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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 SARS-CoV-2 与所有病毒一样，会发生变异和传播；目前的医学对策则不会发生这种情况。动态病毒与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疗法通常需要频繁的重新设计和重新开发，需要重复（有时每年一次）无需采取根本不同形式的干预即可解决制造和部署挑战。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和经济损失相媲美或黯然失色为了克服当前干预措施的障碍，该提案将设计。 SARS-CoV-2 的治疗性分子寄生虫可以在受感染的宿主之间共同适应和传播。这种方法的创新之处在于这些治疗性寄生虫：（i）建立共同进化军备竞赛，共同进化与野生型病毒一起进化以克服耐药性，（ii）复制和自我更新，作为单次给药规避合规性问题的疗法，以及（iii）通过完全相同的风险因素和传播方式传播与 SARS-CoV-2 一样，自主利用超级传播者部署干预措施，从而通过设计，这些“搭载”分子可以规避大规模制造和推广的挑战。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。疗法将克服流行病控制的普遍障碍并降低许多病毒的流行率低于通过疫苗接种或抗病毒治疗活动可达到的水平。分子寄生虫抗病毒药物依赖于消除必需的蛋白质编码元件（即反式作用因子）以创建条件复制载体，在互补时产生治疗干扰颗粒 (TIP) 通过野生型病毒重复感染进行反式感染 TIP 与经典缺陷病毒之间的关键区别。颗粒的特点是 TIP 被设计为具有 R0 > 1——它们有效地动员和传输 As 缺失。在变体中，TIP 充当寄生虫，通过窃取关键的复制和包装，仅在病毒感染的细胞中进行复制通过使野生型病原体缺乏这些关键元素，TIP 会减少。关键的可行性先例包括 TIP 已被设计用于抑制其他病原体。监管和伦理先例包括 FDA 对 HIV TIP I 期临床的初步许可。该提案将筛选 SARS-CoV-2 的随机合成文库。用于识别 TIP 候选者的变体、在动物模型中测试 TIP 功效和传播性、设计和测试交付和剂量配方，并在 I 期临床试验中测试耐受性、安全性和免疫原性。该项目的可交付成果将是创建一种新的范式来对抗 SARS-CoV-2 和新兴的通过开发克服传染性普遍障碍的干预措施并消除风险来控制流行病疾病控制。