Structure of the protective nematode protease complex H-gal-GP and its conservation across roundworm parasites.

Roundworm parasite infections are a major cause of human and livestock disease worldwide and a threat to global food security. Disease control currently relies on anthelmintic drugs to which roundworms are becoming increasingly resistant. An alternative approach is control by vaccination and 'hidden antigens', components of the worm gut not encountered by the infected host, have been exploited to produce Barbervax, the first commercial vaccine for a gut dwelling nematode of any host. Here we present the structure of H-gal-GP, a hidden antigen from Haemonchus contortus, the Barber's Pole worm, and a major component of Barbervax. We demonstrate its novel architecture, subunit composition and topology, flexibility and heterogeneity using cryo-electron microscopy, mass spectrometry, and modelling. Importantly, we demonstrate that complexes with the same architecture are present in other Strongylid roundworm parasites including human hookworm. This suggests a common ancestry and the potential for development of a unified hidden antigen vaccine.

Repeated vaccination against Haemonchus contortus provides continuous protection to young grazing sheep.

Haemonchus contortus is the most important gastrointestinal nematode in the tropics and subtropics causing huge economic losses to the small ruminant industry. Vaccination is potentially a sustainable approach to control this parasite and the performance of Barbervax® a vaccine containing integral membrane glycoproteins from H. contortus intestinal cells, was evaluated in naturally infected grazing sheep during their development from sucking lambs to adults. The sheep were randomly assigned to two groups: Vaccine and Control. The Vaccine group were vaccinated 23 times over the course of this two-year trial at intervals of 3-6 weeks. They responded with anti-vaccine specific antibodies, had 80 % lower Haemonchus egg counts and were less anaemic compared with the controls. Packed cell volumes (PCV) were always greater than 25 % in the vaccinated sheep but averaged between 23 % and 24 % in the controls. Total plasma protein values were higher in the vaccinated group from the third vaccination until the end of the trial. Throughout the trial, 88 % of the control sheep were drenched (average of 3.1 drenches per treated animal) but only 57 % of vaccinates, needed a salvage anthelmintic treatment (average of 1.9 drenches per treated animal), however, between group no differences in body weight were observed. In summary, these results indicate that a continuous course of Barbervax® can provide lambs with substantial year-round protection against H. contortus until they reached adulthood.

Transcriptomic profiling of nematode parasites surviving vaccine exposure.

Some nematode species are economically important parasites of livestock, while others are important human pathogens causing some of the most important neglected tropical diseases. In both humans and animals, anthelmintic drug administration is the main control strategy, but the emergence of drug-resistant worms has stimulated the development of alternative control approaches. Among these, vaccination is considered to be a sustainable and cost effective strategy. Currently, Barbervax® for the ruminant strongylid Haemonchus contortus is the only registered subunit vaccine for a nematode parasite, although a vaccine for the human hookworm Necator americanus is undergoing clinical trials (HOOKVAC consortium). As both these vaccines comprise a limited number of proteins, there is potential for selection of nematodes with altered sequences or expression of the vaccine antigens. Here we compared the transcriptome of H. contortus populations from sheep vaccinated with Barbervax® with worms from control animals. Barbervax® antigens are native integral membrane proteins isolated from the brush border of the intestinal cells of the adult parasite and many of those are proteases. Our findings provide no evidence for changes in expression of genes encoding Barbervax® antigens in the surviving parasite populations. However, surviving parasites from vaccinated animals showed increased expression of other proteases and regulators of lysosome trafficking, and displayed up-regulated lipid storage and defecation abilities that may have circumvented the effect of the vaccine. Implications for other potential vaccines for human and veterinary nematodes are discussed.