Development of VLP vaccine for RSV

呼吸道合胞病毒(RSV)是严重危害人类健康的重要病原体 影响新生儿和幼儿，但没有疫苗保护这一脆弱群体 人口。此外，直接为新生儿接种疫苗可能无效，因为 他们的免疫系统不成熟，新生儿免疫可能不安全。这个 目前的观点是，孕妇接种疫苗是预防疟疾的最好和最安全的方法。 通过被动地将母体中和抗体在子宫内转移给新生儿 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呼吸道合胞病毒感染。因此，任何母体疫苗 必须在预先存在的情况下诱导高水平的保护性抗体，但 中和能力差，抗RSV抗体。 在我们的STTR IIa阶段项目中，我们测试了我们的新型RSV VLP候选疫苗 在怀孕的棉花大鼠中，建立代用人类模型，以确定先前RSV的效果 在这些动物中诱导保护性免疫反应的暴露并评估 免疫母体抗体的转移、保护和子代的安全性。 我们的结果表明，一次VLP免疫对RSV免疫的棉花大鼠有刺激作用 高滴度的NA。此外，水坝的VLP免疫接种保护它们的后代免受 与病理相比，RSV攻击和幼鼠肺部病理降低 未免疫母鸡子代感染RSV后观察。我们还发现， 用含有不同版本融合前F的VLP进行母体免疫 在对接种疫苗的后代的保护程度上，蛋白质的差异很大。我们 确定了一种融合前VLP版本，将对后代的保护提高了十倍 与最初测试的Pre-F VLP相比。 我们的目标是将我们的VLP候选疫苗作为一种 母体疫苗。为此，我们提出了三个具体的任务，使用棉花鼠作为 人类的代孕。 任务1：制定生产和成本净化的协议和流程 大规模有效的GMP VLP候选疫苗。 任务2：完善产妇免疫后新生儿保护的参数。 任务3：评估和改进母亲产后的保护性反应。

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.