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， 每年都有新的感染。尽管存在这种显著的全球负担，但没有RSV疫苗，并且目前存在 严重RSV感染的治疗选择有限。疫苗接种的努力受到了以下因素的阻碍：1）早期疫苗接种的失败 使用福尔马林灭活的RSV（FI-RSV）的疫苗尝试导致呼吸道感染增强的发生， 疾病（ERD）在一些婴儿和2）啮齿动物模型的缺陷，不重述的关键方面， 人婴儿RSV感染。研究表明，FI-RSV疫苗接种和随后的RSV攻毒 使Th 2细胞介导的应答偏向免疫病理学，而先前暴露于活病毒适当地引发 没有ERD的适应性和先天性免疫系统。因此，亚基和失活的可能性 RSV疫苗引起ERD仍然是RSV初治儿科人群的一个特别关注问题。在这一提议中， 我们在RSV的高度相关的临床前模型中提供了一种新的免疫策略， 疫苗开发的障碍。我们建议测试新的母体免疫策略， 保护性母体免疫，并测试中和抗体被动转移的保护效力。我们 假设这种方法将在围产期期间为婴儿提供保护性被动免疫， 最大的RSV易感性。我们建议在RSV感染的非人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 此外，我们将利用这一免疫战略，以提高对孕产妇死亡的关键方面的了解。 包括1）妊娠对疫苗诱导免疫的影响2）母体免疫的动力学 中和抗体应答的转移和3）母亲免疫和保护的效力， 临床相关的幼年灵长类动物模型。此外，我们将定义先天性和适应性免疫相关的 保护成年猕猴的RSV感染，这将是关键的信息，以了解缺陷 在婴儿的肺部环境中。我们预计这些研究将对RSV领域产生催化作用， 建立一个临床前感染模型，用于设计和测试孕产妇免疫策略， 一个高度相关的临床前模型，最接近模拟人类疾病。

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.