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.

Figure 1.

Images of the smallpox vaccination site before, during, and after the patient recovered from progressive vaccinia. A, 28 January. B, 5 March. C, 27 March. D, 27 April. E, 18 June. F, 6 July. Images have been altered to remove features that might identify the patient.

Figure 2.

Anti-orthopoxvirus immunoglobulin G (IgG) and immunoglobulin M (IgM) levels. Arrows correspond to administration of vaccinia immune globulin (human) (VIGIV). VIGIV contains only gamma globulin (IgG) and therefore has no effect on increasing IgM levels. ↓ Administration of VIGIV at 6000 IU/kg. ⤅ Administration of VIGIV at 18 000 IU/kg. ↓ Administration of VIGIV at 24 000 IU/kg.

Figure 3.

White blood cell markers, viable virus and viral DNA load detected from the vaccine site, and viral DNA load in EDTA blood. A, White blood cell count. B, Absolute neutrophil count. C, Absolute lymphocyte count. D, Plaque-forming units per swab of the leading edge of the main vaccine site and satellite lesions. E, Average genome copies per swab of the leading edge of the main vaccine site and satellite lesions. F, Average genome copies per milliliter of blood. *Values were below the limit of detection.

Figure 4.

Time line of the patient's clinical course. Important landmarks in the progression of disease are found along the top portion of the time line. Medications used to treat progressive vaccinia and declining white blood cell counts can be found directly below the time line. Abbreviations: G-CSF, granulocyte colony-stimulating factor; ICU, intensive care unit; ID, infectious disease; MRSA, methicillin-resistant Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; VIGIV, vaccinia immune globulin intravenous (human).

Figure 5.

A, T-cell response to vaccinia infection. Boxed numbers represent the percentage of cells specific to the vaccinia cytotoxic T-lymphocyte epitope. Effector response is measured approximately 2 weeks after vaccination. During this time, vaccinia virus–specific CD8⁺ T cells are highly proliferating, activated, and have Granzyme B. The memory response, approximately 3 months after vaccination, demonstrates that the vaccinia-specific CD8⁺ T cells are more quiescent at this stage. The healthy Dryvax recipient chosen for cell phenotype comparison was matched to the patient on the basis of age, sex, and race. B, CD8⁺ T-cell response after Dryvax vaccination. Plots show the CD8⁺ T-cell responses before vaccination and 12 or 90 days after vaccination, which represent the effector and memory time stages of CD8 differentiation, respectively. The plots are gated on CD3⁺CD8⁺ T cells.