Pre-clinical Vaccine Development for Respiratory Viruses

人类副粘病毒和肺炎病毒是广泛传播的病原体，造成相当大的疾病负担。14型副流感病毒（PIV14）是高度传染性的人类病原体，其中PIV3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PIV3 F预融合稳定三聚体的低温电镜结构，我们在四种PIV融合(F)糖蛋白中分别设计突变以稳定其亚稳态预融合状态。候选疫苗能够引起小鼠PIV类型特异性反应，与其他PIV很少交叉中和。在非人灵长类动物（NHPs）中，用来自PIV14的预灌注稳定Fs进行四价免疫，一致诱导对所有四种piv的有效中和反应。

Human paramyxoviruses and pneumoviruses are widespread pathogens, cause considerable disease burden. Parainfluenza virus types 14 (PIV14) 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 mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states. The vaccine candidates were able to elicit murine PIV type-specific response, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV14 consistently induced potent neutralizing responses against all four PIVs.