key: cord-0704653-lxi6bi6a
authors: Kolber, Adam J
title: Why We (Probably) Must Deliberately Infect
date: 2020-05-11
journal: J Law Biosci
DOI: 10.1093/jlb/lsaa024
sha: 8e2529b9386402ac5045c3f6e09c560d279e0f8d
doc_id: 704653
cord_uid: lxi6bi6a

In the grip of a pandemic of proportions that have not been seen for generations, some have proposed conducting “human challenge” vaccine trials in which healthy volunteers are deliberately infected with the SARS-CoV-2 virus that causes COVID-19. Such trials might substantially speed up the search for a safe and effective vaccine and save many thousands of lives. I argue that such trials are not only permissible, but given reasonable assumptions, they are morally required, subject to some important caveats.

Abstract: In the grip of a pandemic of proportions that have not been seen for generations, some have proposed conducting "human challenge" vaccine trials in which healthy volunteers are deliberately infected with the SARS-CoV-2 virus that causes COVID-19. Such trials might substantially speed up the search for a safe and effective vaccine and save many thousands of lives. I argue that such trials are not only permissible, but given reasonable assumptions, they are morally required, subject to some important caveats.

In a recent article preprint, 2 Nir Eyal, Marc Lipsitch, and Peter Smith note that we could speed up trials of a novel coronavirus (SARS-CoV-2) vaccine by deliberately infecting volunteers. After "normal initial safety, vaccine dose finding, and immunogenicity studies," 3 appropriate subjects would be carefully informed of the risks of infection associated with the experiment and be given the opportunity to participate. The authors believe that "in the circumstances of a devastating global pandemic," the studies they propose "may be an acceptable way to bypass Phase 3 testing, and speed the licensure of efficacious vaccines." 4 I argue that the authors could make a far stronger claim. Given reasonable empirical assumptions, deliberately infecting volunteers is not only "acceptable" but ethically mandatory (subject to some qualifications). Those empowered to fund, organize, and run vaccine trials would be acting impermissibly from a moral perspective if they had the opportunity to significantly speed up the identification of a safe and efficacious vaccine but failed to do so because of unnecessary hand-wringing over the ethics of allowing volunteers to be deliberately infected.

Human challenge studies have often been performed in modern times to improve our understanding of minor illnesses (such as the common cold) and to investigate vaccines for more serious but treatable illnesses (such as malaria). 5 Second, the risks to volunteers in the proposed human challenge studies would be limited. Subjects would be healthy, relatively young, and from places where the virus already poses a serious risk of infection. They would be duly informed about the risks and unusual nature of the trial. Special testing could ensure that subjects properly understand the potential risks and hoped-for benefits of the experiment. 10 Doing so would increase our confidence that participation is rational and not swayed by transient impulses. Testing could also ensure subjects understand their rights to cease participation in the experiment at any time, as well as their obligations to remain in isolation until they are no longer dangerous.

Subjects would receive a carefully measured dose of the virus. Because amount of viral exposure seems to affect symptom severity, 11 the dose would hopefully lead to even lower rates of mortality and morbidity than are seen for people of similar age and circumstances infected in the wild. Subjects who develop COVID-19 would receive state-of-the-art care and benefit from any treatment advances that occur by the time the trials are conducted. There may even be ways to reduce risk further by, for example, using weak strains of the virus or altering the virus to make it weaker. 12

Third, as Eyal and colleagues note, it"s possible that volunteering could represent a net benefit to volunteers under certain assumptions. For example, if most subjects are eventually going to be exposed to the virus anyhow, subjects can develop immunity to the disease with a controlled viral dose, receive top-notch medical care, and not have to fight for limited ventilators and medical staff. Most of those who do develop the disease (and the corresponding at least temporary immunity it likely confers) will be able to return to their normal lives sooner than they otherwise would. And, of course, if a trial has identified an efficacious vaccine, subjects who did not receive placebo would be the first to benefit.

If volunteering confers a net benefit to the health and well-being of subjects and speeds the search for a vaccine, then there are no obvious reasons not to require human challenge trials.

Challenge trials would not be merely morally permissible but morally obligatory, as all else being equal, we must take actions likely to dramatically reduce pain and suffering over actions likely to do so less dramatically. This is particularly so when the actions directly or indirectly invoke the use of public or charitable funds and resources. The only significant ethical issues arise when we think volunteers are likely to experience a net reduction in their health or wellbeing as a result of their participation. Then we face familiar ethical questions about how much risk we should allow altruistic volunteers to take for the greater good.

