tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2024 Aug 5:2389095.
doi: 10.1080/22221751.2024.2389095. Online ahead of print. Disulfide-stabilized Trimeric Hemagglutinin Ectodomains Provide Enhanced Heterologous Influenza Protection
De-Jian Liu[SUP] 1 [/SUP], Xiu-Qin Zhong[SUP] 1 [/SUP], Yan-Xia Ru[SUP] 2 [/SUP], Shi-Long Zhao[SUP] 1 [/SUP], Cui-Cui Liu[SUP] 1 [/SUP], Yi-Bo Tang[SUP] 1 [/SUP], Xuan Wu[SUP] 1 [/SUP], Yi-Shuai Zhang[SUP] 3 [/SUP], Hui-Hui Zhang[SUP] 3 [/SUP], Jia-Yue She[SUP] 1 [/SUP], Mu-Yang Wan[SUP] 1 [/SUP], Yao-Wang Li[SUP] 2 [/SUP], He-Ping Zheng[SUP] 3 [/SUP], Lei Deng[SUP] 1 4 [/SUP]
Affiliations
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.
Keywords: Influenza vaccine; cross-neutralizing antibody; cross-protection; interprotomer disulfide bond; trimeric hemagglutinin ectodomain.
. 2024 Aug 5:2389095.
doi: 10.1080/22221751.2024.2389095. Online ahead of print. Disulfide-stabilized Trimeric Hemagglutinin Ectodomains Provide Enhanced Heterologous Influenza Protection
De-Jian Liu[SUP] 1 [/SUP], Xiu-Qin Zhong[SUP] 1 [/SUP], Yan-Xia Ru[SUP] 2 [/SUP], Shi-Long Zhao[SUP] 1 [/SUP], Cui-Cui Liu[SUP] 1 [/SUP], Yi-Bo Tang[SUP] 1 [/SUP], Xuan Wu[SUP] 1 [/SUP], Yi-Shuai Zhang[SUP] 3 [/SUP], Hui-Hui Zhang[SUP] 3 [/SUP], Jia-Yue She[SUP] 1 [/SUP], Mu-Yang Wan[SUP] 1 [/SUP], Yao-Wang Li[SUP] 2 [/SUP], He-Ping Zheng[SUP] 3 [/SUP], Lei Deng[SUP] 1 4 [/SUP]
Affiliations
- PMID: 39101691
- DOI: 10.1080/22221751.2024.2389095
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.
Keywords: Influenza vaccine; cross-neutralizing antibody; cross-protection; interprotomer disulfide bond; trimeric hemagglutinin ectodomain.