LC16m8: an attenuated smallpox vaccine

Abstract

The frequency of moderate to severe adverse reactions associated with smallpox vaccines currently stockpiled in the US, and the continued threat of bioterrorism have prompted the development of effective vaccines with improved safety profiles. LC16m8, an attenuated, replicating smallpox vaccine derived from the Lister strain of vaccinia, is currently licensed in Japan where it was safely used in over 50,000 children in the 1970s. It has been shown to have markedly less neurotoxicity than unattenuated vaccines in nonclinical studies. LC16m8 is immunogenic after a single dose, and recent studies in two different animal models have demonstrated protective efficacy equivalent to that of the only FDA-licensed smallpox vaccine. This article reviews the history and available scientific literature regarding LC16m8 and provides comparisons to other smallpox vaccines.

Figures

Fig. 1

Virus recovery from inoculated mice. Source: Hashizume et al. .

Fig. 2

The B5R protein produced by vaccinia viruses with SCR domains annotated. SCR, short consensus repeat; Sp, signal peptide; TM, transmembrane domain; CT, cytoplasmic tail. Source: Adapted from figure presented in Herrera et al. .

Fig. 3

Rabbits immunized with LC16m8 protected against lethal RPXV infection. Rabbits immunized with approximately 2 × 105 pfu of LC16m8 or Dryvax, or with placebo (PBS) (n = 20 per group) were challenged 28 days later with either 200 or 1000 pfu of RPV via the intradermal route. Survival was determined 10 days after challenge. At Day 10, surviving rabbits were euthanized. Only high-dose challenge data are shown.

Fig. 4

Antibody responses to LC16m8 and Dryvax in rabbits. Sera obtained from rabbits 14 and 28 days after immunization were tested at a 1:10 dilution for neutralization of IMV and EEV forms of RPV by plaque-reduction assays. Each data point represents the mean of 20 serum samples. Error bars indicate 95% confidence intervals. IMV neutralization titers elicited by LC16m8 were significantly greater than those elicited by Dryvax (p < 0.001, two-sided Wilcoxon rank sum test). Sera obtained from PBS-immunized animals demonstrated no neutralization. These data are not shown.

Fig. 5

Mice immunized with LC16m8 protected against lethal ECTV infection. Mice immunized with approximately 2 × 105 pfu of LC16m8 (n = 9) or Dryvax (n = 10) or with placebo (PBS) (n = 10) were challenged 49 days later with approximately 1–2× LD50 of ECTV by aerosol. At Day 25, surviving mice were euthanized. Survival was determined 25 days after challenge, at which point, surviving rabbits were euthanized for further analysis.

Fig. 6

Geometric mean titer of vaccinia virus-specific antibodies in mice vaccinated with Dryvax or LC16m8. Sera obtained from mice 41 days after immunization were tested for vaccinia virus-specific antibodies by ELISA. The bars represent the geometric mean titers from 29 Dryvax-immunized animals and 28 LC16m8-immunized animals. Although 30 mice were vaccinated with Dryvax or LC16m8, serum volumes from some animals were insufficient for analysis. Error bars indicate 95% confidence intervals. The geometric mean titer elicited by LC16m8 were significantly greater than those elicited by Dryvax (p < 0.001, two-sided Wilcoxon rank sum test). Sera obtained from PBS-immunized animals did not contain detectable vaccinia virus-specific antibodies. These data are not shown.