Autonomously deploying, co-evolving SARS-CoV-2 antiviral: a new paradigm for pandemic prevention

自主部署、共同进化的 SARS-CoV-2 抗病毒药物：预防大流行的新范例

• 批准号: 10845714
• 负责人: Robert Rodick
• 金额: $ 199.71万
• 依托单位: VXBIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10845714
• 关键词: 2019-nCoV; Ablation; Animal Model; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Attenuated Vaccines; Cells; Communicable Diseases; Complement; Culicidae; Development; Disease; Disease Progression; Dose; Elements; Engineering; Ethics; Evolution; Formulation; Gene Mutation; General Population; Genetic Drift; HIV; Herd Immunity; Immune Evasion; Individual; Infection; Intervention; Libraries; Life; Low Prevalence; Molecular; Mutate; Mutation; Parasites; Pharmacologic Substance; Phase I Clinical Trials; Population; Prevalence; Property; Proteins; Randomized; Resistance; Resolution; Rest; Risk Factors; Rodent; Route; SARS-CoV-2 antiviral; SARS-CoV-2 variant; Safety; Starvation; T-Lymphocyte; Testing; Theft; Therapeutic; Trans-Activators; Transgenes; United States National Institutes of Health; Vaccination; Vaccines; Variant; Viral; Virus; Zika Virus; arms race; conventional therapy; cost; design; disorder control; dosage; economic impact; epidemiological model; first-in-human; future pandemic; high risk; humanized mouse; immunogenicity; in vivo; innovation; insight; large scale production; manufacture; medical countermeasure; new pandemic; nonhuman primate; novel; pandemic response; particle; pathogen; pathogenic virus; pressure; prevent pandemics; self-renewal; superinfection; synergism; synthetic biology; therapeutic evaluation; transmission process; vector; viral resistance; viral transmission; virus genetics

PROJECT SUMMARY SARS-CoV-2, like all viruses, mutates and transmits; current medical countermeasures do not. This fundamental mismatch between dynamic viruses and our state-of-the-art static interventions means that vaccines and antiviral therapies often require frequent re-design and re-development, necessitating repeated (sometimes annual) resolutions to manufacturing and deployment challenges. Without fundamentally different forms of intervention to overcome this mismatch, future pandemics could rival or eclipse the catastrophic loss-of-life and economic impacts of SARS-CoV-2. To surmount the barriers thwarting current interventions, this proposal will engineer therapeutic molecular parasites of SARS-CoV-2 that can co-adapt and transmit among infected hosts. The key innovations of this approach are that these therapeutic parasites: (i) establish co-evolutionary arms races, co- evolving with wild-type virus to overcome resistance, (ii) replicate and self-renew, acting as single-administration therapies that circumvent compliance issues, and (iii) spread via the exact same risk factors and transmission routes as SARS-CoV-2—autonomously utilizing superspreaders to deploy the intervention—thereby circumventing manufacturing-at-scale and roll-out challenges. By design, these ‘piggybacking’ molecular parasites cannot replicate in uninfected hosts. Epidemiological models indicate that such molecular-parasite therapies would surmount the universal barriers to pandemic control and lower prevalence for many viruses below levels achievable by vaccination or antiviral therapy campaigns. The molecular rationale for developing molecular-parasite antivirals rests on ablating essential protein-encoding elements (i.e., trans-acting factors) to create conditionally replicating vectors that produce Therapeutic Interfering Particles (TIPs) when complemented in trans by wild-type virus superinfection. The crucial difference between TIPs and classical defective viral particles is that TIPs are engineered to have an R0 > 1—they efficiently mobilize, and transmit. As deletion variants, TIPs act as parasites, replicating only in virus-infected cells by stealing critical replication and packaging elements from the wild-type virus. By starving the wild-type pathogen of these critical elements, TIPs reduce wild-type pathogen levels. Critical feasibility precedents include that TIPs have been engineered to inhibit other viruses in vivo. Regulatory and ethical precedents include initial FDA clearances for HIV TIP Phase-I clinical trials supported by the NIH and DoD. This proposal will screen randomized synthetic libraries of SARS-CoV-2 variants to identify TIP candidates, test TIP efficacy and transmissibility in animal models, devise and test delivery and dosage formulations, and test tolerability, safety, and immunogenicity in a Phase-I clinical trial. The deliverable of this project will be the creation of a novel paradigm to counter SARS-CoV-2 and emerging pandemics by development and de-risking of an intervention that overcomes the universal barriers to infectious disease control.

项目摘要 SARS-CoV-2和所有病毒一样，会变异和传播，而目前的医疗对策不会。这一根本 动态病毒和我们最先进的静态干预措施之间的不匹配意味着疫苗和抗病毒药物 治疗通常需要频繁的重新设计和重新开发，需要重复（有时每年） 解决制造和部署方面的挑战。如果没有根本不同的干预形式 为了克服这种不匹配，未来的流行病可能会与灾难性的生命损失和经济损失相媲美， SARS-CoV-2的影响为了克服阻碍当前干预措施的障碍， SARS-CoV-2的治疗性分子寄生虫，可以在受感染的宿主之间共适应和传播。关键 这种方法的创新是，这些治疗寄生虫：（i）建立共同进化的军备竞赛，共同- 与野生型病毒一起进化以克服抗性，（ii）复制和自我更新，作为单次给药 规避依从性问题的治疗，以及（iii）通过完全相同的风险因素和传播传播 SARS-CoV-2-自主利用超级传播器部署干预-从而 规避大规模制造和推出的挑战。通过设计，这些“搭载”分子 寄生虫不能在未感染的宿主中复制。流行病学模型表明，这种分子寄生虫 治疗将克服流行病控制的普遍障碍，降低许多病毒的流行率。 低于疫苗接种或抗病毒治疗活动可达到的水平。发展的分子基础 分子寄生虫抗病毒药依赖于切除必需的蛋白质编码元件（即，反式作用因子）， 创建条件复制载体，当互补时产生治疗性干扰颗粒（TIP） 通过野生型病毒重复感染反式表达。TIPs和经典缺陷病毒之间的关键区别 TIPs被设计成具有R 0> 1-它们有效地动员和传播。如缺失 变体，TIP作为寄生虫，通过窃取关键的复制和包装，仅在病毒感染的细胞中复制 来自野生型病毒的元件。通过使野生型病原体缺乏这些关键元素，TIPs减少了 野生型病原体水平。关键的可行性先例包括，TIP已经被设计成抑制其他 体内的病毒监管和伦理先例包括FDA对HIV TIP I期临床的初步批准 由美国国立卫生研究院和国防部支持的试验。本研究旨在筛选SARS-CoV-2的随机合成文库 变体以识别TIP候选物，在动物模型中测试TIP功效和可传递性，设计和测试递送 和剂量制剂，并在I期临床试验中测试耐受性、安全性和免疫原性。的 该项目的交付成果将是创建一个新的范例，以应对SARS-CoV-2和新兴的 通过制定和降低干预措施的风险，克服传染性疾病的普遍障碍， 疾病控制。