Project Summary / Abstract The development of vaccines is one of the greatest success stories of biomedical research. Vaccines exploit the remarkable capability of the immune system to recognize pathogens, develop memory and upon re-exposure quickly mount an immune response that culminates with elimination of the pathogen. Vaccines are typically injected intramuscularly and provide long-term systemic immunity. However, they are less efficient at generating immunity at the site of infection: mucosal surfaces. With poor mucosal immunity, vaccinated individuals can still become infected and transmit disease, thereby reducing the herd immunity benefits of a vaccine program. The microbial communities that inhabit our mucosal surfaces elicit precise immune responses upon colonization – without inflammation, and across an intact tissue barrier. I propose to develop a novel and unconventional mucosal vaccine strategy that leverages the extraordinary capability of the commensal microbiota to induce precise and long-term immunity at mucosal surfaces. In addition to their efficacy, commensal vaccines promise to be inexpensive and lend themselves to needle-free and cold-chain-free formulations that enable deployment in low- and middle-income countries. Overall, this project will uncover the molecular mechanisms underpinning the intimate relationship established between commensal microbes and their host over millions of years of coevolution and harness this knowledge to develop new vaccine strategies against pathogens. To achieve this goal, I will exploit commensal microbes that colonize the skin, where microbiome intervention is much more accessible. To gain a broad understanding of the immune responses elicited by the microbiota in the skin, I will study the B cell response to prevalent skin commensal microbes (Aim 1). I will profile the B cell response to a newly identified B cell antigen derived from a ubiquitous skin commensal and generate a new monoclonal mouse model to study the molecular interplay between the skin microbiota and B cells (Aim 2). I will engineer skin commensal microbes to elicit potent B cell responses against pathogens (Aim 3). Overall, this project will 1) uncover the B cell response to skin commensal microbes, 2) generate new technologies to probe commensal-specific immunity at the skin barrier and 3) develop a new mucosal vaccination strategy. To achieve my long-term career goal of developing novel technologies to study commensal-immune interactions and creating commensal-based therapies, I have assembled an outstanding group of mentors who complement my training in mucosal immunology and biochemistry: Dr. Michael Fischbach (primary mentor, microbiology and bacterial genetics), Dr. Yasmine Belkaid (co-mentor, skin immunology and bacterial models of infection), Dr. Gabriel Victora (advisor/collaborator, B cell biology and viral models of infection) and Dr. Christopher Barnes (advisor/collaborator, vaccinology). The training I will r...