Faced with the threat of Covid-19, the world needs a vaccine, and fast. But typical timelines for vaccine development are years, even decades, long.
That’s why some epidemiologists are calling for so-called challenge trials to speed things up. When researchers test vaccines, they typically inject thousands of people with either the vaccine or a placebo, then wait months or years to see who gets sick. Challenge trials present a faster alternative: A few hundred people are given either placebo or the vaccine, and then deliberately are exposed to the virus.
Challenge trials have previously been used to choose the right dosage of vaccines or pick between candidates ahead of larger trials. But they haven’t been used to validate vaccines ahead of widespread use—at least, not since the first vaccine ever created in 1796, whose methods wouldn’t meet today’s ethical standards.
Currently, more than 10,000 people have said they would volunteer for a challenge trial. But no vaccine shortcut is straightforward. Here are some of the challenges to making challenge trials work for Covid-19.
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Based on what we know about Covid-19 infections, scientists would have to wait just three weeks after infecting their participants to start collecting results, says Peter G. Smith, co-author of a Journal of Infectious Diseases article on Covid-19 challenge trials. Within a month or “maybe two” of starting the trial, he expects scientists to have final results. Overall, he estimates challenge trials would be at least four months quicker than standard trials.
The pace of a standard trial, on the other hand, depends on local infection rates. And given protective measures such as self-isolation, a large coronavirus vaccine trial that simply waited for people to get sick might never finish, says Smith’s co-author Nir Eyal, a professor of bioethics at Rutgers University. A coronavirus study that started in Wuhan, China, for example, might now peter out given the low number of cases there. This was a major issue in testing Ebola vaccines; trials in Liberia and Sierra Leone had to be abandoned because there weren’t enough patients to complete the study.
But while challenge trials themselves are faster, it still takes considerable work to prepare for them. Scientists need to grow supplies of the virus, test it in animals, and get it certified for human use. Then they need to determine a dosage that mimics a natural infection, but is less dangerous than a severe case. To be safe, they would start testing low doses and gradually increase how much is used. “This just doesn’t happen overnight,” says Holly Fernandez Lynch, a medical ethics professor at the University of Pennsylvania.
Stanley Plotkin, whose research contributed to the development of vaccines for rubella, rabies, and polio, says he’s speaking with the US Food and Drug Administration and World Health Organization about whether they’ll consider evidence from challenge trials. If they do, scientists should start working to develop the Covid-19 strain immediately. “Unless we start now, challenge studies will be useless. It has to be something we start making now,” he says.
Plotkin also raises the possibility that, in areas where contagion is extremely high, standard vaccine trials could advance extremely quickly. “If the usual way of doing things moves faster, then challenge studies may not be necessary,” he says.
Deliberately infecting trial participants with a deadly disease is morally questionable. Even more so when only a portion of them will receive a vaccine. So a Covid-19 challenge trial would only recruit young, healthy people who are more likely to survive. Smith and his co-authors propose enrolling healthy people aged 20-45.
But, of course, that means a challenge trial would only show how a vaccine works within that limited age group. “Even if a vaccine worked in young people, there would be no guarantee it would work in the same way for elderly people,” says Smith. Older people have weaker immune systems, and it’s common for vaccines to be less effective in elderly people, he says.
Testing vaccines in young people could also make it difficult to determine whether they work at all. Many vaccines don’t prevent infection altogether, but limit the severity of symptoms, and Smith says symptoms would likely be the main readout for efficacy in a challenge trial. If only a tiny proportion of people in their twenties to mid-forties show symptoms after they’re infected, challenge trials would have to enroll far greater numbers of participants to show a clear effect.
Plotkin suggests an alternative: Focus on immune responses, not symptoms. In this kind of challenge trial, the end point would be whether the blood of vaccinated participants includes the same antibodies as people who have been naturally infected. It wouldn’t directly answer the question of whether a vaccine prevents clinical symptoms. But it could help keep minimize the number of participants needed in the earliest stages of research.
A challenge trial can tackle the question of a vaccine’s efficacy. But because of its small sample size, it’s unable to give clear information about the other crucial trait of a vaccine: safety.
The authors of the Journal of Infectious Diseases article suggest that, if a challenge trial had good results, it should be followed by a larger study to assess short-term safety and efficacy in different age and risk groups. It could test around 3,000 people, and take a matter of months.
That plan still wouldn’t provide information about long-term risks, and no vaccine could be formally approved based on such studies. But it could allow wider use of the vaccine in real-world studies, with scientists continuing to collect data on effectiveness and safety. “Challenge studies would give crucial info that would allow the FDA to permit vaccine use, perhaps under some sort of emergency clause, before giving a license later based on an accumulation of information derived from widespread use,” says Plotkin.
In such circumstances, those who receive the vaccine would have to be clearly told that the vaccine is still going through testing procedures, and make a personal choice about whether to be vaccinated. To be absolutely safe, monitoring the long term effects of vaccines takes considerable time. “You have to balance that against the millions who will die in the meantime,” says Smith.