Chemistry: molecular biology and microbiology – Vector – per se
Patent
1992-01-03
1993-11-30
Schwartz, Richard A.
Chemistry: molecular biology and microbiology
Vector, per se
435 691, 4352351, 4351723, 435 693, 536 2372, 424 93A, C12N 1585, A61K 39245
Patent
active
052664899
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to recombinant herpesviruses capable of being used, in particular, in vaccines against virus diseases of man and animals, to a process for preparing them, to the plasmids produced during this process and also to the vaccines obtained. It also relates to a nucleotide sequence corresponding to a portion of the genome of the turkey herpesvirus (HVT), which sequence is capable of being used for the preparation of such viruses.
The turkey herpesvirus (HVT) of the subfamily gammaherpesvirinae is a naturally non-pathogenic and non-oncogenic virus serologically related to the oncogenic virus of Marek's disease, the agent responsible for a lymphoproliferative disease of poultry of considerable economic importance.
These two viruses possess numerous sequence homologies over the whole length of their genome, and recent published data show, in addition, a similarity with the genomes of the herpes simplexviruses(HSV) or the varicella virus (VZV), which suggests at the present time their classification in the family of the alphaherpesviruses rather than that of the gammaherpesviruses, where they were classified on grounds of their tropism (1) (for the bibliographic references, see Appendix 1).
For many years, vaccination using the HVT virus has been very effective for controlling Marek's disease. Nevertheless, the emergence of new highly virulent strains shows the need to use vaccines closer antigenically to the wild-type virus. In this context, vaccines obtained by genetic manipulation are an important possibility.
Live viral vectors such as attenuated strains of poxviruses or of herpesviruses are being developed increasingly. Thus, the HSV virus or Aujeszky's disease virus (PRV) have been used as vectors for the expression of foreign genes (26, 34). For this purpose, the foreign genes were inserted into cloned fragments of non-essential regions of the herpes genomes and then introduced into the viral vector by homologous recombination. This last step is performed simply by cotransfection, since the DNAs of herpesviruses are naturally infectious.
The HVT virus is a candidate of choice for the development of such a viral vector in the avian field, since it has the twofold advantage of being able to be used for its vaccinal properties and as a vaccine for other diseases. In addition, this virus gives rise to a permanent viraemia and may be used in embryo vaccination.
It is possible to insert within the HVT genome genes coding for immunogens of Marek's disease virus, thereby boosting the protective role of the HVT virus. It is also possible to insert within the HVT genome genes coding for immunogens of viral, bacterial or parasitic pathogenic agents of other avian diseases such as Marek's disease (MDV), infectious bronchitis (IBV), Newcastle disease (NDV), fowl plague, Gumboro disease (IBDV), avian anaemia (CAA), egg drop syndrome, coccidiosis, fowlpox, infectious rhinotracheitis, colibacillosis, pasteurellosis and haemophilosis. The HVT virus thus appears to offer itself as a versatile chimera.
The genetic material of herpesviruses consists of a double-stranded DNA containing 100,000 to 180,000 base pairs. Different regions of this genome have been shown to be non-essential to viral replication, and are hence potential sites for insertion of foreign genes or of deletion for the creation of new, more attenuated strains.
Some of these regions are associated with virulence, and their modification causes a decrease in the pathogenicity of the viruses. Thus, the inactivation of thymidine kinase renders human herpes simplex non-pathogenic and does not prevent viral growth in vitro (3, 8, 21, 33); the same applies to the PRV virus (30). In addition, it has been shown that attenuation of the Bartha strain of the PRV virus is linked to a deletion of the glycoprotein gI, the gene for which occurs in the small fragment Us (18).
Other herpesvirus genes have been identified as non-essential to viral growth without, however, being associated with phenomena of virulence. Among these genes, the UL24 gene of
REFERENCES:
Shih et al., PNAS, vol. 81, 1984, pp. 5867-5870.
J. McLauchlan, J. B. Clements, DNA sequence homology between two co-linear loci on the HSV genome which have different transforming abilities, The Embo Journal, 2, (11), 1953-1961 (1983).
J. McLauchlan, J. B. Clements, Organization of the Herpes Simplex Virus Type 1 Transcription Unit Encoding Two Early Proteins with Molecular Weights of 140,000 and 40,000, J. Gen. Virol., 64, 997-1006 (1983).
S. Simpson, J. McLauchlan, J. B. Clements, 14th International Herpesvirus Workshop, Nyborg-strand, Denmark (1989).
M. A. Swain, D. A. Galloway, Herpes Simplex Virus specifies Two Subunits of Ribonucleotide Reductase Encoded by 3'-Coterminal Transcripts, J. Virol., 57, (3), 802-808 (1986).
D. J. Goldstein, S. K. Weller, Herpes Simplex Virus Type 1-Induced Ribonucleotide Reductase Activity is Dispensable for Virus Growth and DNA Synthesis: Isolation and Characterization of an ICP6 lacZ Insertion Mutant, Virology, 62, 196-205 (1988).
D. J. Goldstein, S. K. Weller, Factor(s) Present in Herpes . . . , Virology, 166, 41-51 (1988).
V. G. Preston, A. J. Darling, I. M. McDougall, The Herpes Simplex Virus Type 1 . . . , Virology, 167, 458-467 (1988).
J. G. Jacobson, D. A. Leib, D. J. Goldstein, C. L. Bogart, P. A. Schaffer, S. K. Weller, D. M. Coen, A Herpes Simplex Virus Ribonucleotide . . . , Virology, 173 (1), 276-283 (1989).
Kohen Gilla
Rey-Senelonge Arielle
Guzo David
Rhone Merieux
Schwartz Richard A.
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