Roadmap for the development of candidate vaccines for liver fluke

What are we trying to achieve and why? What is the problem we are trying to solve?

A vaccine giving long-lasting protection with two initial injections followed by annual boosting, ideally in both cattle and sheep

What are the scientific and technological challenges (knowledge gaps needing to be addressed)?

• Need for frequent boosting where hidden antigens are used
• The parasite modulates the hosts immune responses
• Unknown sources of variability in extent of protection in trials with identical protocols
• Need to communicate the level of efficacy likely to be delivered by fluke vaccines – will not be likely to match the 100% or near expected for many bacterial and viral vaccines

What approaches could/should be taken to address the research question?

• Slow release of purified antigens from an adjuvant that drives the immune response in the correct direction.
• Meta-analysis of the results of previous trials to understand the sources of variability
• Continued basic immunological studies to understand fluke-host interactions and fluke-induced immunomodulation
• Adjuvants capable of modulating the response to infection in a protective direction
• Use of a replicating vector to reduce number of boosting doses required
• Nucleic-acid based vaccines based including those based on self – amplifying RNA technology
• A combination of different candidates (subunit/nucleic acid based/peptide/vectored) in a Prime-boost approach
• Multivalent vaccines incorporating pathogens generating strong Th1-responses and counter-acting F. hepatica induced immunoregulation

What else needs to be done before we can solve this need?

• Difficulties in agreeing measures of protection – e.g. fluke burden, egg output, liver damage, specific pathology
• Modelling how much protection is required for an effective and commercial vaccine
• More in-depth knowledge about host-pathogen relationships and the nature of immune response that is capable of being protective

Existing knowledge including successes and failures

Protection of ruminants can be achieved using a number of antigens, both purified and recombinant, derived from F. hepatica E/S molecules. However, this is inconsistent.
Possible reasons for this inconsistency include:

• Genetic variation in fluke strains used for challenge
• Differences in fine-specificity or other parameters of the host response
• Contribution of parasite glycans to protective and non-protective responses
• Host genetic background factors
• Unknown unknowns!