Vaccinia viruses re-engineered to express foreign genes are robust vectors for production of recombinant proteins, the most common being a vaccine delivery system for antigens. Concerns about the safety of the vaccinia virus have been addressed by the development of vectors based on attenuated vaccinia viruses. One of them, the Modified Vaccinia Ankara (MVA) virus, is a highly attenuated strain of vaccinia virus that was developed towards the end of the campaign for the eradication of smallpox by Professor Anton Mayr in Germany. Produced by hundreds of passages of vaccinia virus in chicken cells, MVA has lost about 10% of the vaccinia genome and with it the ability to replicate efficiently in primate cells.
Modified vaccinia Ankara in clinical trials
MVA is widely considered as the vaccinia virus strain of choice for clinical investigation because of its high safety profile. MVA has been administered to numerous animal species including monkeys, mice, swine, sheep, cattle, horses, and elephants, with no local or systemic adverse effects. Over 120,000 humans have been safely and successfully vaccinated against smallpox with MVA by intradermal, subcutaneous, or intramuscular injections. Currently, the use of MVA as a recombinant HIV vaccine is being tested in approximately 300 volunteers in several Phase I studies conducted by the International AIDS Vaccine Initiative. Studies in mice and nonhuman primates have further demonstrated the safety of MVA under conditions of immune suppression. Recently, vaccination with smallpox vaccine (a vaccinia virus related to MVA) has been shown, on rare occasions, to cause heart problems in people who received it: heart inflammation (myocarditis), inflammation of the membrane covering the heart (pericarditis), and a combination of these two problems (myopericarditis). A few cases of cardiac chest pain (angina) and heart attack have also been reported following smallpox vaccination. It is not known at this time if smallpox vaccination causes angina or heart attacks. MVA is an attenuated vaccinia virus and does not replicate in the human body as efficiently as vaccinia. However, whether MVA can induce the same side effects as vaccinia is not known at this time. Compared to replicating vaccinia viruses, MVA provides similar or higher levels of recombinant gene expression even in non-permissive cells. In animal models, recombinant MVA vaccines have been found immunogenic and to protect against various infectious agents including influenza, parainfluenza, measles virus, flaviviruses, and plasmodium parasites.
Immunogenicity
In animal models, MVA vaccines have been found to be immunogenic and protective against various infectious agents including immunodeficiency viruses, influenza, parainfluenza, measles virus, flaviviruses, tuberculosis, Plasmodium parasites and smallpox. A considerable amount of data on MVA vector vaccines has been accumulated from studies in macaques. In addition, combinations of viral vector vaccines have been employed successfully. Studies in mice show that fowlpox-based and MVA-based vaccines used in combination induce immunity and protection against challenge with Plasmodium parasites. In macaques, DNA-based HIV vaccines can be effectively boosted with recombinant MVA-based vaccines expressing HIV antigens.
Challenge Studies in Primates
Immunization regimens incorporating priming with DNA vaccine and boosting with recombinant MVA-based vaccine have been found to provide some protection in non-human primates following challenge with an immunodeficiency virus. While vaccination did not prevent infection in these studies, it did result in lower viral load setpoints, increased CD4 counts, and reduced morbidity and mortality in vaccinated animals, compared to controls.
