Mechanisms of vaccine interference induced by pre-existing anti-staphylococcal antibodies and B cells

About This Grant

Abstract / Summary Staphylococcus aureus (SA) navigates a dual role as both a symbiont and an occasional deadly pathogen, yet no successful vaccines exist to combat SA infection in human. Although exposure to SA in both human and mouse generates robust anti-SA antibodies (anti-SA Ab), these antibodies only provide modest or no signification protection against SA infection. Recently, we identified a likely reason behind the failure of clinical SA vaccines. Our research demonstrates that SA-exposed mice develop anti-SA Ab with shifted epitopes and increased Fc sialylation, which are ineffective in supporting the killing of pathogen both in vitro and in vivo. Staphylococcal vaccination of SA-exposed mice recalls this non-protective immune imprint, thereby interfering with vaccine efficacy. To understand the mechanism behind this vaccine interference, we show that SA-induced inflammatory cytokines directly upregulate sialyltransferase expression, enhancing Fc sialylation and undermine Fc function. Interestingly, the administration of pre-existing anti-SA Ab during staphylococcal vaccination compromises the vaccine efficacy. Furthermore, we show that SA-induced IL-10-secreting suppressive B cells interfere with vaccine responses. Based on these findings, we hypothesize that SA-induced IL-10 disrupts the germinal center reaction, leading to the development of suppressive B cells and non-protective anti-SA Ab thereby interfering with vaccine responses. To test our hypothesis, 1) we propose to study SA- and adjuvant-induced pro- and anti-inflammatory cytokines and their link to humoral vaccine efficacy through distinct antibody glycosylation; 2) we will investigate how SA-B cells limit the germinal center reaction and identify intracellular signaling pathways that control the development of suppressive B cells; 3) finally, we will address the mechanism of pre-existing anti-SA Ab in antigen clearance, epitope masking and shifting in SA infection and SA vaccine, and assess the impact of maternal-derived anti-SA antibodies in neonatal SA vaccination. Overall, our proposal aims to understand the interaction between SA and adjuvant-induced inflammatory cytokines, host humoral immunity, and vaccine to provide new insights for developing effective vaccine approaches in neonate.