A model to assess the efficacy of vaccines for control of liver fluke infection.

Fasciola hepatica, the common liver fluke, causes disease and production losses in grazing animals, particularly sheep and cattle. The highly pathogenic immature flukes migrate through the liver, causing damage to the parenchyma, and adult flukes in the bile ducts feed on blood and cause biliary endothelial hyperplasia. Clinical signs of disease can include weight loss, anaemia and sudden death in heavily parasitized animals. Sub-clinical infections cause reduced growth rates in beef cattle and lower milk yields in dairy cows. It is estimated that the global cost of Fasciola infection is over $3billion per year1. In addition, it has been shown that the disease can adversely affect the results of routine tests for bovine tuberculosis2. The current control of F. hepatica relies primarily on the use on anthelmintic drugs designed to kill the parasite. However, resistance to triclabendazole, the drug with greatest efficacy against the immature stages, is evident in fluke populations worldwide and widespread in many sheep-rearing areas of Europe3,4. A vaccine would greatly enhance control. Several antigens of F. hepatica, potential components of a vaccine, have been characterised and their efficacy in inducing protection investigated. These include cathepsin L1 and L2, fatty acid binding protein, glutathione S-transferase, peroxiredoxin and leucine aminopeptidase5. Antigens have been tested either alone or in combination, with different adjuvants and delivery systems and in different host species including goats, cattle and sheep. Under experimental conditions, protection has been variable, ranging from 29% to 72% in terms of reduction in worm burden. In one study in which calves were naturally exposed to a low level of infection after vaccination with recombinant cathepsin L1 (rFhCL1), a reduction in worm burden of 48% was observed6. In many trials, although vaccination resulted in a relatively modest reduction in worm burden, there was a significantly lower egg output and an anti-embryonic effect5. For nematode and tick vaccines, reduced fecundity has a major impact on subsequent infection challenge7. However the impact of the anti-fecundity effect in F. hepatica is made more complicated since the life cycle relies on an intermediate host (the dwarf pond snail Galba truncatula) in which clonal amplification occurs (see Table 1 for a brief description of the stages that occur outside the definitive (mammalian) host). Moreover it is not clear if protection of around 50% in terms of worm burden is sufficient to warrant commercialisation of a vaccine and most prototype vaccines have not been tested in the field. Table 1 Terms used to describe the various stages of Fasciola hepatica that occur outside the definitive (mammalian) host. It is unlikely that, in the foreseeable future, a vaccine will be developed that offers complete protection against F. hepatica. The aim of this project was, therefore, to develop a model of F. hepatica infection that could be used to assess, under simulated field conditions, the effectiveness of vaccines providing incomplete protection against F. hepatica. Specifically, we assess which potential vaccine effects (reduction in fluke fecundity, increase in fluke maturation time and increase in immature fluke death rate) offer the greatest overall benefit in terms of reducing fluke burden (in the current season) and egg production (potentially affecting pasture contamination the following season). We began by building a mathematical model that describes the acquisition and development of fluke in the definitive host while taking into account heterogeneity in susceptibility between hosts together with seasonal changes in temperature, which affect the development of stages on the pasture. We use the model to assess the efficacy of vaccination and duration of protection required to reduce disease and transmission within a flock or herd in a single season.