Low allelic diversity in vaccine candidates genes from different locations sustain hope for Fasciola hepatica immunization

Abstract

Fasciola hepatica is a trematode parasite that causes fasciolosis in animals and humans. Fasciolosis is usually treated with triclabendazole, although drug-resistant parasites have been described in several geographical locations. An alternative to drug treatment would be the use of a vaccine, although vaccination studies that have been performed mainly in ruminants over the last 30 years, show high variability in the achieved protection and are not yet ready for commercialisation. Since F. hepatica exhibits a high degree of genomic polymorphism, variation in vaccine efficacy could be attributed, at least partially, to phenotypic differences in vaccine candidate sequences amongst parasites used in the challenge infections. To begin to address this issue, a collection of F. hepatica isolates from geographically dispersed regions, as well as parasites obtained from vaccination trials performed against a field isolate from Uruguay and the experimentally maintained South Gloucester isolate (Ridgeway Research, UK), were compiled to establish a F. hepatica Biobank. These collected isolates were used for the genetic analysis of several vaccine candidates that are important in host-parasite interactions and are the focus of the H2020 PARAGONE vaccine project (https://www.paragoneh2020.eu/), namely FhCL1, FhCL2, FhPrx, FhLAP and FhHDM. Our results show that F. hepatica exhibits a high level of conservation in the sequences encoding each of these proteins. The consequential low variability in these vaccine candidates amongst parasites from different geographical regions reinforces the idea that they would be suitable immunogens against liver fluke isolates worldwide.

<p>Human Fascioliasis: Current Epidemiological Status and Strategies for Diagnosis, Treatment, and Control</p>

“…Some of the candidate antigens include FhCL1, FhCL2, FhPrx, FhLAP and FhHDM. 95 FhLAP is one of the better studied antigens inducing protection in between 83% and 90% of livestock. [96][97][98] However, no vaccine is now commercially available and further research is needed to achieve better and sustained responses.…”

Recent Progress in the Development of Liver Fluke and Blood Fluke Vaccines

“…Indeed, antigenic polymorphism has long been considered an important mechanism of immune evasion used by a number of pathogens, including helminths [ 19 ]. However, genetic analysis of several vaccine candidates (FhCL1, FhCL2, FhPrx (peroxiredoxin), FhLAP and FhHDM ( F. hepatica helminth defence molecule [ 8 ])) showed that F. hepatica exhibits only a low level of allelic variability in the sequences encoding each of these proteins amongst isolates from different geographical regions; this suggests the variability reported among vaccine studies are not related to heterogeneity in these genes, thereby reinforcing the idea that they would be suitable immunogens against liver fluke parasites globally [ 15 ]. Further elaboration of host-associated effects and the level of animal susceptibility to infection may be able to explain the variability observed in F. hepatica vaccine trials.…”

“…Approaches used to date to identify vaccine candidates for F. hepatica and F. gigantica include: (I) analysis of antigens that cross-react with sera from animals with other trematode infections; (II) orthologous antigens identified as vaccine candidates in other species; and (III) rational selection of antigens pivotal in liver fluke survival [ 14 ]. Many vaccine studies in livestock have evaluated the value of these candidate antigens, and Table 1 summarises the level of protective efficacy observed with some single or combination experimental F. hepatica vaccines [ 15 ]. Results of a compilation of additional efficacy trials, over the past three decades, with vaccines for both F. hepatica and F. gigantica tested in livestock, are also available [ 14 ].…”

“…The genomes of F. hepatica (size: 1.14–1.3 Gb) and F. gigantica (size: 1.04–1.13 Gb) exhibit a high degree of genomic polymorphism [ 16 , 17 , 18 ], and it has been speculated that the variability in vaccine efficacy widely reported could be attributed, at least in part, to phenotypic differences resulting from the variation in sequences of the vaccine candidates amongst parasites used in each challenge infection [ 15 ]. Indeed, antigenic polymorphism has long been considered an important mechanism of immune evasion used by a number of pathogens, including helminths [ 19 ].…”

“…There is a basic requirement to discover an adjuvant that is as potent as Freund’s Complete Adjuvant that does not produce side effects but is capable of generating strong and effective protective Th1 immune responses in a broad spectrum of hosts to overcome animal variability [ 15 ]. Furthermore, native fluke antigens appear, in general, to promote more effective immune responses than recombinant vaccines, inferring that post-translational modifications (phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation and proteolysis) may be critical in generating the sufficiently robust levels of protective immunity required, an important factor that will need consideration in the future [ 15 ]. It is possible that the key molecules that stimulate the required level of protective immunity have not yet been characterised.…”