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

呼吸道合胞病毒是儿童急性下呼吸道感染的主要原因，估计造成3300万人感染。 每年都有新的感染病例。尽管有这一重大的全球负担，但没有RSV疫苗，目前有 严重呼吸道合胞病毒感染的治疗选择有限。疫苗的努力因早期疫苗的失败而受阻 使用福尔马林灭活呼吸道合胞病毒(FI-RSV)的疫苗尝试导致呼吸增强 一些婴儿的疾病(ERD)和2)啮齿动物模型的缺陷，不能概括关键的方面 人类婴儿呼吸道合胞病毒感染。研究表明，接种FI-RSV疫苗和随后的RSV挑战 偏向Th2细胞介导的免疫病理反应，而先前暴露于活病毒则适当启动 没有ERD的适应性和先天免疫系统。因此，亚单位和灭活的潜力 引起呼吸道合胞病毒病的呼吸道合胞病毒疫苗仍然是呼吸道合胞病毒幼稚的儿科人群特别关注的问题。在这份提案中， 我们在高度相关的RSV临床前模型中提供了一种新的免疫策略，以解决这些问题 疫苗开发的障碍。我们建议测试新的母体免疫策略，以激发 保护母体免疫，检测被动转移中和抗体的保护效果。我们 假设这种方法将在围产期为婴儿提供保护性被动免疫 最易感染呼吸道合胞病毒。我们建议在RSV感染的非人类灵长类动物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……里面 此外，我们将使用这一免疫策略来提高对孕产妇关键方面的理解 免疫包括1)妊娠对疫苗诱导免疫的影响2)母体免疫动力学 中和抗体反应的转移和3)母体免疫和保护的效果 临床相关的婴儿灵长类模型。此外，我们还将定义先天免疫和获得性免疫与 成年猕猴呼吸道合胞病毒感染的保护，对了解缺陷至关重要的信息 在婴儿的肺部环境中。我们预计这些研究将通过以下方式对RSV领域产生催化作用 建立临床前感染模型，以设计和测试孕产妇免疫策略以及 一种高度相关的临床前模型，最接近于人类疾病。

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.