Human Challenge Trials for Pandemic Preparedness
Josh Morrison & Gavriel Kleinwaks
Originally written August 10, 2021
The COVID-19 pandemic was so devastating in part because we were unprepared for it; we debated how to combat the pandemic in its midst, with controversy and misinformation wasting precious time. In order to avoid repeating these mistakes, it is vital that we invest in pandemic preparedness now, while the lessons of this pandemic are still fresh.
Florian Krammer, Professor of Microbiology at the Icahn School of Medicine, has put forth an ambitious proposal to develop a safe and effective vaccine within 3–4 months of the beginning of the next pandemic. His proposal is supported by the Coalition for Epidemic Preparedness Innovation (CEPI), British Prime Minister Boris Johnson, and OSTP Director Eric Lander. There are many moving parts that will work together to make a proposal like this successful — and an essential one is human challenge trials.
Human challenge trials are a type of vaccine trial in which volunteers are deliberately exposed to a virus after being vaccinated. This allows researchers to assess a vaccine’s efficacy much faster than a traditional phase III vaccine trial. At the beginning of the pandemic, we estimated that running challenge trials could shave a month off of vaccine development time — a significant amount of time, both in terms of lives saved and compared to the 100 days goal. However, challenge trials were never run in the US, and were only started in February in the UK. The UK deserves a lot of credit for running challenge trials at all, but they could have been much more useful and impactful if they had been run earlier — that is, if the public health community had already determined acceptable risk-to-reward ratios and mapped out a trial design in advance of the pandemic. We have a chance now to settle the ethical questions in advance and develop a framework for challenge trials for later pandemics. This practice would be useful not only for testing vaccine efficacy but for determining how to proceed when there are questions about how to most responsibly use limited vaccine supply. Once the first vaccines were given emergency use authorization, there was still debate about whether to follow the protocol of two full doses, or whether herd immunity would be more efficiently achieved by a “first doses first” strategy or a fractional dosing regimen. Questions such as those could have been answered by challenge trials, if a challenge trial protocol and preparations had existed in advance, saving time and confusion and perhaps many lives.
Setting up challenge study protocols would be time- and money-intensive, but society would likely see a payoff very quickly in our ability to fight epidemics and lay out medical ethics cleanly. Consider what could have happened if we had challenge study protocols in place at the beginning of the COVID-19 pandemic. The decision to run challenge trials would have been triggered by the WHO announcement of a pandemic on March 11, 2020. In this pandemic, it took from August to December to produce a challenge strain. Assuming work on a challenge strain had instead started in March, the strain would have been ready for challenge trials by July. Imperial College received approval for a challenge study in February 2021 and started the infection study in March. With all the pieces for running a challenge trial already prepared, a challenge study could have started in July 2020 and perhaps an initial vaccine would have been ready by November. Each day saved in vaccine development would save about 6,000 lives — more, earlier in the pandemic — which means that having a challenge protocol prepared in advance would have saved hundreds of thousands of lives.
A full HCT policy would require designing a highly biosecure “Challenge Study Center,” which would be able to produce pathogens of interest quickly. Regulatory bodies and medical institutions would need to develop protocols for running an HCT, including determining the criteria that would trigger an HCT. Disconnect between responsible organizations is often an issue in emergencies, so in the preparedness plan described, the organizations involved would benefit from the cohesion and communication that would be induced by the planning process.
Fighting local epidemics and eradicating current diseases may be excellent practice for future pandemic responses. For example, the WHO or another health organization could declare a target disease and an “emergency conditions” start date. At that point, participating countries would mobilize research to produce a vaccine as quickly as possible, and would mobilize infrastructure bodies to deliver the vaccine to people who need it. Influenza would provide a particularly good testing ground for pandemic practice. In a typical year, there are 3–5 million cases of severe influenza, and 290,000–650,000 deaths related to influenza. However, the family of influenza viruses has a high potential for producing pandemic-causing viruses, and in a pandemic year, the impact can be far higher. Despite the high burden of influenza, current vaccines are relatively ineffective, ranging from 10–60% effectiveness at preventing the flu since tracking began in 2003, due to the difficulties of anticipating which viruses will be most widespread in a given year. A universal flu vaccine could eliminate the need for seasonal flu vaccines. Before the COVID-19 pandemic, NIAID laid out a plan for developing a universal flu vaccine, under the guidance of NIAID director Anthony Fauci. This plan could be aided by human challenge trials at all levels: understanding the influenza virus family, characterizing immunity, and developing a vaccine.
Human challenge trials have enormous potential to benefit humanity in our attempts to fight many different diseases. However, the full potential of these trials can only be unlocked if the pieces are laid out in advance of when the trials are needed. There are many people, including potential volunteers, eager for challenge trials to be developed. If health organizations and governments take this call seriously, we will have a powerful answer to future viruses and never have to face the confusion and scramble of COVID-19 challenge trials again.
