Biological activity of an intravenous preparation of human vaccinia immune globulin in mouse models of vaccinia virus infection

Abstract

The biological activity of a new intravenous (i.v.) preparation of human vaccinia immune globulin (VIGIV) was evaluated in two mouse models of vaccinia virus (VV) infection. In a mouse tail lesion model, female CD-1 mice were inoculated i.v. with 7 x 10(4) PFU of VV to produce >10 lesions per tail 8 days later. In a mouse lethality model, female severe combined immunodeficient (SCID) mice were inoculated i.v. with 3 x 10(4) PFU of VV to produce 100% mortality within 45 days. The ability of VIGIV to reduce tail lesion formation in CD-1 mice and mortality in SCID mice was determined by (i) pretreatment of a lethal VV dose with VIGIV prior to i.v. inoculation into SCID mice and (ii) i.v. administration of VIGIV to CD-1 and SCID mice the day before and up to 8 days after VV infection. VIGIV reduced the proportion of CD-1 mice with >10 tail lesions in a dose-related manner when VIGIV was given 1 day before and up to 1 day after VV inoculation. The pretreatment of VV with VIGIV prolonged survival and decreased mortality. VIGIV (100 and 400 mg/kg) prolonged survival when given up to 4 days after VV inoculation, and the 400-mg/kg dose reduced the mortality rate by 80% when given the day before or immediately after VV inoculation. The biological activity of VIGIV was demonstrated in both the immunocompetent and immunocompromised murine models. The timing of treatment relative to VV inoculation appeared to be important for the demonstration of VIGIV's biological activity.

FIG. 1.

Effect of VV dose on tail lesion formation in CD-1 mice. Tail lesions were counted 8 days after inoculation with VV. A dose-related increase in the proportion of mice with >10 tail lesions was observed (P < 0.001 by chi-square analysis). There were no significant differences among the three study repetitions in the proportions of mice given 7 × 10⁴ PFU VV that developed >10 tail lesions.

FIG. 2.

Effect of VV dose on mortality in SCID mice. Mice were inoculated i.v. with VV on day 0, and mortality was assessed for a period of 35 days. A comparison of the proportions of mice that died from the groups receiving 3 × 10⁴ and 1 × 10⁵ PFU VV indicated that there were no significant differences, either between the two dose levels or across the three studies.

FIG. 3.

In vivo VIGIV biological activity in the mouse tail lesion model. Tail lesions were counted 8 days after inoculation with VV. *, P ≤ 0.05 versus controls (chi-square analysis); n = 25 per group.

FIG. 4.

In vitro VIGIV biological activity in the mouse lethality model. Various amounts of VIGIV (0, 0.5, 1.5, and 5.0 mg) were incubated with 3 × 10⁴ PFU VV for 1 hour at room temperature prior to i.v. injection via the tail vein of SCID mice. Mortality was assessed for a period of 56 days. *, P ≤ 0.05 versus controls (Kaplan-Meier analysis); n = 5 per group.

FIG. 5.

In vivo VIGIV biological activity in the mouse lethality model. SCID mice were inoculated i.v. with VV on day 0 and treated with VIGIV on day −1, 0, 1, 2, 4, or 6, and mortality was assessed for a period of 49 days. *, P ≤ 0.05 versus controls (Kaplan-Meier analysis); n = 5 per group.