LONDON – Support is growing for human challenge trials in COVID-19 to be approved in order to speed up development of effective vaccines against the pandemic infection.

The World Health Organization (WHO) has just released guidelines for assessing the ethical acceptability, saying such trials would allow for more rapid and standardized testing, accelerating development and enabling candidates to be prioritized.

The guidelines are not a go-ahead to conduct human challenge studies, in which volunteers are deliberately infected with SARS-CoV-2, but they do increase the momentum for work to begin on preparing the ground for them to take place.

“Human challenge trials could be very helpful in various parts of the vaccine development process and would provide useful information to speed up the regulatory appraisal of investigational vaccines,” an EMA spokeswoman told BioWorld.

It is vital these kinds of studies are conducted in an ethically acceptable way. “EMA recommends that clinical trial sponsors contact the agency to discuss the design of such trials,” the spokeswoman said.

There also is pressure in the U.S. to consider challenge trials. While expressing some reservations and calling for thorough review, Anthony Fauci, director of the National Institute of Allergy and Infections, and Francis Collins, head of the NIH, express support in an opinion piece on COVID-19 research strategies published in Science on May 11.

“Such experiments, if designed to define potential immune correlates or winnow out less effective vaccine approaches, may have utility,” they say.

In April, WHO published a draft protocol for the Solidarity trial, an international randomized study of vaccines against COVID-19. That protocol said sites taking part must be in places with sufficient transmission rates of COVID-19 to conduct a field trial.

Margaret Harris, WHO spokeswoman, told BioWorld the WHO guidance on human challenge trials outlines the criteria for ethical acceptability, “but does not advocate for a position” on it. “In other words, release of the document does not mean that these kinds of trials will be part of the WHO [clinical study] protocol on vaccines,” Harris said.

The purpose of the guidance is to emphasize that, at all times, the safety of participants is a key priority in challenge study design, and to lay out eight key criteria, from the scientific justification, risk/benefit assessment and engagement with the public, through to site and participant selection, expert review and consent, said Harris.

The guidelines say, if they are allowed, participation should be limited to healthy young adults, ages 18 to 30, which existing data show is the group least likely to be hospitalized or to die from the infection.

Assessing risk

Challenge studies have a documented history going back to the development of a smallpox vaccine in 1796. In recent years, ethically approved challenge trials have accelerated development of vaccines against typhoid and cholera, and have helped in determining correlates of immune protection against influenza.

However, it is not a given that challenge studies get ethical approval. The NIH refused permission for a challenge trial in Zika virus in 2017, after field trials were wound down when the number of new infections decreased significantly.

Pressure to allow human challenge trials in COVID-19 has been growing since leading U.S. and U.K. bioethicists called for them to replace conventional phase III studies, in an article published in the Journal of Infectious Diseases on March 31.

Challenge studies in COVID-19 currently are high risk because the pathogenesis is poorly understood and there is no specific treatment for the infection. But net risk could be acceptable if participants are healthy young adults, who are at relatively low risk of serious disease following natural infection.

The risk should be compared to that facing volunteer firefighters, living organ donors or citizens volunteering for emergency medical service during the pandemic, the article said.

One of the authors, Peter Smith, professor of Tropical Epidemiology at the London School of Hygiene and Tropical Medicine, who also is a member of the WHO ethics group that drew up the acceptability criteria, said preparations should begin now, because human challenge trials will take months to set up.

“If conventional phase III trials can be used to assess efficacy very rapidly, then challenge trials may be redundant, but I think it is far from certain that it will be possible to find phase III trial populations to assess efficacy in a trial lasting less than six months, during which time global COVID-19 attributable mortality will be enormous,” Smith told BioWorld.

As Smith noted, challenge trials would be less controversial if there was an effective treatment for COVID-19 infections, or if there was a strain with reduced virulence. “However, there is no guarantee that either of these will be available in the required timescale,” he said.

It is hard to estimate how much time would be saved using challenge trials, but Smith said, “I think at least four months would be a not unreasonable estimate.”

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