Traditional Phase III Trials

After a vaccine candidate is created in a lab, it is developed through a combination of pre-clinical evaluation and three phases of clinical trials that test its safety and efficacy. In traditional Phase III trials, participants receive the vaccine candidate or a placebo/active comparator, and efficacy is judged by comparing the prevalence of infection in the vaccine group and the placebo/comparator group, to test the hypothesis that significantly fewer participants in the vaccine group get infected.

In the context of COVID-19, after receiving a vaccine candidate, participants return to their normal daily lives to test the treatment under real world conditions. Since only a small proportion of these participants may encounter the disease, it may take a large number of participants and a many months for these trials to reveal differences between the vaccine and placebo groups.

Phase III trials can be both complex and slow. Many people are careful in this outbreak—by practicing self-isolation, for example—so it may take a very long time and a large number of subjects for a Phase 3 trial to produce statistically significant results.

Given the unprecedented urgency of the COVID-19 pandemic, regulators and researchers are likely to try somewhat unconventional methods to speed up this process, whether or not challenge trials are utilized. For example, Phase 3 trials may be conducted in high-risk populations—people more likely to be exposed to COVID-19, such as healthcare workers—to increase the ability to detect effectiveness in a smaller pool of subjects. In some cases, the Phase 1 and Phase 2 trials may be combined so the process moves more quickly.

Human challenge trials

If coronavirus human challenge trials (HCTs) are held, willing participants would receive the vaccine candidate and, once the vaccines takes effect, be deliberately exposed to live coronavirus. The ability to observe participants closely and gather samples while tracing the progress of infection in real time, knowing exactly when they were infected and with what dose, and being able to follow up over a long period, would offer an unprecedented level of scientific and medical insight into an unfamiliar virus. HCTs can complement Phase III trials in four specific ways:

Studying COVID-19 Pathogenesis

HCTs would allow scientists to closely observe the early stages of COVID-19 pathogenesis and people’s immune response. Better understanding the natural development of COVID-19 may have a broad array of applications for the creation of vaccines and treatments.

Learning About Antibodies

By re-exposing seropositive volunteers to the coronavirus, scientists can learn more about the extent to which antibodies confer immunity. This information can inform current CDC guidelines on the subject.

Correlates of Protection

HCTs can help scientists learn about correlates of protection, the biomarkers of immunity to COVID-19. By closely studying people’s immune response to COVID-19 in an HCT, correlates of protection can be determined and then looked for in Phase III trials. Previous vaccines, such as hepatitis B and H5N1 influenza, have been licensed on the basis of producing known correlates of protection.

Second Generation Vaccines

Since exposure to the virus is guaranteed in HCTs, it may be possible to judge a vaccine candidate’s efficacy more quickly and with far fewer participants than a standard Phase III trial. By providing a more rapid signal of efficacy, HCTs could enable earlier decisions about which vaccine candidates to start manufacturing at scale. Meanwhile, by ruling out less effective or more problematic candidates earlier, we avoid unnecessarily subjecting additional tens of thousands of volunteers to the risk of any unanticipated side effects - something we want to minimize wherever possible.

The first vaccine approved for use is rarely the best vaccine, and most of the early candidates will be difficult to distribute in the developing world. HCTs can play an essential role in the development of second generation vaccine candidates aiming to improve upon the first vaccines that may be licensed. Without challenge trials, researchers might not be able to recruit enough study participants to test these second generation vaccines quickly. The National Institutes of Health ACTIV Group wrote in July that challenge trials “might be able to accelerate development of later rounds of vaccine candidates.”

HCTs will also be of particular importance if Phase III trials fail to demonstrate high vaccine efficacy due to low infection rates in the general population (for instance, due to temporary easing of the outbreak). Efficacy data from an HCT combined with safety data from a larger clinical trial could be sufficient for vaccine licensure.

Altogether, there are scenarios in which the speed of HCTs and the precise data they provide are indispensable to the development of an effective and accessible COVID-19 vaccine, with thousands or even millions of lives spared (depending on the pandemic’s long-term trajectory).

At the same time, there are many legitimate concerns about and objections to HCTs. Click the button below to read about objections to COVID-19 challenge trials, 1Day Sooner’s reply, and links to more resources.