Abstract

Influenza viruses are endemic viral pathogens causing mild to severe respiratory illness in humans. Immunologic protection against influenza is determined by immune correlates of protection– factors associated with reduced infection or severe disease. While antibodies specific to viral surface proteins are known correlates, waning seasonal vaccine efficacy and reported infection of patients despite elevated antibody titers suggest that humoral responses alone do not provide complete protective immunity. Indeed, evidence points to a larger role for cell-mediated immunity (CMI; innate cells and antigen-specific T cells) in conferring protection. CMI correlates, which act independently from humoral responses, have yet to be identified. Here, we analyzed samples from adult human subjects across two influenza infection and vaccination cohorts to identify distinct CMI correlates of protection to influenza. We profiled CMI responses using high-dimension flow cytometry from PBMCs collected pre- and post-exposure to influenza infection or vaccination. Statistical comparison of cell frequency and infection status identified candidate CMI correlates, which were validated using logistic regression accounting for vaccination, demographic (age, sex, BMI), and serologic (antibody) covariates. We identified 9 individual and 6 cell clusters across myeloid and lymphoid compartments associated with protection. The strongest correlations were observed in Th17, cTfh, and subsets of NK and dendritic cells. Further, AUROC models identified 3 baseline CMI infection classifiers. Lastly, our study identified correlates of vaccine failure– pre-exposure CMI profiles correlated with positive infection status despite vaccination.

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