Clinical endpoints for trials of Strep A vaccines: report of two expert meetings.

Abstract

Streptococcus pyogenes (group A Streptococcus; Strep A) causes a broad spectrum of diseases ranging from pharyngitis and skin infections to invasive disease and immune-mediated complications including acute rheumatic fever (ARF) and rheumatic heart disease (RHD). RHD remains one of the most important causes of cardiovascular mortality in young people globally, affecting more than 55 million individuals and causing over 370,000 deaths annually, predominantly in low- and middle-income countries. Despite this substantial burden, no licensed Strep A vaccine exists. A critical barrier to vaccine development is that there are many potential clinical trial endpoints capable of supporting regulatory approval while demonstrating meaningful public health impact. However, research gaps remain before these can be fully realised. To address this challenge, the World Health Organization (WHO) and the Strep A Vaccine Global Consortium (SAVAC) convened two international expert consultations in London (September 2024) and Geneva (October 2025). Participants reviewed emerging scientific evidence, epidemiology, and regulatory considerations to define potential clinical development pathways and priority endpoints for Strep A vaccines. Consensus emerged that prevention of Strep A pharyngitis in children represents a feasible primary endpoint for initial proof-of-efficacy trials and potential licensure. Impetigo in children was recognized as an important endpoint, particularly in high-burden settings or where it contributes substantially to transmission and severe invasive infections or progression to RHD. Although prevention of RHD and invasive disease is the ultimate public health objective, advanced RHD was considered infeasible as a pre-licensure endpoint. Early RHD detected by echocardiography was identified as a promising intermediate outcome, but further epidemiological and validation studies could increase confidence in its use in pivotal trials. A clinical development pathway is proposed in which initial licensure is supported by efficacy against pharyngitis and possibly impetigo or early RHD with further evaluation of other severe outcomes such as invasive infections through large-scale trials and post-licensure studies. This pathway informs updates to the WHO Preferred Product Characteristics and Research and Development Roadmap and provides a coordinated strategy to accelerate the development and equitable global introduction of Strep A vaccines.