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Review
. 2017:97:187-243.
doi: 10.1016/bs.aivir.2016.07.001. Epub 2016 Aug 1.

Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development

A Volz  1 , G Sutter  2
Affiliations
Review

Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development

A Volz et al. Adv Virus Res. 2017.

Abstract

Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology.

Keywords: Emergency vaccines; Infectious diseases; Poxvirus; Smallpox vaccine; Vaccine development; Viral vector vaccines; Virus–host interaction; Zoonoses.

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Figures

Fig. 1
Fig. 1
Generation of Modified Vaccinia virus Ankara (MVA) from ancestor virus Chorioallantois Vaccinia virus Ankara (CVA): Continuous serial passages of CVA in CEF resulted in significant loss of genetic information (~ 30 kb) in the genome of MVA. as demonstrated by the occurrence of by six major deletions (I–VI) relative to the CVA genome.
Fig. 2
Fig. 2
Schematic representation of the nonpermissive life cycle of MVA in cells of mammalian origin. While MVA does not productively replicate in most mammalian cells, it can efficiently enter any cell and start its cascade-like life cycle resulting in unimpaired expression of viral early and intermediate genes, synthesis of viral genomic DNA, and the abundant expression of viral late genes. Thus, foreign and MVA proteins are efficiently produced and the block of the MVA life cycle occurs at the step of virion assembly resulting in assembly of immature virus particles that are not released from the infected cell.
Fig. 3
Fig. 3
Selected host-regulatory genes functionally maintained in the MVA genome: a schematic representation of the MVA genome is shown on the top. (A) Viral genes regulating the intracellular host tropism (host range genes) include the open reading frames C7L, F1L, E3L, and B18R. (B) Viral inhibitors of host inflammatory responses and host NF-kB signaling are highlighted by the MVA regulatory genes C12L, C6L, K7R, A41L, A46R, and B16R. (C) VACV N1L, M2L, and K1L genes are deleted or truncated in the MVA genome. Functional repair of these genes in the MVA genome may serve as example for the use of MVA in research addressing the regulation of VACV immune evasion or host tropism.
Fig. 4
Fig. 4
Role of the MVA regulatory proteins E3 and F1 within the intracellular virus life cycle: E3 can efficiently sequester dsRNA produced during infection to counteract the activation of the antiviral host enzymes OAS (2′-5′ oligoadenylate synthetase)/RNaseL (Ribonuclease L) or PKR (Protein kinase RNA-activated). Additional functions of the E3 protein are to prevent the activation of the host proapoptotic protein Noxa and to block the phosphorylation of the transcription factors IRF-3 and IRF-7 inhibiting the production of type I interferons. The MVA protein F1 can bind or prevent the activation of proapoptotic host proteins Bax/Bak or Noxa and acts as efficient inhibitor of cytochrome C release (Cyto C) and apoptosis induction at the level of host cell mitochondria.
Fig. 5
Fig. 5
Remaining MVA inhibitory proteins targeting the innate NF-kB signaling pathway by MVA regulatory proteins: IRAKs, interleukin-1R-associated kinases; TRAF, TIR-domain-containing adapter-inducing interferon-β; IKK, inhibitor of nuclear factor kappa-B kinase; NF-kB, nuclear factor kappa-B; TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAM, TRIF-related adaptor molecule; TIRAP, Toll-interleukin 1 receptor (TIR) domain-containing adapter protein; MyD88, myeloid differentiation primary response gene 88; IL-1R, interleukin-1 receptor; TLRs, Toll-like receptors.
Fig. 6
Fig. 6
Schematic overview depicting the synthesis of MVA regulatory proteins involved in modulation of the host response: Most of these host-regulatory proteins are produced early during MVA infection associated with the rapid intracellular activation of innate host responses including the induction of apoptosis, interferons and interferon stimulated gene products or inflammatory cytokines. Interestingly, a few viral inhibitory proteins, such as the viral receptor of IL-1β (B16), are produced at late times of infection suggesting a predominantly extracellular function of these inhibitors of the host response.
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