• Vaccine Name: MVA
• Target Pathogen: Variola virus
• Target Disease: Smallpox
• Vaccine Ontology ID: VO_0004092
• Type: Replication-defective virus
• Preparation: A vial of MVA passage 572 was plaque-purified, propagated in chick embryo fibroblasts, and purified by sedimentation through a sucrose cushion (Earl et al., 2004).
• Virulence: (Earl et al., 2004; Meseda et al., 2005)
• Description: Modified vaccinia Ankara (MVA) has been studied most extensively out of the replication-defective vaccines. MVA has an excellent safety profile and could be used in groups in whom Dryvax is currently contraindicated. MVA was given to 120,000 people in Germany in the 1970s, followed by vaccination with live virus Elstree. MVA was safe but was not field-tested because smallpox was not present in Europe at that time. MVA has since been evaluated in animal models and in human studies. In phase I human clinical trials, MVA was found to be safe and immunogenic on its own and found to prime for greater immune responses and attenuate lesion formation if given in advance of Dryvax vaccination. MVA is also being evaluated in persons with contraindications to live virus vaccine such as atopic dermatitis and immunosuppression (Parrino et al., 2006).

Monkey Response

• Host Strain: Cynomolgous macaque (Macaca fascicularis)
• Vaccination Protocol: Monkeys were inoculated with 10^8 plaque-forming units (PFU). 24 monkeys were divided into 4 groups: group 1 received an inoculation with 10^8 PFU of MVA at t = 0 and a second 2 months later; group 2 received one injection with 10^8 PFU of MVA followed 2 months later by a standard percutaneous inoculation with Dryvax; group 3 received nothing at t = 0 and 1 Dryvax inoculation 2 months later; group 4 served as the unimmunized control (Earl et al., 2004).
• Persistence: The response to the first MVA inoculation was detected at 1 week, peaked at 2-4 weeks, and was boosted 1 week after the second MVA dose (Earl et al., 2004).
• Side Effects: MVA caused no adverse effects, even when high doses were injected into immune-deficient NHPs (Earl et al., 2004).
• Efficacy: All immunized animals remained clinically well (Earl et al., 2004).
• Description: As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates (NHPs). Here, a highly attenuated MVA is compared with the licensed Dryvax vaccine in an NHP model (Earl et al., 2004).

Mouse Response

• Host Strain: BALB/cByJ
• Vaccination Protocol: To compare the effectiveness of various routes of MVA immunization, male BALB/cByJ mice (obtained from the Jackson Laboratory, Bar Arbor, ME) were immunized through 3 different routes at doses from 10^6 to 10^8 pfu, and sera were collected every 3 weeks for 15 weeks for evaluation of Dryvax-specific antibody by ELISA using inactivated virus (Meseda et al., 2005).
• Persistence: The antibody response to vaccination was observed in mice over a relatively long period of time (12–15 weeks) following the initial dose of vaccine. By each measurement, the elicited immune response was stable over this time frame for both Dryvax and MVA. Further, when animals received a second dose of MVA, the antibody response was elevated compared to a single immunization, and was stable for the remainder of the observation period (6 to 9 weeks) (Meseda et al., 2005).
• Side Effects: A safer smallpox vaccine could benefit the millions of people that are advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. Because the correlates of smallpox protection are unknown, findings of similar humoral and cellular immune responses to MVA and Dryvax in NHPs and substantial protection against a severe monkeypox virus challenge are important steps in the evaluation of MVA as a replacement vaccine for those with increased risk of severe side effects from the standard live vaccine, or as a pre-vaccine. As a result of extreme attenuation, MVA causes no adverse effects even when high doses are injected into immunedeficient NHPs. No adverse local or systemic effects were noted after vaccination with MVA. As expected, pustular skin lesions did develop after Dryvax (Earl et al., 2004).
  Significant adverse events are associated with vaccination with the currently licensed smallpox vaccine. Candidate new-generation smallpox vaccines, such as MVA, produce very few adverse events in experimental animals and in limited human clinical trials conducted near the end of the smallpox eradication campaign. MVA was administered to more than 120,000 individuals in the latter stages of the smallpox eradication campaign without significant adverse events, although the thoroughness of safety data monitoring at that time is unclear. In addition to a vaccination strategy that employs multiple immunizations of MVA, alternative smallpox vaccination strategies may include an initial vaccination with non-replicating virus vaccine followed by a second immunization with a traditional replicating virus vaccine in order to reduce the possibility of vaccine-associate adverse events due to replicating vaccinia virus. Such a scheme of vaccination may be considered as a means of reducing the rate of adverse events associated with traditional smallpox vaccination, provided that vaccine efficacy is not compromised (Meseda et al., 2005).
• Efficacy: Mice immunized intradermally (i.d.) with either 10^8 pfu of MVA, or a prime-boost combination of 10^8 pfu of MVA followed by either 10^6 pfu of Dryvax or 10^8 pfu of MVA survived an intranasal (i.n.) challenge with 25 LD50s of vaccinia virus WR. Furthermore, vaccination with a single dose of 10^8 pfu of MVA resulted in a minimal weight loss (<10%), as did a vaccination combination of 10^8 pfu of MVA followed by 10^6 pfu of Dryvax. When mice that were immunized with a lower dose of 10^6 pfu of MVA were challenged with i.n. vaccinia virus WR, 4/5 survived a challenge with 10 LD50s at either 6 weeks or 12 weeks post-vaccination. When mice received a single immunization of 10^6 pfu of MVA and were challenged with 25 LD50s, 4/5 survived challenge at 6 weeks post-vaccination and 3/5 survived challenge at 12 weeks post-vaccination. In contrast, all animals receiving 10^6 MVA and boosted 6 weeks later with either 10^6 pfu of MVA or 10^6 pfu of Dryvax survived. These results indicate that combinations of MVA are as effective as Dryvax in eliciting immune responses and inducing protective immunity in a mouse model (Meseda et al., 2005).
• Description: The aim of the present study was to compare the immunogenicity and protective ability of MVA (a leading candidate new-generation smallpox vaccine) to the licensed smallpox vaccine Dryvax in a mouse model of vaccination. MVA is a replication-defective vaccinia virus derived from the Ankara strain by more than 500 passages through primary chicken embryo fibroblasts (CEF). This virus grows to high titer in CEF cells but replicates poorly, if at all, in human cells (Meseda et al., 2005).