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Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface

新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体

基本信息

批准号：
10472613
负责人：
Mihai Luchian Azoitei
金额：
$ 78.93万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472613
关键词：
Affinity Animal Model Animals Antibodies Antigens B-Cell Antigen Receptor B-Lymphocytes Binding Binding Sites Breathing Computer Models Computing Methodologies Crystallization Development Disease Engineering Environment Epitopes Exhibits Ferrets Goals Grant Head Health Hemagglutinin Human Immune Immune response Immunization Immunodominant Epitopes Individual Infection prevention Influenza Influenza vaccination Lead Libraries Link Methods Mission Modeling Molecular Molecular Conformation Mus Mutation Outcome Pathway interactions Property Proteins Regimen Research Sampling Scaffolding Protein Serum Site Specificity Structure Surface Testing United States National Institutes of Health Vaccinated Vaccination Viral Virus Work base cross reactivity design glycosylation high throughput screening immunogenic immunogenicity improved in vivo influenza virus strain influenza virus vaccine influenzavirus insight mutation screening novel novel vaccines prevent receptor binding response scaffold screening stem success universal influenza vaccine universal vaccine vaccine trial

项目摘要

Abstract Novel vaccines are needed that have higher efficacy and that provide long-lasting protection against emerging influenza viruses. An attractive approach towards developing a “universal” vaccine is focused on eliciting antibodies that target conserved regions of the hemagglutinin (HA) protein on the surface of the virus. The receptor binding site and the stem are two such HA regions, and the elicitation of humoral responses focused on these sites has been the subject of multiple studies. Recently, a new class of antibodies has been discovered that targets the highly conserved HA head trimer interface. Antibodies against this epitope were found in multiple individuals, have broad heterosubtypic cross-reactivity and provided protection against viral challenges in animal models. Therefore, induction of these type of antibodies as part of a universal influenza vaccine would be valuable. The head trimer interface epitope is occluded in crystal structures of HAs, and likely becomes exposed just transiently through molecular “breathing”. This limited accessibility may explain at least in part why natural humoral responses against this site are rare. In this proposal, we will engineer immunogens that present unobstructed the HA head trimer interface epitope in molecular contexts devoid of other immunodominant sites. Using computational protein modeling and high throughput library screening, HA derived as well as non-influenza based immunogens will be developed that: 1) expose the HA head trimer interface to facilitate immune recognition; 2) preferentially interact with broadly cross-reactive, but not with strain specific, antibodies that target this site and 3) occlude immunodominant regions to focus the immune responses on the epitope. Designed immunogens will be used to vaccinate small animals to assess their ability to protect against live virus. Detailed analysis of the B cell receptor repertoires of vaccinated animals will reveal the developmental pathways that lead to the activation and maturation of humoral responses against the conserved HA head trimer interface. This proposal will provide candidate immunogen towards the development of a universal influenza vaccine, lead to a better understanding of molecular features that control HA conformation and immunogenicity, and establish general approaches for immunogen design.

摘要