Developing a PIV5-based human metapneumovirus (HMPV) vaccine

摘要 在该I期SBIR应用中，我们建议开发一种鼻内的、基于副流感病毒5（PIV 5）的人 偏肺病毒（HMPV）疫苗。HMPV是急性呼吸道感染（阿里斯）的主要原因之一， 儿童、免疫受损个体和老年人。病情从无症状感染到严重 细支气管炎和肺炎，90-100%的儿童在5-10岁之间感染。没有获得许可的 HMPV疫苗是可用的，并且存在开发安全有效的HMPV疫苗的未满足的医学需求。 PIV 5是一种安全的鼻内免疫递送载体。携带PIV 5的COVID-19疫苗（CVXGA 1）和 呼吸道合胞病毒（RSV，婴儿和老年人下呼吸道感染的主要原因）疫苗 目前正在进行第一阶段的临床试验。基于PIV 5的RSV候选疫苗的临床前数据显示， 在各种动物模型，包括棉鼠模型， 证明在福尔马林灭活RSV后观察到缺乏疫苗诱导的增强疾病 预防针在这项拨款提案中，我们将生产两种基于PIV 5的HMPV候选疫苗构建体，一种在 SH基因缺失的W3 A株（W3 A！SH-HMPV-F）和另一种犬副流感病毒 (CPI)疫苗株（CPI-HMPV-F），比较它们的体外复制，体外抗原表达， 免疫原性和针对HMPV攻击感染的保护。疫苗的新奇 在该I期SBIR申请中提出的方法涉及：1）使用嵌合HMPV F蛋白，其含有 PIV 5 F胞质尾区可能增加病毒体表面上的HMPV F抗原暴露2）无针 在安全的、高免疫原性的病毒载体中的鼻内递送方法和3）诱导粘膜免疫的能力， 免疫力，这是必要的，以防止呼吸道病原体。一旦PIV 5-矢量化HMPV 疫苗在小鼠模型中被证明具有免疫原性，第二阶段SBIR提案将重点关注 进入I期临床试验所需的临床前研究，最终目标是产生二价PIV 5- 载体RSV和HMPV疫苗，可提供保护，防止两种主要原因， 婴幼儿和老年人呼吸道感染。

ABSTRACT In this Phase I SBIR application, we propose to develop an intranasal, parainfluenza virus 5 (PIV5)-based human metapneumovirus (HMPV) vaccine. HMPV is one of the leading causes of acute respiratory infections (ARIs) in children, immunocompromised individuals, and the elderly. Illness ranges from asymptomatic infection to severe bronchiolitis and pneumonia, with 90-100% of children infected between the ages of 5-10 years old. No licensed HMPV vaccine is available and there is an unmet medical need to develop a safe and effective HMPV vaccine. PIV5 is a safe delivery vector for intranasal immunization. The PIV5-vectored COVID-19 vaccine (CVXGA1) and respiratory syncytial virus (RSV, a leading cause of lower respiratory tract infection in infants and elderly) vaccine are currently in Phase 1 clinical testing. Preclinical data for PIV5-based RSV candidate vaccines have shown excellent immunogenicity, protection, and safety profiles in various animal models, including the cotton rat model, demonstrating lack of vaccine-induced enhanced disease observed following formalin-inactivated RSV vaccination. In this grant proposal, we will produce two PIV5-based HMPV candidate vaccine constructs, one in the W3A strain with the SH gene deleted (W3A!SH-HMPV-F) and another in the canine parainfluenza virus (CPI) vaccine strain (CPI-HMPV-F) to compare their replication in vitro, antigen expression in vitro, immunogenicity, and protection against HMPV challenge infection in a mouse model. The novelty of the vaccine proposed in this Phase I SBIR application relates to: 1) the use of a chimeric HMPV F protein containing the PIV5 F cytoplasmic tail to potentially increase HMPV F antigen exposure on the virion surface 2) a needle-free intranasal delivery method in a safe, highly immunogenic viral vector and 3) the ability to induce mucosal immunity, which is necessary for protecting against respiratory pathogens. Once the PIV5-vectored HMPV vaccine is demonstrated to be immunogenic in the mouse model, the Phase II SBIR proposal will focus on preclinical studies needed for entering Phase 1 clinical trials with the final goal of generating a bivalent PIV5- vectored RSV and HMPV vaccine which would provide protection against the two leading causes of lower respiratory tract infections in infants and elderly.