(Not Active) Novel approach for development of live & inactivated viral vaccines

（不活跃）实时开发的新方法

• 批准号: 8260254
• 负责人: Aaron Cole Brault
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260254
• 关键词: Acute; Amino Acid Substitution; Attenuated; Cells; Characteristics; Codon Nucleotides; Country; Development; Directed Molecular Evolution; Disease; Emerging Communicable Diseases; Engineering; Genetic Recombination; Immune response; Infection; Infectious Diseases Research; Life; Mediating; Methodology; MicroRNAs; Modification; Pathology; Phenotype; Population; Production; Proteins; Regulation; Safety; Serial Passage; Time; Tissues; Translations; Uncertainty; Vaccines; Viral; Viral Genome; Viral Vaccines; Virus; Virus Diseases; attenuation; base; biodefense; design; improved; novel; novel strategies; pathogen; prophylactic; vaccine candidate; vaccine development; vaccine safety

Currently, no vaccines exist for a significant number of historically important viral pathogens and newly emerging viral zoonotic disease threats. In part, this situation results from the incompatibility of existing methodologies with the challenges posed by a wide array of emerging viruses. The extent of attenuation mediated by approaches such as serial passaging of viruses, viral recombination and directed molecular evolution is unpredictable and this characteristic contributes to the lengthy production times for many vaccines made using these strategies. Likewise, a number of vaccines constructed using these methodologies have demonstrated poor safety profiles due to the inherent uncertainty in the number of attenuation determinants introduced. In this study we aim to further define a novel strategy to intuitively construct live-attenuated viral (LAV) vaccines applicable to the development of vaccines to a broad array of acute viral diseases. Our approach is based on the manipulation of host strategies for the regulation of protein translation. We hypothesize that use of rare codons as attenuation determinants for vaccine candidates will produce more stably attenuated viruses that can be rationally engineered with predictable replication phenotypes within host cells. Moreover, we have demonstrated that these substitutions can be introduced into various places in viral genomes, unlike amino acid substitutions which are conventionally employed to attenuate viruses. We have also designed a second strategy to further improve the safety of vaccines that restricts the replication of vaccine viruses in tissues that are responsible for engendering disease pathology. By introducing the target sequences for tissue-specific miRNAs into the viral genome we have demonstrated the ability to specifically block infection of target cells expressing the cognate miRNA, while permitting normal unaltered levels of replication in the cell populations required for the induction of a protective immune response. Importantly, this strategy is compatible with the modification of existing vaccines to improve their safety profiles. The approaches defined in this study have broad implications for the rapid development of prophylactic agents to a variety of disease threats.

目前，对于许多历史上重要的病毒病原体和新发现的病毒病原体，还没有疫苗