Understanding the impact of imprinted serum antibody repertoire on subsequent vaccine responses

了解印迹血清抗体库对后续疫苗反应的影响

• 批准号: 10271749
• 负责人: Jiwon Lee
• 金额: $ 26.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271749
• 关键词: Adult; Affinity; Affinity Chromatography; Age; Antibodies; Antibody Repertoire; Antibody Response; Antibody titer measurement; Antigens; Automobile Driving; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Biochemical; Biological; Biological Assay; Biophysics; Blood Circulation; Characteristics; Childhood; Communicable Diseases; Competitive Binding; Data; Databases; Engineering; Epidemiology; Epitopes; Exposure to; Future; Goals; Hemagglutinin; High-Throughput Nucleotide Sequencing; Humoral Immunities; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologics; Individual; Infant; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza B Virus; Influenza vaccination; Institutes; Knowledge; Longevity; Mass Spectrum Analysis; Measures; Memory; Modeling; Molecular; Monoclonal Antibodies; Mutate; Nature; Population; Property; Protein Engineering; Proteins; Proteomics; Recombinants; Recording of previous events; Sampling; Seminal; Serology; Serology test; Serum; Techniques; Technology; Testing; Time; Update; Vaccination; Vaccine Design; Vaccines; Virus; base; clinically relevant; design; global health; imprint; influenza infection; influenza virus strain; influenza virus vaccine; novel; pathogen; seasonal influenza; tool; transcriptomics; universal influenza vaccine; vaccine response

Protection against numerous infectious diseases correlates with the quantity and quality of pathogen-specific antibody (Ab) molecules secreted by B cells. Seasonal flu vaccines contain hemagglutinin (HA) proteins designed to elicit anti-HA Abs capable of conferring protective immunity against influenza infection, but the current annual flu vaccines confer protection only in ~60% of the population. Recent studies have focused on designing new HA-based immunogens that can elicit broadly-protective Abs (bpAbs) capable of protecting against diverse influenza strains, but bpAbs elicited by these strategies are often short-lived. A gap in our knowledge regarding the molecular features, functionalities, and longevity of influenza Abs, specifically related to the impact of pre-existing humoral memory from prior exposure, impedes the design of vaccines capable of generating long-lasting bpAbs. Due to the ubiquitous nature of influenza and recommended seasonal vaccinations, most of the population is exposed to influenza at a young age, and many studies have made observations that suggest Ab repertoire generated from the childhood exposure is ‘imprinted’ in the immune system and persists in circulation through ensuing exposures to drifted strains. Despite these observations, information on the clinical relevance and impact of imprinted serum Ab repertoire on subsequent vaccine responses is lacking. Here, we propose to apply cutting edge transcriptomic and proteomic tools to matched pre- and post-vaccination samples to distinguish the imprinted influenza Ab repertoire from newly elicited (de novo) Abs to define the biophysical and functional features of imprinted Abs. Identifying various avenues for overcoming potential restrictions imposed by the imprinted Ab repertoire could be key for the design of a universal flu vaccine that can confer long-lasting protection against diverse influenza strains.

对多种传染病的预防与特定病原体的数量和质量相关 B 细胞分泌的抗体 (Ab) 分子含有血凝素 (HA) 蛋白。 旨在引发能够赋予针对流感感染的保护性免疫力的抗HA抗体，但是 目前的年度流感疫苗只能为约 60% 的人口提供保护。最近的研究主要集中在以下方面。 设计新的基于 HA 的免疫原，可以引发具有广泛保护作用的抗体 (bpAb) 针对不同的流感毒株，但这些策略引发的 bpAb 通常是短暂的。 有关流感抗体的分子特征、功能和寿命的知识，特别是相关知识 由于先前接触而对预先存在的体液记忆产生影响，这阻碍了疫苗的设计 由于流感的普遍性和推荐的季节性，产生持久的 bpAb。 疫苗接种后，大多数人在年轻时就接触过流感，许多研究表明 观察结果表明，童年时期接触产生的抗体库已“印记”在免疫系统中 尽管有这些观察结果，但通过随后暴露于漂移的菌株而持续存在于循环中， 关于印迹血清抗体库的临床相关性和对后续疫苗的影响的信息 在这里，我们建议应用最先进的转录组和蛋白质组工具来匹配。 疫苗接种前和疫苗后样本，以区分印迹流感抗体库和新引出的抗体库（de novo) Abs 来定义印迹 Abs 的生物物理和功能特征，识别各种途径。 克服印记抗体库施加的潜在限制可能是设计的关键 通用流感疫苗，可以针对多种流感毒株提供持久的保护。