• Vaccine Name: MVA-BN
• Target Pathogen: Variola virus
• Target Disease: Smallpox
• Vaccine Ontology ID: VO_0004097
• Type: Highly attenuated clone
• Preparation: MVA-BN has been derived via additional passages in serum free chicken embryo fibroblast (CEF) cultures, and is replication incompetent in mammalian cell lines, avirulent even in immune compromised hosts, highly immunogenic in mammalian animal models, and may be administered both s.c. and i.m. The vaccine was produced by IDT under Good Manufacturing Practice (GMP) conditions and provided by Bavarian Nordic as a liquid frozen product stored at −80 °C. Doses of 2 × 10^6, 2 × 10^7, 2 × 10^8 TCID50/ml were formulated in 10 mM Tris, 140 mM NaCl, pH 7.4. The vaccine was thawed and 0.5 ml were administered to subjects to deliver a dose of 10^6, 10^7, 10^8 TCID50, respectively (Vollmar et al., 2006).
• Virulence: (Vollmar et al., 2006)
• Description: MVA-BN (IMVAMUNE) was developed from the Modified Vaccinia Ankara strain (MVA) that was used as a priming vaccine prior to administration of conventional smallpox vaccine in a two-step program and shown to be safe in more than 120,000 primary vaccinees in Germany and used as a veterinary vaccine to protect against several veterinary orthopoxvirus infections (Vollmar et al., 2006).

Human Response

• Host Strain: Adult males
• Vaccination Protocol: Healthy male subjects aged 20–55 years were eligible for recruitment. The study design was divided into two parts: Part I subjects (n = 68) had no prior history of smallpox vaccination, while Part II (n = 18) subjects had a prior history of smallpox vaccination, documented by a vaccination certificate or a typical vaccination scar. Part I subjects were randomly assigned to receive a dose of either 10^6 (Group 1, n = 18), 10^7 (Group 2, n = 16), 10^8 (Group 3, n = 16) TCID50 MVA-BN in a double-blind manner, or 10^8 TCID50 (Group 4, n = 18) open-label, on day 0 and d28. Part II participants received a single dose of 10^8 TCID50 (Group 5, n = 18), open-label, to evaluate a boost response in previously vaccinated subjects. Study-specific assessments were conducted at screening and on d 0, 7, 28, 35, 42, and 126 (Vollmar et al., 2006).
• Persistence: T-cell immunity can persist for up to 50 years after immunization (Vollmar et al., 2006).
• Side Effects: 15 of the 64 general adverse events were assessed as possibly related to the study vaccine. 2 of these each occurred in Groups 1, 3, and 4, respectively, and 9 (28%) in the pre-immunized subjects. Only 1 serious adverse event was reported during the study: a subject in Group 4 was hospitalized due to an infected epidermal cyst on the face, 12 days after the second injection; however, this event was judged to be unrelated to the study vaccine, and the subject recovered without sequelae (Vollmar et al., 2006).
• Efficacy: The immune responses achieved after administration of MVA-BN were highly dose-dependent. Total IgG seropositivity rates, as determined by the ELISA, reached a maximum of 81% and 88% following a single vaccination using the highest dose (10^8 TCID50) via the s.c. or i.m. routes, respectively. They reached 100% following the second vaccination. On the other hand, the pre-immunized subjects attained 100% seropositivity after a single vaccination with MVA-BN although only 4 of these subjects had detectable antibody titers prior to inclusion, implying a pre-existing boostable immunity more than 20 years post-vaccination (Vollmar et al., 2006).
• Description: The primary objective of the study was to demonstrate safety and tolerability of MVA-BN at different doses administered to healthy subjects with or without a history of smallpox vaccination. Immunogenicity was assessed in all subjects as a secondary endpoint and was also used to evaluate dose-related responses and optimal route of application (Vollmar et al., 2006).

Monkey Response

• Host Strain: cynomolgus macaques (Macaca fascicularis)
• Vaccination Protocol: Four groups of six captive-bred sub-adult healthy monkeys each were vaccinated: the first group was vaccinated twice with a high dose of 10^8 TCID50 MVA-BN at an interval of 4 weeks, the second group was vaccinated with a low dose of 2 x 10^6 TCID50 MVA-BN followed 10 days later by a s.c. vaccination with Elstree-RIVM, the third group was vaccinated with one s.c. standard dose of Elstree-RIVM, and the fourth group was vaccinated s.c. with one standard dose of Elstree-BN. Group V was sham vaccinated. 15 weeks after the last vaccination, all of the animals were challenged intratracheal (i.t.) with either 10^6 PFU (3 animals per group) or 10^7 PFU (3 animals per group) of MPXV, which were chosen as sub-lethal and lethal challenges, respectively (Stittelaar et al., 2005).
• Persistence: (Stittelaar et al., 2005)
• Side Effects: Elevated body temperatures were observed (Stittelaar et al., 2005).
• Efficacy: All vaccinated animals that were challenged showed an episode of elevated body temperature (>1°C; ~2.65%) that occurred between days 5 and 8 post-challenge which returned to normal by d 12. Only one vaccinated animal developed pocks upon MPXV challenge, while all others showed no clinical signs of the disease apart from an elevated body temperature. This animal, which was vaccinated with MVA-BN (group I), initially developed pocks (>70) on d 11 after the challenge with MPXV (Stittelaar et al., 2005).
• Description: The present study investigated different combinations of candidate and traditional vaccines, followed by MPXV challenge i.t. The MVA strain (MVA-BN, or IMVAMUNE) is currently being tested in >300 human subjects in on-going phase I and II clinical studies, including individuals for whom vaccination with traditional smallpox vaccines is traditionally contraindicated. For the present study, the immune response and efficacy of MVA-BN vaccination were compared to those of a primary vaccination with MVA-BN followed by vaccination with a first-generation smallpox vaccine produced on calf skins (Elstree-RIVM). For this purpose, a low dose of MVA was chosen to prime the immune system, thus reducing the side effects of vaccination with a traditional vaccine shortly thereafter without changing the take rate of the traditional vaccine. In addition, vaccination protocols with Elstree-RIVM alone and vaccination with a second-generation vaccine (Elstree-BN) were evaluated. Elstree-BN is based on the same vaccinia virus strain as Elstree-RIVM, but the former was passaged and produced on chicken embryo fibroblasts to further attenuate the virus and to make a better defined vaccine preparation that does not depend on the use of calves (Stittelaar et al., 2005).