Impact of prior influenza exposures on antibody repertoires to new viral strains

大多数人在3岁时感染流感病毒。我们过去的研究 这表明，儿童早期流感感染可留下终身免疫“印记”。在第一 在该基金资助期（4年）内，我们发现人类抗体对季节性流感病毒的反应 典型地集中于在当代病毒株和 在每个捐赠者的童年时期流传。我们发现免疫系统产生的免疫反应 当代流感病毒株由记忆B细胞支配，记忆B细胞识别存在于 过去的病毒株。我们的研究已经检查了一种流感病毒亚型（即， H1N1）影响针对同一亚型（即H1N1）抗原性不同版本的免疫应答。 尽管不同的流感病毒亚型具有非常不同的抗原特性，但存在与流感病毒亚型相同的表位。 在这些病毒中是保守的H1N1、H2N2和H3N2病毒在不同时期在人类中传播 在过去的100年里，一个人的出生年份在很大程度上预测了他们所患的流感病毒亚型。 最初是在儿童时期感染的。重要的是要阐明一种流感亚型的病毒感染 (i.e. H1N1）影响针对完全不同的流感亚型（即H3N2）的免疫应答， 目前，多种流感病毒亚型在人类中共同传播。此外，流行病学研究表明， 人类对大流行性H5N1和H7N9病毒的易感性受到儿童感染的影响， 不同亚型的季节性流感病毒。我们假设儿童早期季节性流感病毒 感染会留下持久的免疫印记，使免疫系统倾向于优先做出反应， 对更密切相关的流感亚型有效，而对更远的流感亚型效果不佳。在这 我们将使用雪貂模型来确定初始季节性流感感染如何形成特异性， 和针对不同的季节性和大流行性流感病毒亚型引发的Ab的中和效率。 然后，我们将检查为儿科队列研究收集的血清样本，以确定最初的儿童期 H1N1与H3N2感染影响针对同源和非同源病毒感染的抗体应答的发展， 异源流感病毒亚型。最后，我们将使用雪貂模型来确定不同的流感 预暴露塑造了由一种领先的“通用”抗体引起的抗体的特异性和中和效率。 流感疫苗候选人。总的来说，这些研究将确定（1）是否感染一种流感病毒 亚型影响针对第二流感病毒亚型引发的Ab的特异性，（2）特异性和 在具有不同流感病毒暴露史的儿童中引起的Ab的功能性和（3）先前如何 流感暴露影响新的“通用”流感疫苗的有效性。

Most humans are infected with influenza viruses by the time they reach 3 years of age. Our past studies suggest that early childhood influenza infections can leave lifelong immunological `imprints'. During the first funding period (4 years) of this grant, we found that human Ab responses against seasonal influenza viruses are typically focused on epitopes that are conserved between contemporary viral strains and viral strains that circulated during each individual donor's childhood. We found that immune responses generated against contemporary influenza strains are dominated by memory B cells that recognize conserved epitopes present in past viral strains. Our studies have examined how viral infections with one subtype of influenza virus (i.e. H1N1) influence immune responses against an antigenically distinct version of that same subtype (i.e. H1N1). Although different influenza virus subtypes have very different antigenic properties, there are epitopes that are conserved among these viruses. H1N1, H2N2, and H3N2 viruses have circulated at different times in humans over the past 100 years and an individual's birth year largely predicts the influenza virus subtype that they were initially infected with in childhood. It is important to elucidate how viral infections with one influenza subtype (i.e. H1N1) influence immune responses against a completely different influenza subtype (i.e. H3N2) since multiple influenza virus subtypes currently co-circulate in humans. Further, epidemiological studies suggest that human susceptibility to pandemic H5N1 and H7N9 viruses is influenced by childhood infections with different subtypes of seasonal influenza viruses. We hypothesize that early childhood seasonal influenza virus infections leave long-lived immunological imprints that bias the immune system to preferentially respond efficiently to more closely related influenza subtypes and poorly to more distant influenza subtypes. In this proposal we will use a ferret model to determine how initial seasonal influenza infections shape the specificity and neutralization efficiency of Abs elicited against distinct seasonal and pandemic influenza virus subtypes. We will then examine sera samples collected for a pediatric cohort study to determine how initial childhood H1N1 versus H3N2 infections affect the development of Ab responses against infections with homologous and heterologous influenza virus subtypes. Finally, we will use a ferret model to determine how different influenza pre-exposures shape the specificity and neutralization efficiency of Abs elicited by a leading `universal' influenza vaccine candidate. Collectively, these studies will determine (1) if infections with one influenza virus subtype influence the specificity of Abs elicited against a second influenza virus subtype, (2) the specificity and functionality of Abs elicited in children with different influenza virus exposure histories and (3) how prior influenza exposures influence the effectiveness of a new `universal' influenza vaccine.