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Posted on June 15, 2020 at 12:37 PM

Experts in infectious disease and public health warn that the Covid-19 pandemic will be with us for a long time unless a vaccine becomes available soon. Estimates of how long it will take for an effective vaccine to come to market have typically ranged from 12 to 18 months or longer. This situation has given rise to calls for human challenge studies. In these types of studies, researchers inject healthy volunteers with an experimental vaccine, after which the participants are infected with a strain of the disease  to test the vaccine’s efficacy.

The standard research method vaccinates large numbers of people at risk for a disease with the experimental vaccine and compares the results with an unvaccinated cohort at similar risk. Proponents of challenge studies cite three main advantages for their use: they involve fewer research participants than the standard research method; they are considerably cheaper to carry out; and most important, they can determine more rapidly whether a vaccine is effective. The last claim was questioned by bioethicist Franklin G. Miller in Hastings Bioethics Forum: “There is reason to be skeptical about whether a coronavirus challenge trial … can in fact facilitate and speed access to a safe and effective vaccine, in view of the complex set of vaccine development efforts already underway.”

Challenge Studies and Covid-19

Advocates of human challenge studies for Covid-19 cite the public-health imperative—save the most lives—along with the other benefits of lower costs and the need to recruit fewer research subjects. Opponents cite a leading principle of research ethics: minimize risks to research participants. Federal regulations place the burden on institutional review boards, in their review of proposed research, to satisfy two requirements: ensure that “risks to subjects are minimized” and use “procedures that do not unnecessarily expose subjects to risks.” In recent years, the World Health Organization (WHO) and the National Institutes of Health have supported human challenge studies, resulting in the development of vaccines against malaria, cholera, and typhoid. However, a long-standing caveat in the use of this research method 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.

On May 6, the WHO issued a document, “Key Criteria for the Ethical Acceptability of COVID-19 Human Challenge Studies.” It states that “there is a consensus among ethicists who have reflected upon human challenge studies that the intentional infection of research participants can be ethically acceptable.” While that is probably true for most ethicists, the WHO list of ethical criteria for the acceptability of such studies for Covid-19 does not mention the requirement that there be an accepted treatment for the disease. In a list of eight criteria for SARS-CoV-2 challenge studies, the second one mentions that “potential benefits and risks should be compared with other feasible study designs” and “risks should be minimized.” However, compared to those in the standard method of studying preventive vaccines, the risks to subjects in challenge studies would appear to be considerably greater. After all, some or many participants in a standard vaccine study may never fall victim to the disease under study. In comparison, the WHO document lists three risk-minimization strategies: “selection of low-risk participants; reducing numbers of participants where feasible;” and “initial challenges conducted one by one, with careful titration of viral dose.” While it is true that the second and third strategies reduce overall risks to the group of enrolled participants taken as a whole, only the first criterion involves the risk to an individual who is injected with a pathogen that causes serious illness and can be fatal.

On May 7, a nongovernmental organization, the AIDS Vaccine Advocacy Coalition (AVAC), issued a statement on ethics in COVID-19 vaccine challenge studies. The AVAC statement acknowledges that the WHO statement “articulated important criteria for assessing a challenge study” but omitted the most important one: “Until there is an approved treatment, a challenge trial with a potentially fatal and as-yet untreatable pathogen is unacceptable.” One vaccine researcher questioned whether it would be ethical, adding that conventional vaccine trials are likely to proceed as quickly.

Taking the other side in this debate, Nir Eyal argues that human challenge trials for Covid-19 vaccines could be ethical, despite the risks. Writing in Ethics & Human Research, he compares to two alternative scenarios and concludes that the net risk from participation in a Covid-19 vaccine challenge study would be negative, small, or unclear. The two scenarios he considers are, for a given individual, either not participating in any SARS-CoV-2 vaccine efficacy trial or participating in a standard efficacy trial for the same vaccine.  Although Eyal makes a persuasive case, his argument omits real-world factors that bear on the ethics of human challenge trials in the current situation—factors that include questions about informed consent and social justice.

Problems of Consent and Participation

There is a lot of interest in participating in challenge studies. Eyal writes that over 21,000 people have volunteered for these studies and mentions altruism as a reason. But without more information, there is no way of knowing how well-informed those individuals about the risks and benefits of participating are or even whether they are, indeed, altruists. They may be at high risk of Covid-19 and harbor the “prevention misconception” that the first attempt at a successful vaccine will succeed in preventing infection. Moreover, the usual practice in medical research with healthy human subjects is to pay them for their participation—sometimes a lot of money. Eyal writes: “Avoiding financial incentives for participation would further help select volunteers with the best motives.” The WHO document on the acceptability of human challenge studies does not mention payment, but given standard practice, it is virtually certain that monetary payment—which may be considerable—will serve as an inducement to enroll. The likely result is that a disproportionate number of volunteers would come from lower-income brackets, including many people who lost their jobs because of the pandemic. It is also likely that many volunteers would be members of racial and ethnic minorities, raising a serious question of social justice that lies at the heart of this proposal.

A passage from the Council for International Organizations of Medical Sciences’ ethical guidelines for research mentions human challenge studies and says, “Some risks cannot be justified, even when the research has great social and scientific value and adults who are capable of giving informed consent would give their voluntary, informed consent to participate in the study.” The examples cited are studies of anthrax and Ebola.

Several  human challenge trials for a Covid-19 vaccine are in progress or about to start. More scientists and ethicists are climbing on board. In late April, 35 members of the House of Representatives sent a letter to the Department of Health and Human Services and the Food and Drug Administration, arguing that challenge studies could greatly accelerate the quest for an effective vaccine. Arguably, however, such a momentous decision should not be made by politicians.

The situation has all the earmarks of a quintessential ethical dilemma: Is it permissible to intentionally inflict serious harm on a few for a possible benefit to many? With several vaccines already in the pipeline, along with worries about a disproportionate number of minorities and poor people likely to enroll, I conclude that a rush to begin human challenge vaccine trials for a grave disease lacking an effective treatment is ethically unjustifiable.

Ruth Macklin is distinguished university professor emerita at Albert Einstein College of Medicine and  Hastings Center fellow. An earlier version of this essay appeared in The Doctor’s Tablet blog.

 

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