The British government has committed to spending about $44 million on the so-called challenge trial, which is being run by Hvivo, a subsidiary of Irish pharmaceuticals research company Open Orphan, which specializes in conducting drug trials of this type.

The study will recruit healthy volunteers between the ages of 18 and 30, the group of adults least likely to become seriously ill from COVID-19, and inoculate them with a coronavirus vaccine, before deliberately exposing them to the virus. If they fail to develop COVID-19 symptoms that will be strong evidence that the vaccine is effective.

But many bioethicists have severe misgivings about conducting challenge trials, especially in the case of a disease such as COVID-19 for which there are few proven treatments and no cure. Usually challenge trials are conducted in cases where there is one or more “rescue drugs” available that can save a volunteer from becoming gravely ill if the vaccine fails. In this case, researchers have said they plan to use Gilead’s remdesivir as the rescue drug, although a large World Health Organization study just concluded the drug has little impact on COVID-19 mortality.

Some virologists and bioethicists worry that a challenge trial won’t provide enough information about a vaccine’s efficacy to justify the risk. Challenge trials are usually used to produce evidence of whether a vaccine works faster than would normally be possible through a standard vaccine clinical trial, in which volunteers receive either the vaccine or a placebo, and the infection rates within the two groups are then compared over a series of months.

‘Harder to justify’

Challenge trials are more useful when the prevalence of a disease is too low to get a clear signal from a standard clinical trial in a reasonable period of time. That looked like it might have been the case with COVID-19 earlier in the year when strict lockdowns drove down infection rates in many parts of the world. But the resurgence of infections in the past two months means that the large-scale Phase III clinical trials already underway for a number of vaccine candidates are likely to yield results within the next few months.

This means the challenge trials, which are not scheduled to begin until January, may not actually help speed introduction of the initial set of vaccines. “It becomes a little bit harder to justify them, and we need to take a close look at the risks,” Seema Shah, a bioethicist at Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, told the science publication Nature.

Shah said the challenge trials might be more helpful for evaluating how well later generation vaccine candidates work compared with the initial ones, and also yielding better insights into how the SARS-CoV-2 virus that causes COVID-19 works and how the immune system responds to it. She said that volunteers for the challenge trial need to be properly informed and not misled into believing they are helping to bring a vaccine to the world when that may not be the case.

Another concern is that volunteers in the U.K. study will be paid more than $5,000 for participating. Arthur Caplan, a medical ethicist at New York University’s Langone medical center, who is in favor of conducting challenge trials owing to the extreme urgency of the global pandemic, has advised against paying volunteers because he worries the money may blind them to the risks.

Then there is the fact that the young volunteers who need to be recruited for a challenge trial are not representative of the population public health experts are most hoping to protect from infection with a vaccine, namely older people who are much more likely to become severely ill from COVID-19. “How is this really going to help us?” wonders John Moore, a professor of microbiology and immunology at Cornell University’s Weill Cornell Medical College in New York.

But some virologists think that because older people are underrepresented in conventional vaccine clinical trials too, those studies may also not provide much insight into whether a vaccine will work in older people. A challenge trial might provide useful data on immune responses that will help researchers extrapolate how old people might respond to a vaccine, Matt Memoli, a virologist at the U.S. National Institute of Allergy and Infectious Diseases who is involved in preparing a possible U.S. human challenge trial, told Nature.

Moore said he worries that if any volunteers in the challenge trial do become seriously ill, it will have a chilling effect on recruiting volunteers for standard clinical trials for other vaccines. He also said it was unclear if the way in which the challenge trial will expose volunteers to the virus actually mimics natural infection closely enough to yield any valuable insights about a vaccine’s effectiveness.

How challenge trials work

In a challenge trial, the first step is to calibrate the virus dose the volunteers will be given. This is done by exposing unvaccinated volunteers to gradually greater virus doses until researchers find an amount that will consistently cause infection—but hopefully be low enough to avoid causing severe disease. In the U.K., about 90 volunteers will take part in the “virus characterization” portion of the trial, which is expected to take three months and will be conducted in a specialized biocontainment suite at London’s Royal Free Hospital. The strain of the virus being used is the one most commonly circulating in the U.K. and is being manufactured at a research facility in London’s Great Ormond Street Hospital.

Once the right viral dose is found, then the actual vaccine trials will begin. The vaccine or vaccines to be tested will be chosen by the U.K. government’s vaccines task force. Those taking part in the study will have to be kept in quarantine for two to three weeks so that they don’t infect others during the trial.

Despite the ethical concerns, many think the challenge trials are worth the risk. Nir Eyal, a bioethicist at Rutgers University in New Jersey, along with Pedro Rosa Dias and Ara Darzi, both economists at Imperial College London, have calculated that moving deployment of an effective coronavirus vaccine forward by just one month would save 720,000 human years worth of life and prevent 40 million human years’ worth of poverty, primarily in low-income countries.

It is logic like that which has provided inspiration for 1Day Sooner, a U.S.-based group that has been campaigning for human challenge trials and which says it has recruited almost 40,000 people globally—including 2,000 in the U.K.—willing to participate in them. Open Orphan and Hvivo say they are working with 1Day Sooner but are also running their own recruitment effort, ultimately looking to select about 500 people to take part in the trial.

The U.K. is not the only government backing human challenge trials, although it is the first to actually green-light such a study. The U.S.’s National Institute of Allergy and Infectious Diseases has funded a lab at Colorado State University in Fort Collins to produce two separate SARS-CoV-2 strains for use in a possible challenge trial. But the agency said it is awaiting data from the ongoing Phase III clinical trials of COVID-19 vaccines already underway before deciding whether to proceed. Meanwhile Belgium has put $23.6 million behind creating specialized facilities to conduct challenge trials for a variety of diseases, including possibly COVID-19.

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