Efficacy of Different COVID-19 Vaccine Combinations in Inducing Long-term Humoral Immunity [PRIBIVAC]

Study Overview
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Brief Summary
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This study will assess heterologous prime-boost-boost vaccine regimens in comparison with an homologous regimen in order to compare short and long-term immunogenicity of different COVID-19 vaccine combinations against the ancestral SARS-CoV-2 as well as different variants of concern (VOCs). Hypothesis: One or more heterologous prime-boost-boost COVID-19 vaccine combinations will produce humoral and cellular immunity that is non-inferior to an homologous prime-boost-boost vaccination against wildtype SARS-CoV-2 and/or 1≥ VOC.

Detailed Description
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ICOVID-19 vaccination programs worldwide have so far focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore two mRNA vaccines developed by Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273), have been granted interim authorisation by Health Science Authority (HSA) under the pandemic special access route (PSAR). Some other COVID-19 vaccines are authorised by HSA for use in Singapore as part of the Special Access Route (SAR) through their addition to the WHO Emergency Use List (EUL). Many of these vaccines have been widely used in other countries, including an inactivated whole virus vaccine developed by Sinovac; an adenovirus-based formulation developed by Oxford-AstraZenaca; and a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector vaccine developed by Johnson & Johnson / Janssen. Vaccination in Singapore started first for frontline and healthcare workers with BNT162b2 at the end of December 2020. Over the following months this vaccine program was extended first to older adults and then the general population, while mRNA-1273 was also introduced alongside BNT162b2. By August 2021 >75% of Singapore's resident population was fully vaccinated. The pivotal phase 3 clinical trials of BNT162b2 and mRNA-1273 reported a vaccine efficacy of >95% against symptomatic and severe disease. However, data from individuals vaccinated with mRNA-1273 showed gradually declining neutralising antibody titres by 6 months post inoculation. In addition, the emergence of variants of concern (VOCs) capable of evading protective immunity (from a wildtype SARS-CoV-2 virus vaccine) has raised the need for a long term COVID-19 immunisation strategy. Several fundamental questions need to be addressed in order to design this: Will a 3rd booster dose offer clinical benefit? Who needs a booster vaccination? How long after the primary series should it be administered? And, which vaccine should be used? This study will assess the immunogenicity and safety of heterologous boost COVID-19 vaccine regimens (intervention groups 1-4) compared with a homologous boost regimen (control arm). Potential participants would have already received a homologous prime-boost vaccination with BNT162b2 or mRNA-1273 prior to randomisation. The booster vaccine for the control arm will be the homologous mRNA vaccine (e.g. BNT162b2 + BNT162b2 + BNT162b2 or mRNA-1273 + mRNA-1273 + mRNA-1273), while for individuals randomised to intervention group 1 the mRNA booster vaccine administered will be heterologous to the primary series (e.g. BNT162b2 + BNT162b2 + mRNA-1273 or mRNA-1273 + mRNA-1273 + BNT162b2). The booster vaccine candidates for intervention arms 2-4 will be an alternative COVID-19 vaccine. This may include vaccines that have received full or interim authorisation from HSA, are available under the Special Access Route (SAR) for vaccines that are part of the WHO Emergency Use List (EUL), or are currently under clinical development. Control group: Homologous mRNA booster vaccine Intervention group 1: Heterologous mRNA booster vaccine Intervention group 2: Non-mRNA booster vaccine A Intervention group 3: Non-mRNA booster vaccine B Intervention group 4: Non-mRNA booster vaccine C Vaccine candidates A, B and C may enter the study at different time points, participants will be randomised at equal probability to the available intervention arms at the time of randomisation. This will reduce the risk of bias (e.g. participant preference for a certain arm) compared with a non-randomised design. An ideal scenario is to have all the selected vaccines approved prior to the start of recruitment. However, due to the unknown time of availability of vaccine candidates A, B and C, and the urgency of the current situation, recruitment to the control and intervention group 1 will start first.

