Bioethics Forum Essay
Accepting the Challenge: Covid Vaccine Challenge Trials Can Be Ethically Justified
The Covid-19 pandemic is unlikely to end until there is a safe, effective, and widely distributed vaccine. How soon can researchers achieve this goal? The answer largely depends on which strategies researchers are willing to adopt. One potential strategy is to conduct human challenge studies, in which researchers give an experimental vaccine to healthy volunteers and then test—or “challenge”—the vaccine by purposely exposing volunteers to the virus. Although a growing number of voices are calling on researchers to employ this strategy, the proposal is generating a heated debate about the ethics of such research.
In conventional vaccine trials, researchers administer either an experimental vaccine or a placebo to tens of thousands of volunteers and then wait for nature to do its work—a process that normally takes years. As curves flatten, conditions worsen for conventional vaccine research, by lowering the natural infection rate and slowing the process of discovering whether the vaccine worked. And, morally, those doing vaccine trials must urge their subjects to avoid infection, thereby lengthening time needed to complete the study. Challenge studies take much less time, require far fewer volunteers, aren’t tethered to natural infection rates, and can therefore accelerate progress. But they might put volunteers at higher risk than conventional vaccine trials.
Advocates think that there are ways to reduce risks to acceptable levels. Plotkin and Caplan propose recruiting only young, healthy volunteers. Eyal, Lipsitch, and Smith further propose recruiting from areas with high infection rates to minimize the additional risk to volunteers. Shah, Miller, and colleagues argue that the risks of controlled SARS-CoV-2 infections are comparable to risks regularly accepted in research. But opponents think the risks remain too high to be worth taking.
In her recent Hastings Bioethics Forum essay, Ruth Macklin objects to using human challenge studies in Covid-19 vaccine research. Like others who oppose such studies, Macklin rests her case on a core principle of research ethics, which morally obligates researchers to minimize risks to volunteers. In her view, exposing volunteers to SARS-CoV-2 would be unethical since there is no accepted treatment for Covid-19. Macklin writes, “a long-standing caveat in the use of [human challenge studies] is a prerequisite that there exists an accepted treatment for the disease under study. That requirement is currently not met in the case of Covid-19.” Although Macklin raises additional concerns about informed consent and fair subject selection, neither of which are unique to challenge studies, her primary worry is about risk. She concludes, “a rush to begin human challenge vaccine trials for a grave disease lacking an effective treatment is ethically unjustifiable.”
We disagree. To be sure, we endorse the principle of minimizing risks in research. However, we think that SARS-CoV-2 challenge studies can meet the minimize-risks requirement. Because of this, and because of the enormous social benefits they promise, human challenge vaccine trials for Covid-19 can be ethically justified.
Macklin’s argument weighs heavily on the fact that there is no accepted treatment for Covid-19. However, let’s distinguish between two issues: on the one hand, whether a treatment exists; on the other, whether risks are minimized. These are not the same thing. Thus, the “long-standing caveat” in challenge studies that there be an accepted treatment is merely a proxy for the minimize-risks requirement, not a requirement itself. There are other ways to minimize risks. We offer five reasons to think that SARS-CoV-2 challenge studies can minimize risks and meet the demands of research ethics.
First, challenge studies have received IRB approval even without an accepted treatment for the disease at hand. For example, they have played an important role in establishing vaccine candidates for dengue. In a study reported in 2016, researchers infected volunteers with a strain of dengue virus to test the experimental vaccine TV003. In that study, the vaccine protected all recipients from dengue, which meant further study was warranted. This was a welcome development after another vaccine, Dengvaxia, caused great harm and controversy in the Philippines. Regardless of TV003’s future—the vaccine is still being studied—the point is that researchers conducted ethical dengue challenge studies even though there was, and is still, no specific medical treatment for the disease.
Second, the risks that volunteers actually face depend on the challenge agent researchers use. A challenge agent is a specific version of a pathogen selected or designed and manufactured for use in challenge studies. The usual aim is to produce infection, not disease, or damage to the body In the dengue challenge study, researchers used a challenge virus, rDEN2D30, which they derived from a particular strain isolated during an outbreak notable for its mild cases. In malaria challenge studies, researchers test malaria strains before infecting volunteers to ensure they’re using strains that respond to treatments. No one can reliably say that SARS-CoV-2 challenge studies are too risky without knowing more about the challenge agent and doses. In the Covid-19 context, Dr. Anthony Fauci recently told Politico, “We are making challenge doses.” It’s natural, but a mistake nonetheless, to think that the risks would necessarily be those associated with worst cases of Covid-19.
