Evolution and Transmission of Influenza Virus in Natural Human Infection

流感病毒在人类自然感染中的进化和传播

• 批准号: 10450656
• 负责人: Adam Lauring
• 金额: $ 74.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450656
• 关键词: Affect; Age; Animal Model; Antibodies; Antibody titer measurement; Characteristics; Clinical Data; Communicable Diseases; Communities; Community-Acquired Infections; Data; Development; Enrollment; Epidemiology; Evolution; Foundations; Genetic Variation; Goals; Hazard Models; Hemagglutinin; Household; Human; Immune; Immunity; Immunization Programs; Individual; Infection; Influenza; Integration Host Factors; Journals; Knowledge; Measures; Modeling; Molecular; Morbidity - disease rate; Mutation; National Institute of Allergy and Infectious Disease; Natural Selections; Neuraminidase; Persons; Play; Population; Predisposition; Process; Property; Proteins; Public Health; Publishing; Research; Resolution; Sampling; Single Nucleotide Polymorphism; Strategic Planning; Swab; Technology; Vaccination; Vaccines; Variant; Viral; Viral Hemagglutinins; Viral Load result; Virus; Work; chronic infection; cohort; community setting; cross reactivity; epidemiologic data; flu transmission; genetic variant; hazard; immunological status; indexing; influenza epidemic; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; mathematical model; mortality; next generation sequencing; novel; pressure; rare variant; seasonal influenza; tool; transmission process; universal influenza vaccine; universal vaccine; vaccine effectiveness; vaccine efficacy; vaccine-induced antibodies; viral transmission; whole genome

Seasonal influenza epidemics result in significant morbidity and mortality, and vaccine effectiveness is disappointingly low. The rapid evolution of influenza viruses is a major barrier to effective vaccines, as new strains with different antigenic properties are continuously generated within a remarkably large population of infected hosts. This problem was highlighted in the recent NIAID strategic plan for influenza and in PA-18-859, which highlight key knowledge gaps with respect to influenza virus evolution in individuals and its transmission between them. The long-term goal of this research is to elucidate the evolutionary and epidemiological dynamics of influenza viruses in naturally infected human hosts. The objectives of this project are to use state-of-the-art molecular approaches to define the host-level evolution of influenza and to identify correlates of infectivity and transmission. This project will combine intensive sampling of viruses, matched sera, and clinical data from naturally infected individuals and their contacts, which will allow for robust analyses of influenza evolution, transmission, and spread. The feasibility of this approach is supported by published preliminary data, which show that (i) serial sampling can be used to characterize the evolutionary dynamics of influenza viruses within naturally infected people; (ii) next generation sequencing (NGS) can be used to identify transmission pairs and to estimate the number of unique viral variants transmitted between individuals; (iii) temporal data on viral load and within- host genetic diversity can inform mathematical models of transmission. Detailed analyses of influenza evolution and transmission will be accomplished in three aims. (Aim 1) Identify the emergent antigenic variants that are positively selected with hosts. NGS of serially sampled within-host viral populations will be used to identify hemagglutinin and neuraminidase variants under positive selection within hosts and their relationship to host immune status. The impact of these mutations on viral antigenicity will be evaluated using sera from enrolled individuals. (Aim 2) Define the transmission bottleneck and the genetic variants that are transmitted. NGS of serial samples from index cases and household contacts will be used to define household transmission chains, the size of the transmission bottleneck, and which within host variants are transmitted. (Aim 3) Identify viral and host factors associated with host susceptibility, infectivity, and transmission. A strain-specific household transmission model, integrating molecular and epidemiologic data, will be used to estimate hazards of infection from the community and each infected household contact. This work is innovative, because it leverages the expertise of an existing productive team to combine state-of-the-art technologies for viral sequencing and sophisticated modeling approaches to study influenza virus evolution and transmission in natural infection. The proposed research is significant, because it will define the evolutionary dynamics of influenza viruses at the level of individual hosts in a community setting.

季节性流感流行病会导致明显的发病率和死亡率，疫苗有效性为 令人失望的低。流感病毒的快速发展是有效疫苗的主要障碍，因为 具有不同抗原特性的菌株在众多人群中不断产生 感染的宿主。最近针对流感的NIAID战略计划和PA-18-859中强调了这个问题， 这突出了关键知识差距有关个体及其传播的流感病毒演变的差距 他们之间。这项研究的长期目标是阐明进化和流行病学动力学 自然感染的人类宿主中流感病毒的。该项目的目标是使用最先进的 分子方法来定义流感的宿主水平进化并确定感染性和 传播。该项目将结合病毒，匹配的血清和临床数据的密集抽样 自然感染的个体及其接触，这将允许对流感进化的强大分析， 传输和传播。这种方法的可行性由已发布的初步数据支持，这表明 （i）串行抽样可用于表征自然中流感病毒的进化动力学 感染人群; （ii）下一代测序（NGS）可用于识别传输对并估算 个体之间传播的独特病毒变体的数量； （iii）有关病毒载荷和内部的时间数据 宿主遗传多样性可以为传播的数学模型提供信息。流感进化的详细分析 传输将以三个目标完成。 （AIM 1）确定新兴的抗原变体 积极选择主机。将使用宿主内病毒种群的连续采样的NG来识别 血凝素蛋白和神经氨酸酶变体在宿主中阳性选择及其与宿主的关系 免疫状态。这些突变对病毒抗原性的影响将使用已注册的血清评估 个人。 （AIM 2）定义传输瓶颈和传播的遗传变异。 ngs 索引案件和家庭接触的串行样本将用于定义家庭传输链， 传输瓶颈的大小以及在主机变体中的大小被传输。 （目标3）识别病毒和 与宿主敏感性，感染性和传播相关的宿主因素。特定于应变的家庭 传播模型，整合分子和流行病学数据，将用于估计感染危害 来自社区和每个受感染的家庭接触。这项工作具有创新性，因为它利用了 现有的生产团队的专业知识，以结合先进的病毒测序技术和 研究自然感染中研究流感病毒进化和传播的复杂建模方法。这 拟议的研究很重要，因为它将定义流感病毒的进化动力学水平的进化动力学 在社区环境中的单个主机。