Integrating measurements of immune escape and in vitro replication with computational models to understand and predict the antigenic evolution of seasonal A/H3N2 influenza viruses

将免疫逃逸和体外复制的测量与计算模型相结合，以了解和预测季节性 A/H3N2 流感病毒的抗原进化

• 批准号: 10565872
• 负责人: Derek James Smith
• 金额: $ 51.31万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565872
• 关键词: Affect; Amino Acid Substitution; Amino Acids; Antibodies; Area; Binding Sites; Biological Assay; Codon Nucleotides; Computer Models; Data; Development; Disease; Evolution; Future; Genetic; Genetic Variation; Goals; Growth; Hemagglutinin; Human; Immune; Immunity; In Vitro; Influenza; Influenza A Virus, H3N2 Subtype; Influenza A virus; Investigation; Laboratories; Maps; Measurement; Measures; Methods; Modeling; Modernization; Molecular; Molecular Evolution; Mutation; Nature; Pattern; Phenotype; Population; Positioning Attribute; Process; Proteins; RNA Viruses; Recommendation; Resolution; Resources; Risk Reduction; Seasons; Serology; Site; Statistical Models; Surface; Testing; Time; Use Effectiveness; Vaccination; Vaccines; Variant; Viral; Virus; Work; computerized tools; cost; data integration; data streams; fitness; fitness test; improved; influenza virus vaccine; influenzavirus; mutant; neutralizing antibody; novel; receptor binding; response; sample fixation; seasonal influenza; transmission process; vaccine candidate; vaccine effectiveness

PROJECT SUMMARY Seasonal influenza virus vaccines have to be reformulated most years primarily due to immune escape caused by mutations in the surface hemagglutinin (HA) protein. The genetic variation in HA only occasionally causes change in antigenic phenotype and consequent immune escape. For extended periods of time strains with genetic differences remain in a single antigenic cluster. In 2013 we (Koel et al.)1 found that the amino acid substitutions responsible for antigenic cluster transitions in human A/H3N2 viruses occurred at only seven key positions on the periphery of the HA receptor binding site (RBS), and that seven out of ten A/H3N2 cluster transitions were caused by just single amino acid substitutions. Furthermore, major antigenic change in other (sub)types of human influenza, as well as influenza viruses in other species, is also primarily due to single amino acid substitutions at the same seven key HA sites, and nearby, on the periphery of the HA RBS. This discovery raises an immediate, and not previously obvious question: If just one amino acid change is typically required to escape immunity, why is the antigenic evolution of influenza viruses so slow? Human seasonal influenza A/H3N2 viruses remain in an antigenic cluster for an average of 3.1 years, and occasionally as long as eight years. This is especially perplexing given that, as an RNA virus, influenza viruses have a fast rate of molecular evolution. A possible explanation for the delay in fixation of cluster transition substitutions is that antigenic change incurs a fitness cost. The proximity of escape mutations to the RBS offers a mechanism for this cost: the virus needs to change close to the RBS as antibodies targeting the RBS need to be escaped, but change in this area also affects receptor-binding function. Substitutions which advance a strain antigenically may only be competitive when sufficient population immunity has built to contemporary circulating variants, such that the gain in fitness from escaping immunity (the “extrinsic” fitness gain) outweighs the potential fitness loss associated with the concomitant distortion of the receptor binding site (the “intrinsic” fitness loss). We refer to this as the “fitness exchange” hypothesis. To understand the evolutionary dynamics of influenza requires understanding what paces antigenic change. In this proposal we set out to test the fitness exchange hypothesis, to gain understanding of the variation and impact of viral intrinsic fitness, and to determine the relative importance of intrinsic fitness and stochastic effects in novel mutations becoming fixed in viral populations, and to integrate empirical measurements of these effects into a probabilistic framework for predicting the antigenic evolution of seasonal influenza viruses.

项目概要 季节性流感病毒疫苗大多数年份都必须重新配制，主要是由于引起的免疫逃逸 由表面血凝素 (HA) 蛋白突变引起。 HA 的遗传变异只是偶尔导致 抗原表型的变化和随后的免疫逃逸。对于长时间应变 遗传差异保留在单个抗原簇中。 2013 年，我们（Koel 等人）1 发现氨基酸 导致人类 A/H3N2 病毒抗原簇转变的替换仅发生在七个关键位置 位于 HA 受体结合位点 (RBS) 外围的位置，十分之七的 A/H3N2 簇 转变仅由单个氨基酸取代引起。此外，其他方面的主要抗原变化 人类流感的（亚）型以及其他物种的流感病毒也主要是由于单氨基酸 在相同的七个关键 HA 位点以及 HA RBS 外围附近进行酸替换。这一发现 提出了一个直接的、以前并不明显的问题：如果通常只需要改变一种氨基酸 逃避免疫，为何流感病毒的抗原进化如此缓慢？人类季节性流感 A/H3N2 病毒在抗原簇中平均保留 3.1 年，有时长达 8 年。这 尤其令人困惑的是，作为一种 RNA 病毒，流感病毒的分子进化速度很快。一个 簇转变取代固定延迟的可能解释是抗原变化导致 健身费用。逃逸突变与 RBS 的接近提供了这种成本的机制：病毒需要 靠近 RBS 的变化，因为针对 RBS 的抗体需要逃脱，但该区域的变化也 影响受体结合功能。使菌株具有抗原性的替代可能只是竞争性的 当对当代流行的变异体建立了足够的群体免疫力时，从而获得健康 逃避免疫力（“外在”健身增益）超过了与免疫相关的潜在健身损失 受体结合位点的伴随变形（“内在”适应性损失）。我们将其称为“健身 交换”假说。要了解流感的进化动态，需要了解什么步调 抗原改变。在这个提案中，我们着手测试适应度交换假设，以了解 病毒内在适应性的变化和影响，并确定内在适应性和病毒内在适应性的相对重要性 新突变的随机效应在病毒群体中变得固定，并整合经验 将这些影响的测量纳入概率框架中，以预测季节性的抗原进化 流感病毒。