By Sue Coons, MA

Lawmakers, academics, and the research community have hotly debated the ethics of a human challenge study (HCS) since the first months of the COVID-19 pandemic. Now that the United Kingdom has started dosing patients in its HCS, some bioethicists say this trial can show vaccine efficacy in ways the larger vaccine trials cannot.

The U.K. human challenge study will expose healthy volunteers, ages 18 to 34 years, to the COVID-19 virus in a controlled environment. Organizers of the trial say it will help show the effect of the virus on the volunteers as well as identify which vaccines seem to be the most effective.

This HCS may answer questions left unanswered by the large vaccine trials, says Arthur L. Caplan, PhD, director of the division of medical ethics at New York University Langone Medical Center and School of Medicine. The large trials that opened the door for emergency use authorization from the FDA are experiencing issues with participants wanting to drop out. Some patients want to make sure they are vaccinated, but unblinding them affects the long-term data. Caplan does not see many people wanting to sign up for new trials for vaccines in the pipeline, either.

“Yet we have questions to ask about which vaccine is better, which lasts longer, which prevents transmission, which does better against new variants, which is cheaper,” he says. “There are a lot of questions that we are still going to want to know the answers to. I think challenge studies could get us to the answer quickly, and they may be the only way in reasonable periods of time to get answers.”

The timing of these trials is not ideal, says Seema K. Shah, JD, a lawyer and medical ethicist at Northwestern University Feinberg School of Medicine. “If early vaccine studies hadn’t been able to complete enrollment, that could have been a good reason to do challenge trials. Alternatively, once vaccines are widely available and it becomes more difficult to test new versions of vaccines because placebo controls are not ethically acceptable, there might be good reason to prioritize vaccine candidates by comparing them in challenge trials. These trials are also testing the old strain of the novel coronavirus, and not the newer variants. Nevertheless, they may identify a correlate of protection (a measure of when people are protected from infection or disease) or develop insights into disease or transmission that are valuable.”

In the longer term, challenge trials to develop a universal coronavirus vaccine might be really useful, Shah says. “Challenge studies involving people who have previously had COVID-19 are a safer option that may produce similar insights, so I wonder why those are not happening first.”

At the beginning of the COVID-19 pandemic, lawmakers, health researchers, and advocates sent letters to U.S. government agencies asking them to consider human challenge studies for COVID-19 development.1 The first letter in April 2020 was sent by 35 members of the House of Representatives to Alex M. Azar, JD, then secretary of the Department of Health and Human Services (HHS), and Stephen Hahn, MD, then commissioner of the U.S. Food and Drug Administration (FDA). The representatives encouraged the agencies to consider human challenge trials.

On July 15, 2020, the organization 1Day Sooner, which advocates for people seeking to participate in high-impact medical trials, wrote an open letter to Francis Collins, MD, PhD, director of the National Institutes of Health (NIH). The letter was signed by 177 Nobel Laureates, experts, and academics urging the U.S. government to consider human challenge or controlled infection trials. “If challenge trials can safely and effectively speed the vaccine development process, there is a formidable presumption in favor of their use, which would require a very compelling ethical justification to overcome,” they wrote. The letter also spelled out several protections that could be put into place for an effective COVID-19 human challenge trial.2

In its guidance, titled Development and Licensure of Vaccines to Prevent COVID-19, published on June 20, 2020, FDA responded with this: “If it is no longer possible to demonstrate vaccine effectiveness by way of conducting clinical disease endpoint efficacy studies, the use of a controlled human infection model to obtain evidence to support vaccine efficacy may be considered. However, many issues, including logistical, human subject protection, ethical, and scientific issues, would need to be satisfactorily addressed. At this time, no controlled human infection models for SARS-CoV-2 have been established or characterized.”3

In a letter dated June 30, 2020, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, responded to the consumer advocacy organization Public Citizen, based in Washington, DC. “Controlled human infection (CHI) studies are one research approach that might help determine the effectiveness of a vaccine,” Fauci wrote. “However, the best way to determine both safety and efficacy is through the current plan of conducting adequately powered, randomized, controlled trials. I agree that CHI studies can raise significant ethical questions, and it is important that these questions be examined and carefully considered prior to undertaking such studies. If the randomized controlled trials prove infeasible for any reason, CHI studies, if able to be conducted safely and ethically, could be an important and scientifically sound complementary strategy to more traditional vaccine development approaches.”4

The chief compliance officer of one of the nation’s largest providers of regulatory and ethical review services spoke about the issues IRBs would experience with human challenge trials. “IRBs would be very reluctant to approve a trial without some kind of mitigation (such as using a weakened strain or a population unlikely to have severe reactions) to protect the safety of subjects,” said David Forster, JD, MA, CIP.5

Researchers also published responses to the debate, including one from November that called human challenge studies “unethical” at that point. “We think proponents’ core claim about speeding vaccine development is flawed, and we believe that the risk-benefit balance for such HCS is both too uncertain and likely to be unacceptable, even with greater information,” the researchers wrote. “In addition, issues of resource allocation are critically important and difficult to justify. Vaccine trials aiming to undertake risky and uncertain steps in human subject research — particularly those that depart from standard approaches to protection of subjects in HCS — risk further exacerbating increasing levels of public mistrust related to SARS-CoV-2 vaccine development. Taken together, we believe that these arguments make undertaking SARS-CoV-2 HCS both unwarranted and unethical. At this critical moment in the response to the pandemic, it would do more harm than good.”6

Nir Eyal, DPhil, director of the Rutgers Center for Population-Level Bioethics, published a paper in March 2020 with two epidemiologist colleagues about how HCS could be used to accelerate coronavirus vaccine licensure.7 In January, Eyal, Caplan, and legendary vaccinologist Stanley Plotkin, MD, published an opinion update, stating HCS should still be considered.

