Commensal bacteria as vehicles for robust mucosal vaccination against lung pathogens

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PROJECT SUMMARY/ABSTRACT The prevalence and severity of respiratory infections is in part because vaccines struggle to elicit robust immunity at the nasal and lung mucosal barriers where early, strong defense is most needed. Specifically, vaccines delivered intramuscularly generate good serum responses but poor mucosal responses; alternatively, vaccinating the mucosa directly, such as with a nasal spray, requires high doses of adjuvants that cause local inflammation and resulting safety concerns. Commensal bacteria safely live at barrier surfaces such as the skin and nose where they generate antigen-specific immunity without any associated inflammation. The goal of this proposal is to investigate commensal bacteria as safe and effective vaccine vehicles. Preliminary data suggests that engineered strains of Staphylococcus epidermidis, a ubiquitous skin commensal, that express influenza A virus (IAV) antigens (S. epi-IAV) can be applied to the skin and function as partially protective vaccines. In the first aim of my proposal, I will elucidate the cells that respond in the skin and subsequently provide pulmonary protection. Specifically, I will use a T cell activation assay to assess for antigen-specific responding cells; I will also label and track immune cells originating in the skin using the ROSA mouse, which will allow me to profile innate cellular effectors too. In my second aim, I will evaluate for improved pulmonary protection in the case when vaccination on the skin is followed by subsequent antigen exposure at the respiratory mucosa. Finally, I will move to the nasopharynx. I will determine if commensal vaccination in the nose more effective than skin vaccination at eliciting pulmonary protection. My project will provide a deeper understanding of the immune- commensal interactions in the nasopharynx, how commensal-generate immunity is shared between barrier surfaces, and lay the foundation for using commensals to generate mucosal vaccines that are both safer and more effective than existing vaccines. This project builds off my expertise modeling host-microbe interactions in the lung from my graduate work and allows me to expand into the fields of mucosal immunology and microbial engineering. Support from the F32 program, the Fischbach lab, the Stanford Pulmonary Division, and the resources available at Stanford University will allow me to develop critical new skills in flow cytometry, bacterial genetic engineering, and mouse models. The training and mentorship I will receive during my F32 award will let me take a critical step towards my career goal of becoming an independent physician scientist engineering new therapies for my clinic and ICU patients with lung infections.