Epidemiological impacts of broadly protective childhood HA imprinting on seasonal and pandemic influenza

甲型流感病毒(IAV)的季节性传播每年会导致相当大的发病率和死亡率 造成的负面经济影响估计高达数十亿美元。流感大流行由以下原因引起 新的人畜共患病IAV的出现构成了更大的威胁。几十年来，流感的一个关键思想 流行病学一直认为，所有人都会对出现的一种新的流感亚型缺乏免疫力 从动物身上引发一场大流行。然而，我们最近的研究表明，人类的大部分 实际上，人群对两种禽流感A/H5N1和A/H7N9有很强的免疫力 人类中出现大流行非常令人担忧的亚型。针对特定子类型的保护 大流行的可能性可以预测地分布在出生年份之间，并且发生在第一个出生的人身上 童年时期接触过血凝素抗原(HA)为同一基因群的甲型流感病毒 作为小说，新兴的兴趣亚类。本文提出的后续研究的目的是(1)使用重建的 HA印迹模式用于预测未来大流行中严重感染的年龄分布和(2)确定 广泛保护性儿童HA印记是否影响季节性流感亚型的流行病学 甲型H1N1流感和甲型H3N1流感。 目标1--大流行流感。我们的目标是确定是否以及通过什么因素来保护童年 HA印记降低了对新型IAV感染的易感性，确实发生了轻度感染的传播性 受保护的个人，或两者兼而有之。为了估计每个可能影响的大小和重要性，我们将应用 多类型分支过程和对所有已知A/H5N1和A/H7N9病例数据的统计推断。 这一分析的结果将提高现有模型的准确性，这些模型可以使用出生信息 特定年份的儿童HA印记以预测未来大流行中严重感染的年龄分布。 这些预报可以为大流行的准备和应对战略提供信息，并有助于针对有限的目标 针对高危年龄组的治疗资源。 目标2-季节性流感。两种IAV亚型h1n1和h3n2在 然而，自1977年以来，人类感染H3N2病毒导致了绝大多数与流感相关的老年人死亡 成年人。不匹配的童年印记可能会增加老年人感染H3N1病毒的风险，但观察到 H3N2病毒与H1N1病毒风险的差异也可以解释为H3N2病毒的内在毒力更高，或者是 其他传统的、特定于年龄的流行病学因素。以确定是否不匹配以及不匹配的程度 童年印记会增加老年人群感染H3N1病毒的风险，我将分析18,000多人的数据 应用统计分析、数学模型和模型相结合的方法研究季节性流感病例 比较一下。这项分析将告知是否以及如何预期老年人感染H3N2病毒和H1N1病毒的风险。 随着时间的推移，具有不同童年时期HA印记的出生队列会变得更老。

Seasonal circulation of influenza A viruses (IAVs) annually causes substantial morbidity and mortality and has negative economic impacts estimated in the billions of dollars. Influenza pandemics caused by the emergence of novel, zoonotic IAVs pose an even greater threat. For decades, a key idea in influenza epidemiology has been that all humans would lack immunity against a novel influenza subtype that emerged from animals to cause a pandemic. However, our recent study showed that large parts of the human population actually have strong, pre-existing immunity against influenza A/H5N1 and A/H7N9, two avian subtypes of great concern for pandemic emergence in humans. Protection against particular subtypes with pandemic potential is predictably distributed across birth years, and occurs in individuals who were first exposed during childhood to an influenza A virus with hemagglutinin antigens (HA) in the same genetic group as the novel, emerging subtype of interest. The follow-up studies proposed here aim to (1) use reconstructed HA imprinting patterns to forecast age distributions of severe infection in future pandemics and (2) determine whether broadly-protective childhood HA imprinting affects the epidemiology of seasonal influenza subtypes A/H1N1 and A/H3N2. Aim 1 - pandemic influenza. We aim to determine whether, and by what factor, protective childhood HA imprinting reduces susceptibility to infection with novel IAVs, transmissibility of mild infections that do occur in protected individuals, or both. To estimate the size and significance of each possible effect, we will apply multitype branching processes and statistical inference to data on all known cases of A/H5N1 and A/H7N9. The results of this analysis will improve the accuracy of existing models, which can use information on birth year-specific childhood HA imprinting to forecast age distributions of severe infection in future pandemics. These forecasts can inform pandemic preparedness and response strategies, and can help target limited treatment resources toward high-risk age groups. Aim 2 – seasonal influenza. Two IAV subtypes, H1N1 and H3N2, have circulated seasonally in humans since 1977, however H3N2 infections cause the vast majority of influenza-related fatalities in elderly adults. Mismatched childhood imprinting may contribute to increased H3N2 risk in the elderly, but observed differences in H3N2 vs. H1N1 risk could also be explained by higher intrinsic virulence of the H3N2 virus, or by other conventional, age-specific epidemiological factors. To determine whether, and how strongly, mismatched childhood imprinting contributes to increased H3N2 risk in elderly cohorts, I will analyze data on over 18,000 cases of seasonal influenza using a combination of statistical analyses, mathematical models and model comparison. This analysis will inform whether and how H3N2 vs. H1N1 risk in the elderly should be expected to change over time, as birth cohorts with different histories of childhood HA imprinting become older.