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.

摘要