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.
