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: 10782567
• 负责人: Mihai Luchian Azoitei
• 金额: $ 18.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-23 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10782567
• 关键词: Affinity; Animal Model; Animals; Antibodies; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Binding Sites; Breathing; Computer Models; Computing Methodologies; 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; cross reactivity; design; glycosylation; high throughput screening; immunogenic; immunogenicity; improved; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; insight; monomer; 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 需要具有更高功效并针对新出现的疾病提供持久保护的新型疫苗 开发“通用”疫苗的一个有吸引力的方法是集中于引发流感病毒。 针对病毒表面血凝素 (HA) 蛋白保守区域的抗体。 受体结合位点和茎是两个这样的 HA 区域，体液反应的引发集中在 最近，一类新的抗体已成为多项研究的主题。 发现针对高度保守的 HA 头三聚体界面的抗体是针对该表位的。 在多个个体中发现，具有广泛的异亚型交叉反应性，并提供针对病毒的保护 因此，诱导这些类型的抗体作为通用流感的一部分。 疫苗将是有价值的。头部三聚体界面表位被封闭在HA的晶体结构中，并且 很可能通过分子“呼吸”而短暂地暴露出来，这种有限的可及性可以解释为： 在这个提案中，我们将至少部分地解释为什么针对该站点的自然体液反应很少见。 免疫原在分子环境中无障碍地呈现 HA 头三聚体界面表位 使用计算蛋白质模型和高通量文库筛选，HA。 将开发衍生的以及非基于流感的免疫原：1) 暴露 HA 头部三聚体 促进免疫识别的界面；2) 优先与广泛的交叉反应相互作用，但不与 菌株特异性、针对该位点的抗体以及 3) 封闭免疫显性区域以集中免疫 设计的免疫原将用于对小动物进行疫苗接种以评估其能力。 对肺炎动物 B 细胞受体库的详细分析将揭示如何预防活病毒。 导致体液反应激活和成熟的发育途径 该提案将为开发提供候选免疫原。 通用流感疫苗的研究，有助于更好地了解控制 HA 的分子特征 构象和免疫原性，并建立免疫原设计的通用方法。