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Genomic sequence of chorioallantois vaccinia virus Ankara, the ancestor of modified vaccinia virus Ankara

Christine Meisinger-Henschel^1,

Michaela Schmidt^1,

Paul Howley^1,

¹ Bavarian Nordic GmbH, Fraunhoferstrasse 13, D-82152 Martinsried, Germany
² Center for Biotechnology, University of Bielefeld, D-33594 Bielefeld, Germany
³ University of Zürich, Zürich, Switzerland

Correspondence
Jürgen Hausmann
juergen.hausmann{at}bavarian-nordic.com

Chorioallantois vaccinia virus Ankara (CVA) is the parental virus of modified vaccinia virus Ankara (MVA), which was derived from CVA by more than 570 passages in chicken embryo fibroblasts (CEF). MVA became severely host-cell-restricted to avian cells and has strongly diminished virulence in mammalian hosts, while maintaining good immunogenicity. We determined the complete coding sequence of the parental CVA and mapped the exact positions of the six major deletions that emerged in the MVA genome. All six major deletions occurred in regions of the CVA genome where one or more truncated or fragmented open reading frames (ORFs) pre-existed. The CVA genome contains 229 ORFs of which 51 are fragments of full-length orthopoxvirus (OPV) genes, including fragmented orthologues of C9L and M1L (encoding two well-conserved ankyrin-like proteins), A39R (encoding a semaphorin-like protein) and A55R (encoding a kelch-like protein). Phylogenetic analysis demonstrated that MVA was most closely related to CVA, followed by the vaccinia virus (VACV) strain DUKE, a patient-derived isolate of the Dryvax vaccine virus. Loss or mutation of genes outside the six major deletions are assumed to contribute to the restricted host range phenotype of MVA. In support of this notion, deletions, insertions and non-synonymous mutations were found in 122 of the 195 ORFs remaining in MVA when compared with their CVA counterparts. Thus, detailed knowledge of the CVA genomic sequence is a prerequisite to further dissect the genetic basis of the MVA host range phenotype as well as the particular immunological properties of MVA.

These authors contributed equally to this work.

Present address: 9 Sing Crescent, Berwick, VIC 3806, Australia.

The GenBank accession number of the sequence reported in this paper is AM501482.

A supplementary table showing the comparison of CVA ORFs with orthologous ORFs in MVA, representative VACV strains and CPXV-GRI is available with the online version of this paper.

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