Heterosubtypic influenza infection antagonizes elicitation of immunological reactivity to HA

Influenza-specific immunity in humans is unique because there are repeated exposures to viral strains containing genetically conserved epitopes recruiting memory CD4 T cells and novel epitopes stimulating naïve CD4 T cells, possibly resulting in competition between memory and naïve lymphocytes. In the studies described here, we evaluated the effect of this competition on CD4 T cell and B cell response specificity using a murine model of sequential influenza infection. We found striking and selective decreases in CD4 T cell reactivity to nonconserved HA epitopes following secondary influenza infection. Surprisingly, this shift in CD4 T cell specificity was associated with dramatic decreases in HA-specific antibody. These results suggest that repeated exposure to influenza viruses and vaccines containing conserved internal proteins may have unintended and negative consequences on the ability to induce HA-specific antibody to novel pandemic strains of influenza. These finding could have important implications on pandemic influenza preparedness strategies.