Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1995-04-03
2001-02-13
Bui, Phuong T. (Department: 1638)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C435S235100, C435S236000, C435S320100, C424S229100, C530S350000, C536S023720
Reexamination Certificate
active
06187320
ABSTRACT:
The present relates to equine herpesviruses (EHV) which contain foreign DNA elements in addition to the genome sequences necessary for the replication thereof, to process for the preparation thereof and to the intermediates employed therein, and to the use thereof in vaccines against infections.
Herpes and influenza viruses as well as equine rhino-viruses, mammalian reoviruses, equine adenoviruses, mycoplasmas and bacteria such as, for example, streptococci and corynebacteria represent the main aetiological problems among the infectious respiratory disorders of horses. In addition to these, in the systemic infections there are arteritisvirus, salmonellae,
E. coli
. clostridia and, with colonisation on the intestine, rota- and coronaviruses. The aim is to develop effective vaccines which are tolerated and simple to use against these pathogens.
Equine herpesviruses are distributed enzootically in all horse-breeding areas of the world and are of predominant importance in the infectious diseases of horses. To date, a total of four equine herpesvirus serotypes have been indentified.
EHV-1 (Equine abortion virus), a pathogen belonging to the alpha-herpesviruses, previously called EHV-1 subtype 1 (rhinopneumonitisvirus),
EHV-2 (Equine cytomegalo-like virus), a beta-herpes-virus,
EHV-3 (Equine coital exantherma virus), belonging to the alpha-herpesviruses and
EHV-4 likewise an alpha-herpesvirus, previously called EHV-1 subtype 2.
Equine herpesviruses cause economic losses in horse breeding throughout the world. These arise, in particular, owing to recurrent epidemics of abortion, respiratory disorders and, in some cases with a dramatic course, encephalitis. The economic importance of the losses during rearing, the missing of training and the losses of performance should not be underestimated.
Herpesviruses generally show only weak immunogenicity leading to a quantitatively small humoral immune response. Thus, for example, the respiratory form after EHV-4 infection frequently results in only a serologically weak humoral immune response. Currently employed in practice are predominantly monovalent EHV-1 live vaccines or inactivated EHV-1 vaccines, in some cases combined with heterologous antigens. Despite the use of these vaccines, clinical illnesses owing to infections with equine herpesviruses repeatedly occur. These may be monocausal illnesses due to herpesviruses of the various serotypes or consequences of mixed infections interacting with others of the said pathogens (factor illness).
Overall, the immunopreventative with the vaccines which can be employed at present is not yet satisfactory. It is therefore desirable to obtain equine vaccines which can be used without difficulty and confer a resilient immune protection against as many pathogens as possible.
Certain vector vaccines, based on apathogenic pathogens which, besides their genome sequences essential for propagation, contain foreign DNA coding for heterologous immunogens are known. It is also known that in some cases antigens of pathogenic pathogens have been inserted into avirulent pathogens, that is to say in vectors.
Alpha- and gamma-herpesviruses which contain foreign DNA, such as, for example, pseudorabies virus (Aujeszky virus) and the virus of Marek's disease and their use in vaccines are known (PCT Patent Application WO87/4463; WO89/1040). However, nothing is known about the use of equine herpesviruses, specifically beta-herpesviruses, such as EHV-2, as vectors for foreign DNA.
Alpha- and gamma-herpesviruses are fundamentally different in their biological behaviour and their structural organisation from the beta-herpesviruses. It is therefore not possible to draw any conclusions about beta-herpes-viruses from the behaviour of alpha- and gamma-herpes-viruses.
The present invention relates to:
1. Equine herpesviruses (EHV), in particular EHV Type 2, which, besides the genome sequences necessary for their replication, carry one or more foreign DNA elements.
2. Non-virulent or attenuated equine herpesviruses (EHV), in particular EHV Type 2, which, besides the genome sequences necessary for their replication, carry one or more foreign DNA elements.
3. Non-virulent or attenuated equine herpesviruses (EHV), in particular EHV Type 2, which, besides the genome sequences necessary for their replication, carry one or more foreign DNA elements which are located in their repetitive DNA sequences or in other genome sequences not necessary for their replication.
4. Equine herpesviruses according to 1, 2 and 3 (above) in which one or more segments in the genome sequences not necessary for their replication are absent, so-called deletion mutants.
5. Equine herpesviruses according to 1, 2, 3 and 4, which contain one or more foreign DNA sequences which code for proteins, and/or inactivate, owing to the insertion, the function of EHV genome sequences, and/or label the EHV genome at a required position.
6. Process for the preparation of the equine herpesviruses according to 1, 2, 3, 4 and 5 (above), characterised in that
a) a gene bank for an EHV strain is established from genome fragments of this virus, and its physical genome map is constructed or, where appropriate, recourse is had to an existent gene bank, or to an isolated EHV DNA fragment,
b) one or more insertion site(s) for the introduction of foreign DNA are identified in a manner known per se in the genome or on one or more genome fragments of this EHV strain, which fragments can be contained in plasmids or other vectors,
c) where appropriate, one or more deletions are made in the genome or on one or more genome fragments with the insertion site(s) identified according to 6b) (above), it being possible for the genome fragments to be contained in plasmids or other vectors,
d) foreign DNA elements are inserted in a manner known per se into the insertion site(s) identified according to 6b) (above) or into one or more regions from which deletion has been made according to 6c) (above), with the aim of constructing a so-called shuttle vector,
e) where appropriate, the shuttle vector according to 6d (above) is co-transfected together with the genome of an equine herpesvirus in cells suitable for virus growth, or is transfected in separate steps, or the cells are transfected with the shuttle vector and infected with the equine herpesvirus,
f) EHV virus recombinants which contain foreign DNA and are obtainable according to 6d) and e) are isolated and grown in a manner known per se.
Part steps b), c), d) can be carried out in any desired sequence.
7. Shuttle vector obtainable according to 6d (above).
8. Process for the preparation of the shuttle vector according to 7 (above), characterised in that one or more insertion site(s) for introducing foreign DNA elements are identified in a manner known per se in the genome or on one or more genome fragments of an EHV strain, which fragments can be contained in plasmids or other vectors,
and, where appropriate, genome fragments which contain the identified insertion sites are inserted into known or newly constructed vectors, for example plasmid vectors, it being possible to insert where appropriate one or more deletions or single nucleotides or nucleotide sequences into the genome fragments either before or after insertion thereof into the vectors,
and foreign DNA elements are inserted in a manner known per se into the identified insertion site(s) or into one or more regions from which there has been deletion.
The stated part steps are carried out in any desired sequence.
9. Expression of genes based on the EHV according to 1, 2, 3, 4 and 5.
10. Vaccines based on the EHV according to 1, 2, 3, 4 and 5 (above)
11. Antigens, immunogens, translation units and epitopes which are prepared in vitro or in vivo with EHV according to 1, 2, 3, 4 and 5 (above).
12. Vaccines containing antigens, immunogens, translation units and epitopes according to 11 (above).
13. Use of EHV according to 1, 2, 3, 4 and 5 (above) as vaccines which allow differentiation of vaccinated from non-vaccinated, infected animals after immunisation.
14. Use of EHV according to
Darai Gholamreza
Ludwig Hanns
Strube Walter
Thein Peter
Akorli Godfried R.
Bayer Aktiengesellschaft
Bui Phuong T.
Gil Joseph C.
LandOfFree
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