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: 10349839
• 负责人: Derek James Smith
• 金额: $ 51.78万
• 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/10349839
• 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; Plant Roots; Population; Positioning Attribute; Process; Proteins; RNA Viruses; Recommendation; Resolution; Resources; Risk; Seasons; Serology; Site; Statistical Models; Surface; Testing; Time; Use Effectiveness; Vaccination; Vaccines; Variant; Viral; Virus; Virus Replication; Work; computerized tools; cost; 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.

项目摘要 季节性影响病毒疫苗在大多数年中必须重新构造，这是由于免疫逃生而导致的 通过表面血凝素（HA）蛋白的突变。 HA的遗传变异仅偶尔原因 抗原表型的变化和随之而来的免疫消除。长时间的应变 遗传差异仍然存在于单个抗原簇中。 2013年，我们（Koel等人）1发现氨基酸 在人A/H3N2病毒中负责抗原簇转变的替换仅发生在七个键 在HA受体结合位点（RB）的外围位置上的位置，十个A/H3N2簇中的七个位置 过渡仅由单个氨基酸取代引起。此外，其他的重大抗原变化 （子）人类影响的类型以及其他物种中的影响力病毒也是主要氨基 在相同的七个关键HA地点和附近的HA RBS外围的酸取代。这个发现 提出直接且以前不是明显的问题：通常只需要一个氨基酸的变化 逃避免疫力，为什么影响者的抗原演变如此慢？人类季节性影响者A/H3N2 病毒在抗原簇中保持平均3。1年，偶尔长达八年。这 尤其令人困惑，因为作为RNA病毒，影响病毒具有快速的分子进化速率。一个 延迟聚类过渡替代固定的可能解释是抗原变化会导致A 健身成本。逃避突变与皇家银行的距离为这一成本提供了一种机制：病毒需要 靠近RB的更改，因为需要逃脱针对RB的抗体，但此区域也更改 影响受体结合功能。抗原促进菌株的替换可能只能有能力 当足够的人口免疫力已建立为现代循环变体时，适应性的增长 逃脱免疫力（“外部”健身增长）大于与之相关的潜在健身损失 接收器结合位点的伴随失真（“内在”健身损失）。我们将其称为“健身 交换”假设。要了解流感的进化动态，需要了解什么步伐 抗原变化。在此提案中，我们着手检验健身交换假设，以了解 病毒固有适应性的变化和影响，并确定内在适应性的相对重要性和 新型突变中的随机效应固定在病毒群体中，并整合经验 这些效应的测量成概率框架，用于预测季节的抗原演化 流感病毒。