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: 10647708
• 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/10647708
• 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 Assay; Biophysics; Characteristics; Childhood; Circulation; 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; Knowledge; Longevity; Mass Spectrum Analysis; Measures; Memory; Modeling; Molecular; Monoclonal Antibodies; Mutate; Nature; Persons; Population; Property; Protein Engineering; Proteomics; Recombinants; Recommendation; Recording of previous events; Sampling; Seasons; Seminal; Serology; Serology test; Serum; Shapes; 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; protein purification; 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.

对许多传染病的保护与病原体特异性免疫的数量和质量相关。 由B细胞分泌的抗体（Ab）分子。季节性流感疫苗含有血凝素（HA）蛋白 旨在引发能够赋予针对流感感染的保护性免疫的抗HA Ab，但 目前每年接种的流感疫苗仅对约60%的人群提供保护。最近的研究集中在 设计新的基于HA的免疫原，其可以引发能够保护 针对不同的流感病毒株，但这些策略引起的bpAb通常是短暂的。我们之间的差距 关于流感抗体的分子特征、功能和寿命的知识，特别是 对先前暴露的预先存在的体液记忆的影响，阻碍了疫苗的设计， 产生持久的bpAb。由于流感的普遍性和建议的季节性 由于疫苗接种，大多数人在年轻时就暴露于流感，许多研究已经表明， 这些观察结果表明，儿童期接触产生的抗体库在免疫系统中是“印记”的。 系统，并通过随后暴露于漂移菌株而持续存在于循环中。尽管有这些意见， 关于印迹血清Ab库对后续疫苗的临床相关性和影响的信息 缺乏回应。在这里，我们建议应用最先进的转录组学和蛋白质组学工具来匹配 疫苗接种前和接种后样本，以区分印迹流感抗体库与新引发的（de novo）Abs来定义印迹Abs的生物物理和功能特征。确定各种途径， 克服印迹抗体库所施加的潜在限制可能是设计一种新的抗体库的关键。 通用流感疫苗，可以提供持久的保护，对不同的流感病毒株。