Development of VLP vaccine for RSV

呼吸道合胞病毒（Respiratory syncytial virus，RSV）是一种严重危害人类健康的重要病原体 影响新生儿和幼儿，但没有疫苗可以保护这些脆弱的人。 人口此外，新生儿的直接疫苗接种可能是无效的， 他们的免疫系统不成熟，新生儿免疫接种可能不安全。的 目前的观点是，孕产妇接种疫苗是保护孕产妇的最佳、最安全的方法。 新生儿通过母体中和抗体在子宫内被动转移到 母体免疫后的胎儿。然而，一个复杂的问题是，大多数人 在他们的一生中经历过RSV感染。因此，任何母体疫苗 必须诱导高水平的保护性抗体存在的预先存在的，但非常 中和性差的抗RSV抗体。 在我们的STTR IIa期项目中，我们测试了我们的新型RSV VLP候选疫苗， 在妊娠棉鼠（一种替代人类模型）中，以确定先前RSV 暴露对诱导这些动物的保护性免疫应答的影响，并评估 免疫母鼠后代的母源抗体转移、保护和安全性。 我们的结果表明，RSV致敏棉鼠的单次VLP免疫刺激了 NA的高滴度。此外，母鼠的VLP免疫可保护其后代免受 与病理学相比，RSV攻毒和幼仔肺部病理学降低 在未免疫母鼠的后代RSV感染后观察到。我们还发现 用含有不同形式的融合前F 蛋白质在接种疫苗的母鼠的后代的保护程度上变化显著。我们 鉴定了一种融合前F VLP，其将后代保护提高了10倍 与最初测试的预F VLP相比。 我们的目标是将我们的VLP候选疫苗推向临床试验， 母亲疫苗为此，我们提出了三个具体的任务，使用棉鼠作为 人类替代品 任务1：制定生产和纯化成本的方案和流程 有效的GMP VLP候选疫苗。 任务2：完善孕产妇免疫后新生儿保护参数。 任务3：评估和改善母亲分娩后的保护反应。

Respiratory syncytial virus (RSV) is a significant human pathogen severely impacting neonates and young children, but no vaccine exists to protect this vulnerable population. Furthermore, direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, and neonate immunization is potentially unsafe. The current view is that maternal vaccination is the best and safest approach to protection of neonates through the passive transfer of maternal neutralizing antibodies in utero to the fetus after maternal immunization. However, a complicating issue is that most people have experienced RSV infections during their lifetimes. Thus, any maternal vaccine must induce high levels of protective antibodies in the presence of pre-existing, but very poorly neutralizing, anti-RSV antibodies. In our STTR phase IIa project, we tested our novel RSV VLP vaccine candidates in pregnant cotton rats, a surrogate human model, to determine the effect of prior RSV exposure on induction of protective immune responses in these animals and to assess maternal antibody transfer, protection, and safety in offspring of the immunized dams. Our results showed that a single VLP immunization of RSV primed cotton rats stimulated high titers of NA. Furthermore, VLP immunization of dams protected their offspring from RSV challenge and decreased pathology in pups' lungs compared to pathology observed after RSV infection of offspring of unimmunized dams. We also found that maternal immunizations with VLPs containing different versions of the pre-fusion F protein varied significantly in the extent of protection of offspring of vaccinated dams. We identified one version of pre-fusion F VLPs that improved protection of offspring ten-fold compared to the originally tested pre-F VLP. It is our goal to move our VLP vaccine candidates toward clinical trials as a maternal vaccine. To this end, we propose three specific tasks using cotton rats as human surrogates. Task 1: Develop protocols and processes for production and purification of cost effective GMP VLP vaccine candidates on a large scale. Task 2: Refine parameters of protection of neonates after maternal immunization. Task 3: Assess and improve protective responses in mothers post-delivery.