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Abstract
Influenza virus infection poses a continual menace to public health. Here, we developed soluble trimeric HA ectodomain vaccines by establishing interprotomer disulfide bonds in the stem region, which effectively preserve the native antigenicity of stem epitopes. The stable trimeric H1 ectodomain proteins exhibited higher thermal stabilities in comparison with unmodified HAs and showed strong binding activities towards a panel of anti-stem cross-reactive antibodies that recognize either interprotomer or intraprotomer epitopes. Negative stain transmission electron microscopy (TEM) analysis revealed the stable trimer architecture of the interprotomer disulfide-stapled WA11#5, NC99#2, and FLD#1 proteins as well as the irregular aggregation of unmodified HA molecules. Immunizations of mice with those trimeric HA ectodomain vaccines formulated with incomplete Freund’s adjuvant elicited significantly more potent cross-neutralizing antibody responses and offered broader immuno-protection against lethal infections with heterologous influenza strains compared to unmodified HA proteins. Additionally, the findings of our study indicate that elevated levels of HA stem-specific antibody responses correlate with strengthened cross-protections. Our design strategy has proven effective in trimerizing HA ectodomains derived from both influenza A and B viruses, thereby providing a valuable reference for designing future influenza HA immunogens.
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Details

1 Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha, People’s Republic of China
2 School of Life Sciences, Southern University of Science and Technology, Shenzhen, People’s Republic of China
3 Bioinformatics Center, College of Biology, Hunan University, Changsha, People’s Republic of China
4 Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha, People’s Republic of China; Beijing Weimiao Biotechnology Co., Ltd., Beijing, People’s Republic of China