Rapid generation and testing of live-attenuated vaccines against SARS-CoV-2

快速生成和测试 SARS-CoV-2 减毒活疫苗

• 批准号: 10184147
• 负责人: Steffen Mueller
• 金额: $ 171.65万
• 依托单位: CODAGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-14 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10184147
• 关键词: 2019-nCoV; Administrative Supplement; Adult; African Green Monkey; Age-Years; Algorithms; Antigens; Applications Grants; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; COVID-19; COVID-19 pandemic; Case Study; Cell Culture Techniques; Cells; Cessation of life; China; Clinic; Clinical; Clinical Trials; Codon Nucleotides; Complementary DNA; Containment; Coughing; Country; Cyclic GMP; DNA biosynthesis; Dengue; Development; Disadvantaged; Dose; Engineering; Ensure; Epidemic; Equilibrium; Etiology; Fatigue; Fever; Funding; Future; Generations; Genes; Genetic Transcription; Genome; Genomics; Genotype; Goals; Grant; Health; Human; Immunity; In Vitro; Influenza; Legal patent; Length; Measures; Modeling; Patients; Persons; Phase; Phase I Clinical Trials; Phenotype; Preclinical Testing; Prevention; Primates; Production; Province; Public Health; RNA; Reaction Time; Recovery; Respiratory Syncytial Virus Vaccines; Respiratory Tract Infections; SARS coronavirus; Safety; Severe Acute Respiratory Syndrome; Shortness of Breath; Technology; Telephone; Testing; Therapeutic; Time; Toxic effect; Toxicology; Transfection; Translating; Translations; Vaccine Design; Vaccines; Vero Cells; Viral; Viral Genome; Virus; Virus Replication; Virus Shedding; Work; ZIKA; attenuation; base; clinical material; combat; design; genomic RNA; high risk; immunogenicity; in vivo; in vivo evaluation; influenza virus vaccine; manufacturing scale-up; medical countermeasure; neutralizing antibody; next generation sequencing; novel strategies; older patient; parent grant; phase I trial; preclinical study; prevent; protein expression; public health emergency; respiratory; response; safety testing; screening; seasonal influenza; transmission process; vaccine candidate; vaccine development; whole genome

There is a clear unmet need for a vaccine against the ongoing epidemic of coronavirus disease 2019 (COVID19) caused by SARS-CoV-2. SARS-CoV-2 was initially detected in the Hubei Province of China late in 2019. SARS-CoV-2 is highly contagious (R0 of 1.4-3.9, greater than seasonal influenza), and presents with fever, cough, fatigue, and shortness of breath. Older patients and those with underlying health conditions may be at a higher risk of severe illness, with most reported cases having occurred in adults (median 59 years of age). There are no vaccines or other medical countermeasures available against SARS-CoV-2. This submission is an Administrative Supplement to 1R44AI131756-01 in response to NOT-AI-20-030, where we describe our approach to pre-clinical testing of our SARS-CoV-2 vaccine candidates. In the parent grant application, Codagenix is developing a safe and effective RSV vaccine based on Codagenix’s algorithm-based platform for rapid generation of vaccines. Together, the respiratory illnesses caused by RSV and SARS-CoV-2 present major public health threats. In this administrative supplement, we seek to apply our “synthetic attenuated virus engineering" (SAVE) platform to design and develop a live-attenuated vaccine (LAV) against SARS-CoV-2. SAVE relies on large-scale DNA synthesis and rational re-design of a target virus to construct a vaccine that is “deoptimized” for protein expression in human cells. The SAVE platform has been used to generate vaccines against multiple viruses including influenza, Zika, dengue, RSV, and others. One SAVE-based vaccine is currently in the clinic in Phase I trials under a US IND, and another entering clinical trials in Q1-20, demonstrating the proof of principle behind SAVE. We already initiated the SARS-CoV-2 vaccine development in a real-time response to the ongoing epidemic of SARS-CoV-2. Using our SAVE platform, we designed six vaccine candidates that are deoptimized to varying extents across the RdRp and Spike genes, along with a synthetic wt SARS-CoV-2. These genomes were synthesized de novo, assembled, sequenced, and are now ready for recovery following transfection in cell culture. Candidate vaccine viruses will be recovered under BSL-3 containment, passaged, deep sequenced, and screened for attenuation, immunogenicity and efficacy in a primate model. We expect at least one, but likely 4 viruses will be recovered from transfection. Three of the best-growing viruses (growing to >104 TCID50/ml) will be tested for safety, immunogenicity and efficacy in African green monkeys, previously used for SARS studies. Following the completion of the work described here, using non-grant funding, two of the viruses that perform best in primate studies will be put through GLP toxicity screening, GMP manufacturing and a Phase I clinical trials.

对于由SARS-CoV-2引起的持续流行的2019冠状病毒病（COVID 19）的疫苗有明显的未满足的需求。SARS-CoV-2最初于2019年底在中国湖北省被发现。 SARS-CoV-2具有高度传染性（R 0为1.4-3.9，大于季节性流感），并表现为发热， 咳嗽、疲劳和呼吸急促。老年患者和有潜在健康状况的患者可能会在 严重疾病的风险较高，大多数报告病例发生在成年人中（中位数为59岁）。 目前还没有针对SARS-CoV-2的疫苗或其他医疗对策。这份文件是一份 1 R44 AI 131756 -01的管理补充，以响应NOT-AI-20-030，其中我们描述了我们的 我们的SARS-CoV-2候选疫苗的临床前测试方法。在家长补助申请中， Codagavirus正在基于Codagavirus的算法平台开发一种安全有效的RSV疫苗， 快速生产疫苗。由RSV和SARS-CoV-2引起的呼吸道疾病共同构成了主要的 公共健康威胁。在这份行政补充文件中，我们寻求将我们的“合成减毒病毒 SAVE平台设计和开发针对SARS-CoV-2的减毒活疫苗（LAV）。 SAVE依赖于大规模DNA合成和靶病毒的合理重新设计来构建疫苗， 对于人类细胞中的蛋白质表达而言是“去优化的”。SAVE平台已用于生产疫苗 针对多种病毒，包括流感、寨卡、登革热、RSV等。一种基于SAVE的疫苗 目前在美国IND的I期临床试验中，另一个在Q1-20进入临床试验， 证明了SAVE背后的原理。我们已经启动了SARS-CoV-2疫苗的研发 实时应对正在流行的SARS-CoV-2。使用我们的SAVE平台，我们设计了六个 在RdRp和刺突基因上不同程度去优化的候选疫苗，沿着 合成野生型SARS-CoV-2。这些基因组被从头合成，组装，测序，现在 准备在细胞培养中转染后回收。候选疫苗病毒将在 BSL-3遏制，传代，深度测序，并筛选减毒，免疫原性和有效性， 灵长类动物模型我们预计至少有一种，但可能有4种病毒将从转染中回收。三 将测试生长最好的病毒（生长至>104 TCID 50/ml）的安全性、免疫原性和有效性， 非洲绿色猴，以前用于SARS研究。在完成上述工作后， 在这里，使用非赠款资金，两种在灵长类动物研究中表现最好的病毒将通过GLP 毒性筛选、GMP生产和I期临床试验。