Innovative synthetic vaccinology approach for helminth parasites

Supervisors: Francisca Mutapi, Susan Rosser

Project description:

Helminths are parasitic worms with a significant economic and health impact in both animals and humans. In the UK alone, consistently the most commonly diagnosed condition in sheep is infection with intestinal helminths. The only intervention currently available is treatment with antihelminthic drugs. However in the past 10 years, anthelmintic resistant worms have become a significant problem in England and the UK. Even so intestinal helminth infection was still the most commonly diagnosed condition prior to this time. This shows that despite the availability of cheap, highly effective anthelmintics, some farmers have been failing to control worms in their sheep. Now that many anthelmintics are less effective, due to the increase in resistant worms, the challenge of controlling worms in sheep is even greater. A recent report showed that intestinal worms cost the British sheep industry  £84 million annually while liver fluke infections cost  £13-15 million for English beef and sheep annually. In human populations, Brazil had to suspend its national control program targeting the blood fluke schistosomiasis due to the development of drug resistance to oxamniquine.

Vaccine research for helminths has stalled with the failure of any candidates to progress to Phase 3 clinical trials in humans or to market for animal hosts. One major drawback is the use of non-efficacious single protein target vaccine candidates.

This project uses a novel approach to identify vaccine candidates targeting more than one protein and more than one antigenic site in silico. Once identified, we will utilise the unique capabilities of the Edinburgh Genome Foundry a UK national synthetic biology facility focusing on automating DNA design, assembly and characterization. The genes encoding a range of potential antigenic peptide domains will be synthesised and combinatorially assembled to produce a series of novel synthetic proteins with multiple antigenic peptide domains in different ratios and orders. These vaccine candidates will be used for immunological assays using samples from hosts known to have developed protective immunity naturally. The study will use as its model the zoonotic parasite Schistosoma, and use immunology samples from a well-characterised human population. Results from this work will be applicable to other host-helminth relationships allowing the approach to be adapted in other systems.

The student will be trained on the in silico generation of vaccine candidates as well as the cellular and serological immunology assays required to conduct the proof of principle studies. They will also be trained in cutting edge synthetic biology techniques and automated DNA assembly using a large-scale robotics platform.

References:

Economic Impact of Health and Welfare Issues in Beef Cattle and Sheep in England, Prepared by: Nerys Wright ADAS UK Ltd, 2013

Mutapi F, Billingsley PF and Secor WE. Infection and treatment immunizations for successful parasite vaccines. Trends Parasitol 2013; 29: 135-141.

Sean D. Colloms et al and Susan J. Rosser. *Rapid metabolic pathway assembly and modification using serine integrase site-specific recombination. Nucleic Acids Res. 2014 Feb; 42(4): e23.

Other: