Consultation report - considerations for a regulatory pathway for bivalent Salmonella Typhi/Paratyphi A vaccines for use in endemic countries

Abstract

Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A and, to a lesser extent, S. Paratyphi B and C, remains a significant cause of mortality and morbidity in resource-constrained settings. Typhoid conjugate vaccines (TCVs) protect against S. Typhi but no vaccine to date protects against paratyphoid fever. There are several bivalent S. Typhi/Paratyphi A products in development; however, the low incidence of paratyphoid fever in many settings limits the feasibility of phase 3 efficacy studies. Two bivalent vaccines adding the S. Paratyphi A-specific O:2 lipopolysaccharide conjugated to a protein carrier to TCV constructs have successfully completed phase 1 studies and will progress rapidly in their development. The WHO's Product Development for Vaccines Advisory Committee (PDVAC) endorsed a regulatory pathway for a bivalent S. Typhi/Paratyphi A vaccine that contemplates demonstrating protective efficacy against S. Paratyphi A infection in a controlled human infection model (CHIM). Since the use of CHIM data in lieu of phase 3 efficacy studies and to identify markers of immune protection is not yet widely accepted by regulatory bodies, the WHO organized a consultation with vaccine developers, manufacturers, and regulators. The purpose of the meeting was to discuss the feasibility and considerations for the licensure of a bivalent S. Typhi/Paratyphi A vaccine. The aim of the consultation was to gain alignment among key stakeholders and facilitate the pathway to licensure in endemic countries.

Keywords: Enteric fever; Paratyphoid fever; Phase 3 study; Regulatory pathway; Salmonella Paratyphi A; Vaccines.

Fig. 1

Clinical development pathway for conjugated bivalent Salmonella Typhi/Paratyphi A vaccines. Outlined in black at the bottom of the figure is the “classic” vaccine clinical development [81]. At the top, in white is the proposed clinical development pathway proposed for bivalent vaccines, where phase 2 & 3 studies to determine safety, immunogenicity, and noninferiority to the typhoid component take place concurrent to a CHIM study, leading to vaccine licensure and, eventually WHO prequalification.