In a recent study published in The Lancet Infectious Diseases, scientists reviewed the history of using human challenge trials in developing vaccines.

The study explored vaccine development for 19 pathogens and the pitfalls and limitations associated with the process.

Study: Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy. Image Credit: solarseven/Shutterstock.com

Background

The human challenge study consists of exposing volunteers to surrogate challenge agents or characterized pathogens under controlled conditions to understand the pathogenesis of the disease and evaluate the efficacy of therapies and vaccines.

Human challenge models have been used over the past several decades to understand and develop vaccines against more than 30 pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Unfortunately, vaccine development has a long history of intentional infection of humans with pathogens, starting with the deliberate and repeated exposure of a child to smallpox by Edward Jenner to demonstrate the efficacy of the vaccinia virus against smallpox.

Since then, human challenge studies have made significant strides in improving the ethical and regulatory aspects and accountability of medical research.

Recent assessments of the ethical frameworks related to human challenge studies have found that the acceptable risk associated with exposure to experimental interventions or pathogens for vaccine development must be balanced against the therapeutic agent's social value or public health benefits.

About the study

In the present study, the scientists conducted a literature search to examine the link between human challenge trials for testing the efficacy of vaccines and the trajectory of vaccine development to distinguish between the facts and fiction concerning the role of human challenge trials in vaccine development.

The vaccine efficacy was first compared by pathogens across the human challenge and subsequent phase trials, and the findings were then further examined based on the contributions of human challenge trials in identifying correlates of protection and the selection of the vaccine.

The authors stated that the findings of this review could not be used to predict the success of using human challenge trials in future vaccine development. Thus, they aimed to assess the study-specific and overall factors related to the successful use of human challenge trials in vaccine development while identifying the intrinsic limitations to the process.

They examined human challenge trials to evaluate candidate vaccines against 19 pathogens, of which seven are in phase three or four trials.

Major findings

The review compared the efficacies of human challenge trials and field trials in vaccine development across various pathogens, including cholera, typhoid, malaria, shigella, influenza, smallpox, mpox, and respiratory syncytial virus.

The findings from these studies have indicated that on the whole, human challenge trials have played a significant role in the progression of vaccine development to subsequent phase trials, as well as in the selection of the adjuvant and immunization route and the designing of the vaccination regimen.

Surprisingly, the one exception has been in developing smallpox and mpox vaccines, where publications from phase three trials seem to prefer the data from animal challenge studies on efficacy and immunogenicity rather than human challenge trials.

The scientists also discussed the various human challenge studies that helped identify vaccine candidates that were not promising and down-select them to avoid further financial and resource expenditure.

These included candidate vaccines for malaria, typhoid, cholera, tuberculosis, Helicobacter pylori, enterotoxigenic Escherichia coli, Streptococcus pneumoniae, and shigella.

Additionally, the authors discussed the multiple aspects in which the fast-tracked production of the coronavirus disease 2019 (COVID-19) vaccine differed from the slow, traditional vaccine development process.

The rapid development of the COVID-19 vaccines was supported by substantial public investments in the form of funds and resources, as well as the presence of a large population of pathogen-naive individuals highly motivated to participate in the vaccine development process.

However, despite the significant difference in the circumstances motivating COVID-19 vaccine development compared to the traditional vaccine development process for other diseases, the advances in vaccine research during the COVID-19 pandemic have highlighted the importance of human challenge studies in accelerating vaccine development.

Furthermore, the impetus provided to vaccine development by the pandemic has also resulted in the development of novel tools, such as computer-generated and in-vitro models, and the use of immunity markers in testing the efficacy and immunogenicity of candidate vaccines.

Conclusions

Overall, the review provided a comprehensive assessment of the role of human challenge trials in developing vaccines overtime against a wide range of pathogens, and discussed the process's various challenges and intrinsic limitations.

Furthermore, the study also compared the major factors that provided impetus to the rapid development of COVID-19 vaccines as compared to the traditional trajectory of vaccine development.

The findings suggested that the ethical and streamlined application of human challenge studies can be used to accelerate the development of vaccines against a wide range of diseases.

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.