Engineering high fidelity mutations to increase safety of live-attenuated alphavirus vaccines

设计高保真突变以提高减毒甲病毒疫苗的安全性

• 批准号: 9300831
• 负责人: Lark L Coffey
• 金额: $ 54.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300831
• 关键词: Adult; Adverse effects; Adverse event; Adverse reactions; Africa; Alphavirus; Americas; Antigen-Presenting Cells; Arthralgia; Arthritis; Asia; Attenuated; Attenuated Live Virus Vaccine; Brain; Cells; Chemicals; Clinical; Clinical Trials; Culicidae; Development; Disease; Dose-Limiting; Encephalitis; Engineering; Formulation; Genetic; Genetic Variation; Genome; Goals; Gold; Human; Immunity; Infection; Kinetics; Laboratories; Lead; Measles; Measures; Morbidity - disease rate; Mus; Muscle; Mutagens; Mutate; Mutation; Organ; Point Mutation; RNA Viruses; Recruitment Activity; Resources; Risk; Safety; Syndrome; Testing; Travel; Tropism; Vaccination; Vaccines; Variant; Venezuelan Equine Encephalitis Virus; Venezuelan Equine Encephalomyelitis; Viral; Viremia; Virulence; Virulent; Virus; Virus Diseases; Virus Replication; Yellow fever virus; attenuation; chikungunya; cost; immunogenic; immunogenicity; improved; lymph nodes; mortality; mouse model; neutralizing antibody; pathogen; pre-clinical; prevent; progenitor; transmission process; treatment strategy; vaccine candidate; vaccine safety; vector; vector mosquito; viral RNA; virus genetics; virus tropism

Project Summary Live-attenuated vaccines are the gold standard for preventing viral illness but they can revert to virulence, sometimes causing severe or fatal disease. The mosquito-borne alphaviruses chikungunya (CHIKV) and Venezuelan equine encephalitis (VEEV) are RNA viruses that produce a debilitating arthritic syndrome or encephalitis, respectively. Both have repeatedly emerged to produce millions of human cases worldwide and CHIKV has expanded into the Americas since 2013, indicating increasing need for vaccines. Although live-attenuated candidate human vaccines have been developed for both viruses, no licensed vaccines currently exist, in part due to adverse events in clinical trials caused by revertant mutations. There is therefore a need to increase the genetic stability of live-attenuated virus vaccine candidates to improve safety. The goal of this project is to develop safe and effective CHIKV and VEEV vaccines to prevent millions of human infections globally each year. Virus variants that mutate less frequently would accrue fewer mutations that confer virulence, and may therefore serve as safer live-attenuated vaccine candidates. This project will use high fidelity variants we already identified and characterized inserted into candidate CHIKV and VEEV vaccines to understand: 1) stability, infectivity, and potential for reversion; 2) whether incorporation of high fidelity mutations improves vaccine safety while maintaining or increasing immunogenicity in established mouse models; and 3) mechanism(s) of attenuation. This approach represents the first use of fidelity modulation to increase safety of live alphavirus vaccine candidates. If successful, this strategy will potentially lead to a broader application of fidelity variants in improving vaccine safety that can be used for other live-attenuated alphavirus vaccine platforms and possibly other RNA viruses.

项目概要 减毒活疫苗是预防病毒性疾病的黄金标准，但它们可以 恢复毒力，有时会导致严重或致命的疾病。蚊子传播的 甲病毒基孔肯雅热 (CHIKV) 和委内瑞拉马脑炎 (VEEV) 是 分别产生使人衰弱的关节炎综合征或脑炎的RNA病毒。 两者都反复出现，在全球范围内产生了数百万例人类病例， 自 2013 年以来，CHIKV 已扩展到美洲，这表明对 疫苗。尽管已开发出候选人类减毒活疫苗 这两种病毒目前都没有获得许可的疫苗，部分原因是由于在 由回复突变引起的临床试验。因此有必要增加 减毒活病毒候选疫苗的遗传稳定性，以提高安全性。目标 该项目的目的是开发安全有效的 CHIKV 和 VEEV 疫苗 每年在全球范围内预防数百万人感染。变异的病毒变种 频率较低会产生较少的赋予毒力的突变，因此可能 作为更安全的减毒活疫苗候选者。该项目将使用高保真 我们已经识别并表征的变体插入候选 CHIKV 中，并且 了解 VEEV 疫苗：1) 稳定性、传染性和逆转潜力； 2） 高保真度突变的掺入是否可以提高疫苗安全性，同时 在已建立的小鼠模型中维持或增加免疫原性；和 3) 衰减机制。这种方法代表了保真度的首次使用 调节以提高活甲病毒疫苗候选物的安全性。如果成功的话，这 策略可能会导致保真度变体在改进方面得到更广泛的应用 可用于其他减毒甲病毒疫苗平台的疫苗安全性 可能还有其他 RNA 病毒。