EVERY MONDAY FOR THE PAST FOUR MONTHS, virologists from the United States and Europe have dialed into an afternoon conference call to discuss a delicate topic: deliberately infecting human volunteers with the SARS-COV2 virus. This approach, called a human challenge trial, can yield a great deal of information about the early stages of infection and offer faster answers about the usefulness of a vaccine or cure than standard clinical trials. But challenge trials are rarely, if ever, done for a deadly disease with few available treatments—a description that still largely fits COVID-19.

The Monday calls are hosted by Josh Morrison, co-founder of 1Day sooner, a nonprofit that supports COVID-19 challenge studies. The organization had signed up 38,000 volunteers from 166 countries by the end of September, and while it began as a way to advocate for and find volunteers for the trials, it soon took on other roles. One was to help scientists tackle the logistical hurdles to a human challenge trial via strategy sessions and brainstorms.

On a recent Monday call in September, for instance, the participants discussed the benefits and downsides of pre-publishing their research protocols (good for transparency and information sharing, bad for potential public scrutiny and pushback); the best manufacturing practices for creating the live viruses that would be used to infect trial volunteers; and a petition to the UK Parliament to help fund a bio-containment unit that could quarantine 100-200 volunteers while the studies took place.

The British government made the bombshell announcement in late September that it would host the first COVID-19 challenge study in January in London. It will be working with partners but did not elaborate on who they would be. The U.S. government, meanwhile, has been less enthusiastic about supporting such a study, even though the National Institutes of Health has some of the foremost experts in challenge studies in the world. That said, if the UK project has moderate success, teams in the United States could quickly follow, says Morrison. “There is real enthusiasm among some of the scientists at the NIH to do these studies,” says Morrison.

A few variables could nudge the United States closer to rolling a challenge study out. One is the outcome of phase 3 clinical trials currently under way for three promising vaccine candidates. Preliminary results are expected by the end of the year. If all three vaccines fail, challenge trials could help researchers quickly test some of the close to 150 other candidates currently under investigation and identify the most promising contenders.

Even if the current phase 3 vaccine trials succeed, more vaccines will still be needed, says Anna P. Durbin, a Johns Hopkins professor with a long history of challenge study work. “To get enough doses of vaccine to cover the global population, you’re going to need multiple candidates,” she says. “And even if you show efficacy in one, there may be candidates down the road that are actually better.”

Challenge studies might not only speed up that process but assist on a number of other critical fronts: evaluating the effectiveness of treatments; providing detailed information about the natural course of COVID-19, including why some people are protected against serious COVID-19 disease; and evaluating how long immunity lasts in patients with SARS-CoV-2 antibodies in their blood. Knowing the course of human immunity to COVID-19 is especially critical, since current vaccine trials will only provide information about immunity in the short-term.

“The beauty of the challenge study is that you know the exact timing of the illness, and the administration of the vaccine, so you can study every aspect of the immune response with a degree of control,” says Matthew Memoli, an NIH expert in flu vaccine challenge studies. “So you can look to see everything that happened, try to understand what failed, what didn’t work optimally, and then make those adjustments in the laboratory to make a better vaccine.”

Memoli is working on one of the first logistical steps towards a challenge trial, which is to develop a standardized strain of the SARS-CoV-2 virus. His strain is designed to be closely related to the virus circulating most widely in humans today, but to also produce a limited and highly specific disease response. Infection would cause mild to moderate clinical illness in 20 to 25 year-olds, the demographic that will make up most challenge study populations. Symptoms will include cough and anosmia—loss of smell and taste—and some fatigue and minor upper respiratory symptoms, but not shortness of breath or signs of severe disease. Memoli wants his viral strain to produce just enough disease to test, but not enough to be debilitating or life-threatening.

In the United Kingdom, several groups, including a team from the Jenner Institute and the Oxford Vaccine Group in the UK, and the Imperial College in London, are in the process of designing challenge strains as well. The Oxford-Jenner team has reported that it expects to have one such virus, which is being manufactured by a confidential third-party provider, ready by October, according to private conversations the group has had with Morrison, while an NIH official said at a congressional hearing in September that the agency should have two to three challenge strains available by December. Johnson & Johnson has also publicly announced that it is working on a challenge strain with an unnamed partner. Unlike the NIH, some of these other labs are looking to standardize strains that are altered slightly, or “attenuated,” to mute disease response.

As these efforts move forward in the lab, scientists are also thinking through trial models that would meet an acceptable ethical standard. The safety of volunteers is obviously of the highest concern, says Durbin. She was part of a World Health Organization working group that recently issued an 81-page report on challenge study logistics. One primary question is the acceptable dose of viral infection. The WHO blueprint suggests that incrementally increasing quantities of the virus be tested in small groups, which will help identify the smallest possible dose that produces mild illness in young, healthy volunteers.

The WHO report also identifies specific biosafety labs equipped to keep these trial strains from leaking to the public in challenge trials. Live SARS-CoV-2 virus must be administered in high-level containment facilities, although there are few of these in the United States or Europe. One such facility is the NIH Clinical Center in Bethesda, Maryland, which could dedicate up to 27 beds to the effort, according to the NIH testimony to Congress. Most challenge trial research groups are planning to follow the WHO blueprint, Morrison says.

Informed consent, through which volunteers accept a statement of risks laid out before they join, is another major hurdle for COVID-19 challenge studies. Scientists don’t yet know all the risks associated with the SARS-COV-2 virus, and some research suggests that, in addition to respiratory problems, it may also cause cardiovascular or neurological damage. It also hasn’t been established what genetic and environmental factors may predispose young, otherwise healthy people to become severely ill when infected with the SARS-COV2 virus. Still, the WHO report includes one draft consent model, and the research team at 1Day Sooner published a report exploring what informed consent needs to include. That organization is also developing a model of risk for potential volunteers and has funded an ethics report on possible volunteer compensation.

One recent development may benefit challenge trials. On Sep. 16, pharmaceutical giant Eli Lilly published findings from a placebo-controlled trial showing promising results for a new monoclonal antibody therapy that reduced hospitalizations in people infected with the virus by up to 72%. One of the biggest roadblocks for challenge studies has been the lack of a “rescue” therapy—ethical guidelines recommend against challenge trials on dangerous diseases that have no proven treatment. But Eli Lilly’s monoclonal antibodies and remdesevir, which has been shown to shorten hospital stays, may begin to ease that concern.

While the U.S. government and some researchers remain cautious, public opinion appears to favor challenge studies. A paper in pre-print from University of California, Berkeley and Harvard and Yale universities reports on a survey of nearly 6,000 people in 11 countries in which some 70% of respondents characterized challenge trials as probably or definitely ethical. But it is the study researchers who must do the most meticulous accounting.

If something goes wrong, it could not only end in human tragedy but also jeopardize future vaccination efforts. “One thing this pandemic has taught us is it’s better to be honest with the public than to try to manage perceptions,” says Morrison.