COVID-19 human challenge volunteers are neither doing too little, nor helping too late

By Abie Rohrig and David Manheim

The world’s first COVID-19 human challenge trial began in early March, with around a dozen healthy, consenting volunteers between the ages of 18-30 deliberately exposed to the virus at a quarantine facility in London. Getz and Baylis recently argued that the questionable harm-benefit ratio of COVID-19 challenge trials make them unethical, and that volunteering for a challenge trial “just should not be asked of others,” especially the youth.

We disagree on both counts. Getz and Baylis’ suggestion that we should prohibit volunteers who wish to take part in challenge trials for fear of asking too much is an affront to the agency of volunteers and to those who stand to benefit most from next-generation vaccine research, namely, those in the developing world who are last in line to receive a COVID-19 vaccine. The many ethicists and regulators who approved the challenge study did so because they believe the research still has enormous social value that justifies its risks— and volunteers agree.


Defending the agency of young volunteers

Getz and Baylis rightly point out that young people have inherited a precarious and unjust world: climate change, extinction risk, and political instability all threaten to cause widespread misery in the next hundred years. For exactly that reason, it is unfair to hamstring young people from taking bold action to fight these crises. Quite the opposite— we have given young people far too little responsibility given that they will bear the brunt of these cascading crises, and now is the time to be especially permissive of projects like challenge trials, in which civic-minded young people can take meaningful action to help the world. Framing the passionate and well-informed volunteerism of trial participants as passively being put “in harm’s way” not only overlooks the voluntary nature of these trials, but also dismisses the heroic sacrifices of volunteers.

Throughout the pandemic, volunteers have spoken for themselves about their willingness to participate in challenge trials. As Alastair Fraser-Urquhart, a current UK human challenge participant, writes:

“I am extremely proud of the UK challenge programme, which has allowed me the agency to volunteer, while minimizing risks to the greatest extent possible. When thinking about how young people evaluate risks, it is important to understand that increasing young people’s autonomy and empowerment works both ways: young people who are not convinced of the utility of the challenge model, or think the risks outweigh the benefits, do not have to participate, and should feel empowered to make their voices heard.”


Understanding the limited risks of COVID-19 challenge trial, and the large potential social value

On some points, such as transparency of the trial protocol, we unreservedly agree with Getz and Baylis: the UK trial team should publish their study protocol, and should have done so before the first volunteer was inoculated, to enhance study transparency. We agree about other potential problems in challenge trials such as undue inducement, but note that such issues have been extensively addressed. On the other hand, we do not think that many objections raised, such as uncertainty of risk, generalizability, and lack of transparency, are unique to challenge trials— rather, they are universal concerns for medical research.

Getz and Baylis argue that we cannot reliably predict the risks of challenge trials, and that the specter of “long COVID” means the potential damage inflicted to volunteers in a challenge trial is unjustifiable.

Firstly, this is an overestimation of our uncertainty. We are now over a year into the pandemic, and several studies have measured the infection fatality ratio of COVID-19 across age groups. Our meta-analysis finds that the risk of death in a COVID-19 human challenge trial for a young, healthy volunteer is around 1 in 10,000— significantly lower than widely accepted risks, such as logging, trucking, and organ donation. We estimated that these risks are mitigated via screening the volunteers to around 2.5 in one million, and is even further reduced by close medical monitoring and immediate access to healthcare. Some uncertainty remains, but this uncertainty is commonplace for other acceptable medical research, such as early-stage trials like phase 1 vaccine trials. Perfect certainty has never been a prerequisite for informed consent or ethical research. On the contrary, reducing this uncertainty is exactly what motivates trials in the first place.

Getz and Baylis argue that comparator risks, such as firefighting, are disanalogous, because unlike challenge trials, they include “benefits or protections that come with career employment and advancement.” Yet, arguing that we properly protect or compensate these risks in dangerous industries, in addition to being dubious factually, does not address organ donors, who take a medical risk without a minimum wage, the power to collectively bargain, or opportunities for career advancement. The same is true for ordinary clinical trial participants. Moreover, the analogy is conceptually misleading because benefits to individuals should not be understood purely in financial terms. The stated motivations of challenge volunteers are primarily altruistic, rather than selfish, and it would be unreasonable to discount the realization of altruistic interests as a legitimate benefit incurred to volunteers in a trial. Finally, the proper response to a lack of robust support for challenge volunteers is not to disallow volunteerism altogether, but rather to ensure support, through the aforementioned compensation, and via healthcare protections, as many have elsewhere argued.

Challenge trials would likely have been more impactful at the beginning of the COVID-19 pandemic— yet even then, Getz and Baylis made similar arguments against their justifiability, which we questioned at the time. Getz and Baylis are correct to raise concerns about the generalizability of challenge trial data, but this is an issue for all clinical trials for which there are well-established ways to address. The UK Medicines and Healthcare products Regulatory Agency is accepting of challenge trials as a means of studying vaccine candidates, and while nearly half of the WHO working group on challenge trials concluded that a challenge model would not predict efficacy in elderly and high-risk adults, a majority thought that challenge trials should still proceed even in the absence of a rescue therapy. Furthermore, basic understanding of COVID-19 is valuable across populations. For example, establishing a correlate of protection in younger volunteers could accelerate the licensure of next-generation vaccines in older populations. In fact, researchers routinely use far larger extrapolations to guide research, as shown by animal trials for early-stage trials of medical investigations.

Beyond extrapolation of impacts of a treatment to the elderly, there are many other use cases for COVID-19 challenge trials at this point in the pandemic. These trials can give an early (even if imperfect) indication of vaccine efficacy, allowing for a fast-to-fail approach that can inform important manufacturing and distribution decisions. This is crucial for low-cost, easily deployable vaccines in early-stage trials that could be the key to vaccinating the developing world. As others have itemized in greater detail, challenge trials have additional benefits, such as testing therapeutics, discerning the quality and duration of natural immunity, and studying virus transmission.



Research always has costs and benefits. Challenge trials allow these risks to be kept as voluntary as possible, and include provisions to minimize risks by using healthy volunteers and including excellent medical care on site. While reasonable disagreements exist, the balance of arguments seems clearly in favor, as indicated by the decision of the UK Research Ethics Committee to approve these trials.

COVID-19 is still taking thousands of lives every day. Easier-to-deploy, less expensive vaccines and more clearly effective treatments are desperately needed for poorer countries. Perhaps the world does not always need heroes willing to sacrifice their own health for the sake of others, but when they step forward, ethicists should think twice before sending them home on the basis that “there are things that just should not be asked of others.” In the context of COVID-19, society should celebrate and honor— not dismiss— the altruism of challenge trial volunteers, and ensure that these brave individuals are as protected during and after the trial as possible.


Authors: Abie Rohrig1,David Manheim2


1  1Day Sooner, New York City, USA

2  Health and Risk Communication Research Center, University of Haifa, School of Public Health, Haifa, Israel

Competing interests: The authors declare no conflict of interest.

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