https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1143678/
Modified Vaccinia Virus Ankara Protects Macaques against Respiratory Challenge with Monkeypox Virus
The use of classical smallpox vaccines based on vaccinia virus (VV) is associated with severe complications in both naïve and immune individuals. Modified vaccinia virus Ankara (MVA), a highly attenuated replication-deficient strain of VV, has been proven to be safe in humans and immunocompromised animals, and its efficacy against smallpox is currently being addressed. Here we directly compare the efficacies of MVA alone and in combination with classical VV-based vaccines in a cynomolgus macaque monkeypox model. The MVA-based smallpox vaccine protected macaques against a lethal respiratory challenge with monkeypox virus and is therefore an important candidate for the protection of humans against smallpox.
Following a worldwide vaccination program, the World Health Organization declared smallpox to be eradicated in May 1980. Soon thereafter, general vaccination against smallpox was discontinued (3). Variola virus, the etiological agent of smallpox, is now ranked high on the list of biological agents that may be used as a bioweapon (9) because infection with this virus results in approximately 30% mortality and, to date, the vast majority of the population lacks protective immunity. In addition, there are growing concerns regarding the observation that other mammalian poxviruses, such as cowpox virus and monkeypox virus (MPXV), may now cross the species barrier to humans more easily (13). While traditional (first-generation) smallpox vaccines based on replicating vaccinia viruses (VV) are efficacious and were the basis for the eradication of smallpox, they are associated with rare but severe side effects, particularly in immunocompromised individuals (1, 2, 14). Indeed, the recent vaccination of U.S. soldiers against smallpox infection was not only a timely reminder of the adverse reactions associated with traditional smallpox vaccines but also showed another complication—myopericarditis—in healthy young males following vaccination (8). Moreover, the fact that it has been estimated that at least 25% of the U.S. population should not receive traditional smallpox vaccines in the absence of a direct threat highlights the growing need for a safe, new generation of smallpox vaccine that is suitable even for immunocompromised individuals (10). One such candidate vaccine is based on modified vaccinia virus Ankara (MVA), which has been attenuated from a VV by being passaged >500 times in chicken embryo fibroblast cells. This resulted in a virus which is replication deficient in most mammalian cell lines (4, 15). MVA has been used as a prevaccine in a two-step vaccination program against smallpox and was shown to be safe for >120,000 primary vaccinees (15, 19). Various MVA strains have also been shown to be safe for a variety of immunodeficient animals (7, 20), and more recently, MVA was shown to be immunogenic and efficacious in both mice and nonhuman primates (5, 23). Efficacy testing of candidate vaccines such as MVA in experimental animals, in comparison with traditional smallpox vaccines, will form an essential part of the data required to register new candidate smallpox vaccines. To this end, animal models that mimic the natural infection of variola virus in humans are particularly important. While a previous study indicated the efficacy of an MVA-based vaccine in a cynomolgus macaque (Macaca fascicularis) model (5), this relied on an intravenous (i.v.) lethal challenge with MPXV, and as such, did not examine the ability of the vaccine to afford protection against a respiratory challenge, which is the most prevalent natural route of infection. Therefore, we have performed vaccination experiments with cynomolgus macaques with different combinations of candidate and traditional vaccines, followed by MPXV challenge via the tracheal route. A sublethal and a lethal challenge dose of MPXV were chosen to meet the regulatory requirements for registration (18). The MVA strain included in this study (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 (15). In addition, vaccination protocols with Elstree-RIVM alone and vaccination with a second-generation vaccine (Elstree-BN) (15, 19) 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. The MVA-BN doses for priming and vaccination as well as the subcutaneous (s.c.) administration of MVA-BN were chosen on the basis of historical data, previous animal studies, and preliminary data from 300 human volunteers (15, 19).
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