Elsevier

Veterinary Parasitology

Volume 115, Issue 2, 25 July 2003, Pages 83-123
Veterinary Parasitology

Vaccination against cestode parasites: anti-helminth vaccines that work and why

This paper is dedicated to the memory of Dr. Susan E. Newton, who passed away on 12 March 2003, for her outstanding contribution to the field of parasitology, and anti-parasite vaccine research in particular
https://doi.org/10.1016/S0304-4017(03)00202-4Get rights and content

Abstract

Highly effective recombinant vaccines have been developed against the helminth parasites Taenia ovis, Taenia saginata and Echinococcus granulosus. These vaccines indicate that it is possible to achieve a reliable, high level of protection against a complex metazoan parasite using defined recombinant antigens. However, the effectiveness of the vaccines against the taeniid cestodes stands in contrast to the more limited successes which characterise attempts to develop vaccines against other platyhelminth or nematode parasites. This review examines the features of the host–parasite relationships among the taeniid cestodes which have formed the basis for vaccine development. Particular consideration is given to the methodologies that have been used in making the cestode vaccines that might be of interest to researchers working on vaccination against other helminths. In developing the cestode vaccines, antigens from the parasites’ infective larval stage contained within the egg (oncosphere) were identified as having the potential to induce high levels of protection in vaccinated hosts. A series of vaccination trials with antigen fractions, and associated immunological analyses, identified individual protective antigens or fractions. These were cloned from cDNA and the recombinant proteins expressed in Escherichia coli. This strategy was independently successful in developing vaccines against T. ovis and E. granulosus. Identification of protective antigens for these species enabled rapid identification, cloning and expression of their homologues in related species and thereby the development of effective vaccines against T. saginata, E. multilocularis and, more recently, T. solium. The T. saginata vaccine provides an excellent example of the use of two antigen components, each of which were not protective when used individually, but when combined they induce a reliable, high level of protection. One important contributing factor to the success of vaccine development for the taeniid cestodes was the concentration on studies seeking to identify native host-protective antigens, before the adoption of recombinant methodologies. The cestode vaccines are being developed towards practical (commercial) application. The high level of efficacy of the vaccines against T. solium cysticercosis and hydatid disease suggests that they would be effective also if used directly in humans.

Introduction

Is it possible to achieve a high level of protection against infection with a helminth parasite using a recombinant antigen? This question can be answered with an unequivocal “yes”; reliable protection of between 90 and 100% has been achieved with recombinant antigens against Taenia ovis infection in sheep, Taenia saginata infection in cattle and Echinococcus granulosus infection in sheep. Less substantial protection has been achieved against numerous other helminths (Klei, 1997, Newton and Munn, 1999, Knox, 2000, Knox et al., 2001, Capron et al., 2002, Lustigman et al., 2002), however, the number of parasites for which complete or near-complete protection has been achieved remains disappointingly small. The remarkable feature of those parasites for which highly effective recombinant vaccines have been developed is that they all belong to one family of cestode parasites, the Taeniidae. What is it about this group of helminths that has led to successful vaccine development, while relatively modest success has been achieved with other helminth species? Are there any lessons in what has been done with these taeniid species that might be useful in attempts to develop vaccines against other helminths? These questions are addressed here in the context of a review of vaccine development for the taeniid cestodes.

Cestodes are tapeworm parasites. Those of greatest medical or economic importance belong to the family Taeniidae which comprises two genera, Taenia and Echinococcus. These parasites have a life-cycle involving two mammalian hosts. The tapeworm stage occurs in the small intestine of the definitive host and typically causes little if any pathology. Eggs containing an infective larval stage, known as the oncosphere, are released with the faeces. The eggs contaminate the environment and when ingested by a suitable species of intermediate host, they hatch under the influences of the host’s intestinal secretions. The activated oncosphere then penetrates the gut mucosa, migrates via the circulatory system to a site within the tissues where the parasite encysts and develops into a mature, infective larval stage (metacestode). It is infection of the body tissues with metacestodes that causes medical problems and economic loss. Some species of the genus Taenia encyst in the striated muscle tissues of sheep (T. ovis), cattle (T. saginata) and pigs (T. solium) and cause a disease known as cysticercosis. These infections lead to economic loss in the livestock industries. The eggs of T. solium are also infective for humans in whom the larvae (cysticerci) have a tendency to encyst in subcutaneous tissue as well as the brain and other parts of the central nervous system, causing neurocysticercosis. A number of other Taenia species are natural parasites of laboratory animals and have been utilised in research into the immunobiology of infection with this group of parasites. Those species which have been the subject of substantial research in this respect are Taenia taeniaeformis (formerly known as Cysticercus fasciolaris) in rats and mice, Taenia pisiformis in rabbits and Taenia crassiceps in mice. The larval stage of Echinococcus parasites form hydatid cysts. Unlike the Taenia species which are relatively species specific in their host preferences, the larval stage of Echinococcus species infect a variety of host species. E. granulosus causes cystic echinococcosis or cystic hydatid disease in a wide variety of host species including humans. E. multilocularis causes alveolar echinococcosis and is transmitted primarily by arvicolid rodents acting as intermediate hosts.

