Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques
The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-02-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.166485 |
| _version_ | 1797634307135635456 |
|---|---|
| author | Kyle Rosenke Matt C. Lewis Friederike Feldmann Eric Bohrnsen Benjamin Schwarz Atsushi Okumura W. Forrest Bohler Julie Callison Carl Shaia Catharine M. Bosio Jamie Lovaglio Greg Saturday Michael A. Jarvis Heinz Feldmann |
| author_facet | Kyle Rosenke Matt C. Lewis Friederike Feldmann Eric Bohrnsen Benjamin Schwarz Atsushi Okumura W. Forrest Bohler Julie Callison Carl Shaia Catharine M. Bosio Jamie Lovaglio Greg Saturday Michael A. Jarvis Heinz Feldmann |
| author_sort | Kyle Rosenke |
| collection | DOAJ |
| description | The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have recently been approved as monotherapy for use in high-risk patients with COVID-19. As preclinical data are only available for rodent and ferret models, here we assessed the efficacy of MK-4482 and PF-07321332 alone and in combination against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with vehicle, MK-4482, PF-07321332, or a combination of MK-4482 and PF-07321332. Clinical exams were performed at 1, 2, and 4 days postinfection to assess disease and virological parameters. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs, resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated in the closest COVID-19 surrogate model of human infection. |
| first_indexed | 2024-03-11T12:06:46Z |
| format | Article |
| id | doaj.art-8c4c6d11714643ca966ef175993be046 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:46Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-8c4c6d11714643ca966ef175993be0462023-11-07T16:25:15ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0184Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaquesKyle RosenkeMatt C. LewisFriederike FeldmannEric BohrnsenBenjamin SchwarzAtsushi OkumuraW. Forrest BohlerJulie CallisonCarl ShaiaCatharine M. BosioJamie LovaglioGreg SaturdayMichael A. JarvisHeinz FeldmannThe periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have recently been approved as monotherapy for use in high-risk patients with COVID-19. As preclinical data are only available for rodent and ferret models, here we assessed the efficacy of MK-4482 and PF-07321332 alone and in combination against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with vehicle, MK-4482, PF-07321332, or a combination of MK-4482 and PF-07321332. Clinical exams were performed at 1, 2, and 4 days postinfection to assess disease and virological parameters. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs, resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated in the closest COVID-19 surrogate model of human infection.https://doi.org/10.1172/jci.insight.166485COVID-19 |
| spellingShingle | Kyle Rosenke Matt C. Lewis Friederike Feldmann Eric Bohrnsen Benjamin Schwarz Atsushi Okumura W. Forrest Bohler Julie Callison Carl Shaia Catharine M. Bosio Jamie Lovaglio Greg Saturday Michael A. Jarvis Heinz Feldmann Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques JCI Insight COVID-19 |
| title | Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques |
| title_full | Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques |
| title_fullStr | Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques |
| title_full_unstemmed | Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques |
| title_short | Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques |
| title_sort | combined molnupiravir nirmatrelvir treatment improves the inhibitory effect on sars cov 2 in macaques |
| topic | COVID-19 |
| url | https://doi.org/10.1172/jci.insight.166485 |
| work_keys_str_mv | AT kylerosenke combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT mattclewis combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT friederikefeldmann combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT ericbohrnsen combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT benjaminschwarz combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT atsushiokumura combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT wforrestbohler combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT juliecallison combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT carlshaia combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT catharinembosio combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT jamielovaglio combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT gregsaturday combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT michaelajarvis combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques AT heinzfeldmann combinedmolnupiravirnirmatrelvirtreatmentimprovestheinhibitoryeffectonsarscov2inmacaques |