Third, accepted treatments, like most tools we live by, have nonzero failure rates. So, even when treatments exist, some risk always remains in challenge studies. Minimizing risks doesn’t mean eliminating them.
Fourth, other types of vaccine research are regularly approved despite serious risks. For example, volunteers in conventional vaccine trials face risks of adverse events from which no rescue agent can save them. Such risks are minimized and routinely accepted by researchers, volunteers, and IRBs. Why, then, should the lack of an accepted treatment be a deal-breaker for challenge studies? We suspect that moral-psychological oddities, not principles, are at work. There is no compelling reason to perceive risk of harm stemming from deliberate infection as morally worse than risk of harm stemming from an experimental vaccine.
Finally, during the pandemic’s first peak, we all not only permitted but praised doctors, nurses, EMTs, cleaning staff, and others taking great risks to provide care for Covid-19 patients. These risks were much greater than those that challenge study volunteers would face, but our communities judged them as worth taking given everything at stake. We’re not suggesting that the upper limit of acceptable risk in research is or ought to be the same as in other avenues of life. Rather, we cite this heroism as a reminder of risk-taking’s moral worth. Altruism and a spirit of public service seem to animate challenge-study volunteers. Those who oppose SARS-CoV-2 challenge studies do not only miscalculate the risks; they also misjudge the value that drives participation.
Kyle Ferguson, PhD, is a postdoctoral fellow in the Division of Medical Ethics, Department of Population Health, at NYU Grossman School of Medicine. Arthur Caplan, PhD, is the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics and the founding director of the Division of Medical Ethics at the NYU Grossman School of Medicine. He is a Hastings Center fellow and a member of The Hastings Center’s advisory council. Twitter: @ArthurCaplan.
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I understand the urgency of a vaccine in this case, but I don’t think the argument made in this article is at all compelling and it is certainly not an ethical justification – more like lawyerly fast-talk. The analogy to front-line health care workers accepting the risk of contagion does not hold; that is their profession and they can’t be compared to random “civilians”. Who will volunteer for such trials? “Young healthy individuals” because they believe the (increasingly in doubt) official line that young people survive this illness. Recent indicators seem to suggest lifelong serious health consequences even in individuals who were asymptomatic – and with COVID-19 there is still so much that we don’t know, including how long immunity lasts and whether or how it is mutating that these people would have to sign up to infected and reinfected at regular intervals. The second group that might “volunteer” are people in financial need, especially since this article proposes recruiting from hard-hit areas. In the early days of medical research, doctors tested their innovations on themselves – that was ethical. The vaccine should be tested on members of the medical profession. They are best able to give informed consent, and they match the description of “at risk anyway”. Or, it should be tested on the shareholders of the giant pharma concerns that will benefit hugely from the vaccines they are developing. Those are the ethical solutions.
Ferguson and Caplan correctly note that my main argument against challenge studies focused on the ethics of intentionally inflicting risks of harm on healthy individuals. All too briefly, I also questioned whether challenge studies are likely to arrive at an efficacious vaccine much more quickly–if at all–than conventional vaccine trials. Many vaccines are currently in the pipeline. As of June 23, 125 preclinical vaccine studies were underway, 9 were in Phase I trials testing for safety and dosage, 9 were already in Phase II expanded safety trials, and 2 are already in large-scale, Phase III efficacy trials. Challenge studies must also go through all of these phases before they are considered for approval. Challenge studies would still have to recruit a large enough study population to achieve statistical significance. And given how rapidly the coronavirus spreads among high-risk populations, it is not at all clear that challenge studies not yet initiated will arrive at an efficacious vaccine more quickly. Just as Ferguson and Caplan marshal several arguments in support of their view, so too are there additional considerations in favor of the traditional approach to studying a vaccine to combat this devastating disease.
Questions around this particular area of medical ethics are fraught with contradictions and appear to be answered ultimately in terms of ‘utility’ rather than the care for individuals which you
appear to be advocating.
Your statement “my main argument against challenge studies focused on the ethics of intentionally inflicting risks of harm on healthy individuals” could equally be applied, judging by historical evidence, to questions about administering vaccines in general, and mandatory vaccination in particular.
The general argument for vaccination (knowing there are serious potential side effects) usually comes down to bleeting about ‘balance of risk’, and the mandatory argument comes down to trying to square sacrificing the rights of the individual against protect the herd.
Unfortunately in the context. of a commercially rapacious pharmaceutical industry and growing government control and politicisation of health, ‘utility’ is simply becoming an excuse to justify taking the risk of inflicting harm on both individuals and on society in the quickest way possible b
The first step on this road was ‘Warp Speed’, the second will be challenge trials, the third administering the vaccine.