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People living in sub-Saharan Africa are underrepresented and their ethnicity is often misrepresented in the global population of study participants for clinical trials evaluating the safety and immunogenicity of experimental vaccines for infectious diseases, argue Alice Taylor and colleaguesThe unprecedented speed of clinical trial set up and execution in response to the covid-19 pandemic was only possible because of long established and experienced clinical trial capacity in almost exclusively high income settings such as the US and Europe. As a result, data from many global populations could not be accommodated in time for emergency use authorisation and the subsequent large scale deployment of vaccines that ultimately resulted in the safe end to the pandemic. The key lesson is the need to strengthen and sustain clinical trial capacity in sub-Saharan Africa to the level of demand experienced in 2020.The speed of covid-19 vaccine development meant very few sub-Saharan African participants were able to take part. The accelerated development of vaccines to control the covid-19 pandemic has many major lessons, and the need to exercise these lessons could soon be realised. The pre-existing pharmaceutical manufacturing capacity and infrastructure in high income settings allowed for an unprecedented speed of response, producing vaccines that undoubtedly saved millions of lives globally. However, the participants of vaccine trials were not proportionally representative of the populations that were in need of the vaccines. By the end of the pandemic, five covid-19 vaccine products collectively accounted for 93% of the 1084.5 million vaccines doses given across the African continent by 2023, but at the time of emergency use authorisation in late 2020/early 2021, only a small fraction of vaccine trial data were derived from trials including participants from sub-Saharan Africa.1 For the lipid nanoparticle mRNA product BNT162b2 (Pfizer-BioNTech), 744 South African participants comprised 2% of the total study population.2 For the evaluation of the viral vector vaccine and genetically modified organism Ad26.COV2.S (Janssen/Johnson & Johnson), 6576 study participants (15%) were recruited from trial sites in South Africa.3 The viral vectored vaccine and genetically modified organism ChAdOx1 nCoV-19 (AZD1222, AstraZeneca) included eight clinical trial sites in South Africa, although data from these sites were not included in the interim analyses for the Medicines and Healthcare Products Regulatory Agency’s and European Medicines Agency’s emergency use authorisation.4 Ad26.COV2.S and BNT162b2 reported on vaccine efficacy in different ethnic subgroups, however these results were not sufficiently powered.Being sub-Saharan African is not the same as having black African ethnicity in clinical trials in another continent. It is difficult to determine what impact on science, if any, this had on covid-19 vaccine control in resource poor settings in sub-Saharan Africa. The absence of sufficient data and low numbers of vaccine trial participants living in sub-Saharan Africa are more than just problems of perspective. Clinical trial conditions in any high income or low income setting have shown inherent variations between individuals in reactogenicity and the magnitude/duration of immune responses to vaccination driven by a plethora of host factors, such as genetic make up and environmental circumstance.5 Genetic diversity has been found to be greater between Africans than between Africans and people of Eurasian genetic ancestry. At the level of single nucleotide polymorphisms, people of Eurasian genetic ancestry are predominantly a subset of African genetic ancestry.6 Genes that code for skin colour and other phenotypic attributes used to characterise different ethnicities can, in some cases, also relate to genetic determinants of reactogenicity and immune mechanisms that underpin vaccination responses. In the case of the IGHV1-69 gene, polymorphisms associated with ethnicity can result in diverse immune responses among people of African, Asian, and European descent following, for example, vaccination against influenza.7Beyond the genetic blueprint, the ability to mount and sustain a protective immune response is heavily influenced by environmental factors such as diet/malnutrition, age, and the prevalence of comorbid disease,8 particularly in the case of maternal vaccines that rely on active placental transfer of maternal antibody to the baby to provide passive immunisation in the first weeks after birth. Studies performed in high income settings too often overlook the impact of the placental burden of chronic malaria and other diseases endemic to resource-poor settings .9 Malnutrition can have a range of consequences, from early thymic atrophy with potential implications for immune responses to early immunosenescence,10 11 as well as affecting the generation and maintenance of antibody. While tackling the root causes of malnutrition is vitally important to many health outcomes, we should maintain an awareness that population specific factors can potentially affect clinical trial estimates of vaccine performance. While increased representation of black African people and other underrepresented ethnic groups in clinical trials performed in US and Europe would be an important achievement, further work is required to fully achieve a just representation for people living in sub-Saharan Africa. During the early stages of the covid-19 response, establishing a portfolio of safe and effective vaccines was paramount. However, the evidence generated on the safety and immunogencity of the vaccine products was derived largely from only a subset of the global population who needed protection.Rapid evaluation of experimental vaccines is often needed in sub-Saharan Africa. The Africa Union has intensified preparedness for future outbreaks: the Partnerships for African Vaccine Manufacturing (PAVM) Framework for Action plans to produce 60% of the continent's vaccine requirements by 2040, increased from the current figure of less than 1%, as part of the African Union’s Agenda 2063.12 Countries in sub-Saharan Africa are seeing many outbreaks of infectious diseases that are important to public health, and are often underreported and underprioritised for experimental vaccine evaluation in these countries. Many diseases identified by the World Health Organization as potential pandemic threats, most notably the viral haemorrhagic fever viruses, are likely to originate from sub-Saharan Africa with precedent from Ebola virus disease and recent outbreaks of mpox clade Ib and Marburg virus. Frequent exposure to animal and environmental reservoirs of infectious disease, and local outbreaks of pathogens with high priority for vaccine development, continually serve both as a warning and an opportunity to pre-emptively develop and maintain healthcare teams for vaccine trials and clinical infrastructure that would be needed for a future covid-19-like scenario. Groups in sub-Saharan Africa have successfully deployed experimental vaccine candidates in rapid response to complex situations, such as the phase 1 trial of the Ebola vaccine rVSV-ZEBOV conducted in Lambaréné, Gabon and Kilifi, Kenya, and the first-in-human trial of the Pfs48/45 malaria vaccine in Burkina Faso.13 14 Continued investment in clinical trials, including biotechnologies and regulatory systems, is an investment in ultra-rapid responsive capabilities for unanticipated demand for vaccines against, for example, the Marburg virus. As well as improving science, demonstrating how vaccine research is conducted in sub-Saharan Africa to high standards of ethical transparency will be important in helping residents of sub-Saharan Africa to decide whether to take part in research, or whether to accept future vaccine products that are offered to them.In conclusion, the accelerated clinical evaluation of new viral-vectored and mRNA vaccine technologies for covid-19 undoubtedly altered the course of the pandemic. Building on lessons from the pandemic and rapid advances in vaccine technology, we now have the opportunity to apply these gains to other pressing global health challenges. There is an urgent need to bring vaccine science closer to where the products are required, and ensure that vaccine equity includes public access to reliable information for all in need of protection.