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.

目前，疫苗接种是预防影响力病毒感染和降低疾病严重程度的最佳方法。不幸的是，目前的疫苗方案遭受了几个主要缺点，效率可能会逐年变化。迫切需要改进的疫苗策略。临床前测试对于评估下一代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，因为有大量试剂和遗传工具允许进行精致的实验方法以及进行严格的机械研究，纵向动力学分析，粘膜组织的采样以及通过致命挑战评估的能力，所有这些都是低成本的。虽然小鼠不是影响力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，某些菌株是直接的致病性，而其他菌株则很容易被小鼠改编。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实验室小鼠暴露于宠物店小鼠的潜水病原体上，概括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，在“肮脏”同子（COH）中，异源保护和影响特异性的血清抗体同种型在动态上改变了，这更像是在人类中观察到的。我们假设与标准小鼠模型相比，COH小鼠将更好地预测对影响力感染和疫苗接种的免疫反应。我们将以三个目标检验这一假设。 AIM 1将将免疫反应与SPF和COH小鼠之间人类使用的调节器小组进行比较。在可用的地方，我们将将转录概况与人类数据进行比较。 AIM 2将确定潜水员感染历史如何影响影响特异性记忆T细胞的产生，功能和耐用性，包括对肺免疫展出的广泛分析，以影响病毒感染和疫苗接种。 AIM 3将确定SPF和COH小鼠中对活衰减，季节性分裂和调整后的分裂疫苗的免疫反应。该目标还将评估对普遍影响较低的免疫原性靶标的免疫响应。总的来说，该提案将严格评估具有潜水感染史和免疫特征的小鼠中病毒感染和疫苗的免疫激素，并与人类更紧密地保持一致。我们建议，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，并增强下一代的翻译潜力影响病毒疫苗。