Helminth parasite antigen with aminopeptidase-like activity

Details Helminth parasite antigen with aminopeptidase-like activity Helminth parasite antigen with aminopeptidase-like activity

1996-06-26

2002-07-02

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Recombinant virus encoding one or more heterologous proteins...

Reexamination Certificate

active

06413521

ABSTRACT:

This invention relates to novel helminth parasite antigens and their use in the control of disease caused by helminth parasites, particularly parasitic nematodes of the gastro-intestinal tract of mammals.
Helminth parasites, particularly nematodes, infect or infest a wide range of animals, including man, and are a widespread and significant source of disease and ill-thrift, not only in animals, but also in man. Such parasites thus represent a considerable worldwide drain on economic resources. This is particularly true in animal husbandry, where parasite infections of grazing animals, such as sheep and cattle, are often difficult and expensive to control and may result in significant economic losses.
Particular mention may be made in this regard of the non-blood feeding nematodes
Ostertagia ostertagi
and
Ostertagia
(
Teladorsagia
)
circumcincta
(
O. circumcincta
has recently been reclassified as
T.circumcincta,
although the new name is not yet in wide usage).
Other parasitic helminths of economic importance include the various species of the following helminth families: Trichostrongylus, Nematodirus, Dictyocaulus, Cooperia, Trichuris, Oesophagostomum, Bunostomum and Metastrongylus. In addition to domestic livestock, pets and humans may also be infected, not infrequently with fatal results.
At present, control of helminth parasites of grazing livestock relies primarily on the use of anthelmintic drugs, combined with pasture management. Such techniques have not proved entirely satisfactory however, due to their expense and inconvenience and to a rapid increase in drug resistance. Anthelmintic drugs need to be administered frequently and 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.
To overcome these problems, attempts have been made to achieve immunological means of control. Although there has been some success in identifying certain protective antigens as potential vaccine candidates, most notably in Haemonchus, this approach has proved difficult and, other than for the cattle lungworm
Dictyocaulus viviparus,
has yet to come to commercial fruition.
The most success to date has been achieved with the protein doublet H110D, an integral membrane protein isolated from the gut of
H.contortus
and described by Munn in WO88/00835. H110D now represents the most promising vaccine candidate to date.
Munn has also described and proposed as a vaccine, contortin, a helical polymeric extracellular protein associated with the luminal surface of
H.contortus
intestinal cells (Munn et al., Parasitology 94: 385-397, 1987).
A third Haemonchus gut membrane protein with protective antigenic properties has also been discovered and termed H45 (Munn and Smith, WO90/11086).
Whilst proteins such as H110 D and H45 can be used as the basis for a vaccine against Haemonchus, there is nonetheless a continuing need for new and improved helminth parasite vaccines and in particular for a vaccine which may be used across a broad range of helminth genera. Most studies to date have concentrated on blood feeding nematodes such as Haemonchus and there is especially a need for vaccines against non-blood feeding helminths such as Trichostrongylus, Cooperia, Dictyocaulus, and particularly Ostertagia.
The present invention accordingly seeks to provide novel antigens for use as helminth parasite vaccines and in particular as protective immunogens in the control of diseases caused by non-blood feeding helminth parasites.
More specifically, the present invention is based on the finding that the gut of non-blood feeding nematodes such as Ostertagia and Cooperia contains an integral membrane protein having aminopeptidase activity which is believed to be an important protective antigen capable of conferring protective immunity against helminth parasites in animals. Such proteins, when liberated from the membranes in which they are integral, for example by the use of detergents, are novel and of use in the manufacture of vaccines against helminth infections.
According to one aspect, the present invention thus provides a protective helminth parasite antigen which is characterised by possessing aminopeptidase-like activity and which, in native form, is an integral membrane protein associated with the gut microvilli of a non-obligate blood feeding helminth parasite, or a functionally-equivalent variant, or antigenic fragment or precursor thereof.
A further aspect of the invention provides such protective antigens, and functionally-equivalent variants, antigenic fragments or precursors thereof, for use in stimulating an immune response against helminth parasites in a human or non-human, preferably mammalian, especially preferably ruminant, animal.
A precursor for the antigen in question may be a larger protein which is processed, eg. by proteolysis, to yield the antigen per se. Such precursors may take the form of zymogens ie. inactive precursors of enzymes, activated by proteolytic cleavage, for example analogous to the pepsin/pepsinogen system or the well known zymogens involved in the blood clotting cascade.
Non-obligate blood feeding parasites are defined for present purposes as those which imbibe host blood rarely and seemingly incidentally (in contrast to obligate blood feeders such as Haemonchus, which feed almost exclusively on host blood) and include both plug feeders and browsers. Plug-feeding worms have enlarged buccal capsules which they use to envelope a plug of host tissue e.g. the intestinal mucosa in the case of
Chabertia ovina
) from which they obtain nutrient. Browsing nematodes do not have mouthparts specialised for attachment. The composition of their diet is not known but is thought to consist either of host tissue, extracellular tissue fluid, mucus or, in the case of gastro-intestinal species, host digesta. Some gastrointestinal species, particularly those which live in close association with the mucosa (e.g.
Osteragia circumcincta
in the abomasal glands and certain Trichostrongylus species (e.g. other than T.axei) which tunnel under the intestinal epithelium may feed on a mixture of these.
Economically important helminth parasites which are not obligate blood feeders include the following genera and their subspecies: Ostertagia (which, for the avoidance of doubt, as used herein includes Teladorsagia), Trichostrongylus spp. (e.g.
T.colubriformis, T.vitrinus
and
T.axei
), Cooperia spp., Nematodirus, Chabertia and Oesophagostomum.
The novel antigens of the invention are not recognised by sera from naturally immune animals. In other words, they are not normally, in native form, accessible to the immune system of the infected host and are thus “hidden”, “concealed” or “cryptic” antigens.
The term “protective antigens” or “protective antigenic activity” as used herein defines those antigens and their fragments or precursors, capable of generating a host-protective, ie. immunogenic, immune response, that is a response by the host which leads to generation of immune effector molecules, antibodies or cells which damage, inhibit or kill the parasite and thereby “protect” the host from clinical or sub-clinical disease and loss of productivity. Such a protective immune response may commonly be manifested by the generation of antibodies which are able to inhibit the metabolic function of the parasite, leading to stunting, lack of egg production and/or death.
As mentioned above, included within the scope of the invention are functionally-equivalent variants of the novel antigens and their fragments and precursors. “Functionally-equivalent” is used herein to define proteins related to or derived from the native protein, where the amino acid sequence has been modified by single or multiple amino acid substitution, addition and/or deletion and also sequences where the amino acids have been chemically modified, including by deglycosylation or glycosylation, but which nonetheless retain protective antigenic activity eg. are capable of raising host protective antibodies and/or functional immunity against

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