Manipulating immunodominance in influenza HA

操纵流感 HA 的免疫优势

• 批准号: 8720678
• 负责人: PHILIP R DORMITZER
• 金额: $ 51.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8720678
• 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; Germ Lines; 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; Work; design; high throughput screening; human subject; improved; influenza virus vaccine; insight; iterative design; neutralizing antibody; pandemic disease; pathogen; 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 "sees." The insights obtained from this mapping will be used to rationally design superior HA immunogens that will be optimized through an iterative cycle of antigen engineering, mouse immunization, repertoire analysis, and antigen redesign. Antigen design techniques will include selective epitope presentation, epitope masking, and germ-line antibody targetting followed by guided affinity maturation. The principles of antigen design revealed by this work could be applied to protective determinants of multiple pathogens for which vaccines are needed.

每个流感血凝素 (HA) 都是保守的和毒株特异性表位的镶嵌体，其中一些表位是 被中和抗体识别。优先引发中和抗体的流感疫苗 识别保守表位的技术将比现在使用的技术具有更广泛的保护作用。了解如何 受试者的暴露史、流感疫苗抗原的差异以及佐剂的添加会产生偏差 针对不同 HA 表位的免疫反应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) 由非复制性流感疫苗和非复制性流感疫苗引发的 B 细胞库 感染的多克隆激活程度和中和范围不同。引发的剧目 佐剂疫苗和非佐剂疫苗有所不同，因为佐剂扩大了识别表位的范围。 (2] 广泛反应性抗体，包括那些识别异亚型茎表位的抗体，在 真正的原发性比继发性流感免疫后的情况要好，因为多个 HA 扩大了反应范围 刺激。 (3) 针对所需表位的抗体的有效诱导需要： 有利的种系抗体和（b）达到所需最终特异性的亲和力成熟途径。有 针对特定表位的抗体的优选种系前体和成熟途径。 假设 1 和 2 将通过绘制人类受试者识别表位的图谱来检验 具有不同的流感感染暴露史和/或接种过佐剂或未佐剂疫苗 疫苗。我们将寻求广泛的中和抗体（我们想要引发的抗体）以了解其种系 前体和成熟途径。我们还将绘制与 HA 结合的全系列抗体的表位图 以确定体液免疫系统“看到”什么。从该映射中获得的见解将用于 合理设计优质HA免疫原，通过抗原迭代循环进行优化 工程、小鼠免疫、库分析和抗原重新设计。抗原设计技术将 包括选择性表位呈递、表位掩蔽和种系抗体靶向，然后进行引导 亲和力成熟。这项工作揭示的抗原设计原理可应用于保护性 需要疫苗的多种病原体的决定因素。