Official Title
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Heterologous Prime-boost-boost Vaccine Combinations for Long-term Humoral and Cellular Immunity Against COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Homologous mRNA booster vaccine
* Biological: Heterologous mRNA booster vaccine
* Biological: Non-mRNA booster vaccine A
* Biological: Non-mRNA booster vaccine B
* Biological: Non-mRNA booster vaccine C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent for participation in this study; Aged ≥21years at the time of study enrolment; Received the second dose of BNT162b2 or mRNA-1273 Coronavirus Disease 2019 vaccines at least 6 months prior to enrolment; Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests and other study procedures. Exclusion Criteria: Known history of SARS-CoV-2 or SARS-CoV-1 infection; Previously received an investigational coronavirus vaccine; Previously received a SARS-CoV-2 monoclonal antibody; Current or planned simultaneous participation in another interventional study; A history of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a COVID-19 vaccine, or otherwise have a contraindication to one of the available study vaccines per the approved label; Individuals who are immunocompromised (e.g. active leukaemia or lymphoma, generalised malignancy, aplastic anaemia, solid organ transplant, bone marrow transplant, current radiation therapy congenital immunodeficiency, HIV/AIDS with CD4 lymphocyte count < 200 and patients on immunosuppressant medications); Received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to Screening (for corticosteroids >/= 20 milligram per day of prednisone equivalent). Topical tacrolimus is allowed if not used within 14 days prior to Day 1; Individuals who are pregnant or breast feeding; Chronic illness that, in the opinion of the study team, is at a stage where it might interfere with trial conduct or completion; Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalised involuntarily; Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the study team; Moderate or severe acute illness/infection (according to study team's judgement) on the day of vaccination, or febrile illness (temperature ≥ 37.5°C). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Homologous mRNA booster vaccine<br>BNT162b2 + BNT162b2 + BNT162b2 or mRNA-1273 + mRNA-1273 + mRNA-1273 | Biological: Homologous mRNA booster vaccine<br>* Single intradermal injection. The vaccine dose will be according to manufacturer's instructions.<br>|
| Experimental: Heterologous mRNA booster vaccine<br>BNT162b2 + BNT162b2 + mRNA-1273 or mRNA-1273 + mRNA-1273 + BNT162b2 | Biological: Heterologous mRNA booster vaccine<br>* Single intradermal injection. The vaccine dose will be according to manufacturer's instructions.<br>|
| Experimental: Non-mRNA booster vaccine A<br>BNT162b2 + BNT162b2 + vaccine A or mRNA-1273 + mRNA-1273 + vaccine A | Biological: Non-mRNA booster vaccine A<br>* Single intradermal injection. The vaccine dose will be according to manufacturer's instructions.<br>|
| Experimental: Non-mRNA booster vaccine B<br>BNT162b2 + BNT162b2 + vaccine B or mRNA-1273 + mRNA-1273 + vaccine B | Biological: Non-mRNA booster vaccine B<br>* Single intradermal injection. The vaccine dose will be according to manufacturer's instructions.<br>|
| Experimental: Non-mRNA booster vaccine C<br>BNT162b2 + BNT162b2 + vaccine C or mRNA-1273 + mRNA-1273 + vaccine C | Biological: Non-mRNA booster vaccine C<br>* Single intradermal injection. The vaccine dose will be according to manufacturer's instructions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARS-CoV-2 anti-spike immunoglobulins | To determine the presence and levels of anti-SARS-COV-2 in human sera | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARS-CoV-2 anti-spike immunoglobulins | To determine the presence and levels of anti-SARS-COV-2 in human sera | Day 1, 7, 180, 360 | 
| Level of SARS-CoV-2 neutralising antibodies | To examine the neutralising capacity of the antibodies in the human sera | Day 1, 7, 28, 180, 360 | 
| Quantitative T-cell responses to spike proteins | Quantitative T-cell responses to the vaccines will be measured using SARS-CoV-2 peptides from spike protein to stimulate the PBMCs isolated from donor's blood. | Day 1, 7, 28, 180, 360 | 
| Solicited local and systemic reaction | The participant will be given a diary to record all the local and general symptoms experienced after receiving the vaccination. | Up to 7 days post-vaccination | 
| Changes from baseline in laboratory safety measures | Blood will be taken from the participant during screening visit prior to vaccination (also known as baseline) for the following clinical labs: a) Full blood count inclusive of differential blood count and platelet count; b) Liver panel including albumin, total bilirubin, ALP and ALT; c) Renal panel including sodium, potassium and creatinine; d) Cardiology panel including creatine kinase and troponin. The results of the above clinical tests will be compared with repeat tests at Day 7 post-vaccination. | Baseline and 7 days post-vaccination | 
| Unsolicited adverse events (AEs) |  | 28 days post-vaccination | 
| Serious adverse events (SAEs) and AEs of special interest (eg. myocarditis, pericarditis), medically attended AEs |  | Up to 360 days post-vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cellular immunity, Vaccine booster, SARS-CoV-2, Coronavirus, Antibody, Humoral immunity, Immunogenicity