Influenza hemagglutinin (HA) protein consists of two components-a globular head and stem region that are folded within six disulfide bonds-plus several N-linked glycans that produce a homo-trimeric complex structure. While N-linked glycosylation sites on the globular head are variable among different strains and different subtypes, N-linked glycosylation sites in the stem region are mostly well-conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Since the HA stem region is constituted by a HA1 N-terminal part and a full HA2 part, we expressed a series of recombinant HA mutant proteins with deleted N-linked glycosylation sites in the HA1-stem and HA2-stem regions of H5N1 and pH1N1 viruses. Unmasking N-glycans in the HA2-stem region (H5 N484A and H1 N503A) were found to elicit more potent neutralizing antibody titers against homologous, heterologous and heterosubtypic viruses. Unmasking the HA2-stem N-glycans of H5HA but not H1HA resulted in more CR6261-like and FI6v3-like antibodies and also correlated with the increase of cell fusion inhibition activity in antisera. Only H5 N484A HA2-stem mutant protein immunization increased the numbers of antibody-secreting cells, the germinal center B cells, and the memory B cells targeting the stem helix A epitopes in splenoctyes. Unmasking the HA2-stem N-glycans of H5HA mutant proteins show a significantly improvement in the protection against homologous virus challenges, but to a less degree for the protection against heterosubtypic pH1N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.
N-linked glycosylation sites in the stem region of influenza hemagglutinin (HA) proteins are mostly well-conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Our studies indicate that unmasking the HA2-stem N-glycans of recombinant HA proteins from H5N1 and pH1N1 viruses induced more potent neutralizing antibody titers against homologous and heterosubtypic viruses. However, only the immunization with the H5N1 HA2-stem mutant protein can refocus B antibody responses to the helix A epitope for inducing more CR6261-like/FI6v3-like and fusion inhibition antibodies in antisera, resulting in a significant improvement for the protection against lethal H5N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.
This research output has an Altmetric Attention Score of 14. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 October 2026.
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