期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：39
DOI：10.1073/pnas.2204624119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
COVID-19 vaccines are exceptionally effective in preventing severe disease and death, but they have mixed efficacy in preventing virus transmission, consistent with established literature that parenteral vaccines for other viruses fail to prevent mucosal virus shedding or transmission. Likewise, small-molecule antivirals, while effective in reducing viral disease pathogenesis, also appear to have inconsistent efficacy in preventing respiratory virus transmission, including for SARS-CoV-2. Recently, we reported the discovery of a single-administration antiviral therapeutic interfering particle (TIP) against SARS-CoV-2 that prevents severe disease in hamsters and exhibits a high genetic barrier to the evolution of resistance. Here, we report that TIP intervention also reduces SARS-CoV-2 transmission between hamsters.
The high transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a primary driver of the COVID-19 pandemic. While existing interventions prevent severe disease, they exhibit mixed efficacy in preventing transmission, presumably due to their limited antiviral effects in the respiratory mucosa, whereas interventions targeting the sites of viral replication might more effectively limit respiratory virus transmission. Recently, intranasally administered RNA-based therapeutic interfering particles (TIPs) were reported to suppress SARS-CoV-2 replication, exhibit a high barrier to resistance, and prevent serious disease in hamsters. Since TIPs intrinsically target the tissues with the highest viral replication burden (i.e., respiratory tissues for SARS-CoV-2), we tested the potential of TIP intervention to reduce SARS-CoV-2 shedding. Here, we report that a single, postexposure TIP dose lowers SARS-CoV-2 nasal shedding, and at 5 days postinfection, infectious virus shed is below detection limits in 4 out of 5 infected animals. Furthermore, TIPs reduce shedding of Delta variant or WA-1 from infected to uninfected hamsters. Cohoused “contact” animals exposed to infected, TIP-treated animals exhibited significantly lower viral loads, reduced inflammatory cytokines, no severe lung pathology, and shortened shedding duration compared to animals cohoused with untreated infected animals. TIPs may represent an effective countermeasure to limit SARS-CoV-2 transmission.
