Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/23/04/05

Date of Protocol:

06-03-2023

Study Title:	A randomised, controlled clinical trial to assess and compare the immunogenicity, safety and reactogenicity of the bivalent Omicron BA.4/BA.5 adapted, and the original Wuhan-Hu-1-strain, BNT162b2 COVID-19 vaccine formulations in healthy unvaccinated East African adults.
	A randomised, controlled clinical trial to assess and compare the immunogenicity, safety and reactogenicity of the Wuhan-Hu-1-strain/Omicron BA.4/BA.5 bivalent, Omicron XBB.1.5, and the original Wuhan-Hu-1-strain, BNT162b2 COVID-19 vaccine formulations in healthy unvaccinated East African adults.
Study Objectives:	To determine superiority of the immune response against the Omicron BA.4/BA.5 sub lineage of SARS-CoV-2, measured as day 28 neutralising antibodies (Nabs) GMT in previously COVID-19 unvaccinated healthy East African adults following vaccinations with two doses of the Omicron BA.4/BA.5 adapted Bivalent BNT162b2 COVID-19 vaccine (28 days apart), versus two doses of the Original BNT162b2 COVID-19 vaccine. To determine non-inferiority of the immune response against the Omicron BA.4/BA.5 sublinage of SARS-CoV-2, measured as day 28 NAbs GMT in previously COVID-19 unvaccinated healthy adults following vaccinations with one dose of the Bivalent BNT162b2 COVID-19 vaccine, versus two doses (28 days apart) of the Original BNT162b2 COVID-19 vaccine. To assess and compare the safety and reactogenicity between the two trial vaccination arms following each of two successive doses of the Bivalent BNT162b2 and the Original BNT162b2vaccines in previously COVID-19 unvaccinated adults.
1	To determine superiority of the immune response against the Omicron BA.4/BA.5 sub lineage of SARS-CoV-2, measured as day 28 neutralising antibodies (Nabs) GMT in previously COVID-19 unvaccinated healthy East African adults following vaccinations with two doses of BNT16262b Bivalent COVID-19 vaccine (28 days apart), versus two doses of the BNT16262b COVID-19 vaccine.
Laymans Summary:	COVID-19 virus infections and cases continue to be reported from most regions around the world, including Africa. Thus, waves of increased COVID-19 virus spreading, which are often characterised by high levels of hospitalisations with severe disease and deaths will remain a major risk for now, and in the future. Besides the large numbers of COVID-19 attributable hospitalisations and deaths that occurred in large cities like Nairobi and Dar es Salaam in 2020 and 2021, data from the Kilifi Demographic Surveillance show increased mortality among older adults since the beginning of the pandemic suggesting that increased vaccination coverage in rural areas may enhance their protection, as well as those with underlying chronic diseases. COVID-19 virus also continues to evolve, with the Omicron variant now being the dominant strain globally. Sequential changes (over time) in the virus makeup are associated with structural modifications that increase its transmissibility, and in the case of Omicron, immune escape from vaccine induced immunity. Because the currently available COVID-19 vaccines were optimized for protection against the originally described (ancestral) COVID-19 virus strain, it is likely that they will be rendered less effective against COVID-19 associated with Omicron and other future variants. Furthermore, the vaccine induced protection also wanes with time, necessitating the administrations of additional vaccine doses to fully vaccinated people to extend the protection afforded by the primary immunisation series. One way to overcome the challenges of waning vaccine efficacy, owing to the introduction of new COVID-19 virus variants and passage of time, is to add components of the Omicron variant to the original vaccines, so that the new generation of “bivalent” vaccines are also optimised to protect against the more recently evolved COVID-19 virus variants. Vaccine manufacturers are now making these bivalent vaccines, and the one from Pfizer-BioNTech is already approved for use in some countries, and already in the market for COVID-19 control. Until now, this vaccine has only been tested in previously COVID-19 vaccinated individuals, as additional booster vaccine doses. For now, it also unclear if two doses of the new bivalent vaccines are necessary to provide sufficient protection against Omicron variants in populations where exposure to COVID-19 virus infection has been very high but with very low vaccine coverage, like in Kenya and Tanzania. Thus, this study will generate data indicating whether unvaccinated, but SARS-CoV-2 exposed adults can be sufficiently protected by single doses of the new vaccine. Importantly, if the new bivalent vaccines can be used as a single dose, this information may encourage increased vaccine use and coverage in regions with low vaccine uptake, as a simplified vaccination programme relying on a single dose will likely be more acceptable than the current two doses for a primary series. Thus, results from the trial will guide local policy recommendations for the rational use of available vaccines, outside of high-income countries. We would now like to compare the performance and safety profiles of the Pfizer-BioNTech Omicron-adapted bivalent COVID-19 vaccine, with that of the corresponding original Pfizer-BioNTech vaccine in previously COVID-19 unvaccinated adults in East African adults, to determine whether it induces a bigger immune response, while retaining a similar safety profile. The present trial is planned in Kilifi, Kenya and in Dar es Salaam, Tanzania.
