Sequence-function relationship of influenza broadly neutralizing antibodies

流感广泛中和抗体的序列-功能关系

• 批准号: 10898173
• 负责人: Nicholas C. Wu
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-25 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10898173
• 关键词: Affinity; Antibodies; Antibody Repertoire; Antibody Response; Antigens; Avian Influenza A Virus; Binding; Biophysical Process; Cross Reactions; Development; Epidemic; Epitopes; Evolution; Frequencies; Genes; Genetic; Head; Heavy-Chain Immunoglobulins; Hemagglutinin; Human; Immunoglobulin Somatic Hypermutation; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Influenza A virus; Influenza Hemagglutinin; Influenza vaccination; Light; Membrane Glycoproteins; Molecular; Pathogenicity; Pathway interactions; Point Mutation; Public Health; Reporting; SARS-CoV-2 antibody; Somatic Mutation; Spanish flu; Specificity; System; Update; V(D)J Recombination; Variant; Virus; Yeasts; Zoonoses; antigen binding; biophysical analysis; complementarity-determining region 3; design; experimental study; global health; influenza infection; influenza virus strain; influenza virus vaccine; innovation; insight; interdisciplinary approach; interest; neutralizing antibody; pandemic disease; pandemic potential; seasonal influenza; stem; structural biology; transmission process; universal influenza vaccine; vaccine effectiveness

PROJECT SUMMARY Influenza A virus continues to be a major global health concern due to antigenic drifts and shifts. Rapid antigenic drifts of circulating human influenza subtypes (H1N1 and H3N2), which are caused by point mutations, can drastically hamper vaccine effectiveness despite annual update of the seasonal influenza vaccine. On the other hand, antigenic shifts, which are caused by genetic reassortment between antigenically distinct strains, can result in devastating pandemic as exemplified by the 1918 Spanish flu. Human infections with different zoonotic subtypes, such as H5N1, H6N1, H7N9, H9N2, and H10N8 have also been reported. As a result, a universal influenza vaccine that can elicit broadly protective antibody responses to diverse influenza strains and subtypes is urgently needed. The discovery of broadly neutralizing antibodies (bnAbs) that target the conserved stem region of influenza hemagglutinin (HA) has raised the possibility of developing a universal influenza vaccine. A number of HA stem bnAbs are encoded by immunoglobulin heavy chain germline gene IGHV6-1. Since these IGHV6-1 HA stem bnAbs can be found in multiple individuals and can cross-react with both group 1 HAs (H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16) and group 2 HAs (H3, H4, H7, H10, H14, and H15), they represent the type of antibody response that needs to be induced by a universal influenza vaccine. This proposed study will use innovative high-throughput experiments to define sequence features in the heavy-chain complementarity-determining region 3, light chain, and somatic hypermutations, that enable an IGHV6-1 antibody to be a cross-group HA stem bnAbs. The underlying molecular mechanisms will be further characterized by structural biology approach. The results will help accurately estimate the germline frequency of IGHV6-1 HA stem bnAbs and understand their affinity maturation pathway, which in turn will benefit the design of a universal influenza vaccine. Furthermore, the experimental framework established in this study will be applicable to characterize any antibody of interest.

项目概要 由于抗原漂移和转变，甲型流感病毒仍然是全球主要的健康问题。迅速的 流行的人类流感亚型（H1N1 和 H3N2）的抗原漂移，这是由点引起的 尽管季节性流感每年都会更新，但突变仍可能严重影响疫苗的有效性 疫苗。另一方面，抗原转变是由抗原之间的基因重配引起的。 不同的毒株可能导致毁灭性的大流行，1918 年西班牙流感就是一个例子。人类感染 还报道了不同人畜共患亚型的病毒，例如H5N1、H6N1、H7N9、H9N2和H10N8。作为 因此，一种通用流感疫苗可以引发针对多种流感的广泛保护性抗体反应 迫切需要菌株和亚型。广泛中和抗体 (bnAbs) 的发现 流感血凝素（HA）的保守茎区提高了开发通用疫苗的可能性 流感疫苗。许多 HA 干 bnAb 由免疫球蛋白重链种系基因编码 IGHV6-1。由于这些 IGHV6-1 HA 干 bnAb 可以在多个个体中找到，并且可以与 第 1 组 HA（H1、H2、H5、H6、H8、H9、H11、H12、H13 和 H16）和第 2 组 HA（H3、H4、H7、H10、H14、 和 H15），它们代表了通用流感需要诱导的抗体反应类型 疫苗。这项拟议的研究将使用创新的高通量实验来定义序列特征 重链互补决定区 3、轻链和体细胞超突变，使 IGHV6-1 抗体是跨组 HA 干 bnAb。潜在的分子机制将是 通过结构生物学方法进一步表征。结果将有助于准确估计种系 IGHV6-1 HA 干 bnAb 的频率并了解其亲和力成熟途径，这反过来将 有利于通用流感疫苗的设计。此外，建立的实验框架 这项研究将适用于表征任何感兴趣的抗体。