Abstract
Although CD4 T cells are critical orchestrators of protective immunity to viral respiratory pathogens, vaccine strategies that optimize generation of these cells have yet to be prioritized. In this manuscript, to mimic the typical human vaccine recipient using a mouse model, we evaluated the impact of previous influenza infection on the adaptive immune response elicited by the recombinant influenza vaccine Flublok, co-delivered with either AddaVax, an MF59 mimetic or a nanolipoparticle innate activator R-DOTAP. In the context of influenza B infection memory, a repolarization of the responding CD4 T cells and dramatic change in the fate of the vaccine-elicited CD4 T cells was discovered. A rapidly evolving CD4 T cell response enriched in TNF-α and IFN-ψ was observed, with the HA-B-specific CD4 T cells also displaying increased expression of chemokine receptors associated with lung homing potential and ultimate accumulation in the lung tissue. Unexpectedly, similar shifts in the features of the H3-specific CD4 T cell and antibody response were also observed, drawn from the naïve repertoire. These results are consistent with the view the microenvironment of the vaccine draining lymph node, developed in the context of immune memory, rather than infection-induced CD4 T cell imprinting, plays the decisive role in the functional phenotype, magnitude, and fate of vaccine-elicited CD4 T cells. These results have important implications for both pre-clinical models of vaccination and future vaccine strategies.