1	Additionally, the study recently received additional funding to follow up the participants for a further 6 months to have a total follow-up period of 12 months. We have also been funded to recruit and enrol a further 290 particiapnts to receive a new mono-valent vaccine that has action against the XBB variant of the Omicron strain of the COVID-19 virus. The overall objective of this study remains as an assessment of the safety and immunogenicity of a single dose of the monovalent XBB vaccine compared to two doses of the bivalent vaccine in previously unvaccinated healthy East African adults. Findings from this arm of the study could help inform policy on vaccination recommendation in the light of a rapidly evolving virus.
Abstract of Study:	SARS-C-oV-2 infection driven COVID-19 cases and associated deaths continue to be reported around the world, indicating a persistent risk for waves of increased transmission, previously characterised by high levels of hospitalisations with severe disease, and death. SARS-CoV-2 virus also continues to evolve, with the Omicron (and it’s sub-lineages), now being the dominant variant globally. The sequential changes in SARS-CoV-2 virus are associated with structural modifications that confer the newly evolved variants the ability for immune escape from vaccine induced immunity. Indeed, there is now evidence that Omicron variants and their sub-lineages can escape from neutralisation of antibodies induced from either prior immunisation with the original BNT162b2 (Pfizer-BioNTech) vaccine, implying a causal link with a reduction in vaccine effectiveness. Furthermore, the original BNT162b2 (similar with other COVID-19) vaccine(s) induced protection is also short-lived, necessitating the sequential administrations of additional vaccine doses (now called “booster immunisations”) to extend and broaden protection from the primary vaccination series. One way to overcome these challenges of the reducing vaccine efficacy associated with either SARS-CoV-2 evolution, and/or a rapidly decaying immune response, is to add components of the current dominant Omicron variant to the original vaccine, as this would extend the initial protection to last longer, whilst also broadening it to cover more SARS-CoV-2 variants. Therefore, the new generation of COVID-19 vaccines are bivalent: combining components of the original Wuhan-Hu-1 and at least one or more of the current Omicron variants. The Pfizer bivalent BNT162b2 COVID-19 vaccine (containing components of the Wuhan-Hu-1 and Omicrons BA.4 and BA.5), being tested here, is currently approved for booster vaccinations in high income countries. However, it has not been formerly tested in unvaccinated individuals. While there are many regional variations in COVID-19 epidemiology, most of Africans are seropositive for SARS-CoV-2 owing to natural infection rather than vaccination. Concurrently, COVID-19 vaccination coverage remains very low in Africa. It is unclear if one dose of the bivalent vaccine will be sufficient to provide protection against Omicron variants and their sub-lineages in sub–Saharan African populations. We propose a clinical trial comparing safety and immunogenicity of the bivalent BNT162b2 COVID-19 vaccine with the corresponding original BNT162b2 (monovalent) COVID-19 vaccine in previously unvaccinated sub-Saharan Africa adults. The evidence generated will guide policies for the rational use of bivalent and the original mRNA vaccines in COVID-19 control.
