Microbial mechanistic requirements for eliciting a topical and intranasal immune response

The skin colonist Staphylococcus epidermidis elicits a potent antibody response that can be redirected against an antigen of interest, but this process relies on genetic engineering. ¹ Here, by adapting bioorthogonal chemistry methods to conjugate antigens to the cell surface, we make the process of generating a commensal vaccine rapid and efficient. A wide variety of bacteria displaying tetanus toxin fragment C (TTFC) elicit an antibody response when applied to mice topically, indicating that the inductive process is not limited to colonists. Colonization occurs at two different sites, the skin and nostril; by colonizing each with S. epidermidis- TTFC, we show that skin colonization yields a moderate IgG response, while nostril colonization elicits a highly potent systemic IgG response and an exuberant IgA response in the nostrils, lungs, and intestine. Two lines of evidence are consistent with the nasal-associated lymphoid tissue (NALT) as the inductive site for nostril colonization: imaging suggesting robust bacterial translocation, and the induction of commensal-specific B cells following colonization. On the skin, TTFC must be conjugated to live S. epidermidis to elicit an antibody response; in the nostrils, live S. epidermidis -TTFC and S. epidermidis mixed with TTFC are equally potent. Commensal vaccination yields a robust response in pet shop mice, and chemical conjugation facilitates antibody responses to a broad array of antigens, including a whole viral capsid and a rotavirus immunogen. Collectively, these findings provide compelling evidence of a translational path for commensal vaccines.