Biomolecular Sciences Seminar Series

Dr. Chih-Ming Tsai

Title:  Immune Imprinting as the Basis for Staphylococcal Vaccine Failures

Abstract: 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 humans. Although exposure to SA in both human and mouse generates robust anti-SA antibodies (anti-SA Ab), these antibodies only provide modest or no significant protection against SA infection. Recently, we identified the reasons behind the failure of all clinical SA vaccines. Our research demonstrated that prior SA-exposed mice develop anti-SA Ab with shifted epitopes and increased Fc sialylation, which are ineffective in supporting the killing of pathogens both in vitro and in vivo. Staphylococcal vaccination in prior SA-exposed mice recalls this non-protective immune imprint, thereby interfering with vaccine efficacy. Mechanistically, IL-10–secreting B10 cells suppress both recalled and de novo B cell responses. IL-10 promotes STAT3 binding upstream of the sialyltransferase gene st3gal4, increasing B cell expression and hyper–α2,3-sialylation of antibodies. This modification diminishes the protective activity of antibodies targeting cell-wall antigens IsdB, IsdA, and MntC. Consistent with these findings, human anti-SA antibodies and anti-Pseudomonas antibodies from cystic fibrosis patients with elevated IL-10 show similar hyper-sialylation compared to antibodies from healthy controls. These results reveal a pathobiont-driven mechanism whereby IL-10–mediated antibody glycosylation rewires humoral immunity, providing a mechanistic explanation for vaccine failure and a potential barrier to effective staphylococcal vaccination.

Host: Dr. Julie Tinker