Evaluation of Salmonella Paratyphi specific antibody quantity and function after vaccination and controlled human infection.

Salmonella Paratyphi A is a major cause of paratyphoid fever. Despite growing global concern, knowledge of S. Paratyphi A immunity remains limited, and no licensed vaccine exists. In a controlled human infection model (CHIM) homologous S. Paratyphi A rechallenge showed a non-significant reduction in risk of acute disease. This study evaluates humoral immunity following experimental S. Paratyphi A exposure and vaccination with a bivalent S. Typhi-S. Paratyphi A conjugate vaccine (Sii-PTCV). Serum samples from 2 UK CHIM studies and a Phase I trial in India of Sii-PTCV were analyzed. S. Paratyphi A-specific IgG, serum bactericidal activity (SBA), antibody-dependent monocyte phagocytosis (ADMP), and neutrophil phagocytosis (ADNP) were measured pre and post-exposure or vaccination. Statistical differences were assessed using Wilcoxon matched-pairs signed rank test or the Mann-Whitney test. Experimental challenge significantly increased IgG, SBA, ADMP, and ADNP (all P < 0.0001), with strongest responses in participants who developed systemic infection. No immune marker correlated with protection in rechallenged individuals. Baseline antibody levels were higher in the Indian cohort than in the United Kingdom (P = 0.0041), suggesting prior natural exposure enhances humoral immunity. Vaccination with Sii-PTCV induced significantly greater responses than challenge, particularly for IgG (P < 0.0001), SBA (P < 0.001), and ADMP (P < 0.001). This study highlights differences in S. Paratyphi A immunity between naive and exposed populations. Both challenge and vaccination with S. Paratyphi A elicited strong humoral responses, with vaccination producing higher magnitude responses. The bivalent vaccine shows promise for paratyphoid prevention, though a clear correlate of protection remains to be defined.