Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-10-19
2002-10-15
Wilson, Michael C. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S093100, C435S320100
Reexamination Certificate
active
06465438
ABSTRACT:
This application claims priority from international patent application no. PCT/EP97/01943, filed Apr. 18, 1997, which is based on German patent application no. 96 10 6217. 1, filed Apr. 19, 1996.
The general field of the invention is a method for nucleic acid vaccination of animals to protect them from parvoviral infections. This invention is more particularly related to the preparation and use of parvoviral DNA and its administration to dogs, cats and mink so as to induce an immune response that can protect these animals from disease caused by virulent parvovirus. Nucleic acid immunogens are designed to include the antigenic portions of the parvoviral genome which are incorporated into bacterial plasmids. These plasmids produce the desired parvoviral gene product when introduced into host cells by transfection. Host cells transfected with the parvoviral immunogen expressing plasmids produce a stream of antigenic proteins to which the host immune system will mount a protective immune response.
Parvoviruses are a family of closely related small DNA viruses composed of a protein capsid containing single stranded DNA. Parvoviruses cause various diseases in a variety of mammalian species. Feline panleukopenia virus, mink enteritis virus and canine parvovirus are host range variants of the feline parvovirus subgroup and share more than 98% DNA homology (Martyn et at, J. Gen. Virol. 71 (1990) 2747-2753). Canine parvovirus is a relatively new pathogen of all canids, having been first recognized in the late 1970's as the causative agent of a world wide pandemic of highly fatal gastroenteritis. This virus is theorized to be a host range mutant of feline parvovirus. When nucleotide sequences of feline and canine parvoviruses were compared, 31 base changes were identified resulting in changes in just 9 amino acids (Martyn et. at., 1990). Six of these amino acid changes were in the major capsid genes VP1 and VP2. The canine specific antigenic epitope is determined by a single amino acid difference from feline panleukopenia virus. Further genetic mapping has recently confirmed the time of origin of canine parvovirus, reinforced the theory of its origin from feline parvovirus, and indicated a continued evolution of the virus in the field strains now being isolated (Truyen et. al., J. of Virology 69 (8) (1995), 4702-4710).
The two nucleocapsid proteins, VP1 and VP2 are expressed from the same RNA with VP2 resulting from an in-frame ATG codon within the VP1 open reading frame. VP2 is expressed at levels nearly 10 fold higher than VP1 indicating that the internal start codon is more efficiently recognized as such by the translational apparatus (Turiso et. al., J. of Gen. Virol. 72 (1991), 2445-2456). Epitope mapping experiments have demonstrated that all of the antigenic epitopes generating neutralizing antibody lie within VP2 (Turiso et. al., 1991, loc. cit.). These include the first 16 amino acids of VP2 (Langeveld et., J. of Virology 68(7) (1994), 4506-4513; Casal et. al., J. of Virology 69 (11) (1995), 7274-7277).
Immunization remains the primary mechanism by which humans and animal species are protected against the scourge of infectious disease. The recent trend in vaccine design away from live, attenuated, agents due to safety concerns, either due to “vaccine breaks”, incomplete attenuation, reversion, or amplification in immunosuppressed patients, has also seen an accompanying decrease in vaccine duration and efficacy. The use of killed agents, cloned recombinant proteins or peptides requires large dosages and the presence of adjuvants. However, the long term effects of such adjuvants have not been explored, and they have recently been implicated as causative agents in vaccine induced sarcomas of cats (Hendrick et. al., J. Am. Vet. Med. Assoc. 205 (1994), 1425-1429). Additionally, the extracellular location of the injected antigen raises questions about the way in which those antigens are presented to the immune system, and their appropriateness to generate protection against naturally occurring infections.
Current immunization practices for canine parvovirus are marginal (Schultz, R.D. (1994), The Challenge of Controlling a Newly Recognized Disease: Canine Parvovirus Vaccines, IBC International Symposium, Oct. 27-28, 108). Vaccines consisting of either attenuated or killed organisms, must be given repeatedly to create immunity, and immunization in the face of circulating maternal antibody titers does not usually occur. This problem is compounded by the ability of maternal antibody to inactivate vaccine while having been reduced to levels that are not protective leading to a “window of vulnerability” (Pollock and Carmichael, J. Am. Vet. Med. Assoc. 130 (1982), 3742). The cloning of canine parvovirus has led to the development of two distinct vaccine strategies. The first was the introduction of the entire VP2 sequence into a baculovirus expression system. The protein product was harvested, and used to successfully immunize dogs (Turiso et. al., J. of Virology 66 (5) (1992), 2748-2753). The second strategy involves the subcloning or synthesis of peptide epitopes which are used to immunize dogs. These peptides have utilized the amino terminus sequence of VP2 (Casal et. al., 1995, loc. cit.) which resulted in successful immunization of dogs. The vaccines developed using these strategies have also been tested with mink enteritis virus, another closely related host range variant of parvovirus. Administration of either recombinant protein or peptide results in protective immunity to this commercially relevant disease of mink (Langeveld et. al., Vaccine 13(11) (1995),1033-1037).
Modified live virus vaccines for feline panleukopenia are effective in protecting adult cats, but may produce birth defects in kitten embryos in utero, consequently they are not recommended for vaccinating intact female cats which could be pregnant. Because of the serious limitations of modified live virus vaccines, investigators began to explore the possibility of transfecting cells in vivo with genes expressing antigens from infectious organisms (reviewed in Donnelly et. al., J. lmm. Meth. 176 (1994), 145152; Fynan et. al., Int. J. Immunopharmac. 17 (2) (1995), 79-83; Whalen et. al. (1995), DNA Mediated Immunization to the Hepatitis B Surface Antigen; Activation and Entrainment of the Immune Response in DNA Vaccines, New York: New York Academy of Sciences). Such a mechanism of immunization would imitate the pathway of viral gene expression without the attendant risk posed by attenuated organisms, while bypassing the need for typical adjuvants. The serendipitous discovery that intramuscular injection of “naked” plasmid DNA carrying a mammalian promoter would cause the DNA to be taken up by muscle cells and expressed (Wolff et. al., Science 247 (1990) 1465-1468), has led to a dramatic expansion of the new field of nucleic acid vaccination. Subsequent to the original study, conditions affecting intramuscular injection of plasmid DNA have been further defined and broadened (Wolff et. al., Biotechniques 11 (1991), 474-485). The efficiency of transfer is relatively low, ranging from 1-5%, however that efficiency can be increased up to 40 fold by inducing muscle degeneration prior to the injection of plasmid DNA (Vitadello et. al., Hum. Gene. Ther. 5 (1994), 11-18; Danko and Wolff, Vaccine 12 (16) (1994), 1499-1502); Davis et. al., Hum. Gene. Ther. 4 (1993), 733-740). Two of the most commonly used myonecrotic agents are the local anesthetic bupivicaine, and cardiotoxin (Danko and Wolff, 1994, loc. cit.; Davis et. al., 1993, loc. cit.). A number of other techniques have been employed to transfer genes to muscle including retroviral vectors, adenoviral vectors, and liposomes. However, direct injection of naked DNA appears to be the most efficient of these delivery mechanisms at transferring and expressing foreign DNA (Davis et. al., 1993, loc. cit.).
Several routes of administration have been explored in addition to intramuscular injection. Common to all of these routes is the lack of a need for any agent or vector to f
Baker Henry J.
Schorr Joachim
Smith Bruce F.
Metin Colpan
Wilson Michael C.
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