Evaluation of pregnancy on vaccine-induced immunity and protection in a pre-clinical model of RSV infection

RSV感染临床前模型中妊娠对疫苗诱导免疫和保护的评价

• 批准号: 10470252
• 负责人: Karen A Norris
• 金额: $ 76.89万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470252
• 关键词: Accounting; Acute; Address; Adult; Affect; Animal Model; Animals; Antibody Response; Blood group antigen f; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Disease; Environment; Etiology; Evaluation; Evolution; Exposure to; Failure; Female; Formalin; Goals; Human; Immune; Immune response; Immunity; Immunization; Infant; Infection; Infiltration; Innate Immune System; Kinetics; Lower Respiratory Tract Infection; Lung; Lymphocyte; Macaca; Maternal antibody; Maternally-Acquired Immunity; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; Mothers; Mucous body substance; Nature; Passive Immunity; Passive Transfer of Immunity; Phenotype; Population; Pre-Clinical Model; Predisposition; Pregnancy; Prevention; Primates; Production; Public Health; Pulmonary Pathology; Reproducibility; Respiratory Disease; Respiratory Signs and Symptoms; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Rodent Model; Route; Second Pregnancy Trimester; Serology; Specificity; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Third Pregnancy Trimester; Vaccinated; Vaccination; Vaccines; Virus; Virus-like particle; base; clinically relevant; design; efficacy testing; experience; human disease; immunopathology; improved; infant infection; maternal vaccination; mature animal; mortality; neonate; neutralizing antibody; neutrophil; nonhuman primate; novel; novel vaccines; offspring; perinatal period; postnatal period; pregnant; prevent; protective efficacy; recombinant virus; response; seropositive; transmission process; vaccination strategy; vaccine candidate; vaccine development; vaccine efficacy; vaccine response; vaccine strategy; vaccine-induced immunity

RSV is the leading cause of acute lower respiratory tract infections in children, causing an estimated 33 million new infections each year. Despite this significant global burden, there is no RSV vaccine and there are currently limited therapeutic options for severe RSV infection. Vaccine efforts have been hindered by 1) failure of early vaccine attempts using formalin-inactivated RSV (FI-RSV) which led to the occurrence of enhanced respiratory disease (ERD) in some infants and 2) deficiencies of rodent models that do not to recapitulate critical aspects of human infant RSV infection. Studies have shown that vaccination with FI-RSV and subsequent RSV challenge skews Th2-cell mediated responses towards immunopathology, while prior exposure to live virus properly primes the adaptive and innate immune systems without ERD. Consequently, the potential for subunit and inactivated RSV vaccines to cause ERD remains a particular concern for RSV naïve pediatric population. In this proposal, we offer a novel immunization strategy in a highly relevant, pre-clinical model of RSV that addresses these barriers to vaccine development. We propose to test novel maternal immunization strategies for eliciting protective maternal immunity and test the protective efficacy of passive transfer of neutralizing antibodies. We hypothesize that this approach will provide protective passive immunity in infants during perinatal period of greatest RSV susceptibility. We propose to test this approach in a non-human primate model of RSV infection using recombinant virus-like particle (VLP) vaccines expressing F antigen in appropriate conformation. In addition, we will use this immunization strategy to improve understanding of critical aspects of maternal immunization including 1) the effects of pregnancy on vaccine-induced immunity 2) the kinetics of maternal transfer of neutralizing antibodies responses and 3) the efficacy of maternal immunization and protection in a clinically relevant infant primate model. In addition, we will define innate and adaptive immune correlates of protection in RSV infection in adult macaques, information that will be critical to the understanding of deficiencies in the infant lung environment. We expect these studies will have a catalytic effect on the RSV field by establishing a pre-clinical model of infection for design and testing maternal immunization strategies as well as in a highly relevant, pre-clinical model that most closely mimics human disease.

RSV 是儿童急性下呼吸道感染的主要原因，估计导致 3300 万人感染 每年都有新的感染。尽管全球负担巨大，但目前还没有 RSV 疫苗 严重 RSV 感染的治疗选择有限。疫苗工作因以下原因受到阻碍：1）早期失败 尝试使用福尔马林灭活的 RSV (FI-RSV) 进行疫苗接种，导致出现增强的呼吸道症状 一些婴儿的疾病（ERD）和2）啮齿动物模型的缺陷，不能概括关键方面 人类婴儿 RSV 感染。研究表明，接种 FI-RSV 疫苗和随后的 RSV 攻击 使 Th2 细胞介导的反应偏向免疫病理学，而之前接触活病毒会正确启动 没有 ERD 的适应性和先天免疫系统。因此，亚基和失活的潜力 RSV 疫苗导致 ERD 仍然是未接触过 RSV 的儿科人群特别关注的问题。在这个提案中， 我们在高度相关的 RSV 临床前模型中提供了一种新颖的免疫策略，可以解决这些问题 疫苗开发的障碍。我们建议测试新的孕产妇免疫策略以引发 保护母体免疫力并测试中和抗体被动转移的保护功效。我们 假设这种方法将为婴儿在围产期提供保护性被动免疫 RSV 敏感性最高。我们建议在非人类灵长类动物 RSV 感染模型中测试这种方法 使用以适当构象表达 F 抗原的重组病毒样颗粒 (VLP) 疫苗。在 此外，我们将利用这一免疫策略来增进对孕产妇关键方面的了解 免疫包括 1) 妊娠对疫苗诱导免疫的影响 2) 母体的动力学 中和抗体反应的转移以及 3) 母体免疫和保护的功效 临床相关的婴儿灵长类动物模型。此外，我们将定义先天性和适应性免疫相关性 成年猕猴 RSV 感染的保护，对于理解缺陷至关重要的信息 在婴儿肺部环境中。我们预计这些研究将对 RSV 领域产生催化作用 建立临床前感染模型，用于设计和测试孕产妇免疫策略以及 高度相关的临床前模型，最接近地模拟人类疾病。