The ethical challenge of human challenge trials

Believe it or not, it is generally unethical to deliberately infect someone with a disease (not the best way to start a medical communications piece, but bear with me). However, when assessing prophylactic treatments (given to prevent, rather than treat, a disease), this may be the most effective means of establishing efficacy and safety in a timely manner.

Let’s take a step back and briefly explain how vaccines are traditionally evaluated. The Pfizer COVID-19 vaccine was assessed in a study of over 43,000 people; half of which received the vaccine, and half of which received a placebo. ¹

The trial participants were then released into the wild to live life as ‘normally’ as possible, during which time they were monitored to track the incidence of COVID-19, as well as any adverse events. The trial reported a total of 170 cases amongst the whole ~43,000 participants. A total of 162 of these were in the placebo arm, and this was enough to demonstrate sufficient efficacy. ¹

Now, just think how expensive and time consuming it is to track 43,000 people. Another, far more controversial, way of evaluating vaccines (and other treatments) is using human challenge trials. Instead of vaccinating participants and sending them on their merry way, hoping (bad choice of word, but accurate) for enough COVID-19 cases to demonstrate the efficacy of your vaccine, you vaccinate participants and then deliberately expose them to COVID-19 under extremely controlled circumstances.

Okay, if you’ve made it this far without fainting from the inhumanity of what I’m suggesting, let’s lay out some ground rules. First and foremost is, we are presuming fully informed consent, no coercion, and that all required safety measures are in place.

Secondly, challenge trials are already used in influenza, typhoid, and malaria, so this is not a precedent-setting proposition. Also, recruitment in these trials is usually restricted to young and healthy populations, reducing the risk of adverse events and death that might be more likely in vulnerable populations.²

The nature of challenge trials is that they require significantly fewer participants and evaluation is greatly expediated compared with waiting for COVID-19 events to happen in field trials. They are therefore far more cost-effective than field studies and, it could be argued, less risky.

Let’s now turn to the reason for this article – the first human challenge study in SARS-CoV-2. In late March, 2022, the first results of a challenge trial were released reporting on 36 healthy volunteers (unvaccinated and with no prior infection) who were deliberately inoculated with SARS-CoV-2.³

It’s worth highlighting that a sample size of 36 is a thousand-fold fewer than the number required for the Pfizer vaccine trial. However, this is not a vaccine trial and is being undertaken more than 2 years since the onset of the pandemic, where we have a number of treatments including antivirals that can be on-hand to treat any major adverse events occurring in infected participants. So, we are not comparing like with like here, and had challenge trials been done at the start of the pandemic, prior to rescue treatments, then the ethics would have been on shakier ground.³

That said, it’s a worthy exercise to speculate what a vaccine challenge trial earlier on in the pandemic might have meant for reduction in mortality and morbidity. The first person vaccinated against COVID-19 received their shot in December, 2020.⁴In the scheme of things, this is a ruthlessly quick turnaround from the sequencing of the virus, to human field trials, to community vaccination. That in itself is a spectacular win for science.

The question I’m probing at here is, would vaccines have been in the arms of the community several months earlier were challenge trials carried out? For the sake of argument, let’s say yes! This would mean populations would have been protected far sooner, greatly reducing death and disease.

However, what if those challenge trials resulted in significant adverse events from an early-stage vaccine? Or, worse yet, what if the people directly infected in the trial died or had significant morbidity? Could this have undermined public support for population health measures? Undermining of trust in health communications such as an event like this can have profound and long-lasting impacts on uptake rates in the future.

This is just a thought experiment two years into a pandemic. Earlier, arguably riskier, trials could have expedited effective vaccines for billions of people, but possibly at the cost of lives taken directly from a challenge trial.

It is impossible to know what a counterfactual world would have looked like. We haven’t even addressed the ethics of paying people (likely those in need of money, which should give us pause as to what ‘pure’ consent is) to undermine their bodily autonomy. Or, the fact that while challenge trials are in healthier, less at risk patients, this means the data gained are less translatable to vulnerable populations.

Reality is, we put ourselves at risk on daily basis through work, sport, or leisure; even field clinical trials! These are certainly not zero risk trials. It is becoming increasingly difficult to find enough COVID- or vaccine-naïve participants for large field trials, and therefore challenge trials might be a more effective way forward for getting COVID treatments to those who need it.⁵

References:

• Polack F, Thomas F, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383:2603-2615
• Eyal N. (2020). Why Challenge Trials of SARS-CoV-2 Vaccines Could Be Ethical Despite Risk of Severe Adverse Events. Ethics & human research, 42:4–34. https://doi.org/10.1002/eahr.500056
• Killingley, B., Mann, A.J., Kalinova, M. et al. Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults. Nat Med(2022). https://doi.org/10.1038/s41591-022-01780-9
• Sandra Lindsay reflects on her vaccine, 1 year later: ‘I felt like it was my civic duty.’ The New York Times. Available at https://www.nytimes.com/2021/12/14/nyregion/sandra-lindsay-covid-vaccine-anniversary.html. Accessed on 17 May 2022.
• Edwards, K.M., Neuzil, K.M. Understanding COVID-19 through human challenge models. Nat Med(2022). https://doi.org/10.1038/s41591-022-01778-3