By Allison Proffitt

July 17, 2020 | More than 100 researchers, clinicians, and Nobel Laureates signed a letter sent to Francis Collins, director of the National Institutes of Health, yesterday emphasizing the “vast importance of human challenge trials” in developing a vaccine for COVID-19.

“The undersigned urge the U.S. government…, its allies, international funders, and world bodies (e.g. the World Health Organization), to undertake immediate preparations for human challenge trials, including supporting safe and reliable production of the virus and any biocontainment facilities necessary to house participants,” the authors write.

The letter—organized by advocacy group 1Day Sooner—is the latest development in a growing debate that has been brewing in scientific circles on the usefulness and justification for these types of trials.

Human challenge trials or controlled human infection models (CHIMs) involve infecting an otherwise healthy volunteer with a well-characterized microorganism to study pathogenesis, characterize the immune response, and test drugs or vaccines. CHIMs are more controlled than “field trials” of the general population; researchers can minimize uncertainty about exposure or disease acquisition inherent in field trials. Participants are quarantined and carefully monitored to track disease progression. Trials are designed to generate robust scientific data quickly.  

But there are obvious ethical risks, especially for COVID-19 for which we do not have a clear “rescue” treatment. And CHIMs require a stockpile of infectious agent with demonstrated stability and consistent infectivity; that stock must be manufactured and then secured.  

These are not new ideas. CHIMs have been successfully used to test drugs and better understand pathogenesis for diseases like smallpox, malaria, yellow fever, and even other coronaviruses. And so far, 1Day Sooner has gathered the names of more than 32,000 volunteers from 140 countries that have volunteered to be infected with the SARS-CoV-2 virus in a challenge trial for vaccine development.

But willing volunteers are not all that is needed; scientific consensus would be a good first step.

On April 20, 35 members of Congress sent a letter to Alex Azar, Secretary of the Department of Health and Human Services and Stephen Hahn, commissioner of the Food and Drug Administration. The letter encouraged HHS and FDA to “consider adopting, in parallel, expedited procedures for testing, approval and use of COVID-19 vaccines.” Challenge trials were among the list of accelerated procedures.

In a personal view published in The Lancet Infectious Diseases in late May, two researchers from Monash University in Australia, Euzebiusz Jamrozik and Michael J Selgelid, also advocated for a COVID-19 challenge trial, though with a host of caveats.

“We argue that these human challenge studies can reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done, can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimize risks to participants, and are done with strict infection control measures to limit and reduce third-party risks,” they wrote (DOI: 10.1016/S1473-3099(20)30438-2).

Their first point—international acceptance—still has a long way to go.

WHO Weighs In

On June 15, the World Health Organization released a draft report from the WHO Advisory Group on Human Challenge Studies on the feasibility, potential value and limitations of establishing a closely monitored challenge model of experimental COVID-19 infection and illness in healthy young adult volunteers.

The 81-page report outlines questions and recommendations about clinical protocol, isolation units, consent, volunteer comprehension, viral strain selection, manufacturing, and more.

A closely-monitored SARS-CoV-2 challenge model in healthy young adult volunteers could gather important information, the WHO Advisory Group argued, including determining whether an initial infection confers protection against subsequent exposures, identifying protective features of the immune system, and allowing studies of different COVID-19 vaccine candidates.

But the group also acknowledged the special challenges to CHIMs in the case of SARS-CoV-2. The group highlighted the severity of COVID-19 disease and uncharacterized risk factors in young adults, the high transmissibility of SARS-CoV-2 from person-to-person, and lack of a reliable “rescue treatment” that can predictably arrest the progression of COVID-19 illness from a mild/moderate illness to serious, potentially life-threatening, illness.

But these are not insurmountable challenges. The WHO Advisory Group was nearly unanimous in recommending that all studies to be done under compulsory isolation, limiting risk to volunteers’ families and communities. “Volunteers would have to be stringently screened to enroll only those who are deemed to be diligent and committed and who understand clearly this unusual concept,” the Advisory Group wrote.

The report recommends conducting trials in two stages. Small Stage 1 studies will establish the model through first-in-human, stepwise, dose-escalation studies with three different dose levels and close monitoring of the volunteers to reveal the clinical response and the virus shedding pattern. Stage 2 studies can run with many more volunteers after Stage 1 is complete. Viral isolates should be gathered and tested from the US/European clade as well as the Chinese clade.

The Advisory Group was divided, though, on whether challenge trials should begin without a rescue treatment. 10 voted “to begin” without an available treatment and 9 voted “not to begin” without a treatment.

The major point of contention was on the likelihood of the controlled human infection models to be useful. The Advisory Group was in agreement that, “the age range of the volunteers should be restricted to healthy individuals 18-25 years of age, as that age group has a lower-case fatality risk among hospitalized cases than older adults.”

But will a model of disease in healthy 18-25 year old volunteers be broadly applicable to the population? Will it help speed our arrival at a working vaccine?

Eight members of the advisory group believed the model derived from young, healthy volunteers would still predict vaccine efficacy in elderly and high-risk adults; 11 believed the model would not be predictive. In fact, the Advisory Group was evenly split on whether a challenge trial in healthy young adults would accelerate the vaccine timeline any more than a large-scale randomized, controlled field trials of efficacy in the high-risk target population

This is the question on which the whole proposal hangs.

On July 1, five physicians representing the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Vaccines Working Group published a Perspective in the New England Journal of Medicine outlining the practical considerations for a CHIM and they raised the same points (DOI: 10.1056/NEJMp2020076).

“By design, the controlled nature of CHIMs limits their generalizability for predicting the effectiveness of a vaccine candidate against natural exposure. Concerns about the generalizability and utility of CHIMs are magnified when disease manifestations vary with patients’ age or coexisting conditions. A model of disease in healthy young volunteers may have questionable scientific validity when extrapolated to older or other at-risk populations that have disproportionate morbidity. Moreover, correlates of protection from SARS-CoV-2 are poorly understood and may vary with the population or the vaccine construct.”

But the authors were completely dismissive of the idea. They make a distinction between studies to establish vaccine efficacy and studies to understand virus immunopathogenesis. There is room, they argue, for many types of trials.

“Large, randomized, controlled trials of SARS-CoV-2 vaccines are currently the most efficient, generalizable, and scientifically robust path to establishing vaccine efficacy,” they write. But, “Parallel development of a potentially attenuated SARS-CoV-2 GMP virus, development of a seasonal coronavirus CHIM, and preparation for a SARS-CoV-2 CHIM would represent a broad and sustained research effort toward understanding coronavirus biology and mitigating the current and future pandemics.”

Volunteers and Voices

In the 1Day Sooner letter published yesterday, the authors emphasize the role of a challenge trial in speeding a vaccine, not understanding virus biology. “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 write.

Whether or not these trials would speed a vaccine is impossible to know for sure. But the 1Day Sooner signatories—18 initial signatories include several professors of bioethics, medicine, and psychology as well as more than 2,000 registered trial volunteers—also argue strongly for the volunteers’ rights to contribute and assume risk.

“The wish of informed volunteers to participate in the trial ought to be given substantial weight,” they write. According to the letter, this includes having input in protocol design and isolation conditions, but it also includes the validity of their intent to volunteer.

“Decades of psychological research on highly altruistic behaviors has demonstrated that a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others due to genuinely altruistic motivation rather than insensitivity to risk, psychopathology, or other ethically concerning motives.”