Manipulating immunodominance in influenza HA

操纵流感 HA 的免疫优势

• 批准号: 8516983
• 负责人: PHILIP R DORMITZER
• 金额: $ 52.92万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516983
• 关键词: Activities of Daily Living; Adjuvant; Affinity; Antibodies; Antigens; B cell repertoire; Binding; Child; Competitive Binding; Complex; Disease; Drug Formulations; Engineering; Epitope Mapping; Epitopes; Escape Mutant; Exposure to; Hemagglutinin; Immune response; Immune system; Immunization; Infection; Influenza; Influenza Hemagglutinin; Influenza vaccination; Instruction; Learning; Libraries; Maps; Masks; Memory B-Lymphocyte; Monoclonal Antibodies; Mus; Pathway interactions; Plasmablast; Race; Recording of previous events; Resolution; Specificity; Structure; Techniques; Testing; Time; Vaccine Antigen; Vaccines; Virus; design; high throughput screening; human subject; improved; influenza virus vaccine; insight; iterative design; neutralizing antibody; pandemic disease; response; stem

Each influenza hemagglutinin (HA) is a mosaic of conserved and strain-specific epitopes, some of which are recognized by neutralizing antibodies. An influenza vaccine that preferentially elicits neutralizing antibodies that recognize conserved epitopes will be more broadly protective than those now in use. Understanding how the exposure history of subjects, differences in influenza vaccine antigens, and the addition of adjuvants bias the immune response towards different HA epitopes will enable us to design optimal vaccines. The following three hypotheses will be tested. (1] The B-cell repertoires elicited by non-replicating influenza vaccines and by infection differ in degree of polyclonal activation and breadth of neutralization. The repertoires elicited by adjuvanted and non-adjuvanted vaccines differ because adjuvant broadens the range of recognized epitopes. (2] Broadly reactive antibodies, including those recognizing the heterosubtypic stem epitope, are less frequent after true primary than after secondary influenza immunization due to broadening of the response by multiple HA stimulations. (3) Efficient induction of antibodies against a desired epitope requires: (a] proliferation of a favorable germline antibody and (b) an affinity maturation pathway to a desired final specificity. There are preferred germline precursors and maturation pathways for antibodies targeting particular epitopes. Hypotheses 1 and 2 will be tested by mapping the epitopes recognized by the repertoires of human subjects with different exposure histories to influenza infection and/or immunization with adjuvanted or un-adjuvanted vaccines. We will seek broadly neutralizing antibodies (those we want to elicit) to understand their germline precursors and maturation pathways. We will also map the epitopes of the full range of antibodies that bind HA to determine what the humoral immune system

每一种流感血凝素(HA)都是由保守的毒株特异性表位拼接而成，其中一些表位可被中和抗体识别。优先诱导识别保守表位的中和抗体的流感疫苗将比目前使用的疫苗具有更广泛的保护作用。了解受试者的暴露史、流感疫苗抗原的差异以及佐剂的添加如何使免疫反应偏向不同的HA表位，将使我们能够设计出最佳的疫苗。以下三个假设将得到检验。(1)非复制型流感疫苗和感染疫苗诱导的B细胞谱系在多克隆激活程度和中和广度上存在差异。由以下因素引起的剧目 佐剂疫苗和非佐剂疫苗不同，因为佐剂扩大了识别表位的范围。(2) 广泛反应的抗体，包括那些识别异亚型干细胞表位的抗体，在真正的一次免疫后比二次流感免疫后更少出现，这是因为多次HA刺激扩大了反应。(3)有效地诱导针对所需表位的抗体需要：(A)良好的生殖系抗体的增殖和(B)达到所需最终特异性的亲和力成熟途径。确实有 针对特定表位的抗体的首选种系前体和成熟途径。 假设1和2将通过绘制具有不同流感感染和/或佐剂或非佐剂疫苗免疫史的受试者的识别表位来进行测试。我们将寻找广泛的中和抗体(那些我们想要诱导的抗体)，以了解它们的生殖系前体和成熟途径。我们还将绘制结合HA的各种抗体的表位图，以确定什么是体液免疫系统