Covid-19 vaccines: Should we allow human challenge studies to infect healthy volunteers with SARS-CoV-2?

Justifiable risks

In The Ethics of Human Testing and the Coronavirus Vaccine, Weijer argues that other challenge studies were ethically permissible since the risk of incurable infection was reduced by the availability of a “rescue therapy.” In other words, “this research was permissible because there are drugs that reliably cure both illnesses.”4

This is not, and ought not to be, the standard of maximal risk that is morally permissible in human participant research. Rescue therapies for respiratory diseases are uncommon and do not exist for influenza or respiratory syncytial virus (RSV), two diseases for which challenge trials are often used. Neither a recent ethics overview of challenges published in Science5 nor the World Health Organization6 has endorsed the “rescue therapy” standard. Indeed, a fellow coauthor to the paper that Weijer cites does not agree with his analysis.7

A rescue therapy, in our view, is not an ethical prerequisite for a covid-19 challenge trial, as the risks of the disease in young healthy volunteers are on a par with or lower than other commonly accepted public service risks, even those in medical contexts. We allow ordinary members of society to risk exposure to covid-19, especially healthcare workers, many of whom lack personal protective equipment. We also let liver donors incur a 1 in 600 risk of death from donation8—orders of magnitude higher than the risk to young healthy volunteers in a covid-19 challenge trial, which would probably be less than 1 in 20 000.9

According to a principle of “risk parity,”10 if we allow some people to take certain risks to help save lives then we should allow other people to take similar, voluntary risks when there are comparable benefits. Put concretely: altruistic risks allowed in operating rooms (for example, kidney donation) should be allowed in clinical research facilities, such as in challenge trials. Any ethical oversight of such trials must, on this principle, consider the immense costs to ordinary people of blocking promising research.

Volunteers are aware of the spectrum of risks facing challenge trial participants, and they will be subject to rigorous criteria to establish sound mental and physical health.11 Already, this is more than is expected in other analogous cases. Claims that such trials should not intentionally recruit people already at higher risk of contracting the virus (for example, healthcare workers or economically disadvantaged groups), so as to minimise the added risk of challenge trials, are well founded. Thankfully, this can be avoided in challenge trials, and thousands of informed volunteers are willing to take the risk so that others don’t have to.

Too much uncertainty

The risks to participants in challenge studies are too uncertain and too great to be permitted. The ethics differ from those of patient clinical trials. Patients in the latter may be exposed to substantial risks provided that there is a reasonable prospect of direct benefit. But challenge studies make healthy people sick solely for scientific ends. Consequently, a more risk averse approach is the norm for challenge studies.

Thousands of volunteers have participated in challenge studies in the past 50 years, and none has died as a result.15 This is because scientists have steadfastly protected volunteers by restricting challenge studies to well understood diseases that would either resolve on their own and have no long term harmful effects or to diseases for which curative treatment is available.

McPartlin et al point to challenge studies with influenza and respiratory syncytial virus (RSV) in making the case for SARS-CoV-2 challenge studies. But SARS-CoV-2 is much less well understood than influenza or RSV. What we do know of the risks of SARS-CoV-2 infection suggests that they are too great to be permitted ethically. The manifestations of SARS-CoV-2 infection are protean and serious. Beyond the lungs, the virus can infect the brain and cardiovascular system, resulting in stroke16 and myocarditis.17 And each of these sequelae has been observed in young people. Further, SARS-CoV-2 infection can be disabling, as demonstrated by people experiencing “long covid.”18

Finally, covid-19 is perhaps 10 times more lethal than influenza, and remdesivir, the drug to be made available to participants in the challenge trials, did not reduce mortality in the WHO Solidarity trial.19

Unjust

Strategies to mitigate research risks by selecting people at high risk of covid-19 for challenge studies are likely to be unjust. For example, advocates of SARS-CoV-2 challenge studies have proposed including people who are at high risk of the disease in the community.20 But this approach to participant selection may violate justice. It has become clear that some social groups, including Black, Asian, and minority ethnic groups, are at higher risk of the virus because of structural injustice.21 Selecting people from these groups for participation in challenge studies would compound unfairness and wrongly increase the burdens they face.

Bringing an end to the pandemic will require more than an effective vaccine: people must also be willing to take it. A recent global survey highlighted the problem of covid-19 vaccine hesitancy and found that the “accelerated pace of vaccine development has further heightened public anxieties and could compromise acceptance.”22 Public disclosure of serious injuries or deaths in SARS-CoV-2 challenge studies may undermine public trust and fuel vaccine hesitancy.

Traditional vaccine trials pose less risk to participants than challenge studies and, when combined with steps to enhance transparency, represent a safer path to vaccines that will be widely accepted.