Rheumatic heart disease (RHD) is a devastating consequence of group A streptococcus (StrepA) infections, being associated with 15.6 million cases and 233,000 deaths annually. A vaccine is urgently needed to prevent StrepA primary infection that can lead to RHD. Peptides, with their molecular compactness, offer significant potential as multicomponent vaccines, strategically incorporating epitopes from diverse antigens. Through a series of systematic amino-acid substitutions within the highly conserved M-protein epitope p145, we pinpointed a super immunogen, denoted as p*17. Peptide p*17 was conjugated to a universal carrier protein (DT/CRM197) and combined with K4S2 (minimal epitope from the neutrophil anti-chemotaxis factor, SpyCEP) also conjugated to DT/CRM197.
Mice vaccinated intramuscularly with the combination vaccine (p*17/K4S2) formulated with aluminium hydroxide were protected against upper respiratory tract (URT) challenge with covR/S mutant StrepA. Enduring IgG antibody levels in the sera and saliva remained high up to 10 months post last-vaccine boost and protection was observed for up to one-year post last vaccine boost. The vaccine lost its efficacy when tested in mice that lack mature B-cells, indicating that antibodies play a major role in vaccine efficacy. Furthermore, passively transferred purified vaccine-specific IgG protected immunosuppressed SCID mice from invasive challenge, and also conferred protection against URT challenge with StrepA pre-opsonised with vaccine antisera. In a whole-cell ELISA, we demonstrated that vaccine-induced serum IgG binds to StrepA strains across multiple emm types.
Overall, we identified a super immunogen that enhances StrepA vaccine development by inducing salivary IgG and providing protection against both invasive and URT infections.