Clinical trials of COVID-19 vaccines involve randomly dividing participants into two groups and giving one group the experimental vaccine, and the other group a placebo. The allocation of participants into groups is done in a blinded manner – so neither the participants nor those running the trial know who has received the placebo – to avoid any bias in the results. Then, scientists wait until a certain number of infections have been detected in the study cohort before unblinding the files to see how many COVID-19 infections occurred in each group. This tells them how well the vaccine prevents infection. Assessing vaccine efficacy this way thus can take time and requires large numbers of people.
No vaccine can be approved on the basis of a challenge study alone. You still need the large numbers for efficacy and safety estimates.
Challenge trials use a different approach – they involve deliberately infecting healthy volunteers with the COVID-19 virus to assess the efficacy and effectiveness of an experimental vaccine.
Now, the world’s first COVID-19 challenge trial is to start in the UK with up to 90 healthy volunteers aged 18-30 years. More than 38,000 people from 166 countries have said they would be interested in participating in such challenge studies with 1Day Sooner, a non-profit organisation advocating for these volunteers.
What do they tell us?
With several COVID-19 vaccines now already being rolled out across the world, challenge trials could still provide vital information. They could for example, compare the real-world effectiveness of two vaccines, offer insights into the dosing and timing of doses, and test vaccines against new variants. They could also triage next-generation vaccines, speeding up their development and roll-out.
Challenge studies can also determine the quantity of a virus required to cause infection, the detailed characteristics of immunity that we build and whether or not we can transmit the virus if we have an asymptomatic infection. Gaining a deeper understanding of the dynamics of virus infection like this can be difficult through large case/control studies which rely on natural virus infection, where the timing or the dose of virus cannot be controlled.
Challenge studies have been used in the past to study the flu virus. They have also helped to speed up vaccine development for typhoid and cholera, and improved our understanding of immunity to malaria and dengue fever.
What are the ethical implications?
Although there are risks with deliberately infecting people, challenge trials often recruit young and healthy volunteers to reduce these risks. In the case of COVID-19, just 0.6-1% of 20-29-year-olds require admission to hospital after infection, meaning they are less likely to develop severe disease when deliberately exposed to the virus. Challenge trials also exclude anyone with pre-existing medical conditions, which should lower the risks even further. Volunteers are closely monitored and given immediate access to medical care, if needed.
COVID-19 challenge trials were being discussed by the World Health Organization as early as May 2020, but it wasn’t until September 2020 that the UK announced plans to undertake the first ever of these trials for COVID-19, with recruitment beginning only now. This could be because the SARS-CoV-2 virus only emerged a year ago, and therefore the risks involved in such studies were still unclear until now.
Some researchers have argued that challenge trials are only ethically viable in infections for which there is a ‘rescue therapy’ available to cure infection. Others argue that this is not a prerequisite for COVID-19 challenge trials as the risk to young, healthy volunteers is low and the need is great.