While some species of taeniid cestode cause economic loss due to their infections in livestock, the principal cause for concern with this group of parasites is the medical consequences of neurocysticercosis and hydatid disease in humans. Transmission of both diseases remains widespread in the world and both cause substantial human morbidity and mortality. Neurocysticercosis is prevalent in many parts of the developing world, particularly in Central America, parts of South America and non-Islamic regions of Asia and Africa. Depending on the number and location of cysts, T. solium neurocysticercosis can cause a variety of serious neurological symptoms and is an important cause of late-onset epilepsy (Garcia et al., 1993, Garcia et al., 1995, White and Garcia, 1999). Hydatid cysts may grow to a volume of several litres and can occur in almost any part of the body. Infections are most common in the liver and lungs. Surgery remains the mainstay for treatment of infections in humans, however, patient management is often complicated by the potential for infective stages contained within the cyst (protoscoleces) to cause secondary infections if these are released into the body tissues due to cyst rupture or during surgical procedures.

The medical burden caused by cysticercosis and hydatid disease has stimulated efforts to control or eliminate transmission of these diseases. The tapeworm stage in the parasites’ life-cycle is particularly susceptible to intervention through the application of highly effective anthelmintics. However, definitive hosts from which tapeworms have been eliminated by anthelmintic treatment remain susceptible to re-infection. Hence, control of these diseases by removal of tapeworm carriers is inherently inefficient unless anthelmintic treatment can be given repeatedly at intervals less than the prepatent period of the parasite. Such a parasite control scheme has been extremely successful for the eradication of hydatid disease from New Zealand (Gemmell et al., 2001). Unfortunately sufficient resources are rarely available for this to be an effective method for control of hydatidosis or cysticercosis and there is a clear need for new tools to assist with their control. One option is the development of vaccines. Concomitant immunity is a hallmark of infection with taeniid cestodes in their intermediate hosts (Rickard and Williams, 1982) and this provides a basis for the development of practical vaccines for use in these host species.

Section snippets

Host-protective responses

Many aspects of the immunological relationship between metacestodes of Taenia species and their hosts were delineated by pioneering work undertaken in rodents with T. taeniaeformis and in rabbits with T. pisiformis during the 1930s and 1940s. These studies elucidated the following principals that have been confirmed to apply generally to natural infection with taeniid metacestodes:

  • 1.

    Infection leads to a state of immunity to re-infection (Miller, 1931, Miller, 1932a, Miller and Gardiner, 1932,

Background and early studies of immunity in sheep

T. ovis metacestodes encyst in striated muscle of sheep and, when these are detected at carcass meat inspection, they can cause carcass condemnation and consequent economic loss. The parasite has been particularly recognised as an economic problem in Australia and New Zealand (Arundel, 1972, Lawson, 1994). Injection of activated oncospheres intramuscularly, subcutaneously or intravenously leads to the growth of the parasite at the injection site and sheep exposed to “infection” with T. ovis by

Background and early studies of immunity in cattle

T. saginata infection in beef meat is a significant cause of production loss in Europe and in other Western countries and is an impediment to the export of beef from many developing countries, especially in Africa (Geerts, 1993). In addition, the parasite is infective for humans in whom infection manifests as a large (up to 10 m) intestinal tapeworm.

