Developing a PIV5-based human metapneumovirus (HMPV) vaccine

开发基于 PIV5 的人类偏肺病毒 (HMPV) 疫苗

基本信息

批准号：
10698491
负责人：
Maria Cristina Gingerich
金额：
$ 25万
依托单位：
CYANVAC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-05 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698491
关键词：
10 year old 2019-nCoV Acute respiratory infection Adenoviruses Age Amino Acid Sequence Animal Model Antibodies Antigens Applications Grants Attenuated Biological Assay Blood group antigen f Bronchiolitis COVID-19 vaccine Canis familiaris Cells Child Classification Cotton Rats Cytoplasmic Tail Data Disease Distemper Dose Elderly Equilibrium Family Formalin GTP-Binding Proteins Gene Deletion Gene Proteins Genes Genetic Genome Glycoproteins Goals Growth Hospitalization Human Human Metapneumovirus Immune response Immunization Immunocompromised Host Immunofluorescence Immunologic In Vitro Inbred BALB C Mice Individual Infant Infection Kinetics Licensing Lower Respiratory Tract Infection Lower respiratory tract structure Medical Methods Modeling Monoclonal Antibodies Mucosal Immunity Mucous Membrane Needles Parainfluenza Phase Phase I Clinical Trials Pneumonia Pneumovirus Proteins Public Health RNA Regimen Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Rhinovirus SARS-CoV-2 spike protein Safety Serum Small Business Innovation Research Grant Surface Symptoms Testing Upper Respiratory Infections Upper respiratory tract Vaccination Vaccines Vero Cells Vertebral column Vial device Viral Vector Virion Virus combat cross immunity delivery vehicle immunogenic immunogenicity in vivo evaluation influenzavirus lead candidate mouse model novel older patient parainfluenza virus pathogenic virus pediatric patients pre-clinical preclinical study programs protective efficacy protein expression recombinant virus vaccine research clinical testing respiratory pathogen success vaccine candidate vaccine development vaccine efficacy vaccine immunogenicity vector vector vaccine

项目摘要

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.

抽象的在此 I 期 SBIR 应用中，我们建议开发一种鼻内、基于副流感病毒 5 (PIV5) 的人类偏肺病毒（HMPV）疫苗。 HMPV 是急性呼吸道感染 (ARI) 的主要原因之一儿童、免疫功能低下的个体和老年人。病情范围从无症状感染到重症细支气管炎和肺炎，90-100%的5-10岁儿童感染。没有许可 HMPV 疫苗已经可用，但开发安全有效的 HMPV 疫苗的医疗需求尚未得到满足。 PIV5 是一种用于鼻内免疫的安全递送载体。 PIV5 载体的 COVID-19 疫苗 (CVXGA1) 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）疫苗目前正在进行一期临床测试。基于 PIV5 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）中具有出色的免疫原性、保护性和安全性，证明福尔马林灭活 RSV 后观察不到疫苗诱导的增强疾病疫苗接种。在这项拨款提案中，我们将生产两种基于 PIV5 的 HMPV 候选疫苗结构，一种在 SH 基因缺失的 W3A 毒株 (W3A!SH-HMPV-F) 和犬副流感病毒中的另一种毒株（CPI）疫苗株（CPI-HMPV-F）比较其体外复制、体外抗原表达，免疫原性，以及在小鼠模型中针对 HMPV 攻击感染的保护作用。疫苗的新颖性该 I 期 SBIR 申请中提出的方案涉及：1) 使用含有以下成分的嵌合 HMPV F 蛋白： PIV5 F 胞质尾部可潜在增加病毒体表面上 HMPV F 抗原的暴露 2) 无针安全、高免疫原性病毒载体的鼻内递送方法以及 3) 诱导粘膜的能力免疫力，这是防御呼吸道病原体所必需的。一旦PIV5载体HMPV 疫苗在小鼠模型中被证明具有免疫原性，II 期 SBIR 提案将重点关注进入 1 期临床试验所需的临床前研究，最终目标是产生二价 PIV5- RSV 和 HMPV 载体疫苗可针对导致低死亡率的两个主要原因提供保护婴儿和老年人的呼吸道感染。