New mouse model to better predict human immunity to influenza vaccination and infection

疫苗接种是目前预防流感病毒感染和降低疾病严重程度的最佳方法。不幸的是，目前的疫苗方案存在几个主要缺陷，而且每年的疗效可能会有很大差异。迫切需要改进疫苗战略。临床前试验对于评估下一代流感病毒候选疫苗的潜在安全性和免疫原性至关重要。小鼠是理想的第一模式生物，因为有丰富的试剂和遗传工具允许完善的实验方法，并有能力进行严格的机制研究，纵向动力学分析，粘膜组织取样，以及通过致命挑战评估保护，所有这些都是低成本的。虽然小鼠不是流感病毒感染的天然宿主，但它们仍然可以重现人类疾病的许多方面。此外，一些菌株是直接致病的，而另一些菌株可以很容易地适应小鼠。不幸的是，许多在小鼠身上成功的治疗干预措施未能转化为人类。这可能是由于多种因素造成的，包括物种遗传差异和/或环境因素。我们之前已经证明，将SPF实验室小鼠暴露于宠物店小鼠的各种病原体中，重现了标准小鼠模型中缺失的许多人类细胞和分子免疫特征。初步研究表明，与SPF小鼠相比，“脏”冷藏（CoH）小鼠的异源保护和流感特异性血清抗体同型显著改变，这更接近于在人类中观察到的情况。我们假设，与标准小鼠模型相比，CoH小鼠可以更好地预测流感感染和疫苗接种的免疫反应。我们将用三个目标来检验这一假设。目的1将比较SPF和CoH小鼠对人类使用的一组佐剂的免疫反应。在可能的情况下，我们将转录谱与人类数据进行比较。目的2将确定不同的感染史如何影响流感特异性记忆T细胞的产生、功能和持久性，包括对肺部免疫监测的广泛分析。预防流感病毒感染及接种疫苗。目的3将确定SPF和CoH小鼠对减毒活疫苗、季节性分裂疫苗和佐剂分裂疫苗的免疫反应。这一目的还将评估通用流感疫苗对免疫原性较低靶点的免疫反应。总的来说，该提案将严格评估具有不同感染史和更接近人类的免疫特征的小鼠对流感病毒感染和疫苗接种的免疫反应。我们认为，CoH小鼠模型的内在优势将显著补充雪貂或其他大型动物模型，以改善临床前测试的渠道，并增强下一代流感病毒疫苗的转化潜力。

Vaccination is currently the best method for preventing influenza virus infection and for reducing disease severity. Unfortunately, current vaccine regimens suffer from several major drawbacks and efficacy can vary dramatically year to year. Improved vaccine strategies are desperately needed. Preclinical testing is critical for evaluating potential safety and immunogenicity of next generation influenza virus vaccine candidates. Mice are an ideal first model organism because there are a wealth of reagents and genetic tools allow refined experimental approaches and the capacity to do rigorous mechanistic studies, longitudinal kinetic analyses, sampling of mucosal tissue, and assessment of protection through lethal challenge, all at low cost. While mice are not natural hosts for influenza virus infection they can still recapitulate many aspects of human disease. Additionally, some strains are directly pathogenic while others can be readily mouse adapted. Unfortunately, many therapeutic interventions that were successful in mice have failed to translate to humans. This could be due to several factors including species genetic differences and/or environmental factors. We have previously demonstrated that exposing SPF laboratory mice to diverse pathogens from pet store mice recapitulates many of the human cellular and molecular immune signatures absent in standard mouse models. Preliminary studies demonstrate that heterologous protection and influenza-specific serum antibody isotypes are dramatically altered in ‘dirty’ cohoused (CoH) compared to SPF mice, which more closely resemble what has been observed in humans. We hypothesize that CoH mice will better predict immune responses to influenza infection and vaccination compared to standard mouse models. We will test this hypothesis in three aims. Aim 1 will compare the immune response to a panel of adjuvants used in humans between SPF and CoH mice. Where available, we will compare transcriptional profiles to human data. Aim 2 will determine how a diverse infection history impacts the generation, function, and durability of influenza-specific memory T cells, including extensive analyses of lung immune surveillance.to influenza virus infection and vaccination. Aim 3 will determine the immune response to live attenuated, seasonal split and adjuvanted split vaccinations in SPF and CoH mice. This aim will also evaluate the immune response to less immunogenic targets of universal influenza vaccines. Collectively, this proposal will rigorously evaluate the immune response to influenza virus infection and vaccination in mice with diverse infection histories and immune signatures that more closely align with humans. We propose that the intrinsic advantages of the CoH mouse model will significantly complement ferret or other large animal models to improve the pipeline for preclinical testing and enhance translation potential of next generation influenza virus vaccines.