PROJECT SUMMARY This is a proposal for a two-year career transition award to study atypical B cells as a novel immunologic and metabolic target to improve vaccine responses in immunosuppressed individuals. The candidate is currently a postdoctoral research fellow at the Johns Hopkins University School of Medicine. The proposal builds on the candidate's extensive experience in vaccine immunology and immunometabolism to understand how metabolic reprogramming of B cells contributes to successful vaccine responses. The COVID-19 pandemic has highlighted the need to develop and rapidly deploy highly immunogenic vaccines. However, insufficient immune responses in immunocompromised individuals have emphasized that novel vaccine formulations may be required for specific populations to overcome immunosuppression. To date, the basic immunology behind successful vaccine responses during immunosuppression has not been well characterized. By dissecting the immunologic and metabolic landscape following vaccination in immunosuppressed individuals, we hope to generate building blocks to reverse engineer vaccines for specific patient populations. Preliminary data from the principal investigator indicates that solid organ transplant recipients, who respond poorly to vaccination due to a variety of immunosuppressive drugs, manage to successfully respond to COVID-19 vaccination by expanding atypical B cells that are reliant on fatty acid oxidation. To further these findings, the principal investigator has proposed a research plan consisting of 3 specific aims. Aim 1 will define populations of immunosuppressed individuals who utilize atypical CD11c+ B cells as a salvage pathway to successful vaccine responses. Aim 2 will assess atypical CD11c+ B cell and T cell interaction to determine specific immunological contexts that drive CD11c+ B cell expansion. Aim 3 will target fatty acid oxidation using vaccine adjuvants to enhance atypical CD11c+ B cell development. Together, these studies will answer how atypical B cells develop in the presence of immunosuppression, what agents we can use to metabolically target them, and who will benefit from vaccine strategies targeting atypical B cells. The principal investigator will also learn new techniques necessary to accomplish the proposed research under the advisory team (Drs. Cox, Bailey, Durbin, Ji, and Pearce), all of whom have pioneering expertise in vaccinology, immunology, immunometabolism, and biostatistics. Importantly, her advisory committee collectively has a very strong track record of training both clinical and postdoctoral fellows who have successfully transitioned into independent investigators at top tier research institutions. She will also engage in and present at national seminars, take coursework on metabolic modeling, clinical vaccinology, Jr. Faculty leadership program, grant-writing seminars, and training on running a laboratory. The outlined career development and research plan will provide the candidate w...