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

新的小鼠模型可以更好地预测人类对流感疫苗接种和感染的免疫力

• 批准号: 10663220
• 负责人: Ryan Langlois
• 金额: $ 61.53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663220
• 关键词: Acceleration; Adjuvant; Adult; Animal Model; Animals; Antibodies; Antibody Response; Attenuated; Attenuated Vaccines; Biological Models; Body Weight decreased; C57BL/6 Mouse; Cells; Cellular biology; Complement; Data; Disease; Environmental Risk Factor; Evaluation; Ferrets; Gene Expression; Gene Expression Profile; Generations; Genetic; House mice; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Inbred Strain; Infection; Influenza; Influenza vaccination; Innate Immune Response; Innate Immune System; Kinetics; Laboratory mice; Lung; Lymphocyte; Mediating; Memory; Methods; Modality; Modeling; Molecular; Mucous Membrane; Mus; Parabiosis; Pathogenesis; Pathogenicity; Pattern; Physiological; Preclinical Testing; Reagent; Recording of previous events; Regimen; Research; Research Personnel; Safety; Sampling; Seasons; Serum; Severity of illness; Shapes; Speed; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Translating; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Virus Replication; antiviral immunity; chronic infection; cost; experience; germ free condition; human data; human disease; immunogenic; immunogenicity; improved; influenza infection; influenza virus vaccine; microbial; model organism; mouse model; next generation; pathogen; pre-clinical; prevent; response; tissue resident memory T cell; tool; translational potential; universal influenza vaccine; universal vaccine; vaccine candidate; vaccine development; vaccine strategy; virology

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.

接种疫苗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点，并且效力每年都有很大差异。迫切需要改进疫苗策略。临床前试验对于评价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型生物体，因为有大量的试剂和遗传工具允许精细的实验方法和能力进行严格的机制研究，纵向动力学分析，粘膜组织取样，并通过致命的挑战，保护评估，所有在低成本。虽然小鼠不是流感病毒感染的天然宿主，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，而其他菌株可以容易地适应小鼠。不幸的是，许多在小鼠中成功的治疗干预措施未能转化为人类。这可能是由于几个因素，包括物种遗传差异和/或环境因素。我们先前已经证明，将SPF实验室小鼠暴露于来自宠物店小鼠的不同病原体，重现了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，异源保护和流感特异性血清抗体同种型在“脏”共饲养（CoH）中发生了显着变化，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小鼠将更好地预测对流感感染和疫苗接种的免疫应答。我们将从三个方面来检验这一假设。目的1将比较SPF和CoH小鼠对人类使用的一组佐剂的免疫应答。在可用的情况下，我们将比较转录谱人类数据。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，包括对肺免疫流感病毒感染和疫苗接种的广泛分析。surveillance.to目的3将确定SPF和CoH小鼠对减毒活疫苗、季节性裂解疫苗和含佐剂裂解疫苗的免疫应答。这一目标还将评估对通用流感疫苗的免疫原性较低的靶标的免疫应答。总的来说，该提案将严格评估对流感病毒感染的免疫反应，并在具有不同感染史和与人类更接近的免疫特征的小鼠中接种疫苗。我们认为，CoH小鼠模型的固有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。