Abstract
Abstract The biggest challenge in developing a universal influenza vaccine is the extensive antigenic drift. In contrast to humoral immunity, cell-mediated immunity is more cross-reactive and can protect against various subtypes and drift variants. Our research group has described computationally optimized broadly reactive antigens (COBRA) to develop HA-based broadly protective influenza vaccine. However, studies that characterize the potential of COBRA-HA to elicit a functional T-cell response have yet to be developed. Cross-reactive response to conserved T cell epitopes from previous exposure can provide an efficient heterologous immunity. Thus, we aim to immune profile the pre-existing and cross-reactive COBRA-HA T cell response at the functionality and epitope conservation level to identify potential targets to be included in universal flu vaccine design. To achieve this goal, 50 donors who received the seasonal influenza vaccine (Fluzone, Sanofi) for two consecutive seasons were HLA typed, and the epitopes of COBRA-HA vaccine candidates Y2 (H1) and NG2 (H3) were predicted using IEDB software. Using the high dimensional flow cytometry, eight peptides for Y2 and 15 for NG2 were combined in pools to determine the phenotypes and cytokine secretion. We found that the vaccination induced a cross-reactive COBRA HA-specific CD4+ and CD8+ T cell response independent of antibody titers. Next, we will evaluate the Th helper subsets (Th1/Th2/Th17/cTfh) and the breadth of immune response by deconvoluting the pools in IFNγ Fluospot assay. Nonetheless, the next generation of the universal influenza vaccine recalled a functional CD4+ pre-existing response, demonstrating the potential efficacy of COBRA-HA in clinical trials. National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Department of Health and Human Services contract 75N93019C00052 (TMR).
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