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Antibody Profiling by Proteome Microarray Reveals the Immunogenicity of the Attenuated Smallpox Vaccine Modified Vaccinia Virus Ankara Is Comparable to That of Dryvax ^,

D. Huw Davies,^1* Linda S. Wyatt,² Frances K. Newman,³ Patricia L. Earl,² Sookhee Chun,¹ Jenny E. Hernandez,^1, Douglas M. Molina,⁴ Siddiqua Hirst,¹ Bernard Moss,² Sharon E. Frey,³ and Philip L. Felgner¹

Division of Infectious Diseases, Department of Medicine, Hewitt Hall, University of California, Irvine, California 92697,¹ Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892,² Division of Infectious Diseases and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63110,³ ImmPORT Therapeutics Inc., Irvine, California 92618⁴

Received 6 August 2007/ Accepted 15 October 2007

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts. Several immunomodulatory genes and genes that influence host range are deleted or mutated, and replication is aborted in the late stage of infection in most nonavian cells. The effect of these mutations on immunogenicity is not well understood. Since the structural genes appear to be intact in MVA, it is hypothesized that critical targets for antibody neutralization have been retained. To test this, we probed microarrays of the Western Reserve (WR) proteome with sera from humans and macaques after MVA and Dryvax vaccination. As most protein sequences of MVA are 97 to 99% identical to those of other vaccinia virus strains, extensive binding cross-reactivity is expected, except for those deleted or truncated. Despite different hosts and immunization regimens, the MVA and Dryvax antibody profiles were broadly similar, with antibodies against membrane and core proteins being the best conserved. The responses to nonstructural proteins were less well conserved, although these are not expected to influence virus neutralization. The broadest antibody response was obtained for hyperimmune rabbits with WR, which is pathogenic in rabbits. These data indicate that, despite the mutations and deletions in MVA, its overall immunogenicity is broadly comparable to that of Dryvax, particularly at the level of antibodies to membrane proteins. The work supports other information suggesting that MVA may be a useful alternative to Dryvax.

Published ahead of print on 31 October 2007.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095.