Studies of IGHV Germline Gene Polymorphism, Utilization & Shifting for Seasonal Influenza Vaccine Induced Broadly Neutralizing Antibody Responses

IGHV种系基因多态性研究及利用

• 批准号: 9178624
• 负责人: Wayne A. Marasco
• 金额: $ 83.41万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-09 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178624
• 关键词: Adult; Affect; Alleles; Antibodies; Antibody Formation; Antibody Repertoire; Antibody Response; Antibody titer measurement; Antigen Targeting; B-Lymphocytes; Binding; Biological; Blood specimen; Clinical Data; Clone Cells; Copy Number Polymorphism; Dana-Farber Cancer Institute; Data; Enrollment; Epitopes; Family; Frequencies; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Health Personnel; Health Status; Hemagglutinin; Heterogeneity; Human; Hydrophobicity; Immune Response Genes; Immune system; Immunity; Immunoglobulin M; Immunoglobulins; Immunologic Factors; Individual; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza Hemagglutinin; Influenza vaccination; Maps; Measures; Membrane Glycoproteins; Memory; Memory B-Lymphocyte; Monitor; Outcome; Phenotype; Plasmablast; Play; Population; Recording of previous events; Recruitment Activity; Research Personnel; Role; ST14 gene; Sampling; Serological; Serum; Shapes; Structure; T-Lymphocyte; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Viral; anti-influenza; base; cohort; combinatorial; cytokine; design; genetic linkage; health difference; human monoclonal antibodies; influenza virus vaccine; inter-individual variation; interest; neutralizing antibody; neutralizing vaccine; pathogen; personalized medicine; public health relevance; response; seasonal influenza; stem; vaccine response; vaccine trial

 DESCRIPTION (provided by applicant): Neutralizing antibody responses to influenza infection and vaccination is highly variable in the population which can be explained by differences in health status, exposure history, and polymorphism of immune response genes. Since protection is also correlated with neutralizing antibody titers, any role that immunoglobulin germline gene polymorphism may play in this variability is important to establish, but has been difficult to investigate due to the use of numerous V, D and J genes in the genesis of immunoglobulins and the enormous combinatorial diversity that results from the pairing of rearranged VH and VL genes. However, the discovery of biased usage of the IGHV1-69 germline gene in antibodies targeting the stem domain of (HA) hemagglutinin (HV1-69-sBnAbs) has provided a unique opportunity to investigate any biological role that IGHV1-69 germline gene polymorphism might have in the anti-influenza antibody response. Importantly, HV1-69-sBnAbs mostly originate from the IGHV1-69 51p1 allele-like group that encodes a conserved CDR-H2 Phe54 that serves as major anchor residue with HA. Here we present an association analysis between IGHV1-69 polymorphism and the frequency of stem reactive Abs by using blood samples and clinical data obtained from an NIH H5VN04 vaccine trial. Our data shows a remarkable effect of IGHV1-69 locus polymorphism on the serum BnAb titers to the HA stem. Analyses of their expressed Ab repertoires have also provided evidence that copy number variation (CNV) also impacts IgM HV1-69-sBnAb responses. Results of heat map analysis show that there may be a shift in global IGHV germline gene usage in individuals based on the IGVH1-69 genotype. We propose that underlying genetic variation within the human IGHV1-69 locus might explain a significant fraction of inter- individual variation to influenza vaccination. Here we plan to enroll a cohort o 100 adult healthcare workers to participate in a study to examine the effects of IGHV1-69 polymorphism in shaping the BnAb response to seasonal influenza vaccination. Three blood specimens will be obtained from each subject, pre-vaccination, day 7 post vaccination (plasmablast peak) and at 32-56 days post-vaccination (memory B cell pool). In Aim 1 pre vaccination blood samples will be used to study the role IGHV1-69 locus polymorphism in shaping global IGHV germline gene utilization and in establishing the anti-influenza BnAb memory B cell pool. Genotyping will be by SNP and copy number variation (CNV) and phenotyping by serologic MN, HAI, HA binding studies, anti- HA single B cell cloning and antibodyome analysis. In Aim 2 heterogeneity at the IGHV1-69 locus will effect global germline gene utilization in the BnAb response to seasonal influenza vaccination. We propose that there is a direct genotypic-phenotypic relationship at the IGHV1-69 locus with regard to an individual's capacity to mount an anti-influenza BnAb response. This study is designed to provide the first evidence of this linkage. This new information on the role of IGHV polymorphism in influenza immunity can be used translationally to predict and monitor vaccine responses and to design vaccines to achieve universal responsiveness.

 描述（由适用提供）：对影响力感染和疫苗接种的中和抗体反应在人群中高度可变，这可以通过健康状况，暴露历史和免疫增强基因多态性的差异来解释。 Since protection is also correlated with neutralizing antibody titers, any role that immunoglobulin germline gene polymorphism may play in this variability is important to establish, but has We were difficult to investigate due to the use of numerous V, D and J genes in the genesis of immunoglobulins and the enormous combinatorial diversity that results from the pairing of rearranged VH and VL genes.然而，发现（HA）血凝素（HV1-69-SBNABS）的抗体中IGHV1-69种系基因的偏见使用，为研究IGHV1-69种生殖基因多态性的任何生物学作用提供了一个独特的机会，可以反应抗抗反应。重要的是，HV1-69-SBNAB主要来自IGHV1-69 51P1等位基因样组，该基团编码构成的CDR-H2 PHE54，该cdr-h2 Phe54用作HA的主要锚固式住宅。在这里，我们提出了通过使用血液样本和从NIH H5VN04疫苗试验获得的血液样本和临床数据之间的IGHV1-69多态性和茎反应性ABS的频率之间的关联分析。我们的数据显示了IGHV1-69基因座多态性对HA茎的血清BNAB滴度的显着影响。对其表达的AB曲目的分析还提供了证据，表明拷贝数变化（CNV）也会影响IGM HV1-69-SBNAB响应。热图分析的结果表明，基于IGVH1-69基因型的个体中，全球IGHV种系基因使用可能会发生变化。我们建议，人IGHV1-69基因座内的潜在遗传变异可能解释了影响Za疫苗接种的个体间变异的很大一部分。在这里，我们计划招募100名成人医疗保健工作者的同类，以参与一项研究，以检查IGHV1-69多态性对塑造BNAB对季节性影响力疫苗接种的反应的影响。将从每个受试者中获得三个血样，疫苗接种前，第7天疫苗接种（Plasmablast Peak），在接种疫苗后32-56天（记忆B细胞池）。在AIM 1中，将使用prevacination血液样本来研究IGHV1-69基因座多态性在塑造全球IGHV种系基因利用和建立抗Influenza BNAB记忆B细胞库中的作用。基因分型将通过SNP和拷贝数变化（CNV）以及血清学MN，HAI，HA结合研究，抗HA单B细胞克隆和抗体组分析的表型。在AIM 2的AIM 2异质性中，在IGHV1-69基因座上将影响全球种系基因利用率在BNAB对季节性影响疫苗接种的反应中。我们建议，在IGHV1-69基因座上存在直接的基因型 - 表型关系。这项研究旨在提供这种联系的第一个证据。有关IGHV多态性在影响ZA免疫中的作用的新信息，可以翻译用于预测和监测疫苗反应并设计疫苗以实现普遍反应性。