Development of VLP vaccine for RSV

 描述（由申请方提供）：呼吸道合胞病毒（RSV）是对人类健康的重大威胁，最严重影响三大人群：婴儿、幼儿和老年人。尽管RSV疾病在这些不同人群中具有重要意义，但没有可用的疫苗。该II期STTR项目的目标是继续临床前试验， 一种新的RSV候选疫苗，一种不同于任何先前测试的候选疫苗。该候选物是建立在纽卡斯尔病病毒核心蛋白M和NP上的病毒样颗粒（VLP），并且含有插入颗粒膜中的RSV/AF和G蛋白。目的是确定VLP作为疫苗的潜力，为每个人群的严重疾病的风险，使用良好表征的棉鼠模型作为这些群体的替代品。具体目标1：优化幼龄动物的保护性反应。 2-5岁的儿童在RSV疾病负担中占很大比例，并可能成为新生儿感染的宿主。该年龄组被认为比新生儿（0-6月龄组）具有更少的安全性限制，并且最有可能是应认真考虑直接接种疫苗的人群。因此，对于VLP作为该群体的疫苗的用途，将通过测试VLP递送的不同途径和用于针对RSV/B感染的交叉保护的VLP制剂的选择来优化幼龄动物中的免疫应答。具体目标2：确定母体免疫在保护新生儿方面的有效性由于新生儿免疫系统的不成熟、安全性问题以及母体抗体对疫苗保护的抑制，新生儿直接接种疫苗可能无效。另一种方法是通过母体疫苗接种保护新生儿免受RSV感染，这将增强和延长母体中和抗体向胎儿的被动转移。因此，将通过RSV攻毒后幼鼠肺和鼻组织中的病毒滴度来测量未经处理和经历过RSV的母鼠VLP接种对棉鼠幼鼠的保护作用。此外，将通过测量幼仔RSV攻毒后的肺组织学来确定子代中母体免疫的安全性。具体目标3：评估VLP免疫在老年人群中的有效性老年人的免疫系统不如年轻人的免疫系统活跃，因此对候选疫苗的反应可能与年轻人不同。此外，老年人群在其一生中经历过RSV感染。因此，将通过病毒攻击后的血清应答和肺中的病毒滴度来评估不同剂量和途径的VLP免疫对未感染和经历RSV的老年棉鼠的保护，以评价该群体中的不同疫苗接种策略

 DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is a substantial threat to human health most severely affecting three large populations, infants, young children, and the elderly. Despite the significance of RSV disease in these different populations, there are no vaccines available. The goal of this Phase II STTR project is to continue preclinical testing of a novel RSV vaccine candidate, a candidate unlike any previously tested. This candidate is a virus-like particle (VLP) built on the Newcastle disease virus core proteins, M and NP, and containing the RSV/A F and G proteins inserted into the membrane of the particle. The objective is to determine the potential of VLPs as a vaccine for each of the human populations at risk for serious disease using well-characterized cotton rats models as surrogates for these groups. Specific aim 1: Optimize protective responses in young animals. Children from 2-5 years of age comprise a substantial proportion of RSV illness burden and likely provide a reservoir for infection of newborns. This age group is considered to have less safety constrains than the newborn, 0-6 month age group, and is, most likely, the population where direct vaccination should be seriously considered. Thus for use of VLPs as a vaccine for this population, the immune responses in young animals will be optimized by testing different routes of VLP delivery and options for VLP formulations for cross protection from RSV/B infections. Specific aim 2: Determine the efficacy of maternal immunization in protection of neonates Direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, safety concerns, and inhibition of vaccine protection by maternal antibodies. An alternative approach is protection of newborns from RSV infections through maternal vaccination that will enhance and extend passive transfer of maternal neutralizing antibodies to the fetus. Thus, the protection of cotton rat pups by VLP vaccination of naïve and RSV experienced mothers will be measured by virus titer in the pups' lungs and nasal tissue after RSV challenge. In addition, safety of maternal immunization in offspring will be determined by measuring lung histology after RSV challenge of pups. Specific aim 3: Assess efficacy of VLP immunization in elderly populations Elderly immune systems are less vigorous than younger adult populations, thus the responses to a vaccine candidate may be different than those of younger adults. Furthermore, the elderly population has experienced RSV infections in their lifetime. Therefore the protection of both naïve and RSV experienced elderly cotton rats by different doses and routes of VLP immunization will be assessed by serum responses and virus titers in lungs after virus challenge to evaluate different strategies of vaccination in this population