With thousands of people dying of Covid-19 every day, the sooner a vaccine can be deemed safe and effective, the better. But vaccine development is a lengthy process that isn’t easy to rush. In part, that’s because of the final step in testing any vaccine: the phase III trial.
Phase III trials require tens of thousands of volunteers, each of whom get either a placebo or an experimental vaccine. Then vaccine developers have to wait until a statistically significant number of them, going about their lives normally, eventually get naturally infected. This step alone can often take years.
When it comes to Phase III trials for a Covid-19 vaccine specifically, there are extra concerns relating to the reality of fluctuating infection rates throughout the world, making it difficult to set up a successful trial where participants are likely to get naturally infected.
The Oxford University vaccine researchers have already had to change the location of their Phase III trial from the UK — where, in June, rates of infection had fallen — to Brazil and South Africa, where rates had started to surge. A team in China did something similar, changing the location of their Phase III trial from mainland China to the United Arab Emirates.
In light of those concerns, some epidemiologists and scientists are calling for something called a human challenge trial. Instead of chasing the moving target of infection rates and waiting for participants to get sick naturally, a human challenge trial involves a small group of young, healthy participants becoming deliberately infected in a lab setting. The challenge study alone could take as little as a month, but it would need to happen after a trial to determine the correct dosing of a virus, and before a larger scale safety study. But all of that could still be faster than a typical Phase III trial.
This isn’t a new concept. Human challenge trials have been used to develop vaccines or treatments for lots of diseases, like cholera, typhoid, malaria, influenza, and common cold viruses. But what sets Covid-19 apart from those diseases is that it currently has no effective treatment. Because it’s so new, we also aren’t fully aware of its long-term health effects. Unlike other human challenge trials, a Covid-19 challenge trial would entail a risk of serious illness — and even death.
It’s because of those risks that a Covid-19 challenge trial would be limited to the young and healthy, who would be at the lowest risk of harm. But there are questions beyond the ethics. Would artificially infecting someone in a lab setting provide useful information on how to prevent natural infection?
“I should say that one of the problems with the challenge model … is that it’s an unnatural inoculation,” said Dr. Ronald Turner of the University of Virginia, who has been doing challenge studies for common cold viruses since the 1980s. Turner says that determining an accurate viral dose and route of infection to replicate a natural infection could pose scientific problems. “That raises issues about the ability to extrapolate your result into the natural setting. And so I think those technical issues, together with the ethical issues associated with a potentially lethal challenge, pose some real issues.”
Other questions regarding human challenge studies involve whether data derived from a group of only young and healthy people would be valuable in developing a vaccine that works for everyone. But advocates for human challenge studies say that a vaccine that protects that group would still help slow the spread of the virus.
“If we could protect young, healthy people with a good vaccine, especially one that blocked transmission and infection, that would hugely help our ability to get back to normal because they would be out of the transmission loop and be able to work and be able to go to school and other things,” said epidemiologist Marc Lipsitch, who co-authored an article in March advocating for preparing for possible human challenge studies.
Another question is whether we will actually need to resort to this ethically questionable form of clinical trial, given that a handful of vaccines are already in Phase III trials. It’s possible those Phase III trials will be quick and successful, especially given high rates of infection at clinical trial locations, like in the US, South Africa, and Brazil.
Even though no Covid-19 human challenge trials are currently planned, more than 30,000 people from nearly 150 countries have already said they would volunteer for one if the opportunity presented itself, through the grassroots movement 1DaySooner.
The question is, should we let them?
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