Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1999-02-19
2004-01-13
Graser, Jennifer E. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S185100, C424S193100, C424S265100, C530S300000, C530S333000, C530S350000
Reexamination Certificate
active
06676944
ABSTRACT:
The invention relates to the use of a peroxiredoxin (thiol-specific antioxidant) and/or a &bgr;-tubulin as a protective antigen against helminth parasites.
Each species of domestic animal can be parasitised by a number of different species of helminth, a process which usually causes disease. For example, the parasitic trematode
Fasciola hepatica
is known to be one cause of the economically important disease fascioliasis in ruminants, such as cattle and sheep. The parasite enters the mammalian host by penetrating the gut wall and spends approximately seven weeks feeding on and burrowing through the liver mass before migrating into the bile duct. Following infection, development of immunity in the host can be poor and resistance to reinfection in already infected hosts may be only partial or non-existent. Other parasitic flukes include
Fasciola gigantica
and Dicrocoelium spp., Paramphistomum spp. and also Schistosoma spp., eg
S. bovis
and
S. mansoni.
Problems are also caused by nematodes such as hookworms (e.g. Necator, Ancylostoma, Uncinaria and Bunostomum spp.).
Of the blood feeding nematodes the genus Haemonchus causes anaemia and weight loss and if untreated frequently leads to death. Animals infected with the related non-blood feeding nematode Ostertagia similarly fail to thrive and may die if untreated.
Other parasitic worms of economic importance include the various species of the following helminth genera:—
Trichostrongylus, Nematodirus, Dictvocaulus, Cooperia, Ascaris, Dirofilaria, Trichuris and Strongylus. In addition to domestic livestock, companion animals and humans may also be infected, not infrequently with fatal results and helminth infections and infestations thus pose a problem of considerable worldwide significance.
Control of helminth parasites of grazing livestock currently relies primarily on the use of anthelmintic drugs combined with pasture management. Such techniques are often unsatisfactory, firstly because anthelmintic drugs may have to be administered frequently, secondly because resistance against anthelmintic drugs is becoming increasingly widespread and thirdly because appropriate pasture management is often not possible on some farms and even where it is, it can place constraints on the best use of available grazing.
Numerous attempts have been made to control helminth parasites of domestic animals by immunological means. With very few exceptions (e.g. the cattle lungworm,
Dictyocaulus viviparus
) this has not proved possible.
A vaccine against
F. hepatica
has been proposed in WO90/08819 comprising a glutathione-S-transferase from
F. hepatica
as antigenic material. Further vaccines against
F. hepatica
have been proposed in WO94/09142, WO94/28925 and PCT/GB95/02350 comprising respectively a Cathepsin L, a dipeptidyl peptidase and a class of haemoproteins from
F. hepatica
as antigenic material.
Bennett (UK Patent No. 2169606B) extracted various antigens from Fasciola organisms by a process which separates antigens specific to the juvenile stage from antigens present throughout the juvenile and adult stages.
Furthermore crude in vitro excretory/secretory (E/S) products can under some circumstances confer immunity on rats (Rajasekariah et al, Parasitol. 79 (1979), p. 393-400).
It has now been found that animals vaccinated against
F. hepatica
using a relatively impure haemoprotein preparation, the pure counterpart of which is described in PCT/GB95/02350, produce antibodies against peroxiredoxin and &bgr;-tubulin molecules of fluke origin. This discovery opens up the possibility of vaccines against
F. hepatica
and other helminths based on the use of peroxiredoxin and/or &bgr;-tubulin molecules and/or corresponding proteins produced by other helminth parasites as antigens.
Accordingly an aspect of the present invention provides a vaccine composition for use in combating a parasitic infestation of helminths in a mammal wherein the antigenic material comprises a peroxiredoxin and/or a &bgr;-tubulin molecule, in at least partially purified form, or an antigenic fragment or epitope, component, precursor, analogue, variant or functionally equivalent derivative thereof, together with a carrier and/or adjuvant.
The invention also provides a method of combating a parasitic infestation of helminths in a mammal comprising administering to said mammal a vaccine according to the invention as hereinbefore defined in an amount effective to combat said infestation.
Alternatively viewed, the invention provides for the use of the molecules as hereinbefore described in the preparation of a vaccine composition for combatting a parasitic infestation of helminths in a mammal.
The mammal is preferably a ruminant, for example cattle or sheep, but the vaccine and method of the invention may also find application in humans, companion animals such as dogs and cats or in other domestic animals.
Preferably the peroxiredoxin and/or &bgr;-tubulin molecules are derived from flukes such as Fasciola or Dicrocoelium, in particular from the liver fluke
Fasciola hepatica
. Alternatively it is preferred that the peroxiredoxin and/or &bgr;-tubulin molecules should be capable of stimulating an immune response which will be effective against Fasciola or Dicrocoelium, in particular
F. hepatica
and
F. gigantica
, such peroxiredoxin and/or &bgr;-tubulin molecules from other species as are capable of conferring a cross-protective immune response thus forming a particularly preferred aspect of the invention.
The
F. hepatica
peroxiredoxin and &bgr;-tubulin molecules shown hereinafter to possess cDNA sequences and predicted amino acid sequences as shown in
FIGS. 2 and 4
respectively are particularly preferred for use in the vaccine and method of the invention.
The peroxiredoxin and/or &bgr;-tubulin molecules incorporated in the vaccine according to the invention are in at least partially purified form. Preferably the molecules of the present invention are at least 75% pure and more preferably at least 95% pure. It will be appreciated that once peroxiredoxin and/or &bgr;-tubulin molecules of at least 95% purity have been obtained they can be admixed with one or more further purified antigenic proteins, to form a polyvalent vaccine.
According to the present invention the peroxiredoxin and/or &bgr;-tubulin molecules incorporated in the vaccine may be in the form of antigens, antigenic fragments, epitopes, components, precursors, analogues or functionally-equivalent derivatives thereof.
A preferred form of polyvalent vaccine according to the invention will contain peroxiredoxin and/or &bgr;-tubulin polypeptides as referred to above in combination with a Cathepsin L-type antigen as described in more detail in International Patent Application No. WO94/09142 or a dipeptidyl peptidase antigen as described in more detail in International Patent Application No. WO94/28925 or a class of haemoprotein molecules as described in more detail in International Patent Application No. PCT/GB95/02350. Thus the Cathepsin L and/or dipeptidyl peptidase and/or haemoproteins are preferably derived from flukes such as Fasciola or Dicrocoelium, in particular the liver fluke
F. hepatica
. Such a polyvalent vaccine will, by inducing immunity in the host species against two or more separate aspects of the invading helminth parasite, significantly increase the likelihood of protection against the helminth and significantly reduce the chances of infestation occurring.
Monovalent vaccines according to the invention may also have an anti-fecundity effect on helminth parasites, and this effect should be still more marked with polyvalent vaccines.
In a preferred aspect the polyvalent vaccine comprises peroxiredoxin and/or &bgr;-tubulin polypeptides according to the present invention together with a Cathepsin L1 having molecular weight of 27 kDa by sodium dodecyl sulphate polyacrylamide gel electrophoresis as disclosed in WO94/09142 and/or a Cathepsin L2 having molecular weight of 29.5 kDa by the same technique as disclosed in WO94/09142 and/or a dipeptidyl peptidase having molecular weight of 200 kDa by t
Andrews Stuart John
Dalton John Pius
Dalton John P.
Graser Jennifer E.
Rothwell Figg Ernst & Manbeck
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