Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Reexamination Certificate
1999-07-02
2001-09-11
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
C424S204100, C424S233100, C435S235100, C435S320100, C536S023720
Reexamination Certificate
active
06287571
ABSTRACT:
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
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 (5×10
9
pfu, 1×10
10
pfu and 2×10
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 wild-life immunization [B. Brochier et al,
Vaccine,
22:1368-1371 (1994)]. However, doses above 10
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 THE INVENTION
The inventors have surprisingly found compositions and methods of vaccinating a human and/or animal against a disease using an adenovirus defective vaccine composition, which produces a high level of protection upon administration of a low vaccine dose. For example, vaccination with a vaccine composition described herein, which is directed against rabies, has been found to require as little as a single dose of 10
4
pfu of rabies vaccine vector to induce complete protection. This effect is also accomplished by administration routes other than the oral route.
Thus, in one aspect, the invention provides a replication-defective recombinant adenovirus (rAd) vaccine containing DNA encoding a selected heterologous protein from a disease-causing agent, which elicits a protective immune response against the agent. This recombinant adenovirus of the invention contains at least a partial, but functional, deletion of the Ad E3 gene. Further in the site of the E1a/E1b deletion which renders the Ad replication-defective, the recombinant virus contains a sequence comprising a non-adenovirus promoter directing the replication and expression of the DNA encoding the heterologous protein. For example, an exemplary rAd is Adrab.gp, which contains a rabies gp gene and is useful in a method for treating or preventing rabies.
In another aspect, the invention provides pharmaceutical and veterinary compositions which contain the rAd of the invention.
In still another aspect, the invention provides for the use of the rAd in the manufacture of the compositions described above.
In yet a further aspect, the invention provides a method of vaccinating a human or animal against disease comprising administering to said human or animal an effective amount of a replication-defective recombinant adenovirus vaccine containing DNA encoding a selected heterologous protein which elicits a protective immune response against an agent causing the disease. This adenovirus of the invention contains at least a partial, but functional, deletion of the Ad E3 gene. Further in the site of the E1a/E1b deletion which renders the Ad replication-defective, the recombinant virus contains a sequence comprising a non-adenovirus promoter directing the replication and expression of the DNA encoding the heterologous protein.
In another aspect, the present invention provides a method of preventing rabies infection in an animal comprising administering to the animal an effective amount of a recombinant replication-defective Adrab.gp adenovirus containing DNA encoding a rabies virus glycoprotein.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
REFERENCES:
patent: 4393201 (1983-07-01), Curtis et al.
patent: 5820868 (1998-10-01), Mittal et al.
patent: WO93/19191 (1993-09-01), None
patent: WO94/12649 (1994-06-01), None
patent: WO94/26914 (1994-11-01), None
patent: WO94/28152 (1994-12-01), None
patent: WO94/28938 (1994-12-01), None
patent: WO95/00655 (1995-01-01), None
patent: WO95/02697 (1995-01-01), None
K. Kozarksy t al, “In Vivo Correction of Low Density Lipoprotein Receptor Deficiency in the Watanabe Heritable Hyperlipidemic Rabbit with Recombinant Adenoviruses”,J. Biol. Chem.,269(18):13695-13702 (May 6, 1994) [Kozarsky I].
K. Kozarsky et al, “Adenovirus-Mediated Correction of the Genetic Defect in Hepatocytes from Patients with Familial Hypercholesterolemia”,Somatic Cell and Molecular Genetics,19(5):449-458 (Sep., 1993) [Kozarsky II].
K. Kozarsky et al, “Gene Therapy: Adenovirus Vectors”,Curr. Opin. Genet. Devel.,3:499-503 (Mar., 1993) [Kozarsky III].
Y. Yang et al, “MHC Class I-Restricted Cytotoxic T Lymphocytes to Viral Antigens Destroy Hepatocytes in Mice Infected with E1-Deleted Recombinant Adenoviruses”,Immunity,1:433-442 (Aug., 1994) [Yang I].
Y. Yang et al, “Cellular Immunity to Viral Antigens Limit
Ertl Hildegund C. J.
Wilson James M.
Howson and Howson
Salimi Ali R.
The Wistar Institute of Anatomy and Biology
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