1	SARS-C-oV-2 infection driven COVID-19 cases and associated deaths continue to be reported around the world, indicating a persistent risk for waves of increased transmission, previously characterised by high levels of hospitalisations with severe disease, and death. SARS-CoV-2 virus also continues to evolve, with the Omicron (and its sub-lineages), now being the dominant variant globally. The sequential changes in SARS-CoV-2 virus are associated with structural modifications that confer the newly evolved variants the ability for immune escape from vaccine induced immunity. Indeed, there is now evidence that Omicron variants and their sub-lineages can escape from neutralisation of antibodies induced from either prior immunisation with the original BNT162b2 (Pfizer-BioNTech) vaccine, implying a causal link with a reduction in vaccine effectiveness. Furthermore, the original BNT162b2 (similar with other COVID-19) vaccine(s) induced protection is also short-lived, necessitating the sequential administrations of additional vaccine doses (now called “booster immunisations”) to extend and broaden protection from the primary vaccination series. One way to overcome these challenges of the reducing vaccine efficacy associated with either SARS-CoV-2 evolution, and/or a rapidly decaying immune response, is to add components of the currently circulating dominant Omicron sub-variant to the original vaccine, as this would extend the initial protection to last longer, whilst also broadening it to cover more SARS-CoV-2 variants. An alternative solution would be to develop a monovalent vaccine containing the currently dominant sub-variant of Omicron. Therefore, the new generation of COVID-19 vaccines are either bivalent (combining components of the original Wuhan-Hu-1 and at least one or more of the currently circulating Omicron variants), or monovalent (containing only the currently dominant circulating Omicron sub-variant). The Pfizer BNT162b2 BivalentCOVID-19 vaccine (containing components of the Wuhan-Hu-1 and Omicrons BA.4 and BA.5), being tested here, is currently approved for booster vaccinations in high income countries. Similarly, the Pfizer monovalent vaccine containing the Omicron XBB.1.5 subvariant is currently approved for booster vaccinations in high income countries. Neither of these vaccines are approved in Kenya, and they have not been formerly tested in unvaccinated individuals. While there are many regional variations in COVID-19 epidemiology, most of Africans are seropositive for SARS-CoV-2 owing to natural infection rather than vaccination. Concurrently, COVID-19 vaccination coverage remains very low in Africa. It is unclear if one dose of the bivalent vaccine will be sufficient to provide protection against Omicron variants and their sub-lineages in sub–Saharan African populations. It is also unclear whether the Omicron XBB.1.5 vaccine will be inferior to the BNT162b2 Bivalent vaccine. We propose a clinical trial comparing safety and immunogenicity of the BNT162b2 Bivalent COVID-19 vaccine with the corresponding original BNT162b2 (monovalent) COVID-19 vaccine in previously unvaccinated sub-Saharan Africa adults. We will also compare safety and immunogenicity of single doses of the Omicron XBB.1.5 BNT162b2 COVID-19 vaccine with the corresponding BNT162b2 BivalentCOVID-19 vaccine. It is a double-blinded trial, and will include a minimum of 580 participants, equally randomised to receive one of the following vaccinations: a) cohort 1 ( n = 290) - either the original BNT162b2 vaccine, or the Omicron adapted bivalent vaccine; cohort 2 (n = 290) – either the BNT162b2 Bivalent, or the Omicron XBB.1.5 containing vaccine . Participants will be recruited from the Kilifi health and demographic surveillance system (KHDSS). Upon recruitment, each vaccinee will make at least five study related visits for screening, vaccination, and collection of immunology samples. The evidence generated will guide policies for the rational use of bivalent and the original mRNA vaccines in COVID-19 control.