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.

项目摘要 由于抗原漂移和转变，流感病毒仍然是全球主要的健康问题。迅速的 循环人类流感亚型（H1N1和H3N2）的抗原漂移，这是由点引起的 突变，尽管季节性流感会年度更新，但仍会极大地阻碍疫苗的效率 疫苗。另一方面，抗原转移是由抗原之间的遗传重组引起的 1918年西班牙流感所用的巨大菌株可能导致毁灭性的大流行。人类感染 也已经报道了不同的​​人畜共患亚型，例如H5N1，H6N1，H7N9，H9N2和H10N8。作为 结果是一种普遍的流感疫苗，可以引起对多种流感的广泛保护抗体的反应 迫切需要菌株和亚型。发现靶向广泛中和抗体（BNAB）的发现 流感血凝素（HA）保守的茎区域增加了发展通用的可能性 流感疫苗。许多HA茎BNAB由免疫球蛋白重链种系基因编码 IGHV6-1。由于这些IGHV6-1公顷茎可以在多个个体中找到，并且可以与 两组1都有（H1，H2，H5，H6，H8，H9，H11，H12，H13和H16），并且第2组具有（H3，H4，H7，H7，H10，H14，H14， 和H15），它们代表需要由普遍流感引起的抗体反应的类型 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 重链互补性确定的区域3，轻链和躯体高压，使得 IGHV6-1抗体是跨组HA茎bnabs。潜在的分子机制将是 进一步以结构生物学方法为特征。结果将有助于准确估计种系 IGHV6-1 HA茎bnabs的频率并了解其亲和力成熟途径，这又会 受益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。