What are the risks associated with human challenge trials for SARS-CoV-2 vaccine candidates?

The timely development of preventive vaccines and new therapeutic drugs will be crucial in managing the burden caused by the coronavirus disease 2019 (COVID-19) pandemic. While there are currently no approved vaccines for COVID-19, global vaccine production is estimated to reach 8 billion doses by 2021, assuming the best candidate vaccine passes clinical trials as expected.

Traditional clinical trials are time consuming and require large numbers of subjects to detect the therapeutic effects of drug and vaccine candidates. To speed up these trials, several institutions have proposed exposing human subjects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to test new vaccines and drugs.

Although these human provocation trials (HCTs) have been useful in the past to produce vaccines and treatments for other diseases such as cholera, malaria, and influenza, the limited understanding of the risks of COVID-19 and the lack of rescue therapies make it difficult to assess possible adverse effects of these studies in volunteers. Furthermore, the optimal viral dose of SARS-CoV-2 that should be administered to volunteers is unknown.

To help address these concerns, researchers from the University of Haifa, Israel, and WAW Statistical Consulting Ltd, UK, and 1DaySooner, US, designed a model that helps determine the risks faced by participants in a hypothetical study COVID-19 dosage. Your study is available on the prepress server, medRxiv*.

An interactive model to assess the risks of a SARS-COV-2 dosing study

In this article, the researchers present an interactive model to explore some of the risks of a SARS-COV-2 dosing study, which is a prerequisite for COVID-19 human challenge trials. The risk estimates used are based on a Bayesian evidence synthesis model, which can integrate new data on mortality rates from infections in patients and collect hospitalization rates. They also created a web tool to study risk under various participant scenarios and study design parameters. The model can be used to estimate individual risk as well as overall risk of hospitalization and mortality in a dosing study.

Based on the results of the Bayesian model, the expected infection mortality rates for people between the ages of 20 and 30 were estimated to be 17.5 in 100,000 with an uncertainty interval of 95%. Using these data, the researchers found that a 50-person dosing trial among younger individuals has a 99.1% chance of zero deaths and a 92.8% chance that no participant will require hospitalization.

However, given that this infection mortality rate will be further reduced in true HCT by screening for comorbidities and aggressive treatment of cases that occur, the team projects that the true risk will be only 3.1 per 100,000. with a 99.85% probability of no fatalities and a 98.7% chance that no one will be hospitalized.

HCT: a viable method to rapidly test vaccine efficacy during pandemics

Experts believe that while TCHs are not without risks, weighing the risks against the benefits appears to favor their authorization. Although this is disputed by some, the real question is whether the empirical and moral arguments lead to the same conclusion. According to the authors, HCTs are likely a viable method to rapidly test the efficacy of the vaccine, which is even more critical during a violent pandemic.

“It seems likely that Challenge trials are a viable way to rapidly test vaccine efficacy, which is particularly critical now for testing second-generation vaccines, which may prove superior to first-generation vaccines, or at least help meet the demand not satisfied by the first generation candidates “.

A dosing study is a critical first step in HCTs, and the authors believe that the risk estimates and tools developed in this study can help plan HCTs and inform volunteers. They claim that their model provides information on the overall risk of such trials in various sizes and can better inform HCT volunteers about the risks they face.

“Given that an HCT can help select the multiple vaccines needed for global immunization and at the same time help with therapeutic testing, the risk of an initial study on the pathogenesis of SARS-CoV-2 seems justified.”

If a dosing study is successful, future COVID-19 HCTs can offer a rapid and systematic way to screen vaccine candidates to determine their efficacy and safety, which is a considerable benefit. The model developed in this study is already being used to inform potential HCT volunteers and can be adapted to new data and expanded in the future.

*Important news

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.