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

• 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
• 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

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.

抽象的 需要具有较高效率的新型疫苗，并且可以为新兴的疫苗提供持久的保护 流感病毒。开发“通用”疫苗的一种有吸引力的方法集中在引起 靶向靶向血凝素（HA）蛋白在病毒表面上的抗体。这 受体结合位点和茎是两个这样的HA区域，并引起体液反应的启发 在这些站点上，已经是多项研究的主题。最近，一类新的抗体已经 发现针对高度保守的HA头触发接口。针对此表位的抗体是 在多个个体中发现，具有广泛的异质型交叉反应性，并提供了防止病毒的保护 动物模型的挑战。因此，将这些类型的抗体诱导作为普遍影响的一部分 疫苗很有价值。头部触发界面表位在HAS和 可能只是通过分子“呼吸”瞬时暴露。这种有限的可访问性可以解释 至少在某种程度上，为什么对该站点的天然体液反应很少。在此提案中，我们将设计 在分子环境中呈现出HA头三聚体界面发作的免疫剂 其他免疫主导地点。使用计算蛋白建模和高吞吐量库筛选，HA 将开发出衍生的和非氟伦扎免疫原子，即：1）暴露HA头夹子 接口促进免疫识别； 2）优先与广泛的交叉反应相互作用，但与 特异性抗体，靶向该部位，3）闭塞免疫主导区域以聚焦免疫 情节的回应。设计的免疫原子将用于接种小动物以评估其能力 防止活病毒。接种动物的B细胞受体库的详细分析将显示 导致体液反应激活和成熟的发展途径 保守的HA头触发接口。该建议将为发展提供候选免疫原 通用影响疫苗的疫苗，可以更好地理解控制HA的分子特征 构象和免疫原性，并建立免疫原设计的一般方法。