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减轻疾病严重程度的最佳方法。不幸的是，当前的疫苗方案存在几个主要缺点，并且功效每年都有很大差异。迫切需要改进疫苗策略。临床前测试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。小鼠是理想的第一个模型生物体，因为有丰富的试剂和遗传工具允许精细的实验方法和进行严格的机制研究、纵向动力学分析、粘膜组织采样以及通过致死挑战评估保护的能力，所有这些都以低成本进行。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，一些菌株具有直接致病性，而另一些菌株则很容易适应小鼠。不幸的是，许多在小鼠身上取得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多种病原体中，可以重现标准小鼠模型中不存在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”共养小鼠 (CoH) 的异源保护和流感特异性血清抗体同种型发生了显着改变，这更类似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 小鼠能够更好地预测对流感感染和疫苗接种的免疫反应。我们将从三个目标来检验这个假设。目标 1 将比较 SPF 小鼠和 CoH 小鼠对人类使用的一组佐剂的免疫反应。如果有的话，我们会将转录谱与人类数据进行比较。目标 2 将确定不同的感染史如何影响流感特异性记忆 T 细胞的生成、功能和持久性，包括对流感病毒感染和疫苗接种的肺部免疫监视的广泛分析。目标 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。该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，该提案将严格评估具有不同感染史和与人类更接近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着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.