Syrian hamsters as an animal model for influenza virus research

项目总结 为了促进NIAID开发通用流感疫苗的战略计划，PAR-19-248征求 “提高动物模型在概括人类免疫力方面的预测价值的研究项目 流感感染和疫苗接种“。在这里，我们解决PAR-19中确定的一些主要研究需求- 248通过继续发展金色叙利亚仓鼠(以下简称仓鼠)作为动物 流感病毒研究的模型。这是基于我们之前的发现，流感病毒的组成 仓鼠呼吸道中的受体与人类呼吸道中的受体相似，而人类呼吸道中的受体 甲型流感病毒在仓鼠的呼吸道中复制，包括最近的人类H3N2型流感病毒， 它们不能在小鼠身上高效复制。在具体目标1中，我们计划建立一种流感病毒气雾剂 仓鼠的暴露平台。目前，大多数流感病毒感染研究都涉及鼻腔病毒。 接种，这不是自然的感染途径(即，气雾剂接触)。通过建立一个气雾剂 仓鼠的暴露平台，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 仓鼠在模拟首次接触流感病毒对机体影响中的预测价值 后续曝光(印记)。除少数例外，流感病毒感染和疫苗接种研究 都是在幼稚的动物身上进行的，因此不能反映大多数人类的免疫状态 通过感染和/或接种疫苗接触多种流感病毒。在这里，我们将按顺序感染 仓鼠(通过鼻腔感染或气雾剂暴露)携带与引起 儿童第一次和第二次感染(基于我们从儿科队列中获得的临床样本 研究)。然后，将比较仓鼠和人类血清对第一次和第二次感染的B细胞反应。 在具体目标3中，我们将评估仓鼠在模拟人类免疫反应方面的预测价值。 到多重感染、疫苗接种和挑战。仓鼠会先后感染两种不同的病毒 流感病毒，然后用灭活疫苗接种。引起的B细胞反应将是 与接种相同疫苗株前后获得的人体样本进行比较 将被用来给仓鼠接种疫苗。在另一项研究中，仓鼠将先后感染两种不同的病毒 流感病毒，随后接种了一种研究用(可能具有广泛保护作用的)疫苗 并受到一种异源病毒的挑战。激发的B细胞免疫反应将与 来自2a期临床试验，该试验使用了相同的研究疫苗和挑战病毒。通过利用 我们的初步数据和对人体样本的获取，我们将讨论PAR-19-248的几个关键主题， 包括评估新的动物模型、评估气雾剂暴露和预先暴露于 流感病毒对免疫反应的影响，以及免疫机制的重述，如印记和 在动物模型中进行背部助推。

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.