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

项目总结 像所有病毒一样，SARS-CoV-2会变异和传播；目前的医学对策不会。这一基本原则 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(有时是每年) 应对制造和部署挑战的解决方案。没有根本不同的干预形式 为了克服这种错配，未来的大流行可能会与灾难性的生命损失和经济损失相匹敌或相形见绌 SARS-CoV-2的影响。为了克服阻碍当前干预的障碍，这项提案将推动 SARS-CoV-2的治疗性分子寄生虫，可在感染宿主之间共适应和传播。钥匙 这种方法的创新之处在于，这些治疗性寄生虫：(I)建立共同进化的军备竞赛，共同 与野生型病毒一起进化以克服抗药性，(Ii)复制和自我更新，作为单一给药 规避遵从性问题的治疗，以及(Iii)通过完全相同的风险因素和传播传播 作为SARS-CoV-2的路线--自主地利用超级传播器部署干预--从而 规避规模化制造和铺设挑战。在设计上，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 治疗方法将跨越控制大流行和降低许多病毒流行率的普遍障碍。 低于疫苗接种或抗病毒治疗活动所能达到的水平。发育的分子基础 分子寄生虫抗病毒药物依赖于去除必要的蛋白质编码元件(即反式作用因子)以 创建有条件的复制载体，在互补时产生治疗性干扰粒子(TIPS) 在由野生型病毒重叠感染的情况下。TIPS和经典缺陷病毒之间的关键区别 粒子被设计成具有R0&gt；1--它们有效地动员和传递。作为删除 变种，TIP充当寄生虫，通过窃取关键的复制和包装，仅在感染病毒的细胞中复制 野生型病毒的成分。通过饥饿野生型病原体的这些关键元素，TIPS减少了 野生型病原体水平。关键的可行性先例包括TIPS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美国国防部支持的试验。这项建议将筛选SARS-CoV-2的随机合成文库 在动物模型中识别候选TIP、测试TIP有效性和传播性的变体，设计和测试交付 并在I期临床试验中测试耐受性、安全性和免疫原性。这个 该项目的成果将是创建一种新的范式来对抗SARS-CoV-2和新兴的 通过发展和降低干预措施来克服传染病的普遍障碍，从而防治大流行病 疾病控制。

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.