The emergence of protective natural immunity to Streptococcus pyogenes in The Gambia: a focus on candidate vaccine antigens

Developing a vaccine against Streptococcus pyogenes (Group A Streptococcus, Strep A) remains a key global health priority. Through the work presented in my thesis, we address critical knowledge gaps relating to protective immunity in a high-burden setting, leveraging a unique opportunity presented by a longitudinal household transmission study alongside two additional paediatric cohorts from birth to five years of age in The Gambia. We optimised high-throughput serological techniques to characterise serum and mucosal antibody responses to candidate vaccine antigens. We demonstrated serological responses to S. pyogenes carriage detected by PCR in a post-hoc analysis of children aged 2 to 4 receiving live attenuated influenza vaccine (LAIV), despite only modest impacts of LAIV on S. pyogenes carriage. We next explored age-dependent antibody dynamics following both disease and carriage episodes in a prospective longitudinal household cohort study, and explored the functionality of these antibodies in vitro using functional immunoassays. We showed that after the waning of maternally transferred IgG, intense exposure, to S. pyogenes in early childhood, regardless of the site and presence of symptoms, rapidly primes serological immunity. These data provide vital insights into the optimal timing for Strep A vaccine administration within childhood immunisation schedules in high-burden settings. We demonstrated that antibody responses to several vaccine candidate antigens, both conserved and serotype specific, are associated with protection from culture-confirmed S. pyogenes carriage and disease events. These clinical events are key precursors to rheumatic heart disease and represent primary endpoints for future vaccine trials. Our data provide optimism for the inclusion of conserved and type specific antigens in emerging vaccines. This work provides the first description of a protective role for antibodies against conserved S. pyogenes vaccine antigens in humans, all of which are included in vaccines now entering Phase I trials. Furthermore, we define putative 50% protective thresholds for these antibodies in blood, providing a critical benchmark for interpreting immunogenicity data from Phase I and II clinical trials. Binding antibody levels above putative protective thresholds were associated with in vitro functionality. We explored mucosal immunity demonstrating compartmentalised evolution of IgA responses, again demonstrating association between two conserved antigens and protection as well as attenuation of systemic responses. Our data support the evaluation of vaccines capable of inducing mucosal immune responses. This thesis advances the understanding of natural immunity to S. pyogenes in endemic settings and generates data to inform the design and evaluation of future vaccine strategies.