To challenge or not to challenge? That is the question!

Sue Tansey is a member of the Nuffield Council on Bioethics and an independent Consultant Pharmaceutical Physician. She has previously worked in industry on vaccine research, but is not currently working on a COVID-19 vaccine.

Back in March, discussion started as to whether it would be appropriate to consider challenge trials to speed up vaccine development during the COVID-19 pandemic. Challenge trials are a specific kind of vaccine trial where otherwise healthy volunteers are given an experimental vaccine prior to being intentionally exposed to the virus the vaccine is targeting (or a milder version of it) to see if they are protected. (To read more about challenge trials, see Katharine Wright’s earlier blog How ethically challenging are challenge trials?). These types of clinical trials have been used to test vaccines for other serious infections such as typhoid, malaria, and cholera, and are carried out in very specialised centres that are able to minimise risks to the volunteers and staff conducting them.

In order to carry out human challenge trials, a challenge virus must be produced and there are reports that work on this aspect is underway both in the US and in the UK. Adrian Hill from Oxford’s Jenner Institute has said he hopes to be conducting a challenge trial either in parallel or following their phase 3 trial as early as the end of the year. Once a suitable challenge virus is available, tests would first need to determine the infectious dose to be used and regulatory approval needs to be obtained.

Soon after challenge trials were first mentioned in the context of COVID-19, an organisation called 1Day Sooner was set up to advocate on behalf of volunteers who would be willing to participate in a COVID-19 challenge trial. The WHO also published guidelines setting out the ethical arguments that need to be considered both for and against conducting this kind of trial in the COVID-19 pandemic. Challenge trials require far fewer people to be included, which means they can be carried out far more quickly than traditional phase 3 trials.

Back in early 2020, there was limited knowledge about COVID-19 and no effective treatments had been recognised. Although there is still much that we do not know, we now have evidence that some medicines, such as dexamethasone and remdesivir, decrease mortality and hospitalisation time, respectively. We also have a better idea of which groups are most at risk of death due to COVID-19 infection. However, it is still argued that it might not be ethical to even consider challenge trials since there is no ‘rescue‘ therapy.

We now have nine COVID-19 vaccines in late clinical development, although they are considered unlikely to be available even for health workers and vulnerable groups for at least another couple of months and probably well into 2021.

Healthy people aged 18-30 are proposed as the likely group who would be recruited into a challenge trial were one to be conducted. We know that the mortality risk for this group is extremely low - estimated to be around 0.03% - and in this type of trial an infection should be picked up and treated early with the best available interventions. On the other hand, we are increasingly hearing about the disabling long-term complications termed ‘long COVID’ that can follow COVID-19 infection, even in younger people who did not require hospitalisation for the initial infection.

The balance of risks and benefits is complex and needs to be considered for not only the individuals volunteering, but also for society and for those conducting the trials within experienced clinical trial centres. The scientific justification put forward is that a challenge trial could help give us an answer as to whether one or more of the vaccines in late development provide protection against COVID-19 more quickly than the large clinical trials currently being conducted, but by complementing them, not replacing them. The phase 3 trials are particularly important to look at safety in large numbers of people. However, to show if a vaccine protects against infection, they look to see if there is a difference between the infection rate between the vaccinated and non-vaccinated groups.

Therefore, the larger vaccine clinical trials being conducted in the field can take many months depending on how quickly a pre-determined number of subjects get infected – the lower the infection rate, the longer the studies take. As we wait for a vaccine, the population is being asked to avoid social interactions and endure many restrictions on our activities. Although of course, there is no certainty that any of these vaccines will be effective.

For the potential volunteers at 1Day Sooner and some of those with family members who are restricted to their homes for months, the risks of conducting challenge trials may seem worth the potential advantages of not only identifying an effective vaccine(s) more quickly, but also gaining important information about vaccine effects, including transmission of infection. The latter can be investigated by looking at viral shedding after vaccination, which can indicate whether the vaccine is likely to reduce infection rates in those either unable or unwilling to be vaccinated. Experts such as Adam Finn have emphasised how important this is.

However, despite the possible beneficial outcomes we could see, I think that the wider public should be involved in consideration of potential challenge trials. As the Nuffield Council on Bioethics discussed in our call to the Government, transparency and trust is extremely important as we navigate our way through the pandemic. While most people see a vaccine as our way out of the crisis there are those who, having lost trust in our advisors, have serious concerns about newly developed vaccines being offered to the public as a solution.

Therefore, our scientists and regulators need to engage with everyone concerned, not just those who are keen to conduct or volunteer in challenge trials, to discuss the pros and cons and decide if the time is right to consider this next step.