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）：抗原变异是目前面临疫苗开发的大量最关键问题的基础。流感病毒是解决此问题的理想主题：它是我们可以有效疫苗接种的最可变的病原体，但其主要表面抗原的变化很快，以至于必须每年引入新的疫苗。我们建议在结构研究中使用B细胞库和新的可能性的创新分析，以了解交叉反应性和免疫主持的结构和免疫机制，作为设计免疫原子的基础，这些免疫原理将产生比当前使用的免疫原理。我们将测试以下三个假设，每个项目的三个目标对应。 （1）被灭活的疫苗和感染引起的B细胞曲目在多克隆激活程度和中和的广度上不同；通过佐剂和非辅助的TIV引起的免疫引起的曲目有所不同，因为佐剂增加了公认的表位的广度。 （2）在True初级后，由于多个HA刺激扩大了反应而导致的次级TIV免疫后，真实原发性杆的宽大ABS，包括识别异质型茎表位的ABS的频繁。 （3）有效诱导ABS针对所需的表位需要：（a）有利种系AB的增殖，以及（b）与所需的最终特异性的亲和力成熟途径；有首选的种系前体和成熟途径，用于靶向特定表位。加入该提案的研究者小组汇集了免疫学，病毒学，结构生物学和疫苗开发方面的优势。首席研究人员在过去的合作中已经紧密合理地合作。