Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance

Cell. 2021 Dec 9;184(25):6022-6036.e18. doi: 10.1016/j.cell.2021.11.004. Epub 2021 Nov 10.


Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.

Keywords: RNA; SARS-CoV-2; coronavirus; defective interfering particles; evolution; intranasal; lipid nanoparticle; therapeutic interfering particles; variants; virus-like particle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • COVID-19 / drug therapy*
  • COVID-19 / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Culture Media, Conditioned / pharmacology
  • Defective Interfering Viruses / metabolism*
  • Defective Interfering Viruses / pathogenicity
  • Drug Delivery Systems / methods
  • Epithelial Cells
  • Humans
  • Male
  • Mesocricetus
  • Nanoparticles / therapeutic use
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / pathogenicity
  • Vero Cells
  • Virus Replication / drug effects*


  • Antiviral Agents
  • Culture Media, Conditioned

Supplementary concepts

  • SARS-CoV-2 variants