Treatment with the smallpox antiviral tecovirimat (ST-246) alone or in combination with ACAM2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection

Abstract

The therapeutic efficacies of smallpox vaccine ACAM2000 and antiviral tecovirimat given alone or in combination starting on day 3 postinfection were compared in a cynomolgus macaque model of lethal monkeypox virus infection. Postexposure administration of ACAM2000 alone did not provide any protection against severe monkeypox disease or mortality. In contrast, postexposure treatment with tecovirimat alone or in combination with ACAM2000 provided full protection. Additionally, tecovirimat treatment delayed until day 4, 5, or 6 postinfection was 83% (days 4 and 5) or 50% (day 6) effective.

FIG 1

Efficacy of smallpox antiviral tecovirimat given alone or in combination with smallpox vaccine ACAM2000 after MPXV exposure. Cynomolgus macaques (n = 7 or 8 animals/group) were intravenously infected with a target challenge dose of 5 × 10⁷ PFU of MPXV Zaire-79 on study day 0 and vaccinated with vaccine diluent (mock vaccination) or ACAM2000 (one-time percutaneous scarification; 2.5 μl/2.5 × 10⁵ to 12.5 × 10⁵ PFU) on study day 3 and treated concurrently with a placebo or tecovirimat (10 mg/kg; oral gavage) once daily for 14 consecutive days (from study day 3 to day 16). The animals were then monitored for survival (A), clinical signs of disease (B), temperature (C) and weight (D) changes, viremia (E), body lesion formation (F), and development of humoral (G) and cellular (H) immune responses. Macaques that survived the initial MPXV challenge were rechallenged with a target challenge dose of 5 × 10⁷ PFU of MPXV Zaire-79 2 months later (day 63; represented by an arrow) to assess for acquisition of immunological memory. Each curve in graphs B to G represents the arithmetic (B, C, D, and F) or geometric (E and G) mean value of the 7 or 8 animals in each treatment group. In order to avoid obscuring the mean data, the standard deviations are not shown (C to G). In panel H, the whiskers represent the minimum and the maximum values for the 7 or 8 animals in each treatment group. The dashed lines in panels E and G represent the lower limits of quantification for the assays. An asterisk (*) indicates statistical significance.

FIG 2

Effect of delayed tecovirimat treatment initiation on antiviral efficacy in cynomolgus macaques that are both symptomatic and lesional. Cynomolgus macaques (n = 3 to 6 animals/group) were intravenously infected with a target challenge dose of 5 × 10⁷ PFU of MPXV Zaire-79 on study day 0 and treated with a placebo or tecovirimat (10 mg/kg; oral gavage) once daily for 14 consecutive days starting on study day 4, 5, or 6. The animals were then monitored for survival (A), clinical signs of disease (B), weight change (C), body lesion formation (D), viremia (E), and development of neutralizing humoral immune responses (F). Each curve in graphs B to F represents the arithmetic (B, C, and D) or geometric (E and F) mean value for the 3 to 6 animals in each treatment group. In order to avoid obscuring the mean data, the standard deviations are not shown (C to F). The dashed lines in panels E and F represent the lower limits of quantification for the assays. An asterisk (*) indicates statistical significance.