When Human Challenge Studies are a Better Option

By Adrian Wildfire, Director of Scientific and Business Strategy at hVIVO  

COVID-19 vaccine distribution has been operational on a global scale since December 2020 and infection rates have dropped in relation to the pace and extent of the roll-out. While COVID-19 vaccines have proven effective against the early viruses, researchers are still studying how well they protect against new, more resistant SARS-CoV-2 strains. The existence and evolution of these variants means that current vaccines will have to be modified to ensure continued high rates of effectiveness. 

Emerging variants will continue to challenge our ability to test updated vaccines through traditional clinical trial processes as they may not be fast enough to provide data in a timely manner and populations are becoming increasingly resistant to disease as they are either vaccinated or are exposed to the virus naturally. 

Human challenge studies are a promising, alternative option and have been safely carried out for decades in the investigation of infectious disease and preventative interventions. This efficient and scientifically validated method for testing drugs and vaccines has been used to validate treatments against diseases such as malaria, norovirus, RSV, flu and most recently cholera and typhoid. 

The need for rapid vaccine development

The traditional clinical trial process is highly regulated and systematic. We know that proven methodologies and predictive endpoints have led to a broad pipeline of products across all disease areas. However, one of the challenges with conventional clinical trial testing is the time it takes to advance promising candidates from the laboratory to the market. Individual clinical trials can last for months, seasons or even multiple years and require many different types or stages of testing before enough evidence is accumulated to fulfil the requirements of the Regulatory Authorities. This standardized approach is structurally not conducive to rapid vaccine development (note the large number of Emergency Use Authorizations issued during the current COVID-19 pandemic). Issues that can delay or extend clinical trials out range from complexities in trial design, to niche patient recruitment or the requirement for operationally challenging systems to collect samples or data, analyze and interpret it. 

There is also an inherent desire for statistical significance in clinical trials which is predicated on numbers (‘n’), with proofs of efficacy and safety requiring hundreds, if not thousands of participants to be valid. Cost thus becomes a driving factor as trial sizes grow; especially where infection and disease is infrequently observed in the general population and cannot be controlled or selected for e.g. seasonal illnesses. 

While the regular clinical trial process has been effective in safely advancing novel products in the majority of cases and clinical conditions with rigorous standards upheld and enshrined in law (e.g. ICH-GCP or good clinical practice), we should also be enabling processes that allow for timeliness and targeted effectiveness to lower the economic bar to entry. The global scale of COVID-19; the potential for uneven vaccine delivery, and the risk of breakthrough infections mean that standard clinical trial models are increasingly suboptimal. 

When human challenge trials are a better option 

Where there is limited capacity to test COVID-19 vaccines in the field and in the case where rapid solutions are needed, human challenge studies offer an accelerated pathway to compare new vs established vaccines and to help develop a strategic plan to effectively immunize vulnerable groups going forward. The World Health Organization (WHO) defines human challenge studies as “…trials in which participants are intentionally challenged (whether or not they have been vaccinated) with an infectious disease organism. This challenge organism may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or no pathogenicity, or genetically modified in some manner.”

In short, a human challenge study involves administering a small amount of an infectious agent to small groups of healthy volunteers in a controlled, clinical environment within a well-regulated and ethically approved framework. Patients are closely monitored and can therefore be treated immediately, if out-of-normal events occur. This agile process, with guaranteed high infection rates and well characterized symptoms, results in a need for fewer participants, faster recruitment and translatable results. The human challenge model has the ability to select study participants specifically on immune-status and exclude anyone that has been shown to be susceptible to severe COVID-19 disease or who is likely to be resistant to infection.  

Another benefit of a human challenge study is that it enables researchers to build a more comprehensive profile of volunteers’ natural immune responses to pathogens e.g. COVID-19 infection. This ability to observe and sample subjects from the time of infection through to recovery helps to better understand how the virus affects peoples’ health and wellbeing (including predisposing factors to severity of disease), how to detect symptoms early on and also how each vaccine performs in reducing or preventing infection and disease. This is enabled by trialing vaccines on currently circulating strains of virus, thus not being reliant on extrapolation or predictive modeling from trials with antigenically irrelevant strains, potentially further shortening the timeframe for authorization. 

As with all models for vaccine and drug testing, it is important to note that human challenge studies are subject to regulation by the Food and Drug Administration (FDA) and EU regulatory bodies as well as Ethical and other review mechanisms or organizations. Human challenge modelling is both accepted and approved for providing proofs of efficacy in the EU, US, UK and many other countries. 

Protecting the World Against Variants 

To address the ever-present threat of emergent, COVID-19 vaccine-escape variants, researchers need a trial process that is fast, prognostic to the field and agile enough to address new variants of concern as they as identified, not months after escape and expansion into naïve populations. Human challenge studies have the ability to adapt rapidly to new strains and, because significant data can be accessed with relatively small patient cohorts, can do so in a cost-effective manner prior to large scale field trials. 

Traditional clinical trials have served the industry well and have demonstrated consistent benefits; however, such systems are not optimized for rapid or targeted deployment in times of crisis nor for the accelerated dose-finding, go / no-go decisions required to advance the best candidates into the community during a pandemic. 

In contrast, human challenge trials offer the flexibility and efficiencies needed to be able to readily identify and progress potent vaccines against emergent strains. Before the appearance of COVID-19 in late 2019, human challenge trials were routinely employed for flu viruses, yielding valuable insights into the early phases of previous pandemic strains. Such understanding included early symptoms, the dynamics of virus shedding (timing, volume) and markers associated with protective immune responses. Influenza challenge trials assisted researchers on the path to improved vaccine design and novel routes of inoculation.  

Given the innate ability of viruses to rapidly mutate, jump species and cross global borders, researchers will need to embrace cutting-edge technologies and agile methodologies as they appear. This may be especially true for upper respiratory tract viruses that present on-going, challenges annually to effective interventions in severe disease and death in vulnerable groups. Where public-private partnerships are promoted, this allows commercial and public organizations to expand their drug and vaccine portfolios and bolster efficacy trials with human challenge modelling to ultimately get vaccines for specific COVID-19 variants to patients faster. A win-win surely?

About the Author 

Adrian Wildfire is Director of Scientific and Business Strategy at hVIVO and CEO at CHIMagents. He is a leader in manufacturing challenge agents for global clients and leads a team of professional experts in viral agent design, GMP manufacture, and testing.