Abstract
Although CD4 T cells are critical orchestrators of protective immunity, vaccine strategies that optimize generation of these cells are not yet 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 AddaVax, an MF59 mimetic or with a nanolipoparticle innate activator R-DOTAP. In the context of influenza B infection memory, a repolarization 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-γ was observed, with the 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 suggest that 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.