Modified Vaccinia Ankara Vaccine Efficacious For Smallpox Protection in Phase 3 Study

While smallpox was declared eradicated globally in 1980, the specter of the virus still haunts public health. Routine vaccination was halted in 1971 and the possibility of a resurfacing outbreak remains. Many countries maintain stockpiles of smallpox vaccines due to this possibility, but these vaccines are based on replicating vaccinia viruses and carry potential side effects.

Results from a phase 3 efficacy trial of modified vaccinia Ankara as a vaccine against smallpox published in The New England Journal of Medicine, however, show promise for the new vaccine candidate in protecting against variola infection. Additionally, no safety concerns associated with the modified vaccinia Ankara vaccine were raised.

The modified vaccinia Ankara was evaluated for efficacy by randomly assigning 440 study participants to receive 2 doses of modified vaccinia Ankara followed by 1 dose of the currently employed replicating vaccinia vaccine ACAM2000, or to receive only 1 dose of ACAM2000.

This allowed investigators to evaluate noninferiority of the modified vaccinia Ankara vaccine in comparison to ACAM2000 by looking at peak serum neutralizing antibody titers and attenuation of the ACAM2000-associated major cutaneous reaction by previous modified vaccinia Ankara vaccination, measured by maximum lesion area and derived area attenuation ratio.

Participants were enrolled at the Yongsan US Military Garrison and Camp Hovey, in South Korea. The participants were recruited from Department of Defense personnel who were scheduled to receive a smallpox vaccination as part of their orientation. Eligible individuals were healthy persons aged 18 to 42 years, with body-mass index between 18.5 and 34.9. Participants also required a negative serum pregnancy test, no known or suspected history of smallpox-based or poxvirus-based vaccination, no history of or active immunodeficiency, no history of certain heart conditions or high cardiovascular risk, and must not have had certain skin conditions.

A total of 220 participants were randomly assigned to the modified vaccinia Ankara group, and 213 participants were randomly assigned to the ACAM2000-only group. Additionally, 208 participants received both modified vaccinia Ankara vaccinations.

At peak visits, the modified vaccinia Ankara vaccine induced a mean titer of neutralizing antibodies of 153.5 at 6 weeks, compared with 79.3 at 4 weeks with ACAM2000 (a ratio of 1.94 [95% confidence interval {CI}, 1.56 to 2.40]). By day 14, the geometric mean titer of neutralizing antibodies induced by a single modified vaccinia Ankara vaccination (16.2) was equal to that induced by ACAM2000 vaccination. Additionally, the percentages of seroconversion were comparable at 90.8% and 91.8%, respectively.

There were fewer adverse events and events of grade 3 or higher after both modified vaccinia Ankara vaccination periods than in the ACAM2000 group, with 17 and 64 participants reporting adverse events of grade 3 or higher, respectively. Pain at administration site was the most prevalent reaction after modified vaccinia Ankara vaccination, whereas erythema and pruritus were the most prevalent adverse effects after ACAM2000 vaccination. There were no deaths in either group during the trial.

Study authors concluded that their phase 3 trial results met the proposed efficacy criteria for modified vaccinia Ankara, and noted that the modified vaccinia Ankara vaccine met primary end points with a better safety profile than ACAM200. The peak neutralizing antibody titer of the former was also higher than that induced by the latter. Modified vaccinia Ankara additionally reduced the lesion area from ACAM2000 vaccination, which is a historical surrogate for smallpox protection.