UC San Diego

Infections with the bacterial pathogen group B Streptococcus (GBS, S. agalactiae) cause significant morbidity and mortality in pregnant women and neonates, especially in resource-poor countries where implementation of universal screening programs and intrapartum antibiotic prophylaxis remain challenging. Furthermore, potential negative impacts of antibiotic treatment used for GBS prophylaxis on the developing neonatal microbiome is gaining increased scrutiny. For these reasons, a vaccine to prevent GBS infection is an important public health priority. Our laboratory has been collaborating with Vaxcyte, Inc. (Foster City, CA) in advanced preclinical development of the multivalent vaccine, VAX-A1, for prevention of infections by another common childhood pathogen, group A Streptococcus (GAS, S. pyogenes). Due to high sequence homology (98%) between one key VAX-A1 component, the surface anchored GAS C5a peptidase (ScpA) and its GBS homolog (ScpB), we predicted that VAX-A1 could provide a measure of cross-protection against GBS infection. In addition, the functional role of ScpB in GBS virulence remains unclear. Here we generate a GBS ScpB deletion mutant (∆ScpB) paired with heterologous expression of the ScpB gene in nonvirulent Lactococcus lactis for loss and gain of function analyses of the role of C5a peptidase in both GBS virulence and VAX-A1 efficacy. Rabbits immunized with VAX-A1 were protected against lethal infection with three GBS strains of different serotypes prevalent in human newborn infection. Serum from rabbits immunized with VAX-A1 cross-react with WT GBS, but not the ∆ScpB mutant, suggesting the protein is the target antigen responsible for cross protection. These were corroborated by cross reactivity of the antisera specific to L. lactis expressing GBS ScpB. WT GBS opsonized with serum from rabbits immunized with VAX-A1 were more readily killed by human neutrophils. C5a peptidase in both GAS and GBS cleaves human C5a, a major chemoattractant and component of the complement cascade, to impair host immunity. We thus applied our loss- and gain-of-function GBS bacterial reagents to study the contribution of ScpB to GBS neutrophil resistance and virulence in a murine challenge model. Our research highlights potential added efficacy of VAX-A1 in preventing not only GAS but also GBS infection, a clear added benefit of its future adoption into the routine immunization schedule. Likewise, our studies shed new light on the significance of C5a peptidase as a GBS virulence factor.