Development of a live-attenuated vaccine challenge model of Yersinia pestis in humans: Expert consultation on clinical trial considerations, January 2025

Yersinia pestis is the causative agent of plague – the archetypal bacterial pandemic disease. Plague remains endemic in several countries in Africa, South America, and Asia, posing high risks of zoonotic spill-over and epidemic spread or threat of deliberate release. Plague vaccine development remains a priority for pandemic preparedness initiatives but generating sufficient field data for vaccine licensure is challenging. Controlled human infection studies have been deployed to test candidate vaccines against diseases with low and sporadic incidences of outbreaks where field trials are difficult. Typically, such studies use live attenuated or vaccine-type strains to measure clinical or microbiological end points of interest. To assess the feasibility of conducting a human vaccine-challenge study for Y. pestis, we hosted a one-day expert consultation workshop in January 2025. The aim was to discuss the practical, regulatory landscape and future use-case of such a model. We invited attendees from academia, industry, regulatory bodies, funders, and other stakeholders with expertise in Y. pestis biology and infection. The workshop combined presentations with breakout discussions and was divided into five sessions: i) Introduction to live attenuated Y. pestis vaccines; ii) Update of the contemporary plague vaccine landscape; iii) Assessment of biosafety and bio-security considerations; iv) Clinical and ethical considerations and v) public perceptions. Several challenges were identified, and potential strategies to address them were discussed. This perspective builds on this workshop and lays the foundation for a collaborative consortium to develop a Y. pestis vaccine challenge model. Next steps include early-stage public engagement, strain characterization, and regulatory discussions to define how data from these studies could be used for assessing vaccine efficacy. Our vision is to establish a global network dedicated to advancing new vaccine technologies for an ancient disease.