First-in-Human Therapeutic Interfering Particle (TIP) Targeting a Respiratory Virus

Respiratory viruses, such as Influenza A Virus (IAV), present aerosolizable biothreats with mass-casualty potential. Therapeutic Interfering Particles (TIPs) have been proposed as resistance-proof interventions to counteract these threats—given the potential capability of TIPs to adapt and co-evolve with rapidly evolving viral agents. Yet, the majority of extant TIPs are unlikely to control an acute respiratory threat or pandemic in humans. The fundamental barrier limiting these respiratory TIPs is the speed at which acute respiratory biothreats either resolve or kill patients. To be effective against acute infections, antivirals need to be delivered by the first hours of infection—often, before a patient knows that he or she is infected and in need of treatment. Unfortunately, the vast majority of existing TIPs cannot be delivered prophylactically in advance of a viral threat, because most TIPs are delivered into cells as (unmodified) RNA molecules that are rapidly degraded by cells, generally within 24-48 hours. Here, we propose to translate the first influenza TIPs capable of long-term, prophylactic efficacy through Phase I human clinical trials.