Human challenge trials, also known as controlled human infection models, are an essential tool for developing new vaccines. But unless we start preparing now for Covid-19 challenge trials by quickly manufacturing an unadulterated version of SARS-CoV-2, the virus that causes the disease, they might not be available in time to develop a vaccine against it.
Why on earth would anyone volunteer to be deliberately infected with a disease-causing pathogen, and even receive an experimental vaccine? I’ve been hearing a range of reasons from the 26,000-plus people from more than 100 countries that 1Day Sooner, an organization I helped found, has already registered to participate in a Covid-19 challenge trial down the road.
Some volunteers see challenge studies as akin to military service: “I signed up to serve in the army years ago for the betterment of the country and I am glad to do this again. People must be willing to take risks to get past this and it shouldn’t just be the poor.”
Some want to feel to empowered to fight the disease: “I have a PhD in biomedical engineering working in cancer research but am not an essential worker and have felt mostly helpless during this time. I would be happy to risk infection for the sake of vaccine development.”
Some are just fed up with the virus: “I’m a health worker; a nurse to be specific. We want to get rid of this pandemic and go back to our normal lives. Sierra Leoneans are dying here and if this vaccine is not out early we will lose more lives.”
The mission of 1Day Sooner is to advocate on behalf of challenge volunteers, which is somewhat different than advocating for the studies themselves. We want to help people participate in challenge studies that would accelerate a vaccine, but don’t want volunteers to take unnecessary risks that aren’t justified by a clear public benefit. My colleagues and I are optimistic that challenge trials will prove useful, although there are still questions about the applicability of a challenge study among young, healthy volunteers for a disease that mainly harms older people or those with heart disease, diabetes, and other health conditions.
But while the utility of challenge trials is not a foregone conclusion, there is no question that they have enormous potential value. Challenge trials established foundational elements of our understanding of the common cold and flu. The drug oseltamivir, better known as Tamiflu, was developed using challenge studies led by Dr. Fred Hayden in the late 1990s. More recently, vaccines for malaria, cholera, and typhoid have been approved that would likely have been impossible without the use of challenge trials. In fact, the first time a coronavirus was isolated in humans was in a common cold challenge study in 1965.
Our international research team elucidated a number of ways that challenge studies could extend our knowledge of Covid-19. They could identify correlates of protection — signs that the immune system is effectively fighting off the disease — that could then be targeted by vaccine candidates, helping conventional trials establish evidence that a vaccine would be effective earlier and with greater certainty. Challenge trials could provide an early (though imperfect) indicator of effectiveness that could help accelerate vaccine manufacture, possibly allowing for deployment months sooner and saving hundreds of thousands of lives and potentially trillions of dollars in economic activity.
Two arguments have recently been offered as reasons not to conduct challenge studies:
- They will take too long to develop.
- There currently are no rescue therapies for Covid-19 infection.
Will human challenge studies — where volunteers are deliberately infected — speed development of #Covid19 vaccines? Maybe not the early candidates. Would they be useful. Most likely. Will they be done? Not clear. https://t.co/5ZOi9PSNv2
— Helen Branswell (@HelenBranswell) May 1, 2020
Considered carefully and in tandem, however, these points actually support organizing challenge trials now and taking steps like mass-producing the unattenuated (or “wild type”) virus under good manufacturing practices. If challenges are worthwhile only if a rescue therapy exists, it makes sense to start preparing for challenge trials now because a proven therapy might be available later. There are grounds for optimism, given the promising data about remdesivir published last week in the New England Journal of Medicine. And the Lancet recently published a report on the use of a triple-combination therapy of beta-1b, lopinavir-ritonavir, and ribavirin, which helped alleviate symptoms and shortened the duration of viral shedding and hospital stays by half in patients with mild-to-moderate Covid-19.
Even without a rescue therapy, the risks to young volunteers, while significant, are well within the range of choices like kidney donation or childbirth in the United States that people commonly make. Since more than 80% of Covid-19 deaths in New York City among those between the ages 18 to 45 involved preexisting conditions, for challenge tests that include only healthy volunteers who would be under constant medical observation, the real risk may be lower still.
As advocates of challenge testing, my colleagues and I would never undersell the risks, which are clearly meaningful. And knowledge about the disease is incomplete and evolving. But serving in the military or in a hospital amid a pandemic are also risky choices made under conditions of uncertainty. Just as it wouldn’t make sense to prevent health care workers from choosing to serve in hospitals during a pandemic, we should not prevent well-informed volunteers from taking risks to find a vaccine that works against SARS-CoV-2.
Uncertainty is a reason to be prepared, not an argument for paralysis. The vaccine development process has rightly proceeded with explosive acceleration, with Moderna’s candidate anticipated to begin Phase 3 trials just nine months after the first known case of Covid-19 was identified. The preparation of challenge trials should also be treated with similar Manhattan-Project-like urgency, given their potential value and the comparatively microscopic costs of preparation. Developing the challenge model and building needed biocontainment capacity would cost millions of dollars but might save tens of billions on unnecessary vaccine manufacturing alone. 1Day Sooner has secured interested funders to support producing the virus and has identified a vendor who has estimated it would take three to four months to make enough of the virus to start challenge testing. If the federal government provided meaningful support, that timeline could be accelerated significantly.
It may seem counterintuitive to think of urgency and caution in the same breath, but even those who oppose challenge trials without an identified rescue therapy must admit, once such a therapy exists, it would be better if challenge testing was ready for use rather than lagging far behind. Anything less is reckless behavior that endangers people who will die without a vaccine in the future and dishonors the sacrifice that challenge volunteers stand willing to take.
Josh Morrison is one of the founders of 1Day Sooner. He previously founded Waitlist Zero, an advocacy group for living organ donors, and the Rikers Debate Project.