aspects of vaccine development. To compliance with GCP, it may be necessary for the Sponsor 
to conduct a site audit. This may occur at any time from start of the study to the period after the conclusion 
of the study. The Investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. When an investigator will provide 
direct access to source data/documents including the following: 
• 
ERC/IRB approval 
• 
Vaccine accountability 
• 
Approved study protocol and amendments 

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• 
Informed consent of the participants 
• 
Medical records and other source documents supportive of CRF data 
• 
Reports to the ERC/IRB, and the Sponsor 
• 
Record retention 
The study sites have SOPs for quality management that include staff training methods, product 
accountability records, specimen tracking logs, questionnaires, audio or video recordings. The Quality 
Control (QC) procedures will be implemented beginning with the source documents, data entry system 
and data QC checks. Any missing data or data anomalies will be communicated to the site(s) for 
clarification or resolution. Following written SOPs, the monitors will verify that the clinical trial is 
conducted, data are generated, documented, and reported in compliance with the protocol, GCP, and 
applicable regulatory requirements. 
10.11 DATA HANDLING AND RECORD KEEPING 
10.11.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the clinical study staff at the site under the supervision of the site 
Principal Investigator (PI). The PI is responsible for assuring that the data collected is complete, legible, 
attributable, accurate, and recorded in a timely manner. Data recorded in the eCRF should be consistent 
with the data recorded on the source documents. All source documents and laboratory reports must be 
reviewed by the site team, who will ensure that they are accurate and complete. 
SOURCE DATA 
All information in original records and certified copies of original records or clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents (original records or certified copies). [ICH E6 section 1.51]. 
SOURCE DOCUMENT  
Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, participant diaries, evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, participant files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial are considered Source Documents. [ICH E6 section 1.52] 
DATA CAPTURE METHOD 
Clinical data recorded in source documents, should be completed in a neat, legible manner to ensure 
accurate interpretation of data in accordance with ALCOA principles of Good Documentation Practice. 
Source documentation supporting the CRF data should document the dates and details of study 
procedures, AEs and participant status. The PI will ensure that all information in the CRFs and all source 

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documents that support the data collected from each participant are maintained in a secure area and 
treated as confidential material. 
 
The clinical data in the source documents (including AEs, concomitant medications, and expected adverse 
reactions data) will be entered by remote data entry into an EDC system by trained and qualified study 
staff. Data reported in the CRF derived from source documents should be consistent with the source 
documents, and it is the PI’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the participant’s CRF and any supporting documentation. The CRF for the study will be 
developed and provided by the Sponsor. 
  
Additionally, a description of this clinical trial will be available on https://www.ClinicalTrials.gov and the 
Pan African Clinical Trial Registry (PACTR) at https://pactr.samrc.ac.za. The clinical trial registries will not 
identify any individual participants and will include a summary of the results. 
DATA MANAGEMENT  
The Sponsor or designee is responsible for the data management of this trial including quality checking of 
the data. 
DATA STORAGE 
All study documentation containing personal information relating to study participants like consent forms 
and other documents that might link participant ID with other participant personally identifiable 
information (PII) will be kept in a secure locked area with limited access at the study sites. Such 
documentation will only be made available to authorized personnel. These study documents will be made 
available to the investigators, clinical personnel who require this information to treat the participants and 
the above-mentioned personnel for inspection or auditing reasons. In addition, access to participants’ 
medical records will be granted to representatives of the Sponsor, regulatory agencies, and ethics 
committees for the purpose of validating data. 
10.11.2 STUDY RECORDS RETENTION AND DISPOSAL 
 
Study documents will be retained for the duration required by the Sponsor, applicable local regulations, 
and in accordance with GCP standards, in a safe and secure facility. No records will be destroyed without 
the written consent of the Sponsor. Upon study completion, all records will be stored safely at the 
respective study sites archiving facilities or at a secure contracted storage facility. If storage at an 
alternative facility is considered, this will be documented, and the documentation will be filed in the 
study’s regulatory file. Should longer storage be recommended by the Sponsor or relevant authorities, 
the site will contact the reviewing ERC/IRBs for consideration and approval. Study files can be stored either 
as paper or digitally. Digitization, if done, will consist of the scanning of all paper records according to site 
SOPs to ensure accurate and complete representation of the same. This may be done by the site staff of 
a contracted third-party. All digitized records will be maintained on a secure, password protected 
computer system with access limited to those with access to study as previously listed in this protocol as 
well as VIBRI’s archivist(s) and IT personnel who will maintain the database. Upon completion of 

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digitization of study records, and receipt of a Sponsor’s approval, paper copies may be destroyed by 
incineration according to site SOPs. 
 
