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应用程序中，我们建议开发一种普遍的鼻内，副膜粉病毒5（PIV5）的基于 呼吸综合病毒（RSV）和人元病毒（HMPV）二价疫苗。 RSV和HMPV是 儿童急性呼吸道感染（ARI）的两个主要原因，免疫功能低下的个体， 和老人。疾病的范围从无症状感染到严重的细支气管炎和肺炎，有90-100％ 在2岁时感染了RSV的儿童以及5-10岁的HMPV。没有许可 RSV或HMPV疫苗可用，并且有未满足的医疗需求以开发安全有效的疫苗 对于这两种疾病。最新的原则研究表明，可以创建嵌合F蛋白 （RHMS-1）通过将RSV F和HMPV F的免疫主导表位结合在一起，该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，可保护小鼠RSV和HMPV挑战。然而， 这种纯化的蛋白需要辅助和多剂量方法，细胞介导的免疫反应为 未研究，尚未确定抗体反应的持续时间，并且存在潜在的安全性 由于疫苗是免疫原性所需的高剂量蛋白质而引起的儿童的关注。 PIV5是安全的 鼻内免疫的递送载体。 PIV5向量的RSV候选疫苗（BLB-2011）已经是 由FDA清除今年的I期临床试验（NCT05281263）。由于RSV和 HMPV F蛋白，疾病表现和靶种群，需要一种二价疫苗来防止 两种病毒引起的ARI疾病。在这里，我们建议将RHMS-1的新序列引入PIV5- 矢量疫苗平台。我们还将对RHMS-1序列进行修改以改善F蛋白 表达及其免疫原性。要评估的构建体包括：1）RHMS-1融合；和2） RHMS-1的前融合形式与跨膜结构域和细胞质取代了三聚化结构域 PIV5 F蛋白的尾巴。将比较候选疫苗病毒的复制和抗原 在体外表达，免疫原性和针对RSV和HMPV挑战感染的免疫原性和保护性疗效 体内。此R21应用中提出的疫苗的新颖性与：1）使用嵌合RSV+HMPV F蛋白针对两种病原体（二价疫苗）； 2）在安全性高度的安全性中无针鼻内递送方法 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，这是防止呼吸道病原体所必需的。该项目非常 有望产生有效的二价疫苗，该疫苗可以为两个主要原因提供保护 儿童和老年人的急性下呼吸道感染。