An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.
Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that neutralize enzymatic activity and interrupt blood-feeding. Toward developing a human hookworm vaccine, we expressed both wild-type (Na-APR-1(wt)) and mutant (Na-APR-1(mut)-mutagenesis of the catalytic aspartic acids) forms of Na-APR-1 from the human hookworm, Necator americanus. Refolded Na-APR-1(wt) was catalytically active, and Na-APR-1(mut) was catalytically inactive but still bound substrates. Vaccination of canines with Na-APR-1(mut) and heterologous challenge with A. caninum resulted in significantly reduced parasite egg burdens (P=0.034) and weight loss (P=0.022). Vaccinated dogs also had less gut pathology, fewer adult worms, and reduced blood loss compared to controls but these did not reach statistical significance. Vaccination with Na-APR-1(mut) induced antibodies that bound the native enzyme in the parasite gut and neutralized enzymatic activity of Na-APR-1(wt) and APR-1 orthologues from three other hookworm species that infect humans. IgG1 against Na-APR-1(mut) was the most prominently detected antibody in sera from people resident in high-transmission areas for N. americanus, indicating that natural boosting may occur in exposed humans. Na-APR-1(mut) is now a lead antigen for the development of an antihematophagy vaccine for human hookworm disease.
Pearson
Mark S
MS
Division of Infectious Diseases, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, Brisbane, Australia.
Bethony
Jeffrey M
JM
Pickering
Darren A
DA
de Oliveira
Luciana M
LM
Jariwala
Amar
A
Santiago
Helton
H
Miles
Aaron P
AP
Zhan
Bin
B
Jiang
Desheng
D
Ranjit
Najju
N
Mulvenna
Jason
J
Tribolet
Leon
L
Plieskatt
Jordan
J
Smith
Tracey
T
Bottazzi
Maria Elena
ME
Jones
Kathryn
K
Keegan
Brian
B
Hotez
Peter J
PJ
Loukas
Alex
A
D000723:Ancylostomatoidea / Q000276:immunology; D000818:Animals; D000909:Antibodies, Helminth / Q000008:administration & dosage / Q000627:therapeutic use*; D003546:Cysteine Endopeptidases / Q000276:immunology*; D004285:Dogs; D006725:Hookworm Infections / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D007422:Intestines / Q000469:parasitology; D017221:Necator americanus / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods; D014612:Vaccines / Q000494:pharmacology / Q000627:therapeutic use; D015431:Weight Loss
D000909:Antibodies, Helminth; D014612:Vaccines; D003546:Cysteine Endopeptidases