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THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE 1 December 2004
Dear friends and colleagues, RE: NEW PAPER HIGHLIGHTS RISKS AND UNINTENDED EFFECTS OF USING GE VIRUSES AS VACCINES We wish to bring to your attention a recently published paper in the journal Vaccine (Hansen, H. et al. Vaccine 23: 499-506, 2004), which highlights some of the risks associated with using poxviruses as transgenic or genetically engineered (GE) vaccine vectors. Some poxviruses are very attractive as live GE vaccine vectors for humans, domestic animals and wildlife. There are more than 100 such vaccines in different stages of clinical and field trials at the moment. One such orthopoxvirus, MVA (Modified Vaccinia Ankara), has a number of practical advantages as a GE vaccine vector. It can be used to prevent infectious diseases and cancer in humans and domestic animals; to immunize wildlife reservoirs for human and animal disease agents, and to induce sterility in pest mammals. The advantages are particularly attractive for developing countries, due to the good immunological responses, practical administration and economical costs. However, and maybe due to that fact that MVA has been such a success, human, animal and ecosystem health issues have neither been contemplated nor empirically or experimentally investigated. The vaccination of “free-ranging” human and animal recipients with a live GE virus vector is equal to deliberate release of that GE virus into the environment. Vaccination with live GE virus vectors should therefore be regulated as a deliberate release of a GMO. Vacccinia virus has an unknown number of relatives circulating in different ecosystems all over the world. These naturally occurring relatives can provide a pool of possible recombination partners for deliberately released or escaped GE poxviruses. The scientists’ hypothesis was: If a GE vaccine virus and a naturally occurring relative infect the same individual, hybrid recombinants with totally unpredictable characteristics may result. This paper demonstrates, in a cell culture system, that the hypothesis may be correct. Especially disturbing is the finding that the transgene is rapidly deleted from a viral hybrid, which had distinct cell-killing potential. This is significant in a risk assessment context, as the transgene would be the only logical “tag” for monitoring unwanted spread and non-target effects related to a MVA-vectored vaccine. The deletion of the transgene means that monitoring would be impossible, and the effects of such a viral hybrid with distinct cell-killing potential would thus remain undetected. Furthermore, MVA has been claimed “safe” because it transcribes and replicates its DNA in mammalian cells, but does not complete an infectious cycle. This dogma has, however, been now demonstrated to be wrong, as the same scientists have shown that MVA carries out an efficient productive infection in rat intestinal epithelial cells [Okeke MI, Nilssen Ø and Traavik T (2004). Morphogenesis and multiplication of modified vaccinia virus Ankara (MVA)-vectored influenza vaccine in mammalian cells: evidence of productive infection of rat intestinal epithelial IEC-6 cells. The Williamsburg Bioprocessing Foundation 11th Annual Meeting on Viral Vectors and Vaccines. Williamsburg Lodge, Williamsburg, VA, USA, 8-11 November 2004. Poster No. 5.]. Thus, MVA can infect mammalian cells. This paper thus provides an early warning about potential unintended harms and hazards of using GE vaccine viruses. It is imperative that putative recombination events involving genetically engineered and naturally occurring viruses be included in health and environmental risk assessments of GE viruses used as vaccines. The abstract of the paper is attached below.
With best wishes, Lim
Li Ching Email: twnet@po.jaring.my Website: www.twnside.org.sg
REF: Doc.TWN/Biosafety/2004/D ******************************************************************* doi:10.1016/j.vaccine.2004.06.032 Recombinant viruses obtained from co-infection in vitro with a live vaccinia-vectored influenza vaccine and a naturally occurring cowpox virus display different plaque phenotypes and loss of the transgene Hilde Hansena, 1, Malachy Ifeanyi Okekea, Øivind Nilssenb and Terje Traavika, c,* aDepartment of Microbiology and Virology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway bDepartment of Medical Genetics, University Hospital of Northern Norway, N-9038 Tromsø, Norway cNorwegian Institute of Gene Ecology, Tromsø Science Park, N-9291 Tromsø, Norway Received 20 November 2003; revised 5 May 2004; accepted 16 June 2004. Available online 29 July 2004. Abstract Some poxviruses are very attractive as transgenic vaccine vectors for humans, domestic animals and wildlife. Poxviridae family members circulate in different ecosystems and parts of the world, providing a pool of possible recombination partners for released or escaped genetically modified poxviruses. We performed in vitro double infections with a vaccinia virus strain Ankara (MVA) vectored influenza vaccine and a cowpox virus isolate from Norway, isolated hybrids, and further analyzed three hybrid viruses with different plaque phenotypes. One of the hybrids was genetically unstable, and during adaptation to new host cells its MVA derived influenza gene was deleted at a high frequency. This is significant in a risk assessment context, since the transgene would be the only logical tag for monitoring unwanted spread and non-target effects of a vaccine virus. Putative recombination events involving genetically modified and naturally occurring viruses should be included in health and environmental risk assessments. Keywords: Poxvirus; Orthopoxvirus; MVA recombinant vaccines; Risk assessment; Safety *Corresponding author. Tel.: +47 77 644379; fax: +47 77 644488. E-mail address: terjet@genok.org (T. Traavik). 1 Present address: Institute of Marine Biotechnology, Norwegian College of Fishery Science, University of Tromsø, N-9037 Tromsø, Norway.
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