“It is true that in some ways, challenge trials are less urgent now that vaccines have been found safe and efficacious,” Eyal wrote. “But in other ways, challenge trials have never been as urgent.”8 Eyal and colleagues argued that challenge trials could:

  • determine the efficacy of vaccines in preventing infection;
  • determine whether vaccines prevent mucosal infection;
  • measure the comparative efficacy of different vaccines in these two roles;
  • measure the comparative efficacy of regimens for vaccines (e.g., half-dose, spaced out);
  • determine vaccine efficacy against new viral variants;
  • determine the correlates of vaccine protection to assess efficacy in different populations;
  • quickly triage for unpromising next-generation vaccine candidates;
  • determine the duration of immunity by challenging participants months after they receive the vaccine;
  • determine the quality and duration of post-natural infection immunity by challenging people previously infected with COVID-19;
  • help test therapeutics.

“Multiple vaccines for SARS-CoV-2 have proven highly efficacious in preventing disease,” the authors concluded. “Global health requires testing both these and further vaccines in the critical additional role of blocking infections, and in defining the correlates and duration of vaccine protection. Large, randomized field trials comparing vaccines to controls have now become much harder to perform. Yet human challenge studies, such as the ones that the U.K. is planning, can and should play an important role in the necessary investigations we still have to carry out.”

Critics of the HCS say it is too risky for the participants. Caplan believes the risk benefit is reasonable, about the same faced in a kidney donation. COVID-19 treatments are improving, he says, and researchers can develop a dose that produces biological changes without symptoms.

The risks still are fairly uncertain. “I worry about the risks of long-term symptoms from COVID-19 infection or an unexpected death among the participants, and the risks to society of a study like this, especially if it has negative outcomes, increasing distrust in vaccines or vaccine hesitancy,” Shah says. “Given that the social value of these trials is not very high or clear, I think it is a close call about whether these studies are justified.”

Another question is how to ensure the trial participants give fully informed consent. “Part of what we need to verify is that the participants know that only a bit is known about some of the risks and potential complications of long COVID,” Eyal says. “A fairly distinctive aspect is that the ‘right answer’ to some questions should be ‘I don’t know, and nor do you.’ But that’s not entirely unique. There are often deep unknowns in medical trials. In fact, in the recent field trials for COVID vaccines, there were many such unknowns about the product used. It was the first time that these vaccines were tested in humans, and some of them were from a wholly new family of vaccines.”

Also, what is appropriate compensation for a patient who is deliberately exposed to a virus? Adequate compensation depends on the time they will spend in the study and the burdens they take on, Shah says. “I think the best way to address and minimize risk is not to give them money up front but to make sure they receive prompt, free treatment if they end up being harmed.”

Caplan says he also would argue against compensation. Instead, they should be altruistic volunteers. “I don’t want the issue of money mixing or confusing with the question of motivation.”

The U.K. trial can help set up the speed of HCS trials in the future, Caplan says. It would help the process to go faster, he explains, if researchers already knew how to trigger challenge studies at a particular isolated location. They should also maintain a registry of people who are willing to participate.

Caplan says he is seeing less resistance to the idea of a HCS than when he spoke about it in April 2020, especially since the large trials are not always possible to complete. “I think there’s been some shift in thinking now that people see what the impact is on existing trials.”

REFERENCES

  1. Letter to HHS, FDA on rapid vaccine deployment for COVID-19. Congress of the United States. April 20, 2020. https://www.documentcloud.org/documents/6845762-2020-04-20-Ltr-to-HHS-FDA-on-Rapid-Vaccine.html
  2. 1Day Sooner. US: Challenge trials for COVID-19 open letter. July 15, 2020. https://www.1daysooner.org/us-open-letter
  3. Food and Drug Adminisrtation. Development and licensure of vaccines to prevent COVID-19. June 30, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19
  4. National Institutes of Health, National Institute of Allergy and Infectious Diseases. NIH response letter. June 30, 2020. https://mkus3lurbh3lbztg254fzode-wpengine.netdna-ssl.com/wp-content/uploads/2531_NIH-Response-Letter_July-30-2020.pdf
  5. WCG. Group urges challenge trials for COVID-19 vaccine, but FDA and ethicists balk. WCG CenterWatch. April 27, 2020. https://www.centerwatch.com/articles/24665-group-urges-challenge-trials-for-covid-19-vaccine-but-fda-and-ethicists-balk
  6. Kahn JP, Meltzer Henry L, Mastroianni AC, et al. Opinion: For now, it’s unethical to use human challenge studies for SARS-CoV-2 vaccine development. Proc Natl Acad Sci U S A 2020;117:28538-28542.
  7. Eyal N, Lipsitch M, Smith, PG. Human challenge studies to accelerate coronavirus vaccine licensure. J Infect Dis 2020;221:1752-1756.
  8. Eyal N, Caplan A, Plotkin S. Human challenge trials of COVID-19 vaccines still have much to teach us. The BMJ Opinion. Jan 8, 2021. https://blogs.bmj.com/bmj/2021/01/08/human-challenge-trials-of-covid-19-vaccines-still-have-much-to-teach-us/