Developing a PIV5-based human metapneumovirus (HMPV) vaccine

开发基于 PIV5 的人类偏肺病毒 (HMPV) 疫苗

• 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
• 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

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阶段的SBIR应用中，我们建议开发鼻内帕拉素氟兰扎病毒5（PIV5）的人类 Metapneumovirus（HMPV）疫苗。 HMPV是急性呼吸道感染（ARIS）的主要原因之一 儿童，免疫功能低下的个人和老年人。疾病范围从无症状感染到严重 支气管炎和肺炎，有90-100％的儿童感染了5-10岁的年龄。没有许可 可以使用HMPV疫苗，并且有未满足的医学需要开发安全有效的HMPV疫苗。 PIV5是鼻内免疫的安全递送载体。 PIV5向量的COVID-19疫苗（CVXGA1）和 呼吸综合病毒（RSV，婴儿和老年人的下呼吸道感染的主要原因）疫苗 目前正在1阶段临床测试中。已经显示了基于PIV5的RSV候选疫苗的临床前数据 在包括棉花大鼠模型在内的各种动物模型中的出色免疫原性，保护和安全概况 证明缺乏疫苗诱导的增强的疾病，在福尔马林灭活的RSV后观察到 疫苗接种。在此赠款建议中，我们将生产两个基于PIV5的HMPV候选疫苗构建体，一个在 带有SH基因的W3A菌株（W3A！SH-HMPV-F），另一个在犬parainfluenza病毒中 （CPI）疫苗菌株（CPI-HMPV-F）以比较其在体外，抗原表达的体外复制， 免疫原性和防止小鼠模型中HMPV挑战感染的保护。疫苗的新颖性 在此阶段I中提出的SBIR应用程序涉及：1）使用含有嵌合的嵌合HMPV F蛋白 PIV5 F细胞质尾巴可能会增加病毒体表面上的HMPV F抗原暴露2）无针 鼻内递送方法在安全，高度免疫原性病毒载体中，3）诱导粘膜的能力 免疫力，这是防止呼吸道病原体的必要条件。一旦PIV5向量的HMPV 疫苗在小鼠模型中已证明是免疫原性的，II期SBIR建议将重点放在 进入1期临床试验所需的临床前研究，其最终目标是产生二价PIV5- 载体的RSV和HMPV疫苗，可为较低的两个主要原因提供保护 婴儿和老年人的呼吸道感染。