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二硫键稳定的三聚体血凝素胞外结构域提供增强的异源流感保护。

Disulfide-stabilized trimeric hemagglutinin ectodomains provide enhanced heterologous influenza protection.

机构信息

Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha, People's Republic of China.

School of Life Sciences, Southern University of Science and Technology, Shenzhen, People's Republic of China.

出版信息

Emerg Microbes Infect. 2024 Dec;13(1):2389095. doi: 10.1080/22221751.2024.2389095. Epub 2024 Aug 18.

DOI:10.1080/22221751.2024.2389095
PMID:39101691
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11334750/
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.

摘要

流感病毒感染持续威胁着公众健康。在这里，我们通过在茎部建立蛋白间二硫键来开发可溶性三聚体 HA 外域疫苗，这有效地保持了茎部表位的天然抗原性。与未修饰的 HA 相比，稳定的三聚体 H1 外域蛋白表现出更高的热稳定性，并显示出与一组针对茎部交叉反应性抗体的强烈结合活性，这些抗体识别蛋白间或蛋白内表位。负染透射电子显微镜（TEM）分析揭示了 WA11#5、NC99#2 和 FLD#1 蛋白的稳定的蛋白间二硫键连接的三聚体结构，以及未修饰的 HA 分子的不规则聚集。用不完全弗氏佐剂配制的这些三聚体 HA 外域疫苗免疫小鼠，引发了更有效的交叉中和抗体反应，并提供了针对异源流感株致死性感染的更广泛免疫保护，优于未修饰的 HA 蛋白。此外，我们的研究结果表明，HA 茎特异性抗体反应水平的升高与交叉保护的增强相关。我们的设计策略已被证明在三聚化来自甲型和乙型流感病毒的 HA 外域方面是有效的，从而为设计未来的流感 HA 免疫原提供了有价值的参考。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/90a86989262e/TEMI_A_2389095_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/83de42d2d682/TEMI_A_2389095_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/8f0849a3c5e5/TEMI_A_2389095_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/0135fe619043/TEMI_A_2389095_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/828150d64684/TEMI_A_2389095_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/90a86989262e/TEMI_A_2389095_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/83de42d2d682/TEMI_A_2389095_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/8f0849a3c5e5/TEMI_A_2389095_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/0135fe619043/TEMI_A_2389095_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/828150d64684/TEMI_A_2389095_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0866/11334750/90a86989262e/TEMI_A_2389095_F0005_OC.jpg

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Boost immunizations with NA-derived peptide conjugates achieve induction of NA inhibition antibodies and heterologous influenza protections.用 NA 衍生肽缀合物增强免疫可诱导 NA 抑制抗体和异源流感的保护作用。
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Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine.
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