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