Lipid core peptide targeting the cathepsin D hemoglobinase of Schistosoma mansoni as a component of a schistosomiasis vaccine.
The self-adjuvanting lipid core peptide (LCP) system offers a safe alternative vaccine delivery strategy, eliminating the need for additional adjuvants such as CpG Alum. In this study, we adopted the LCP as a scaffold for an epitope located on the surface of the cathepsin D hemoglobinase (Sm-CatD) of the human blood fluke Schistosoma mansoni. Sm-CatD plays a pivotal role in digestion of the fluke's bloodmeal and has been shown to be efficacious as a subunit vaccine in a murine model of human schistosomiasis. Using molecular modeling we showed that S. mansoni cathepsin D possesses a predicted surface exposed α-helix (A₂₆₃K) that corresponds to an immunodominant helix and target of enzyme-neutralizing antibodies against Necator americanus APR-1 (Na-APR-1), the orthologous protease and vaccine antigen from blood-feeding hookworms. The A₂₆₃K epitope was engineered as two peptide variants, one of which was flanked at both termini with a coil maintaining sequence, thereby promoting the helical characteristics of the native A₂₆₃K epitope. Some of the peptides were fused to a self-adjuvanting lipid core scaffold to generate LCPs. Mice were vaccinated with unadjuvanted peptides, peptides formulated with Freund's adjuvants, or LCPs. Antibodies generated to LCPs recognized native Sm-CatD within a soluble adult schistosome extract, and almost completely abolished its enzymatic activity in vitro. Using immunohistochemistry we showed that anti-LCP antibodies bound to the native Sm-CatD protein in the esophagus and anterior regions of the gastrodermis of adult flukes. Vaccines offer an alternative control strategy in the fight against schistosomiasis, and further development of LCPs containing multiple epitopes from this and other vaccine antigens should become a research priority.
Australian Institute of Tropical Health and Medicine; Centre for Biodiscovery and Molecular Development of Therapeutics; James Cook University; Cairns, QLD Australia.
Annette M
AM
Dougall
Australian Institute of Tropical Health and Medicine; Centre for Biodiscovery and Molecular Development of Therapeutics; James Cook University; Cairns, QLD Australia; The University of Queensland; School of Chemistry and Molecular Biosciences; St. Lucia; QLD Australia; The University of Queensland; School of Pharmacy; Wooloongabba, QLD Australia.
Mariusz
M
Skwarczynski
The University of Queensland; School of Chemistry and Molecular Biosciences; St. Lucia; QLD Australia.
Makan
M
Khoshnejad
The University of Queensland; School of Chemistry and Molecular Biosciences; St. Lucia; QLD Australia.
Saranya
S
Chandrudu
Australian Institute of Tropical Health and Medicine; Centre for Biodiscovery and Molecular Development of Therapeutics; James Cook University; Cairns, QLD Australia.
Norelle L
NL
Daly
Australian Institute of Tropical Health and Medicine; Centre for Biodiscovery and Molecular Development of Therapeutics; James Cook University; Cairns, QLD Australia; The University of Queensland; School of Chemistry and Molecular Biosciences; St. Lucia; QLD Australia; The University of Queensland; School of Pharmacy; Wooloongabba, QLD Australia.
Istvan
I
Toth
Australian Institute of Tropical Health and Medicine; Centre for Biodiscovery and Molecular Development of Therapeutics; James Cook University; Cairns, QLD Australia.
Alex
A
Loukas
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005260:Female; D008297:Male; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011487:Protein Conformation; D012550:Schistosoma mansoni / Q000201:enzymology* / Q000276:immunology*; D012552:Schistosomiasis / Q000276:immunology / Q000517:prevention & control*; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000909:Antibodies, Helminth; D057134:Antibodies, Neutralizing; D000939:Epitopes; D014612:Vaccines; D002402:Cathepsin D
cathepsin D; conformational epitope; lipopeptide; peptide antigen; schistosomiasis; self-adjuvanting; vaccine delivery