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

接种疫苗是目前预防流感病毒感染和减轻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，每年的效果可能会有很大不同。迫切需要改进疫苗策略。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。小鼠是一个理想的第一模式生物，因为有丰富的试剂和遗传工具允许改进实验方法，并有能力进行严格的机制研究、纵向动力学分析、粘膜组织采样和通过致命挑战评估保护，所有这些都是以低成本完成的。虽然老鼠不是流感病毒感染的自然宿主，但它们仍然可以概括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老鼠。不幸的是，许多在老鼠身上成功的治疗干预措施未能应用到人类身上。这可能是由于几个因素，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商店小鼠的不同病原体下，可以概括许多标准小鼠模型中缺乏的人类细胞和分子免疫特征。初步研究表明，与在人类中观察到的更接近于人类的SPF小鼠相比，异源保护和流感特异性血清抗体亚型在“脏”笼子(COH)中发生了显著变化。我们假设，与标准小鼠模型相比，COH小鼠将更好地预测流感感染和疫苗接种的免疫反应。我们将在三个目标上检验这一假设。目标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，我们会将转录特征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，包括对肺免疫监测的广泛分析。目的3将测定SPF和CoH小鼠对减毒活疫苗、季节性裂解疫苗和佐剂裂解疫苗的免疫应答。这一目标还将评估通用流感疫苗对免疫原性较低的目标的免疫反应。总的来说，这项建议将严格评估对流感病毒感染和免疫接种的免疫反应，这些小鼠具有不同的感染史和免疫特征，与人类更接近。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管道，并增强下一代流感病毒疫苗的翻译潜力。

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.