Treatment efficacy of cidofovir and brincidofovir against clade II Monkeypox virus isolates

• Published in: Antiviral research 2024-11, Vol.231, p.105995, Article 105995
• Main Authors: Prévost, Jérémie, Sloan, Angela, Deschambault, Yvon, Tailor, Nikesh, Tierney, Kevin, Azaransky, Kimberly, Kammanadiminti, Srinivas, Barker, Douglas, Kodihalli, Shantha, Safronetz, David
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antiviral therapy; Brincidofovir; Chlorocebus aethiops; Cidofovir; Cidofovir - pharmacology; Cidofovir - therapeutic use; Cytosine - analogs & derivatives; Cytosine - pharmacology; Cytosine - therapeutic use; Disease Models, Animal; Female; Humans; Medical countermeasures; Mice; Mice, Inbred BALB C; Monkeypox virus; Monkeypox virus - drug effects; Mpox; Mpox (monkeypox) - drug therapy; Mpox (monkeypox) - virology; MPXV; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Orthopoxvirus; Tembexa; Treatment Outcome; Vero Cells; Virus Replication - drug effects
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2024.105995

While historically confined to endemic areas, Monkeypox virus (MPXV) infection has increasingly garnered international attention due to sporadic outbreaks in non-endemic countries in the last two decades and its potential for human-to-human transmission. In 2022, a multi-country outbreak of mpox disease was declared by the World Health Organization (WHO) and nearly 100 000 mpox cases have been reported since the beginning of this pandemic. The clade II variant of the virus appears to be responsible for the vast majority of these infections. While there are no antiviral drugs currently approved to treat mpox specifically, the use of tecovirimat (TPOXX®) and brincidofovir (Tembexa®) is recommended by the Centers for Disease Control and Prevention (CDC) for compassionate use in severe mpox cases, since both are FDA-approved for the treatment of the closely related smallpox disease. Given the emergence of multiple tecovirimat-resistant infections, we aimed to evaluate the treatment efficacy of brincidofovir and its active compound, cidofovir, against MPXV clade II strains. Following intranasal infection, we show that cidofovir and brincidofovir can strongly reduce the viral replication of MPXV clade IIa and IIb viruses in the respiratory tract of susceptible mice when administered systemically and orally, respectively. The high antiviral activity of both compounds against historical and currently circulating MPXV strains supports their therapeutic potential for clinical application. •Cidofovir and brincidofovir display broad-spectrum antiviral activity against MPXV clades I, IIa, and IIb in vitro.•Systemic administration of active compound cidofovir prevents MPXV replication in mouse respiratory tract.•Oral treatment with brincidofovir limits viral replication in vivo against a non-lethal MPXV clade IIb challenge.•Brincidofovir therapy affords partial protection and reduces viral burden upon lethal challenge with MPXV clade IIa.