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 no approved vaccines for COVID-19 currently, as per estimates, global vaccine production will reach 8 billion doses by 2021, assuming the best vaccine candidate passes clinical trials as expected.
Traditional clinical trials are time-consuming and need a large number of subjects to detect the therapeutic effects of drug and vaccine candidates. In order to accelerate 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 such human challenge trials (HCTs) have been helpful in the past to produce vaccines and treatments for other diseases like cholera, malaria, and influenza, limited understanding of COVID-19’s risks and the lack of rescue therapies make it tough to assess the possible adverse effects of these studies on the volunteers. Also, the optimum SARS-CoV-2 viral dose that needs to be administered to the volunteers is unknown.
To help address these concerns, researchers from the University of Haifa, Israel, and WAW Statistical Consulting Ltd, UK, and 1DaySooner, USA, designed a model that helps determine the risks faced by participants in a hypothetical COVID-19 dosing study. Their study is available on the preprint server, medRxiv*.
An interactive model for assessing the risks of a SARS-COV-2 dosing study
In this paper, the researchers present an interactive model for exploring 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 infection fatality rates in patients and gather hospitalization rates. They also created a web tool to study the risk under various participant scenarios and study design parameters. The model can be used to estimate individual risk as well as the overall hospitalization and mortality risk in a dosing study.
Based on the results from the Bayesian model, expected infection fatality rates for individuals aged between 20 and 30 years was estimated to be 17.5 in 100,000 with a 95% uncertainty interval. Using this data, the researchers found that a 50-person dosing trial among younger individuals has a 99.1% probability of zero fatalities and a 92.8% probability of no participants requiring hospitalization.
However, since this infection fatality rate will be further reduced in an actual HCT through screening for comorbidities and providing aggressive treatment for any cases that do occur, the team projects the actual risk to be only around 3.1 per 100,000, with a 99.85% probability of no fatalities and a 98.7% chance of no one getting hospitalized.
HCTs - a viable method of rapidly testing vaccine efficacy during pandemics
Experts believe that, although HCTs are not risk-free, weighing the risks against the benefits seems to favor allowing them. 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, it is likely that HCTs are a viable method of rapidly testing vaccine efficacy, which is even more critical during a raging 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 fill the demand unmet by first-generation candidates.”
A dosing study is a critical first step in HCTs, and the authors believe that risk estimates and tools developed in this study can help plan such HCTs and inform volunteers. They claim that their model offers insight into the overall risk of such trials across various sizes, and can better inform HCT volunteers about the risks they face.
“Given that an HCT may help select the multiple vaccines necessary for global immunization while also assisting with therapeutic testing, the risk of an initial study into SARS-CoV-2 pathogenesis seems justified.”
If a dosing study is successful, future COVID-19 HCTs may offer a rapid and systematic way of screening vaccine candidates for 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 novel data and expanded in the future.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.