Strong influenza-induced T FH generation requires CD4 effectors to recognize antigen locally and receive signals from continuing infection

Abstract

Significance Influenza infection elicits strong, long-lived protective antibodies, but most current influenza vaccines give weaker, short-lived protection. We noted that live virus is still replicating, making antigen and causing inflammation at 7 d postinfection (dpi), while an inactivated vaccine provides antigen for at most 4 dpi. We show that the generation of key T follicular helper cells (T FH ) requires they recognize antigen locally at 6 dpi in the presence of ongoing viral infection. This creates a checkpoint that restricts T FH responses to dangerous infections that persist through the checkpoint. Using a live attenuated vaccine, akin to Flumist, we found that adding a second dose at 6 d generated a strong T FH response, suggesting an approach to improve vaccine strategies.