Determining the effects of imprinting on the humoral response induced by H5N1 influenza vaccines

PROJECT SUMMARY Influenza A viruses (IAV) continue to impose a major global health burden. The recent spread of highly pathogenic avian H5N1 across continents and into United States dairy cows and wildlife increases its potential for zoonotic adaptation and pandemic spread and necessitates the development of effective vaccines. However, responses to novel IAV antigens are shaped by immune imprinting, a phenomenon where pre-existing immunity to prior IAV antigens biases the response toward cross-reactive epitopes at the expense of generating de novo, more protective antibodies against the new antigens. As most adults have been exposed to IAV, it remains unclear how much of an antibody response elicited by H5 hemagglutinin (HA) vaccines reflects imprinted recall versus de novo protective responses. The proposed research addresses these gaps through two complementary aims. In Aim 1, we will develop serological assays that distinguish and quantify vaccine-induced H5-specific versus cross-reactive imprinted antibody responses across different prior IAV experience. In Aim 2, we will characterize the B cell populations and repertoire induced by H5 HA vaccines and assess the functionality of generated monoclonal antibodies to determine whether vaccine antigen design can preferentially target neutralizing epitopes on the H5 HA and engender more protective responses. We propose to mutate the conserved stem epitope on H5 HA to disrupt binding by B cell receptors on cross-reactive memory B cells and reduce imprinting. Collectively, this project will address a fundamental barrier to effective H5 vaccination and provide broadly applicable insights for improving vaccines against emerging IAV in antigen-experienced populations. As part of this fellowship training plan, I will pursue both scientific and clinical activities to expand my intellectual inquiry, technical expertise, and scientific communication skills towards my goal of excelling in a postdoctoral fellowship and eventually becoming an independent physician-principal investigator in the field of viral immunology. My fellowship training plan at WashU in St Louis, one of the nation's leading Medical Scientist Training Programs, integrates strong mentorship from leading immunology and virology experts as my thesis advisor/sponsor and collaborators, rigorous genomics coursework, manuscript writing, and presentation at local and international research meetings. This environment will provide me the mentorship, resources, and scholarly and research opportunities to accomplish my aims and position me to succeed in my long-term goal of leading an independent laboratory and caring for patients.