A parainfluenza virus 5 (PIV5)-based bivalent vaccine for respiratory syncytial virus (RSV) and human metapneumovirus (HMPV)

基于副流感病毒 5 (PIV5) 的呼吸道合胞病毒 (RSV) 和人类偏肺病毒 (HMPV) 的二价疫苗

• 批准号: 10644266
• 负责人: Maria Cristina Gingerich
• 金额: $ 15.7万
• 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: 2023-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644266
• 关键词: 10 year old; 2 year old; Acute; Acute respiratory infection; Adjuvant; Affect; Age; Antibodies; Antibody Response; Antigens; Binding; Biological Assay; Blood group antigen f; Bronchiolitis; Canis familiaris; Cells; Child; Childhood; Chimeric Proteins; Cytoplasmic Tail; Data; Disease; Distemper; Dose; Elderly; Epitopes; FDA approved; GTP-Binding Proteins; Genes; Genome; Glycoproteins; Goals; Growth; Hospitalization; Human; Human Metapneumovirus; Immune response; Immunization; Immunocompromised Host; Immunodominant Epitopes; Immunofluorescence Immunologic; Immunoglobulin G; In Vitro; Individual; Infant; Infection; Influenza; Integral Membrane Protein; Kinetics; Licensing; Lower Respiratory Tract Infection; Lower respiratory tract structure; Mediating; Medical; Methods; Mind; Modification; Molecular Conformation; Monoclonal Antibodies; Mucosal Immunity; Mus; Needles; Phase I Clinical Trials; Phenotype; Plasmids; Pneumonia; Proteins; Public Health; RNA; Rabies; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; SARS coronavirus; Safety; Serum; Site; Structure; Surface; Symptoms; Tail; Target Populations; Testing; Transfection; Transmembrane Domain; Upper Respiratory Infections; Upper respiratory tract; Vaccination; Vaccines; Vero Cells; Vertebral column; Viral Vector; Virus; Virus Diseases; cell mediated immune response; combat; delivery vehicle; design; immunogenic; immunogenicity; improved; in vivo; in vivo evaluation; mouse model; neutralizing antibody; novel; older patient; parainfluenza virus; pathogen; pathogenic virus; pediatric patients; protective efficacy; protein expression; protein purification; recombinant virus vaccine; research clinical testing; respiratory pathogen; success; vaccine access; vaccine candidate; vaccine development; vaccine efficacy; vaccine platform; vector; vector vaccine

ABSTRACT In this R21 application, we propose to develop a universal, intranasal, parainfluenza virus 5 (PIV5)-based respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) bivalent vaccine. RSV and HMPV are two 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 with RSV by 2 years of age, and HMPV between the ages of 5-10 years old. No licensed RSV or HMPV vaccine is available and there is an unmet medical need to develop safe and effective vaccines for both diseases. A recent proof-of-principle study has shown that it is possible to create a chimeric F protein (RHMS-1) by combining immunodominant epitopes from RSV F and HMPV F that retains antigenicity for both viruses, the purified protein is immunogenic and protective against RSV and HMPV challenge in mice. However, this purified protein requires an adjuvant and a multi-dose approach, the cell-mediated immune response was not studied, the duration of the antibody response has not been determined, and there is a potential safety concern for children due to the high dose of protein required for the vaccine to be immunogenic. PIV5 is a safe delivery vector for intranasal immunization. A PIV5-vectored RSV candidate vaccine (BLB-201) has already been cleared by the FDA for a phase I clinical trial this year (NCT05281263). Due to the similarities between RSV and HMPV F proteins, disease manifestation, and target populations, a bivalent vaccine is desirable to protect against ARI diseases caused by both viruses. Here, we propose to introduce the RHMS-1 novel sequence into the PIV5- vectored vaccine platform. We will also make a modification to the RHMS-1 sequence to improve F protein expression and its immunogenicity. The constructs to be evaluated include: 1) RHMS-1 pre-fusion; and 2) RHMS-1 pre-fusion form with the trimerization domain replaced with the transmembrane domain and cytoplasmic tail from the PIV5 F protein. The candidate vaccine viruses will be compared for their replication and antigen expression in vitro, and immunogenicity and protective efficacy against RSV and HMPV challenge infection in vivo. The novelty of the vaccine proposed in this R21 application relates to: 1) the use of a chimeric RSV+HMPV F protein against two pathogens (bivalent vaccine); 2) a needle-free intranasal delivery method in a safe, highly immunogenic viral vector; 3) ease of administration; and 4) the ability to induce cellular and antibody responses including mucosal immunity, which is necessary for protecting against respiratory pathogens. The project is very promising in generating an effective bivalent vaccine that could provide protection against the two leading causes of acute lower respiratory tract infections in children and older adults.

抽象的 在此 R21 应用中，我们建议开发一种基于鼻内的通用副流感病毒 5 (PIV5) 呼吸道合胞病毒（RSV）和人类偏肺病毒（HMPV）二价疫苗。 RSV 和 HMPV 是 儿童、免疫功能低下个体急性呼吸道感染 (ARIs) 的两个主要原因， 和老人。疾病范围从无症状感染到严重细支气管炎和肺炎，90-100% 2 岁以下儿童感染 RSV，5-10 岁儿童感染 HMPV。没有许可 RSV 或 HMPV 疫苗已经可用，但开发安全有效的疫苗的医疗需求尚未得到满足 对于这两种疾病。最近的一项原理验证研究表明，创建嵌合 F 蛋白是可能的 (RHMS-1) 通过组合来自 RSV F 和 HMPV F 的免疫显性表位，保留了两者的抗原性 病毒，纯化的蛋白质具有免疫原性，并能保护小鼠免受 RSV 和 HMPV 的攻击。然而， 这种纯化的蛋白质需要佐剂和多剂量方法，细胞介导的免疫反应是 未研究，抗体反应持续时间尚未确定，存在潜在安全性 由于疫苗需要高剂量的蛋白质才能具有免疫原性，因此引起了儿童的关注。 PIV5 是一个安全的 用于鼻内免疫的递送载体。 PIV5 载体 RSV 候选疫苗 (BLB-201) 已经上市 今年获得 FDA 批准进行 I 期临床试验（NCT05281263）。由于 RSV 和 RSV 之间的相似之处 HMPV F 蛋白、疾病表现和目标人群，需要二价疫苗来预防 由这两种病毒引起的 ARI 疾病。在这里，我们建议将 RHMS-1 新颖序列引入 PIV5- 载体疫苗平台。我们还将对RHMS-1序列进行修饰以改进F蛋白 表达及其免疫原性。待评估的构建体包括： 1) RHMS-1 预融合；和 2) RHMS-1预融合形式，其中三聚结构域被跨膜结构域和细胞质结构域取代 来自 PIV5 F 蛋白的尾部。将比较候选疫苗病毒的复制和抗原 体外表达，以及对 RSV 和 HMPV 攻击感染的免疫原性和保护功效 体内。 R21申请中提出的疫苗的新颖性涉及：1）使用嵌合RSV+HMPV 针对两种病原体的F蛋白（二价疫苗）； 2）无针鼻内给药方法，安全、高效 免疫原性病毒载体； 3）易于管理； 4) 诱导细胞和抗体反应的能力 包括粘膜免疫，这是防御呼吸道病原体所必需的。该项目非常 有希望产生一种有效的二价疫苗，可以针对两种主要原因提供保护 儿童和老年人的急性下呼吸道感染。