Pre-clinical Vaccine Development for Respiratory Viruses

人类副粘病毒和肺炎病毒是广泛分布的病原体，造成相当大的疾病负担。副流感病毒1-4型（PIV 1 -4）是高度传染性的人类病原体，其中PIV 3最常导致新生儿、老年人和免疫功能低下个体的严重呼吸道疾病。基于工程化PIV 3 F融合前稳定三聚体的冷冻电子显微镜结构，我们在四种PIV融合（F）糖蛋白中的每一种中设计了与我们先前发表的修饰不同的其他突变，以进一步稳定其亚稳态融合前状态。候选疫苗能够引起鼠PIV类型特异性应答，几乎没有其他PIV的交叉中和。我们评价了候选疫苗在非人灵长类动物（NHP）中的中和反应。 我们将类似的概念和设计应用于hMPV F蛋白。在过去的一年中，我们设计了各种突变以进一步稳定PIV F融合前三聚体和hMPV融合前三聚体。此外，我们设计了将修饰后的三聚体表达在不同纳米颗粒表面作为疫苗免疫原。 我们现在试图评估修饰的三聚体的抗原性，并选择最稳定的三聚体用于小鼠和NHP动物免疫原性研究。动物研究正在积极进行中。

Human paramyxoviruses and pneumoviruses are widespread pathogens, cause considerable disease burden. Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. Based on a cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, we engineered in additional mutations different from our previous published modifications in each of the four PIV fusion (F) glycoproteins to further stabilize their metastable prefusion states. The vaccine candidates were able to elicit murine PIV type-specific response, with little cross-neutralization of other PIVs. We evaluated the neutralization responses of the vaccine candidates in nonhuman primates (NHPs). We applied similar concept and designs to hMPV F proteins. In the past year, we designed various mutations to further stabilize the PIV F prefusion trimers and hMPV prefusion trimers. In addition, we designed expression the modified trimers on the surface of different nanoparticles as vaccine immunogens. We are now trying to evaluate the antigenicity of the modified trimers and we selected the most stable ones for mice and NHP animal immunogenicity study. The animal studies are actively going on.