Utilizing human tonsil organoids to identify host and antigen correlates of protection to influenza vaccines 3311

Abstract Description Despite the broad success of vaccines in reducing global morbidity and mortality from infectious diseases, significant challenges persist in rational vaccine design and determining correlates of protection. This is largely due to a continued reliance on blood as a readout for vaccine responses, which poorly reflects the dynamic immune processes occurring in lymphoid tissues. To advance rational vaccine design, there is a critical need to better understand the complex immune mechanisms that potentiate productive vaccine responses. Here, we leveraged an immune organoid model to capture human immune diversity and systematically identify the relative influence of host and antigen features on influenza vaccine response variability. In a cohort of 100 donors, we identified established and novel immune signatures correlated with enhanced neutralizing antibody responses across seven different influenza vaccine and antigen formats. Robust antibody responses elicited by inactivated influenza vaccines were predicted by, and correlated with, higher ex vivo Th1 cell frequencies. Analysis of publicly available human influenza immunization data confirmed that elevated Th1 signatures correlate with antibody responses after in vivo vaccination. These findings establish a role for Th1 functions in successful influenza vaccination and demonstrate the utility of human in vitro models for identifying novel in vivo correlates of protection, thereby informing more pragmatic vaccine design. Funding Sources This work is supported by funding through the National Institutes of Health (NIH) grant R01AI173023 and the Wellcome Leap HOPE Program (awarded to L.E.W.). Z.W.W received fellowship support from the UCI T32 Immunology Training Grant Program (T32AI177324-01) funded through the NIH National Institute of Allergy and Infectious Diseases. Topic Categories Vaccines and Immunotherapy (VAC)