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Development of live attenuated respiratory syncytial virus vaccines with novel thermal stable fusion protein

新型热稳定融合蛋白呼吸道合胞病毒减毒活疫苗的研制

基本信息

批准号：
9410335
负责人：
Martin Lawrence Moore
金额：
$ 22.41万
依托单位：
MEISSA VACCINES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9410335
关键词：
1 year old 2 year old Ablation Age Animals Attenuated Attenuated Live Virus Vaccine Birth Caregivers Caring Cells Cessation of life Characteristics Child Chimeric Proteins Clinical Clinical Research Clinical Trials Codon Nucleotides Contracts Cotton Rats Cyclic GMP Data Data Analyses Development Disease Dose Down-Regulation Electroporation Engineering Epidemiology Epithelial Epithelial Cells Equilibrium Evaluation Exhibits Formalin Generations Genes Genetic Genomics Goals Health Priorities Hospitalization Human Hydrophobicity Immune response Immunity Immunize Immunoglobulin A In Vitro Income Infant Infection Lead Life Lower Respiratory Tract Infection Manufacturer Name Maternal antibody Measures Medical Modeling Molecular Conformation Mus Mutation Natural History Nose Outcome Study Paper Pharmacology Study Phase Phenotype Plasmids Point Mutation Pre-Clinical Model Preparation Preventive vaccine Process Property Proteins Public Health Publishing Reagent Reporter Genes Research Respiratory Process Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Safety Seeds Serum Silent Mutation Structure Subgroup Translations Vaccinated Vaccine Production Vaccines Variant Vero Cells Viral Viral Genome Viral Proteins Virulence Virus Virus Diseases World Health Organization attenuation base cGMP production clinical candidate clinical development cohort cost fusion gene global health immunogenic immunogenicity immunopathology improved in vivo innovation neutralizing antibody novel pathogen pre-clinical productivity loss protein expression reconstitution respiratory unpublished works vaccine candidate vector vaccine

项目摘要

Respiratory syncytial virus (RSV) can cause lower respiratory illness (LRI) in otherwise healthy children and developing an effective prophylactic vaccine to mitigate RSV disease in infants is a public and global health priority according to the World Health Organization. The overall goal of this project is to develop a safe and efficacious RSV vaccine for immunizing sero-negative 4 months to 2 years old infants, who are beyond the reach of protective RSV maternal antibodies, against RSV hospitalizations and medically attended LRI. Globally, there are 34 million new RSV infections annually with 3.4 million hospitalizations and 66,000 to 199,000 deaths. Although most people are infected in the first year of life, recurring RSV infections occur throughout life. It was estimated that in the US, 2 million children under the age of 5 required care for RSV infections annually and 78% are over the age of one year. In the US, medical costs for managing RSV disease in infants were estimated at $1.15 billion annually with additional lost income and caregiver costs estimated at $625 million annually. Vaccinating the birth cohort with a RSV vaccine that has 50% efficacy and protection for 12 months was estimated to reduce medical costs by $236 million and income and productivity losses by $134 million annually in the US. A live attenuated RSV vaccine mimics natural RSV infection. RSV epidemiology and natural history studies have demonstrated that natural infection results in lasting protection against severe RSV disease. The Moore lab recently published on a vaccine candidate that was uniquely engineered to replicate like wild-type virus in infected cells and yet is less able to spread because of the down-regulation of virulence genes. The attenuation phenotype is stable because it is conferred by hundreds of mutations in the RSV genome. The other distinguishing characteristic is a proprietary fusion protein that is enriched for the more immunogenic pre- fusion conformation. The combination of these properties resulted in high levels of attenuation in cotton rats with almost wtRSV level neutralizing antibodies and complete protection against wtRSV challenge making this a promising vaccine candidate for clinical development. In Phase 1 the objectives are to generate research stocks of two live attenuated RSV vaccine candidates called OE4 and DB1Quad and establish a pre-seed process that can be transferred to a cGMP facility for initiation of vaccine production. In Phase 2, we will evaluate attenuation of OE4 and DB1Quad in human airway epithelial cells ex vivo and in cotton rats in vivo and perform studies in cotton rats to verify that they do not cause RSV vaccine-enhanced disease. The outcome of these studies will allow Meissa complete IND-enabling pharmacology studies and to prioritize a lead candidate for clinical development.

呼吸道合胞病毒（RSV）可引起其他健康儿童的下呼吸道疾病（LRI）