Protein Vaccination Directs the CD4⁺ T Cell Response toward Shared Protective Epitopes That Can Be Recalled after...

Vaccination is widely used to generate protective immunity against influenza virus. CD4⁺ T cells contribute in diverse ways to protective immunity, most notably, in the provision of help for the production of neutralizing antibodies. Several recent reports have suggested that influenza virus infection elicits CD4⁺ T cells whose specificity only partially overlaps that of T cells elicited by vaccination. This finding has raised serious concerns regarding the utility of currently licensed inactivated influenza virus vaccines and novel protein-based vaccines. Here, using controlled animal models that allowed a broad sampling of the CD4⁺ T cell repertoire, we evaluated protein vaccine- versus infection-generated CD4⁺ T cell epitopes. Our studies revealed that all the infection-elicited CD4⁺ T cell epitope specificities are also elicited by protein vaccination, although the immunodominance hierarchies can differ. Finally, using a reverse-engineered influenza virus and a heterologous protein vaccination and infection challenge strategy, we show that protein vaccine-elicited CD4⁺ memory T cells are recalled and boosted after infection and provide early help to accelerate hemagglutinin (HA)-specific antibody responses. The early CD4⁺ T cell response and HA-specific antibody production are associated with lowered viral titers during the infection challenge. Our data lend confidence to the ability of current protein-based vaccines to elicit influenza virus-specific CD4⁺ T cells that can potentiate protective immunity upon influenza virus infection.IMPORTANCE Most current and new influenza vaccine candidates consist of a single influenza virus protein or combinations of influenza virus proteins. For these vaccines to elicit CD4⁺ T cells that can be recalled after infection, the peptide epitopes should be shared between the two modes of confrontation. Recently, questions regarding the relatedness of epitope selection by influenza virus infection and protein vaccination have been raised. However, the studies reported here show that the specificity of CD4⁺ T cells elicited by protein-based vaccines overlaps that of T cells elicited by infection and that CD4⁺ T cells primed by protein vaccines are recalled and contribute to protection of the host from a future infection.