Seasonal Influenza Can Poise Hosts for CD4 T-Cell Immunity to H7N9 Avian Influenza

Abstract

The emergence of avian H7N9 viruses has raised concerns about its pandemic potential and prompted vaccine trials. At present, it is unknown whether there will be sufficient cross-reactive hemagglutinin (HA)-specific CD4 T-cell memory with seasonal influenza to facilitate antibody production to H7 HA. There has also been speculation that H7N9 will have few CD4 T-cell epitopes. In this study, we quantified the potential of seasonal influenza to provide memory CD4 T cells that can cross-reactively recognize H7 HA-derived peptides. These studies have revealed that many humans have substantial H7-reactive CD4 T cells, whereas up to 40% are lacking such reactivity. Correlation studies indicate that CD4 T cells reactive with H7 HA are drawn from reactivity generated from seasonal strains. Overall, our findings suggest that previous exposure of humans to seasonal influenza can poise them to respond to avian H7N9, but this is likely to be uneven across populations.

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

“…Confirmation that this epitope is recognized in human CD4 T cells elicited by seasonal influenza was provided by Kwok and co-workers using HLA-DR1 tetramers (64). We have also obtained strong evidence that CD4 T cells generated by seasonal influenza can cross react with H7-derived peptides (62). In these studies, 17-mer peptides representing the most highly conserved segments of H7 HA relative to its closest seasonal strain (H3) were identified and tested.…”

“…There is a growing appreciation that vaccine strategies that more fully engage the cellular response can enhance protection. A number of recent studies have sought to quantify and characterize the repertoire of circulating memory CD4 T cells with specificity towards influenza antigens (59, 60, 62, 63, 83–87). Many studies by other groups have concluded that the most prominent influenza-reactive CD4 T cells are those specific for internal virion proteins, particularly M1 and NP (84–86), as well as HA (63).…”

Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

“…We suspect that the major mechanism that underlies poor responses of humans to avian vaccines is simply a low abundance of memory helper CD4 T cells that are recruited into the response. In our studies on CD4 T cell reactivity to H7 HA-derived epitopes in humans that have never encountered H7 avian viruses or vaccines, we have found that cross-reactivity is detectable in many but is of relatively low abundance for most individuals (24). In contrast, memory CD4 T cells specific for seasonal H1N1-and H3N2-derived HA proteins are readily detectable in humans (25,26).…”

Prospects for antibody-based universal influenza vaccines in the context of widespread pre-existing immunity

“…A strong correlation between neutralizing antibody responses following TIV vaccination and the expansion of a circulating CD4+ T-cell population with a Tfh-like phenotype has been reported [140,141]. Furthermore, broadly cross-reactive memory CD4+ T cells capable of recognizing antigenic shift variants can be primed by seasonal influenza exposure [142][143][144]. This population of HA-specific CD4+ memory cells may constitute an expanded pool of Tfh to provide cognate help for HAbinding B cells to subsequent immunization.…”