Structure-function analysis of infection- and vaccine-induced B-cell repertoires

感染和疫苗诱导的 B 细胞库的结构功能分析

• 批准号: 8516979
• 负责人: STEPHEN COPLAN HARRISON
• 金额: $ 210.02万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516979
• 关键词: Adjuvant; Affinity; Antibodies; Antigenic Variation; Antigens; Archives; B cell repertoire; B-Lymphocytes; Clinical; Collaborations; Complex; Cryoelectron Microscopy; Data; Electron Microscopy; Epitope Mapping; Epitopes; Equipment and supply inventories; Foundations; Genes; Genetic; Goals; Hemagglutinin; Human; Immune response; Immunization; Immunology; Inactivated Vaccines; Individual; Infection; Influenza Hemagglutinin; Lead; Link; Methods; Molecular; Pathway interactions; Principal Investigator; Property; Publishing; Reagent; Recombinants; Research Personnel; Role; Sampling; Series; Specificity; Structure; Sum; Surface Antigens; Technology; Testing; Time; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral Antigens; Work; cross reactivity; design; experience; improved; influenza virus vaccine; influenzavirus; innovation; method development; movie; novel; novel vaccines; pathogen; programs; response; stem; structural biology; technological innovation; three dimensional structure; vaccine development; virology

DESCRIPTION (provided by applicant): Antigenic variation underlies a large number of the most critical problems now facing vaccine development. Influenza virus is an ideal subject for tackling this issue: it is the most variable pathogen against which we can effectively vaccinate, but its principal surface antigen varies so rapidly that new vaccines must be introduced almost yearly. We propose to use innovative analyses of B-cell repertoires and new possibilities in structural studies to understand the structural and immunological mechanisms underlying cross reactivity and immunodominance, as a foundation for designing immunogens that will elicit a more broadly neutralizing response than those currently in use. We will test the following three hypotheses, to which the three Aims of each Project correspond. (1) The B-cell repertoires elicited by inactivated vaccines and by infection differ in degree of polyclonal activation and breadth of neutralization; the repertoires elicited by immunization with adjuvanted and non-adjuvanted TIV differ because adjuvant increases the breadth of recognized epitopes. (2) Broadly reactive Abs, including those recognizing the heterosubtypic stem epitope, are less frequent after true primary than after secondary TIV immunization due to broadening of the response by multiple HA stimulations. (3) Efficient induction of Abs against a desired epitope requires: (a) proliferation of a favorable germline Ab and (b) an affinity maturation pathway to a desired final specificity; there are preferred germline precursors and maturation pathways for Abs targeting particular epitopes. The group of investigators that joins in this proposal brings together strengths in immunology, virology, structural biology, and vaccine development. The principal investigators have worked closely and effectively together in past collaborations.

描述（由申请人提供）：抗原变异是疫苗开发目前面临的许多最关键问题的基础。流感病毒是解决这一问题的理想课题：它是我们可以有效接种疫苗的变异最大的病原体，但其主要表面抗原变化如此之快，以至于几乎每年都必须推出新疫苗。我们建议利用 B 细胞库的创新分析和结构研究的新可能性来了解交叉反应性和免疫优势背后的结构和免疫机制，作为设计免疫原的基础，该免疫原将比目前使用的免疫原引发更广泛的中和反应。我们将测试以下三个假设，每个项目的三个目标都对应这些假设。 (1) 灭活疫苗和感染引起的 B 细胞库在多克隆激活程度和中和广度上有所不同；使用佐剂和非佐剂 TIV 免疫所引发的谱系有所不同，因为佐剂增加了识别表位的广度。 (2) 广泛反应性抗体，包括那些识别异亚型茎表位的抗体，由于多次 HA 刺激的反应范围扩大，真正初次免疫后的抗体频率低于二次 TIV 免疫后的频率。 (3) 有效诱导针对所需表位的抗体需要：(a) 有利种系抗体的增殖和 (b) 达到所需最终特异性的亲和力成熟途径；针对特定表位的抗体有优选的种系前体和成熟途径。加入该提案的研究小组汇集了免疫学、病毒学、结构生物学和疫苗开发方面的优势。主要研究人员在过去的合作中密切有效地合作。