Efficacy of Multiple- or Single-Dose Cidofovir against Vaccinia and Cowpox Virus Infections in Mice

Abstract

Orthopoxviruses, including variola and monkeypox, pose risks to human health through natural transmission or potential bioterrorist activities. Since vaccination has not recently been utilized for control of these infections, there is renewed effort in the development of antiviral agents not only for postexposure smallpox therapy but also for treatment of adverse reactions following vaccination. The objectives of this study were to expand on the results of others that cidofovir (CDV) is effective in mice inoculated with cowpox virus (CV) or vaccinia virus (VV) and to document the efficacy of single and interval dosing beginning prior to or after infection, particularly including evaluations using suboptimal doses of CDV. We utilized BALB/c or SCID mice inoculated with CV or VV as models for systemic poxvirus infections. BALB/c mice were inoculated intranasally with CV or VV and treated with CDV prior to or after virus inoculation. CDV, at concentrations as low as 0.7 to 6.7 mg/kg of body weight/day for 5 days, conferred significant protection when treatment was initiated as late as 72 to 96 h postinfection. A single-dose pretreatment or posttreatment with CDV at 3 to 100 mg/kg was effective when given as early as 5 days prior to infection or as late as 3 days after infection with either VV or CV. Interval treatments given every third day beginning 72 h postinfection using 6.7 or 2 mg of CDV/kg also proved effective against CV infections. When SCID mice were inoculated intraperitoneally with CV or VV and treated for 7 to 30 days with CDV, all the mice eventually died during or after cessation of treatment; however, significant delays in time to death and reduction of virus replication in organs occurred in most treated groups, and no resistance to CDV was detected.

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

“…Otherwise, the type of infection in mice resulting from the 50-μl i.n. challenge with the SF strain of cowpox virus is similar to the infection with the typical cowpox virus strain [1,5,6].…”

“…The drug treatment regimen used in the present investigations involved two consecutive days of treatment, as was done previously [7,9]. Other investigators have reported using lower daily doses of the compound, but by administering it for more consecutive days against poxvirus infections [5]. The shorter term of treatment mimics the one that will likely be given to humans, since the drug must be administered intravenously.…”

“…However, other investigators believe hepatitis is the cause of death. The rationale for this hypothesis is that although cidofovir protects mice from lethal cowpox virus infection, the surviving mice have only moderate decreases in lung virus titer, yet exhibit much more profound declines in liver virus titer [5,6]. A third proposed factor that may lead to death is the overproduction of inflammatory mediators (commonly referred to as a "cytokine storm") during such infections.…”

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

“…Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5,10,12); however, these compounds are inactive when given orally.…”

Coadministration of Cidofovir and Smallpox Vaccine Reduced Vaccination Side Effects but Interfered with Vaccine-Elicited Immune Responses and Immunity to Monkeypox

“…Cidofovir is a potent antiviral drug that is currently being investigated for treating deadly smallpox (variola) and monkeypox, although it is licensed for human immunodeficiency virus-associated cytomegalovirus retinitis (1,5,26,31). Given the possibility that cidofovir or other antiviral drugs can limit initial active vaccinia virus replication, cidofovir and Dryvax (cidofovirϩDryvax) coadministration may reduce Dryvax-mediated vaccination complications.…”