Pre-clinical Vaccine Development for Respiratory Viruses

呼吸道病毒临床前疫苗开发

• 批准号: 10274170
• 负责人: John Mascola
• 金额: $ 274.8万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274170
• 关键词: Cryoelectron Microscopy; Elderly; Engineering; Glycoproteins; Human; Immunocompromised Host; Individual; Infection; Modification; Mus; Mutation; Newborn Infant; Paramyxovirus; Pneumovirus; Process; Publishing; Rhesus; Structure; Vaccines; base; burden of illness; human pathogen; immunogenicity; nonhuman primate; parainfluenza virus; pathogen; pre-clinical; respiratory; respiratory virus; response; vaccine candidate; vaccine development; vaccine response

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 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 are now in the process of evaluating the neutralization responses of the vaccine candidates in nonhuman primates (NHPs).

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14型（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。我们现在正在评估候选疫苗在非人灵长类动物（NHP）中的中和反应。