Syrian hamsters as an animal model for influenza virus research

项目摘要 为了促进NIAID开发通用流感疫苗的战略计划，PAR-19-248征求 “研究项目，以提高动物模型的预测价值，在重演人类免疫， 流感病毒感染和疫苗接种”。在这里，我们解决了PAR-19中确定的一些主要研究需求- 248通过继续我们的发展黄金叙利亚仓鼠（以下简称仓鼠）作为一种动物 流感病毒研究的模型。这是基于我们以前的研究结果，即流感病毒的组成 仓鼠呼吸道中的受体类似于人呼吸道中的受体，并且人呼吸道中的受体类似于人呼吸道中的受体。 甲型流感病毒在仓鼠的呼吸道中复制，包括最近的人H3 N2流感病毒， 它们在小鼠体内不能有效复制。在具体目标1中，我们计划建立流感病毒气溶胶 仓鼠的暴露平台。目前，大多数流感病毒感染研究涉及鼻内病毒 接种，这不是感染的自然途径（即，气溶胶暴露）。通过建立一种气溶胶 暴露平台的仓鼠，我们正在解决PAR-19-248的一个关键主题。在具体目标2中，我们将评估 仓鼠在模拟首次暴露于流感病毒对 后续曝光（压印）。除了少数例外，流感病毒感染和疫苗接种研究 在幼稚动物中进行，因此不能反映大多数人的免疫状态， 通过感染和/或接种疫苗暴露于多种流感病毒。在这里，我们将依次感染 仓鼠（通过鼻内感染或气雾剂暴露）感染引起 儿童首次和第二次感染（基于我们从儿科队列中获得的临床样本 研究）。然后比较人血清和人血清对第一次和第二次感染的B细胞应答。 在具体目标3中，我们将评估仓鼠在模拟人类免疫反应中的预测价值 多重感染疫苗接种和挑战仓鼠会被两种不同的病毒依次感染 流感病毒，并随后接种灭活疫苗。引发的B细胞应答将是 与用相同的疫苗株接种前后获得的人样品相比， 将用于给仓鼠接种疫苗。在另一项研究中，仓鼠将依次感染两种不同的 流感病毒，随后接种研究性（可能具有广泛保护性）疫苗 用异源病毒攻击将引发的B细胞免疫应答与那些 来自使用相同研究疫苗和攻击病毒的2a期临床试验。通过利用 我们的初步数据和我们对人类样本的访问，我们将解决PAR-19-248的几个关键主题， 包括评估新的动物模型，评估气溶胶暴露和预暴露于 流感病毒对免疫反应的影响，以及免疫机制的重演，如印迹和 在动物模型中的背部提升。

PROJECT SUMMARY To facilitate NIAID’s strategic plan for the development of a universal influenza vaccine, PAR-19-248 solicits “Research Projects to Improve the Predictive Value of Animal Models in Recapitulating Human Immunity to Influenza Infection and Vaccination”. Here, we address some of the major research needs identified in PAR-19- 248 by continuing our development of golden Syrian hamsters (hereafter referred to as hamsters) as an animal model for influenza virus research. This is based on our previous findings that the composition of influenza virus receptors in the respiratory tract of hamsters is similar to that in the respiratory tract of humans, and that human influenza A viruses replicate in the respiratory tract of hamsters, including recent human H3N2 influenza viruses, which do not replicate efficiently in mice. In Specific Aim 1, we plan to establish an influenza virus aerosol exposure platform for hamsters. Currently, most influenza virus infection studies entail intranasal virus inoculation, which is not the natural route of infection (i.e., aerosol exposure). By establishing an aerosol exposure platform for hamsters, we are addressing a key topic of PAR-19-248. In Specific Aim 2, we will assess the predictive value of hamsters in simulating the impact of the first exposure to influenza viruses on subsequent exposures (imprinting). With few exceptions, influenza virus infection and vaccination studies have been conducted in naïve animals, thus not reflecting the immune status of most humans who have been exposed to multiple influenza viruses through infections and/or vaccinations. Here, we will sequentially infect hamsters (via intranasal infection or aerosol exposure) with the same human influenza viruses that caused the first and second infections in a child (based on clinical samples that we have obtained from a pediatric cohort study). Hamster and human sera will then be compared for B cell responses to the first and second infections. In Specific Aim 3, we will assess the predictive value of hamsters in simulating human immune responses to multiple infections, vaccination, and challenge. Hamsters will be sequentially infected with two different influenza viruses, and subsequently vaccinated with an inactivated vaccine. The B cell responses elicited will be compared to those of human samples obtained before and after vaccination with the same vaccine strain that will be used to vaccinate the hamsters. In another study, hamsters will be sequentially infected with two different influenza viruses, and subsequently vaccinated with an investigational (potentially broadly protective) vaccine and challenged with a heterologous virus. The B cell immune responses elicited will be compared with those from a Phase 2a clinical trial that used the same investigational vaccine and challenge viruses. By leveraging our preliminary data and our access to human samples, we will address several key topics of PAR-19-248, including the assessment of novel animal models, the assessment of aerosol exposure and pre-exposure to influenza viruses on immune responses, and the recapitulation of immune mechanisms such as imprinting and back-boosting in animal models.