Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Patent
1997-12-03
2000-02-01
Mosher, Mary E.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
4242041, 4242331, 4352351, 4353201, 536 2372, 935 57, 935 65, A61K 3912, C12N 1500, C12N 700, C07H 2104
Patent
active
060199784
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates generally to recombinant adenoviruses as vaccine components, and more particularly, to the use of replication deficient adenoviruses as vaccine carriers, which induce protective immune responses in mammalian hosts.
BACKGROUND OF THE INVENTION
A replication competent, recombinant adenovirus (Ad) is an adenovirus with intact or functional essential genes, (i.e., E1a, E1b, E2a, E2b and E4). Such recombinant viruses containing a variety of inserted genes have been used as vaccine compositions with some success [see, e.g. Davis, U.S. Pat. No. 4,920,309].
One of these recombinant adenoviruses expressing the rabies G protein was shown to induce protective immunity in animals upon challenge with rabies virus [L. Prevac, J. Infect. Dis., 161:27-30 (1990)]. However, doses above 10.sup.6 plaque-forming units (pfu) of this replication-competent virus were required to induce complete protection to viral challenge. Further, the use of these viruses in a live form capable of replicating in vivo is an undesirable attribute of a vaccine component.
In contrast, adenoviruses which have been made replication deficient by deletion of the Ad E1a and E1b genes have been used primarily for gene therapy protocols [See, e.g., Kozarsky and Wilson, Curr. Opin. Genet. Dev., 3:499-503 91993); Kozarsky et al, Som. Cell Mol. Genet., 19:449-458 (1993); see also, International Patent Application No. WO95/00655, published Jan. 5, 1995]. Such recombinant, replication deficient adenoviruses have been found to induce cell-mediated immune responses [Y. Yang et al, Proc. Natl. Acad. Sci. USA, 91:4407 (1994) and Y. Yang et al, Immunity, 1:433-442 (August 1994)] and neutralizing antibodies [T. Smith et al, Gene Therapy, 5:397 (1993); K. Kozarsky et al, J. Biol. Chem., 269:13695 (1994)]. None of these articles relating to the use of recombinant replication deficient Ad in gene therapy have measured the induction of a protective immune response.
Others have described the insertion of a foreign gene into a replication-defective adenovirus for putative use as a vaccine [See, e.g. T. Ragot et al, J. Gen. Virol., 74:501-507 (1993); M. Eliot et al, J. Gen. Virol., 71:2425-2431 (1990); and S. C. Jacobs et al, J. Virol., 66:2086-2095 (1992)]. Jacobs et al, cited above, describes a recombinant E1-deleted, E3 intact, Ad containing encephalitis virus protein NS1 under the control of a heterologous cytomegalovirus (CMV) promoter. When mice were immunized with the recombinant Ad vaccines and challenged with virus, Jacobs et al obtained only partial protection (at most a 75% protection) for an average survival of 15 days. Eliot et al, cited above, describe a recombinant E1-deleted, partially E3-deleted Ad with pseudorabies glycoprotein 50 inserted into the E1 deletion site under the control of a homologous Ad promoter. In rabbits and mice, after immunization and challenge, only partial protection was obtained (i.e., about one-third). Ragot et al, cited above, describe a recombinant E1-deleted, partially E3-deleted Ad with Epstein Barr virus glycoprotein gp340/220 inserted into the E1 deletion site under the control of a homologous Ad promoter. In marmosets (tamarins) after three high dose (5.times.10.sup.9 pfu, 1.times.10.sup.10 pfu and 2.times.10.sup.10 pfu), intramuscular immunizations and viral challenge, full protection was obtained.
For certain highly infectious diseases, such as rabies, there is a demand for an effective vaccine. Desirably, a vaccine should be effective at a low dosage to control the occurrence of side effects or to enable sufficient amounts of vaccine to be introduced into animals in the wild. Currently, a vaccinia rabies glycoprotein (VRG) vaccine is being used for oral wildlife immunization [B. Brochier et al, Vaccine, 12:1368-1371 (1994)]. However, doses above 10.sup.6 pfu are required to induce complete protection.
There thus remains a need in the art for a method of vaccinating against various disease states, and particularly rabies, which is safe and highly effective.
SUMMARY OF TH
REFERENCES:
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Ertl Hildegund C. J.
Wilson James M.
Mosher Mary E.
Salimi Ali R.
The Trustees of the University of Pennsylvania
The Wistar Institute of Anatomy and Biology
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