Paper or digitized records may be disposed of after storage duration has been met (15 years or as 
otherwise specified above) and with the Sponsor’s written approval. Any remaining paper records will be 
incinerated and if digitized, the records will be securely deleted. The final disposal of any remaining paper 
or digitized records will be witnessed by a representative of VIBRI’s regulatory affairs department and will 
be documented. The documentation of records disposal will be provided to the Sponsor and a copy will 
be stored at the Regulatory Affairs department. 
10.12 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence is critical. The study sites have no 
conflict of interest to disclose. 
10.13 ADDITIONAL CONSIDERATIONS 
10.13.1 EXPECTED APPLICATION OF THE RESULTS 
 
The results of this trial will add to the body of scientific knowledge on the safety and immune responses 
of the two COVID-19 vaccines in pediatric populations and HIV populations in Africa. The current design is 
to provide a standard booster (per current guidelines) at 5-7 months from the time of completion of the 
primary series for adult participants and ≥5 months after the primary series for adolescent participants.  
The optimal booster is defined by the current guidelines.  We are looking at durability of response and that 
can inform on if and when another booster might be needed, depending on response to heterologous 
boosting in this population. 
10.13.2 PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with Sponsor and CEPI policies. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a clinical trials registration policy as a condition for 
publication. The final study results will be shared with the study team, the study participants, the medical 
community, the study sponsor, study funder and the general public. The results will be published in peer 
reviewed scientific journals, abstracts, posters and symposium presentations at local and international 
conferences. The results will be shared with the media and through dissemination activities with relevant 
stakeholders including the Ministry of Health 

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11 ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ALT 
Alanine aminotransferase 
CBC 
Complete Blood Count 
CEPI 
Coalition for Epidemic Preparedness Innovations 
CHW 
Community Health Worker 
CI 
Confidence Interval 
CMI 
Cell Mediated Immunity 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRC 
Clinical Research Center 
CRO 
Contract Research Organization 
CVD 
Cardiovascular Disease 
eCRF 
Electronic Case Report Forms 
DMP 
Data Management Plan 
DOD 
Department of Defense 
ECCT 
Expert Committee on Clinical Trials (ECCT) 
eCRF 
Electronic Case Report Form 
EDC 
Electronic date capture 
ELISA 
Enzyme-linked immunosorbent assay 
ERC 
Ethics Review Committee 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FV 
Field visit 
GCP 
Good Clinical Practice 
H0 
Null hypothesis 
HA 
Alternative hypothesis 
Hb 
Haemoglobin 
HDSS 
Health and Demographics Surveillance System 
HIV 
Human immunodeficiency virus 
HTN 
Hypertension  
IB 
Investigator's Brochure 
IMP 
Investigational Medical Product 
IRB 
Institutional Review Board 
ICH 
International Council for Harmonization 
IM 
Intramuscular 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PII 
Personal identifying information 
PIMMC 
Potential immune mediated medical conditions 
PLT 
Platelet 
PPB 
Pharmacy and Poisons Board 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
UNIKIN 
University of Kinshasa 
US 
United States 
VE 
Vaccine efficacy 
VIBRI 
Victoria Biomedical Research Institute 
WBC 
White blood count 
WHO 
World Health Organization 

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12 REFERENCES 
 
1. WHO Weekly Epidemiological Update on COVID-19– Edition 73. 06 January 2022. 
2. WHO SAGE Report. 10 Feb 2021.  
3. US Department of Health and Human Services. Emergency Use Authorization for Vaccines to 
Prevent COVID-19. Guidance for Industry. 2021 February 22.  
4. Kenya Population-based HIV Impact Assessment (KENPHIA) 2018 National AIDS and STI Control 
Programme (NASCOP), Ministry of Health, Kenya 
5. UNAIDS Report. 2017 
6. Increased HIV in Greater Kinshasa Urban Health Zones: Democratic Republic of Congo (2017–2018). 
Pour M, James L, Singh K, Mampunza S, et al. AIDS Research and Therapy volume 17: 67 (2020) 
7. Kamar N. mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med 
2021;385:661-2.  
8. Krause PR, Fleming TR, Peto R, et al. Considerations in boosting COVID-19 vaccine immune 
responses. Lancet 2021;398:1377-80. 
9. Callaway E. COVID vaccine boosters: the most important questions. Nature 2021;596:178-80. 
10. WHO. Interim statement on booster doses for COVID-19 vaccination. Update 22 December 2021. 
11. Vaccines and Related Biological Products Advisory Committee Meeting February 26, 2021.  
12. J&J press release, 21 Sep 2021.  
13. Novavax.com/covid-19-coronavirus-candidate-updates. 2021  
14. Extraordinary meeting of the Committee for Medicinal Products for Human Use (CHMP): 20 
December 2021.  
15. Interim recommendations for use of the Novavax NVX-CoV2373 vaccine against COVID-19. Interim 
Guidance. 20 December 2021.  
16. Ontario Ministry of Health. COVID-19 Vaccine Booster Recommendations. Version 9.0 August 31, 
2022.  
17. Guidance-on-administration-of-COVID-19-vaccine-boosters-in-Africa. Africa Centres for Disease 
Control and Prevention, 2022.  
18. COVID-19 Vaccines for People Who Are Moderately or Severely Immunocompromised. 
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html. 22 
December 2022.