Progressive Vaccinia: Case Description and Laboratory-Guided Therapy With Vaccinia Immune Globulin, ST-246, and CMX001

Abstract

Progressive vaccinia (PV) is a rare but potentially lethal complication that develops in smallpox vaccine recipients with severely impaired cellular immunity. We describe a patient with PV who required treatment with vaccinia immune globulin and who received 2 investigational agents, ST-246 and CMX001. We describe the various molecular, pharmacokinetic, and immunologic studies that provided guidance to escalate and then successfully discontinue therapy. Despite development of resistance to ST-246 during treatment, the patient had resolution of PV. This case demonstrates the need for continued development of novel anti-orthopoxvirus pharmaceuticals and the importance of both intensive and timely clinical and laboratory support in management of PV.

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

“…However, no therapeutic is currently licensed by the Food and Drug Administration (FDA) for the treatment of smallpox. A case report described an army recruit diagnosed with acute mylogenous leukemia M0 (AML M0) following vaccination with the ACAM2000 smallpox vaccine that resulted in life-threatening progressive vaccinia (9). The case management demonstrated that even high doses of VIGIV (6 to 24,000 U/kg) together with the investigational antiviral drug tecovirimat (ST-246) failed to ameliorate disease in an immune-deficient patient.…”

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

“…Clinical trials showed that ST-246 was well tolerated by human subjects after daily oral administration (15). Moreover, ST-246, together with VIGIV and CMX001, was recently successfully used for the treatment of progressive vaccinia, demonstrat-ing the advantage of combination therapy utilizing drugs that target different stages of VACV infection (16).…”

Enhanced Efficacy of Cidofovir Combined with Vaccinia Immune Globulin in Treating Progressive Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice

“…A primary component of the treatment of such infections is vaccinia immune globulin (VIG) (4,5). VIG is expensive and difficult to produce in large quantities.…”

“…As an example, in 2012, the case of an immunosuppressed military vaccinee with a severe progressive vaccinia infection was reported. The individual was successfully treated, but treatment required 341 vials of VIG over the course of 75 days in addition to oral and topical treatments with tecovirimat (ST-246) and brincidofovir (CMX001, an orally active prodrug of cidofovir [CDV]) (4).…”

“…Vaccinia infections in SCID mice are difficult to treat due to the profound immunosuppressive state of the mice, and a cure is not generally possible unless treatment is initiated very early postexposure (13). The delayed-treatment SCID mouse model may be a good representation of the treatment of vaccinia infections in immunocompromised humans, who require aggressive antiviral/ VIG therapy (3)(4)(5). In an alternative mouse model, we developed a progressive vaccinia virus cutaneous infection model in normal hairless mice (SHK-1 strain) that were immunosuppressed with cyclophosphamide (15).…”