Epitope focusing by molecular grafting of subdominant epitopes to achieve a universal-influenza vaccine

通过亚优势表位的分子移植进行表位聚焦，以实现通用流感疫苗

• 批准号: 10437634
• 负责人: Aaron Gregory Schmidt
• 金额: $ 76.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437634
• 关键词: Affinity; Antibodies; Antibody Affinity; Antigen-Antibody Complex; Antigenic Variation; Antigens; B-Cell Activation; B-Lymphocytes; Benchmarking; Binding Sites; Biochemical; Biological Assay; Cell Culture Techniques; Complex; Crystallization; Cysteine; Data; Development; Directed Molecular Evolution; Disulfides; Ensure; Epitopes; Evolution; Foundations; Frequencies; Goals; Head; Hemagglutinin; Histamine H1 Receptors; Histamine H3 Receptors; Homo; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Individual; Influenza; Influenza Hemagglutinin; Influenza vaccination; Lead; Masks; Modification; Molecular; Molecular Conformation; Monitor; Mus; Pattern; Polysaccharides; Population; Property; Protein Engineering; Proteins; Recombinants; Research; Roentgen Rays; ST14 gene; Scaffolding Protein; Serum; Sialic Acids; Site; Specificity; Structure; Testing; Vaccine Design; Vaccines; Variant; Viral; Viral Hemagglutinins; Virus; Yeasts; antibody diagnostic; base; biophysical techniques; design; experience; immunogenicity; in vivo; in vivo evaluation; influenza virus strain; influenzavirus; interest; monomer; neoantigens; neutralizing antibody; novel; pandemic disease; pathogen; receptor; receptor binding; response; scaffold; stem; universal influenza vaccine; universal vaccine; vaccination strategy

Project Summary Antigenic variation and viral evolution have thwarted traditional influenza vaccination strategies. The development of a “universal influenza vaccine” is a goal of current influenza research. The definition of “universal” should include a vaccine that can induce broad immunity a) within circulating H1 and H3 subtypes, b) across subtypes (heterosubtypic) and c) pre-pandemic. A stepwise approach to accomplishing these criteria are goals of this proposal. The broad protection afforded by a universal influenza vaccine will likely come from immunogens that elicit humoral responses targeting conserved epitopes on the viral hemagglutinin (HA), such as the receptor binding site (RBS) and the “stem”. The focus of this proposal is on the former. The RBS coordinates sialic acid using conserved “core” residues and the surrounding periphery limits the range of protective responses. We will use structure- guided resurfacing to graft the RBS from circulating H1 and H3 HAs onto exotic, non-circulating HAs. These “acceptor” HAs will serve as molecular scaffolds to present the conserved H1 and H3 RBS core, but with a heterologous periphery. This approach will force elicited responses to maintain core contacts, while adapting to the foreign periphery and thus broadening the response. We will design chimeric, disulfide-stabilized, head-only trimers that present the grafted H1 and H3 RBS. Trimerization will conceal neo-epitopes present on monomers, and the exotic, acceptor HAs will remove epitopes targeted by strain-specific responses in immune-experienced individuals. The designed immunogens will be tested for in vivo efficacy. Our strategies will provide candidate immunogens for a universal flu vaccine, by exploiting the immunogenicity of the conserved RBS. They will also be applicable to other rapidly evolving pathogens and to contexts in which preexisting immunity within the population must be factored into vaccine design.

项目概要 抗原变异和病毒进化阻碍了传统的流感疫苗接种策略。 开发“通用流感疫苗”是当前流感研究的目标。 “通用”应包括能够在 a) 循环 H1 和 H3 中诱导广泛免疫的疫苗 亚型，b) 跨亚型（异亚型）和 c) 大流行前的逐步方法。 实现这些标准是本提案提供的广泛保护的目标。 流感疫苗可能来自引发针对保守基因的体液反应的免疫原 病毒血凝素 (HA) 上的表位，例如受体结合位点 (RBS) 和“茎”。 该提案的重点是前者。 残留物和周围的外围限制了保护反应的范围，我们将使用结构- 引导表面重修将循环 H1 和 H3 HA 中的 RBS 移植到外来非循环 HA 上。 这些“受体”HA 将作为分子支架来呈现保守的 H1 和 H3 RBS 核心， 但在异质的外围，这种方法将迫使引发的反应来维持核心联系， 同时适应国外周边，从而扩大反应范围，我们将设计嵌合体， 二硫键稳定的、仅头部的三聚体将呈现接枝的 H1 和 H3 RBS。 隐藏单体上存在的新表位，而外来的受体 HA 将去除表位 设计的免疫原以具有免疫经验的个体的菌株特异性反应为目标。 将测试体内功效，我们的策略将为通用流感提供候选免疫原。 通过利用保守 RBS 的免疫原性，它们也适用于其他疫苗。 快速进化的病原体以及人群中预先存在的免疫力必须被改变的环境 纳入疫苗设计的因素。