Establishing a relevant mouse model with susceptibility to non-adapted influenza viruses for vaccine challenge studies

建立对非适应性流感病毒易感的相关小鼠模型，用于疫苗攻击研究

基本信息

批准号：
10211108
负责人：
Jacob Yount
金额：
$ 22.37万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211108
关键词：
Animal Model Animals Antibodies Antibody titer measurement Antiviral Agents Avian Influenza A Virus Body Weight decreased Characteristics Defect Development Dose Engineering Genes Genetic Health Human IFNAR1 gene Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Infection Infectious Disease Immunology Influenza A virus Influenza B Virus Influenza vaccination Integral Membrane Protein Interferons Knockout Mice Libraries Measurable Measures Modeling Mus NON Mouse Natural Immunity Outcome Pathogenicity Pathology Population Preclinical Testing Predisposition Proteins Publishing Pulmonary Pathology Research SCID Mice Technology Testing Vaccination Vaccine Research Vaccines Validation Viral Virulent Virus Weight Weights and Measures Wild Type Mouse Work Zoonoses adaptive immune response adaptive immunity cost effective genetic association improved in vivo influenza infection influenza virus strain influenza virus vaccine influenzavirus insight mouse model novel vaccines pathogenic virus pre-clinical research and development seasonal influenza swine influenza universal influenza vaccine vaccine candidate vaccine development vaccine efficacy vaccine evaluation

项目摘要

SUMMARY Influenza virus infection is a major health concern worldwide. Our best defense against seasonal influenza virus infections is vaccination, but current vaccine strategies are not fully effective and may not offer protection against viruses that emerge from animals. One impediment to the development of better vaccines is the lack of a tractable and cost-effective small animal model for testing new vaccine technology. Mice are ubiquitously used in research, but influenza viruses that infect humans often require adaptation in order to infect and cause pathology in mice. This requirement for virus adaptation limits the utility of the mouse model for testing human vaccine candidates in challenge studies with relevant non-adapated human viruses. However, we found that mice engineered to lack a critical antiviral restriction factor known as interferon-induced transmembrane protein 3 (IFITM3) show increased susceptibility to a variety of influenza virus strains, including human isolates that otherwise do not cause significant pathology in wild type mice. We propose that IFITM3 knockout mice may thus serve as a long-sought mouse model for influenza virus vaccine testing. We will test whether these mice possess the two characteristics needed in a pre-clinical testing model: 1) Whether IFITM3 knockout mice possess the ability to mount protective adaptive immune responses upon vaccination, and 2) Whether IFITM3 knockout mice are fully susceptible to a wide breadth of human and animal-derived influenza viruses. In addition to allowing more rapid and cost-effective testing of new seasonal and universal influenza virus vaccines, this research will also provide insights into humans who possess IFITM3 defects in terms of virus susceptibility and the ability to counteract this immunodeficiency with vaccination.

概括流感病毒感染是全世界的一个主要健康问题。我们对抗季节性流感的最佳防御措施病毒感染就是疫苗接种，但目前的疫苗策略并不完全有效，可能无法提供保护对抗来自动物的病毒。开发更好疫苗的障碍之一是缺乏用于测试新疫苗技术的易于处理且具有成本效益的小动物模型。老鼠无处不在用于研究，但感染人类的流感病毒通常需要适应才能感染并引起小鼠病理学。这种病毒适应的要求限制了小鼠模型用于测试人类的效用与相关非适应性人类病毒进行挑战研究的候选疫苗。然而，我们发现转基因小鼠缺乏一种关键的抗病毒限制因子，即干扰素诱导的跨膜蛋白 3 (IFITM3) 显示对多种流感病毒株的敏感性增加，包括人类分离株否则不会在野生型小鼠中引起明显的病理变化。我们建议 IFITM3 敲除小鼠可能因此可以作为流感病毒疫苗测试的长期寻找的小鼠模型。我们将测试这些老鼠是否具备临床前测试模型所需的两个特征：1）是否为IFITM3基因敲除小鼠具有在疫苗接种后产生保护性适应性免疫反应的能力，以及 2) IFITM3 是否基因敲除小鼠对多种人类和动物源性流感病毒完全敏感。在除了允许对新的季节性和通用流感病毒进行更快速和更具成本效益的检测之外疫苗，这项研究还将深入了解具有 IFITM3 病毒缺陷的人类易感性以及通过疫苗接种抵抗这种免疫缺陷的能力。