The coronavirus disease 2019 (COVID-19) pandemic brings out the best of the human race. Increased collaboration between global institutions and rethinking traditional paradigms of practice are recipes for human progress. Hurdle after hurdle, our endurance is displayed more clearly. Simultaneously, the pandemic accentuates unresolved social issues. Vaccination becomes an increasingly politicised topic. Limited cohort diversity in COVID-19 vaccine trials particularly poses questions regarding the reproducibility of results, and systemic racism.
COVID-19 vaccines are indispensable in controlling the disease. Latest figures show that daily cases in the UK still exceed 20,000. Over 34,000 COVID-19 patients are hospitalised.1 Therefore, mass vaccination is crucial to confer community immune protection and lessen the burden on healthcare resources. Widely publicised vaccine trials include the BNT162b2 mRNA Covid-19 Vaccine funded by Pfizer and BioNTech (‘Pfizer Vaccine’), ChAdOx1 nCoV-19 vaccine studied by Oxford University (‘Oxford Vaccine’), and mRNA-1273 SARS-CoV-2 Vaccine (‘Moderna Vaccine’). These studies carried out trials in multiple clinical sites. The Pfizer and Oxford studies were also international. Results on vaccine efficacy are promising. A two-dose regimen of the Pfizer Vaccine conferred 95% protection (95% confidence interval: 90.3-97.6%), with low incidence of serious adverse events.2 Overall vaccine efficacy for the Oxford Vaccine was 70.4% (54.8-80.6%), although the figure reached 90.0% (67.4-97.0%) for participants who received the low dose/standard dose regimen. The Moderna Vaccine reported 94.1% (89.3-96.8%) efficacy with an acceptable safety profile.4
While COVID-19 knows no demographic boundaries when claiming its victims, vaccine trials are plagued by limited cohort diversity. In many western vaccine trials, the typical trial participant is young, white and resides in a developed nation. In terms of racial diversity, ethnic minorities in western countries are consistently side-lined in these trials. In the Pfizer study, 82.9% of participants in both the intervention and control arms were white.2 Black or African Americans accounted for less than 10%. Just over 4% of participants were Asian. The situation was even worse for the Oxford study.3 In the interim analysis,[[1]] the vast majority of participants in the intervention and control arms (92.0% vs 93.0%) of the low dose/standard dose UK trial (COV002) were white. Figures were similar in the standard dose/standard dose UK trial (COV002) (90.6% vs 91.1%). Even in Brazil, where 56% of the national population self-identified as black,5 they only accounted for approximately one-tenth of the trial cohort (COV003) in the Oxford study.3 White participants were also in the majority in the Moderna study (total: 79.2%; intervention: 79.2%; control: 79.1%).4
Racial disparities are augmented by discrepancies in participant recruitment at foreign sites in the Pfizer and Oxford studies. Although the Pfizer study was conducted in four countries, the vast majority (76.7%) of the cohort came from the United States.2 South African participants merely accounted for 2.0%. Nearly twice as many participants were recruited in the UK than Brazil in the Oxford Study (7548 vs 4088).
On the other hand, gender representation is less skewed. The male-to-female ratio was near 1:1 in Pfizer and Moderna study cohorts.2, 4 More females than males were recruited by the Oxford study.3 In the low dose/standard dose UK trial, female participants accounted for more than 64% of the cohort.
Fewer elderly patients were recruited by vaccine trials. Only the Pfizer study reflected a good balance between younger (<55 years) and older subjects (57.8% vs 42.2%).2 In the Moderna study, only 24.8% of participants in total were above 65 years of age.4 In the Oxford study, due to study design peculiarities, enrolment of the UK trials initially targeted at participants working in high-risk settings only.3 Older participants (>55 years) were only recruited from 8 August 2020, nearly three months after initial participant recruitment.3 Thus, all participants receiving the low dose/standard dose regimen, and the vast majority of those receiving two standard doses (intervention: 79.0% vs control: 79.1%), were younger than 55 years old.3
There are inherent problems in limited cohort diversity. Firstly, this decreases the reproducibility of study results. The typical vaccine trial participant is dehiscent from the rationale of national vaccination programmes. In the UK, people aged over 80 years are prioritised to receive the vaccine in January and February 2021.1 It is recognised that older individuals have higher risk of contracting COVID-19 and require earlier conferment of protection. However, trial results are barely validated for older individuals. This gives off the mirage that what works for the young automatically works for the elderly. Furthermore, black people are four times more likely to die from COVID-19 than their white peers.1 Genetic differences between races may explain the difference in survival outcomes and disease prevalence. Non-white individuals may also have a slightly different post-vaccination response, thus requiring fine-tuning of dosage and vaccination timing. However, this area remains under-explored. Although the Pfizer and Moderna studies displayed similar vaccine efficacies in non-white individuals, the results had wide confidence intervals. This is attributable to the relatively few non-white participants recruited. In the Pfizer study, the vaccine efficacy for black/African Americans ranged from 31.2 to 100.2 It is therefore uncertain whether a non-white individual can reap the same benefits of vaccination as a white counterpart. This issue was not even explored in the Oxford study interim analysis.3
Secondly, limited cohort diversity perpetuates racial and social inequality. Regarding the invasiveness of current lockdown measures and pervasiveness of the disease, the COVID-19 vaccine is popularised as a panacea for all that stems from the bitter pandemic. It is a beacon of hope. However, non-white individuals are again confronted with the idea of being neglected by the community. Even at times of public health emergency, their welfare is ignored time and again. This applies to broad swathes of one’s daily living, encompassing aspects such as housing, access to healthcare, and mental health support. Now, the exclusion is made even more apparent by COVID-19 vaccine studies. Vaccine efficacy figures are mostly accompanied by an asterisk – white only. Although remarkable strides in racial equality are made since the Black Lives Matter movement in 2020, subtle hints of systemic racism still shine through the façade we created for ourselves.
Some may claim that limited cohort diversity boils down to practicality issues, especially when the UK and US are white-majority nations. However, regarding the international nature of some studies (such as Pfizer and Oxford), a more racially representative cohort can be obtained by recruiting more participants from other countries. As time goes by and recruitment activity increases, hopefully such discrepancies can be evened out. Also, more sub-analyses should be carried out in dedication to analysing demographic-specific responses to the vaccine. The Pfizer and Moderna studies are making progress already. All that is needed is more equitable recruitment in the long run.
While a COVID-19 vaccine is desperately required, we should not forsake cohort diversity and representativeness. Not only does it reduce the reproducibility of results, it reinforces the idea of systemic racism and non-white exclusion. Only by increasing cohort diversity, can we make the COVID-19 vaccine accessible, available, and applicable to all. This is non-negotiable.
Reference List:
1 Covid-19 in the UK: How many coronavirus cases are there in your area?. BBC News. https://www.bbc.co.uk/news/uk-51768274. Published 2021. Accessed January 31, 2021.
2 Polack F, Thomas S, Kitchin N et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine. 2020;383(27):2603-2615. doi:10.1056/nejmoa2034577
3 Voysey M, Clemens S, Madhi S et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;397(10269):99-111. doi:10.1016/s0140-6736(20)32661-1
4 Baden L, El Sahly H, Essink B et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine. 2020. doi:10.1056/nejmoa2035389
5 Schipani A. Racial diversity in Brazil ‘turns to a new page’. Financial Times. https://www.ft.com/content/abe60816-3cc9-11e8-bcc8-cebcb81f1f90. Published 2018. Accessed January 31, 2021.
[[1]] The interim analysis did not include results from the South African trial (COV005), which is a continuing, double-blind phase 1/2 study.