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A role for genetic susceptibility in proposed controlled human vaccine challenge studies

A recent article ( has suggested the intriguing and ethically charged possibility of testing the efficacy of candidate SARS-CoV2 vaccines on healthy volunteers. The authors suggest testing candidate vaccines for efficacy by dosing the vaccines to healthy volunteers, infecting those volunteers with SARS-CoV2, and then closely monitoring signs of viral infection (while ensuring top-notch care during the testing period). They suggest that such studies, which would occur after Phase 1/2 safety and dosing trials and would be followed by an expanded placebo-controlled field trial, could subtract months from the vaccine development process.

It is widely believed that the COVID-19 pandemic will not be quenched until the widespread rollout of effective vaccines. Due to the potentially enormous public health benefit of shaving months off of the vaccine testing process without added cost, I think that this idea deserves serious attention. It also deserves serious scrutiny due to the obvious downsides of societally encouraging healthy volunteers to put their health at risk for these studies. The merits and drawbacks of this approach should be considered through open discussion taking into account multiple perspectives, and thus I don’t think my perspective in this issue should carry much weight. One contingency worth considering, though, is that if we do not move forward with such an idea but another country does so in an ethically problematic way (testing a vaccine in a compulsory manner and/or on disadvantaged groups) and has a tested vaccine months earlier than we have one, would we distribute that vaccine? Having seriously considered vaccine challenge in a way we find ethically least objectionable thus seems wise.

The authors propose the following inclusion criteria for volunteers:

“Volunteers for human challenge studies would be drawn from previously uninfected individuals

at relatively low risk of complications or mortality from SARS-CoV-2 infection (e.g. young adults,

without chronic health conditions and not otherwise sick) [3-7] and who are at substantial risk

of natural exposure to SARS-CoV-2 (e.g. resident in areas with high transmission rates). Such a

target group might comprise uninfected persons aged 20-45 years, an age range in which the

risk of death or serious complications following infection is substantially lower than in older age


It is in this area where I think statistical human genetics could have a role to play. One step further than limiting the pool of volunteers by age and lack of chronic health conditions, could human genetics efforts further subset a population with less risk of adverse consequences? The field of polygenic risk prediction has now demonstrated that, for a number of complex genetic diseases, risk can be stratified to identify subpopulations with up to 5-fold elevated risk or decreased risk of disease as compared to the average person. If we as a society are going to be exposing young, healthy people to risk of disease, it seems worthwhile to determine whether we can identify subpopulations with diminished risk of adverse events. I could think of several ways in which human genetics could play a role here:

1.       Are there alleles or polygenic risk calculations that correlate with lower risk of SARS-CoV2 complications (or viral response in general)?

2.       Are there alleles or polygenic risk calculations that correlate with beneficial/non-adverse response to current front-line COVID-19 drugs (remdesivir and hydroxychloroquine are currently under most intensive clinical trials)?

Datasets that could be used will be emerging soon (eg The prospect of controlled human vaccine challenge studies lends urgency to their analysis as a matter of doing our part to mitigate the risk involved in exposing healthy volunteers to a potentially deadly virus.

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