Development of Broadly Immunogenic and Universal Influenza Virus Vaccines

广泛免疫原性和通用流感病毒疫苗的开发

基本信息

批准号：
10928003
负责人：
Audray Harris
金额：
$ 48.53万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10928003
关键词：
1918 influenza pandemic 3-Dimensional Address Admixture Affect Animals Antibodies Antigens Architecture Area Attenuated B-Lymphocytes Biochemical Communicable Diseases Competence Complex Coupled Development Electron Microscopy Epitopes Evaluation Female Goals Health Hemagglutinin Human Immune response Immunity Immunoassay Immunologics Individual Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A virus Influenza Hemagglutinin Investigation Membrane Glycoproteins Mission Molecular Mus Nature Persons Pharmaceutical Preparations Phase Population Proteins Public Health Recombinants Research Seasons Starfish Structure Subunit Vaccines Testing United States National Institutes of Health Vaccine Production Vaccines Viral Vaccines Virus Virus-like particle Work Zoonoses cross reactivity design future pandemic immunogenic immunogenicity influenza outbreak influenza virus vaccine influenzavirus innovation molecular modeling mosaic nanodisk nanotechnology platform neutralizing antibody novel pandemic disease particle transmission process universal influenza vaccine vaccine formulation

项目摘要

Influenza viruses remains a major health burden due to their abilities to change the epitopes of their major surface glycoprotein hemagglutinin. Although conserved influenza epitopes have been identified, there is a fundamental gap in understanding and correlating the disposition of conserved influenza epitopes on HA-based subunit vaccines with immunogenicity. Lack of such information represents important problems and until they are addressed optimal display of conserved influenza epitopes cannot be understood in molecular details. In FY 2023, using electron microscopy coupled with immunoassays and animal studies we identified both structural and immunogenic differences between different commercial influenza vaccine formulations. We identified structures including individual HAs, starfish structures with up to 12 HA molecules, and novel spiked nanodisc structures that displayed over 50 HA molecules along the complex's perimeter. Vaccines containing these spiked nanodiscs elicited the highest levels of heterosubtypic cross-reactive antibodies in female mice. These results indicate that HA structural organization can be an important commercial influenza subunit vaccine parameter and can be associated with the induction of cross-reactive antibodies to conserved HA epitopes. These results are expected to aid the development of more efficacious seasonal vaccines and facilitate the development of universal influenza vaccines. This work is significant and relevant to public health because influenza viruses are a large burden to human health.

由于其能力改变其主要表面糖蛋白血凝集素的表现能力，因此流感病毒仍然是重大的健康负担。尽管已经确定了保守的流感表位，但在理解和关联保守的流感表位对基于HA的基于HA的亚基疫苗具有免疫原性的处置方面存在基本差距。缺乏这样的信息代表了重要的问题，直到解决这些问题的最佳表现为保守的流感表位，就无法通过分子细节来理解。在2023财年，使用电子显微镜与免疫测定和动物研究结合，我们确定了不同商业流感疫苗配方之间的结构和免疫原性差异。我们确定了包括个体有多达12 ha分子的海星结构在内的结构，以及新型的尖刺纳米散发结构，沿综合体的周长显示超过50公顷的分子。含有这些尖刺纳米盘的疫苗引起了雌性小鼠的最高水平的异质性交叉反应抗体。这些结果表明，HA结构组织可能是重要的商业流感亚基疫苗参数，并且可以与对保守的HA表位的交叉反应性抗体诱导有关。这些结果有望有助于开发更有效的季节性疫苗，并促进普遍流感疫苗的发展。这项工作很重要，并且与公共卫生有关，因为流感病毒是人类健康的巨大负担。