Cardiac monitoring safety assessment framework for early phase group a streptococcal vaccine trials.

This paper presents a comprehensive cardiac safety framework for early clinical development of Streptococcus pyogenes (Group A Streptococcus) vaccines, endorsed by the Strep A Vaccine Global Consortium (SAVAC) and the Australian Strep A Vaccine Initiative (ASAVI). Given historical concerns about vaccine-associated acute rheumatic fever (ARF), we have established standardized echocardiography protocols integrated with clinical assessment for monitoring cardiac safety in early-phase vaccine trials. We recommend that the Modified Jones Criteria for ARF should be the primary focus for cardiac Adverse Events of Special Interest (AESI) monitoring in S. pyogenes vaccine trials, with echocardiography utilized within this clinical context. Two echocardiography protocols-comprehensive for baseline screening and diagnostic confirmation and abbreviated for interval monitoring-should be performed using full-capability equipment by certified professionals. The framework includes specific exclusion criteria for trial participants, active and passive surveillance for ARF symptoms, and a structured approach to investigating suspected cases. This pragmatic approach enables advancement of S. pyogenes vaccine clinical development with appropriate safety oversight while maintaining operational feasibility. While designed for phase 1 and 2 trials in low-endemic settings, these recommendations provide a foundation that can be adapted for later-phase trials in high-endemic regions as vaccine development progresses.