Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice

Abstract

The threat of smallpox as a bioweapon and the emerging threat of human monkeypox, among other poxviral diseases, highlight the need for effective poxvirus countermeasures. ST-246, which targets the F13L protein in vaccinia virus and its homologs in other orthopoxvirus species, provides full protection from lethal poxviral disease in numerous animal models and seems to be safe in humans. All previous evaluations of ST-246 efficacy have been in immunocompetent animals. However, the risk of severe poxviral disease is greater in immunodeficient hosts. Here we report on the efficacy of ST-246 in preventing or treating lethal poxviral disease in immunodeficient mice. After lethal challenge with the Western Reserve strain of vaccinia, Nude, SCID, and J H knockout mice additionally depleted of CD4 + and CD8 + T cells were not fully protected by ST-246, although survival was significantly extended. However, CD4 + T cell deficient, CD8 + T cell deficient, J H knockout, and J H knockout mice also deficient for CD4 + or CD8 + T cells survived lethal challenge when treated with ST-246 starting on the day of challenge. Delaying treatment until 72 h after infection reduced ST-246 efficacy in some models but provided full protection from lethal challenge in most. These findings suggest that ST-246 may be effective in controlling smallpox or other pathogenic orthopoxviruses in some immunodeficient human populations for whom the vaccine is contraindicated.antiviral | immunodeficiency | ST-246 | smallpox | orthopoxvirus

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

“…The data showed that a three-dose or nine-dose regimen of BCV extended survival of nude mice. These data are in agreement with previous reports on another VACV inhibitor, ST-246, including our own studies, demonstrating that the virostatic drug protected immune-deficient mice from lethality while they were on treatment (29,37). As expected, nude mice succumbed after BCV was stopped.…”

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

“…The therapeutic window of ST-246 provides a feasible approach to protect such individuals from vaccine related adverse reactions, including generalized vaccinia. Previous studies have shown that ST-246 significantly extended the survival of nude and SCID mice after lethal challenge with vaccinia virus strain WR and that mice eventually succumbed after therapy was stopped (13). In the present study, we used nude mice that were reconstituted with T cells purified from naive BALB/c mice in order to better mimic different patient groups with various levels of T cell immune deficiencies.…”

“…In vivo, the daily administration of ST-246 for 5 to 14 days has been shown to protect normal mice from lethal intranasal challenge with ectromelia and cowpox viruses (11,12). In immune-deficient mice, protection was observed in mice receiving treatment; however, the mice succumbed after ST-246 treatment ceased (13). Importantly, in nonhuman primates, ST-246 has been shown to protect from poxvirus disease, reduce viral loads, and enhance survival (14).…”

Monkeypox Transmission, Need and Treatment of Humans with an Antiviral Drug

“…Postponing treatment until 72 h after disease diminished ST-246 adequacy in a few models however gave full insurance from deadly test in most. These discoveries propose that ST-246 may be successful in controlling smallpox or other pathogenic orthopoxviruses in some immunodeficient human populaces for whom the antibody is contraindicated (Grosenbach et al, 2010).…”