Monday, February 10, 2025
2/10/2025
Abstract / Summary Staphylococcus aureus (SA) is a leading cause of infection worldwide and a major driver of antibiotic resistance. Although there have been close to thirty vaccine trials targeting the pathogen, all successful pre-clinical vaccines taken to human trials have failed for unclear reasons. Recently, we provided evidence that SA vaccine failures occurred because of routine and frequent human exposure to SA compared to laboratory mice. We showed that prior exposure of mice to SA leads to the development of anti-SA antibodies with increased Fc sialylation, incapable of supporting opsonophagocytic killing of the pathogen. Staphylococcal vaccination of these pathogen-exposed mice recalls the non-protective antibody response and leads to vaccine failure. Using this model, we have successfully explained the failure of all clinical SA vaccines we have tested to date. To understand the mechanistic basis for the vaccine failures, we now show that SA induces abundant IL10 that enhances Fc sialylation of non- protective antibodies. IL10 also blocks anti-SA cellular immunity by antagonizing TH17 generation. Taken together, we hypothesize that non-protective immune imprints develop as a result of IL10 induced by the pathogen, and IL10 underlies the development of non-protective responses by subsequently administered T and B vaccines targeting SA. To test our hypothesis, 1) we propose to investigate the molecular link between IL10 and Fc glycosylation, and the mechanism whereby Fc glycosylation leads to aborted opsonic killing of SA. 2) We will seek to identify the bacterial source of IL10 induction and address the mechanism of IL10+T cell expansion and IL10-mediated suppression of TH17 development. 3) Finally, we will address the practical strategic implications of these findings on vaccine development. Overall, our proposal aims to understand the interaction between SA, the host, and the vaccine to provide new insights on anti-SA vaccine approaches. Our findings has the potential to shed light on why vaccines targeting other pathogens also failed.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).