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: 10269922
• 负责人: Karen A Norris
• 金额: $ 77.12万
• 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/10269922
• 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; Lung diseases; 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 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-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3300万 每年新感染。尽管伯宁（Burnen）如此重要，但没有RSV疫苗，目前有 严重RSV感染的治疗选择有限。疫苗的努力受到1）早期失败的阻碍 使用福尔马林灭活的RSV（FI-RSV）的疫苗尝试，导致呼吸道增强 某些婴儿的疾病（ERD）和2）啮齿动物模型的缺陷，这些模型不概括的关键方面 人类婴儿RSV感染。研究表明，FI-RSV和随后的RSV挑战接种 偏向Th2细胞对免疫病理学的介导的反应，而事先暴露于Live病毒是正确的素数 没有ERD的适应性和先天免疫系统。因此，亚基的潜力和灭活的潜力 引起ERD的RSV疫苗仍然是RSV幼稚的小儿人群的特别关注。在此提案中， 我们在RSV的高度相关的临床前模型中提供了一种新颖的免疫策略，该策略解决这些问题 疫苗开发的障碍。我们建议测试新的孕产妇免疫策略以引起 保护性母体免疫力并测试中和抗体被动转移的受保护效率。我们 假设这种方法将在围产期的婴儿中提供受保护的被动免疫 最大的RSV敏感性。我们建议在RSV感染的非人类私人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，我们将使用这种免疫策略来提高对母亲关键方面的理解 免疫包括1）怀孕对疫苗诱导的免疫的影响2）母体动力学 中和抗体反应的转移和3）孕产妇免疫和保护的效率 临床相关的婴儿主要模型。此外，我们将定义先天和适应性免疫。 RSV感染中成人猕猴的保护，这对于理解缺陷至关重要 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 建立用于设计和测试遗产免疫刺激策略的临床前感染模型以及 一种高度相关的临床前模型，最紧密地模仿人类疾病。