Penfold and Penfold (1937) and Urquhart (1958) found that cattle which had a pre-existing infection with T. saginata were solidly resistant to

Background and studies of immunity in pigs induced using parasite extracts

T. solium is the most difficult of the taeniid species to investigate in vaccination studies. This is because of difficulties with obtaining supplies of parasite’s eggs, which must be obtained in order to undertake challenge trials in pigs. The adult tapeworm occurs only in humans and at low prevalence even in communities with a high rate of porcine and human cysticercosis (Pawlowski and Schultz, 1972, Sarti et al., 1994). Limited success had been achieved with the development of gravid T.

Background and early studies of immunity in sheep

The public health significance of hydatid disease has stimulated a sustained period of investigation of immunity to E. granulosus, particularly in sheep which are the most common intermediate host involved in transmission of the parasite. A number of studies have investigated immunity to re-infection following an initial infection given either by oral administration of E. granulosus eggs (Sweatman et al., 1963, Dempster et al., 1995) and/or the parenteral injection of eggs or activated

Identification of host-protective epitopes

The T. ovis, T. saginata, T. solium and E. granulosus recombinant vaccines are all produced currently as GST fusion proteins expressed in E. coli. Theoretically, such proteins can be produced in unlimited amounts, however, commonly there are practical difficulties in scaling-up production of recombinant proteins. Such limitations have needed to be dealt with in the practical development of the T. ovis vaccines (Dempster et al., 1996, Lightowlers et al., 1996a) and for the other taeniid vaccines

Modular protein structure of cestode antigens and predicted structural and functional features

The taeniid oncosphere antigens have been found to be modular proteins and to have features in common (Gauci and Lightowlers, 2003). Homologous proteins in different species show high levels of conservation of both the encoded protein as well as gene structure. In each antigen, the gene exon/intron boundaries define a secretory signal sequence and one or two fibronectin type III domains (FnIII). FnIII domains are widely distributed in nature, being present in approximately 2% of animal proteins

Defining conformational epitopes—application of peptide mimotopes

Evidence from the immunological analyses which have been undertaken with the host-protective cestode antigens, particularly EG95, has indicated that the humoral immune response in vaccinated animals is directed towards the protein’s linear epitopes (corresponding to a continuous sequence of amino acids within the protein) as well as discontinuous epitopes (involves amino acids from different parts of the protein that are held in close proximity due to the particular tertiary conformation of the

Antigenic variation/diversity—will it be a problem for taeniid cestodes?

Antigenic variation is one of the paradigms of the study of pathogenic organisms, including a number of protozoan parasites. Evidence to implicate a major role for antigenic variation or diversity in the relation to immunobiology of infections with helminth parasites is less available, although the selection of anthelmintic resistance in helminths could be considered an analogous phenomenon and such resistance is arguably the most pressing concern in helminth parasitology at this time (Waller,

Challenges remaining in translation of experimental success to practical (commercial) vaccines

For the taeniid cestodes, the challenges in vaccine development are no longer in the identification of potent, protective recombinant antigens. The challenges for the immediate and medium-term future lie in the delineation of operational characteristics which are suitable for incorporation into normal farm management procedures for the target species, and to deliver the vaccine at an acceptable cost. In retrospect, it is becoming clear that these challenges may be more substantial than the

Major factors contributing to successful vaccine development for taeniids—lessons for other anti-helminth vaccines?

A large number of nematode species contribute to the very great significance of helminth parasitoses for both human health and for livestock production. Among the platyhelminths, schistosomiases remain major human diseases in much of the tropical world and fascioliasis is an important cause of production loss in livestock where conditions favour transmission of this parasite. Effective vaccines to control these infections would represent a major advance, particularly in the face of increasing

Concluding remarks

T. ovis and T. saginata are parasites of relatively minor significance economically or medically. In many respects, these parasites were used as models for development of methodologies and antigen sources to be used in the production of vaccines against the important human pathogens T. solium and E. granulosus. Both T. solium and E. granulosus vaccines were developed for use in the animal intermediate hosts of the zoonotic parasites. However, the biology of infection with cysticerci and hydatid

Acknowledgements

Funding is acknowledged from the National Health and Medical Research Council of Australia.

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    Present address: Hokkaido Institute of Public Health, North 19 West 12, North Ward Sapporo, Hokkaido 060-0819, Japan.

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