Ethicists who take a consequentialist approach focus on the expected societal benefits of human challenge trials relative to the expected societal costs. Josh Morrison and Sophie Rose, founders of a group that has already recruited thousands of COVID-19 human challenge volunteers, pose the benefits this way: if "one-sixth of the world"s population is infected each

year and a vaccine could prevent 0.5 percent of those infected from dying, one month"s faster vaccine deployment would represent close to a half-million lives saved. Speeding up the process Similarly, volunteers for human challenge trials, like healthcare workers, would be well informed of the risks they take (or possibly better informed than healthcare workers today as our knowledge of the virus improves over time). As discussed, volunteers may be gaining net health benefits. Under more conservative assumptions, they may take on risks that are at least roughly on par with those taken by many healthcare workers today. Indeed, they are likely taking on less risk than healthcare workers who practice in their seventies or eighties or have lung disease,

S C R I P T 8 cardiovascular disease, or compromised immunity. Moreover, assuming the trials offer no compensation to participants above the payment of costs associated with COVID-19 related illness and injury, subjects may be feel less pressure to put themselves at risk than do healthcare workers whose livelihood may require them to give care during a pandemic. 17

In fact, policies that prohibit healthcare workers from voluntarily serving patients could be viewed as inappropriately restricting healthcare workers" autonomy. And the same could be said of properly-informed human challenge volunteers. A person who volunteers for a challenge study in hopes of benefiting an immune-compromised relative should be allowed to make that decision, and possibly benefit thousands as a side effect. Thus, all things considered, it seems inconsistent to think hospital administrators must allow willing healthcare workers to treat COVID-19 patients but think human challenge trials are prohibited or merely permitted.

Second, even if there are deontological constraints at risk, given the overwhelming benefits of human challenge trials, based on reasonable assumptions about the toll the novel coronavirus has already taken and will likely continue to take on the world, the risk of violating such constraints is too low-for all but the most dogmatic deontologists-to justify a substantial delay in the search for a safe and effective vaccine. 

anything, merely fails to benefit people. Many deontologists think there is an asymmetry that makes failures to benefit less morally weighty than direct causation of harm. If these views are correct, we cannot simply weigh costs and benefits as a traditional consequentialist might because doing so ignores the special relationship between researchers and subjects as well as the asymmetry between causing harm and failing to benefit.

The long way to respond is to relitigate centuries-old battles between consequentialists and deontologists. Instead, let us assume there are special duties to experimental subjects and that there are no duties to the general public except for general obligations of beneficence (a very conservative assumption given the public funding behind much medical research). Let us further assume that causing harm of a particular magnitude is more serious than failing to provide an equal-sized benefit.

Nevertheless, given the scope of the pandemic, the benefits of a speedier vaccine clearly outweigh the risks from human challenge trials. Except for extreme, absolutist deontologists, even the most precious deontological constraints can and should be violated when the benefits of doing so are sufficiently high. Few in the legal academy have done more to defend deontology than Michael Moore, yet Moore recognizes that: While threshold deontology has been used to justify breaking even the most serious deontological constraints against torture or deliberately killing innocents, human challenge trials require nothing of the sort. At worst, they involve a modest expansion of the risks we permit experimental vaccine subjects to voluntarily take, and they do so for what is shaping up to be the most serious international medical crisis in generations. What makes human challenge trials mandatory is the comparatively low risk to well-informed volunteers relative to the tremendous gains we reasonably hope to achieve. Plotkin, thinks a human challenge trial could give us key efficacy information in two to three months, another expert, Myron Levine, believes that given the special attention and urgency that will be given to finding a novel coronavirus vaccine, human challenge trials may not speed discovery of a cure by very much. 20 This might also be true if there are sufficiently high-risk groups (perhaps health care workers) who will be exposed to the virus in the ordinary course of their lives such that we can get efficacy results relatively quickly without deliberate infection.

Clearly, if Eyal and colleagues are mistaken about key assumptions, it could substantially change the analysis.

Second, there is no uniform, generic group of "vaccine trial personnel." Rather, there are many people with distinct roles, responsibilities, and places in the organizational hierarchy. They don"t each have the power to decide how a trial will be run. Since "ought" usually implies "can,"

people have no moral obligation to run a challenge trial if they lack the power to do so. Still, those who authorize or run trials might have weaker obligations. For example, they may be obligated to raise the possibility of challenge trials or to present arguments in their favor. down-the-line effects that must also be considered as matters of realpolitik.

Irrational fear of vaccines or vaccine research can itself cause harm because vaccines work best when used by a substantial portion of the population. Similarly, those running vaccine trials may have regulatory or liability concerns associated with human challenge trials. Whether such concerns are well-founded or not, it is better to run a traditional trial than a trial that will consume resources and face so much regulatory scrutiny that it never actually benefits anyone.

Such concerns can be difficult to assess but are important to manage nonetheless because trials will not be approved swiftly if they garner too much lawyerly headwind.

Therefore, I argue, given reasonable empirical assumptions, human challenge trials are ethically mandatory subject to certain hard-to-assess considerations related to public relations, we cannot entirely ignore the complex psychological and political factors that ultimately affect how vaccine trials are perceived by others even when they are conducted with the best motivations and intentions.

Studies That Intentionally Infect People with Disease-Causing Bugs Are on the Rise, SCIENCE

Letter from Bill Foster et al, to Alex M. Azar II, Secretary, Department of Health and Human Services, and Stephen Hahn, M.D., Commissioner, Food and Drug Administration

Yushun Wan et al, Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry

Eyal and colleagues suggest challenging small groups of volunteers sequentially to rule out increased danger from subsequent infections and note that the risk of such paradoxical effects are better addressed in smaller human challenge trials than larger traditional trials

Speed Coronavirus Vaccine Testing by Deliberately Infecting Volunteers? Not So Fast