HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.09-131433v1 23/9/3007    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pearson, M. S. Articles by Loukas, A. Search for Related Content PubMed PubMed Citation Articles by Pearson, M. S. Articles by Loukas, A.

An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection

Mark S. Pearson^*, Jeffrey M. Bethony, Darren A. Pickering^*, Luciana M. de Oliveira, Amar Jariwala, Helton Santiago, Aaron P. Miles, Bin Zhan, Desheng Jiang, Najju Ranjit^*, Jason Mulvenna^*, Leon Tribolet^*, Jordan Plieskatt, Tracey Smith, Maria Elena Bottazzi, Kathryn Jones, Brian Keegan, Peter J. Hotez and Alex Loukas^*,1

^* Division of Infectious Diseases, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, Brisbane, Australia; and

Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington, District of Columbia, USA

¹ Correspondence: Division of Infectious Diseases, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, 300 Herston Rd, Brisbane, QLD 4006, Australia. E-mail: alex.loukas{at}qimr.edu.au

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, M. S., Bethony, J. M., Pickering, D. A., de Oliveira, L. M., Jariwala, A., Santiago, H., Miles, A. P., Zhan, B., Jiang, D., Ranjit, N., Mulvenna, J., Tribolet, L., Plieskatt, J., Smith, T., Bottazzi, M. E., Jones, K., Keegan, B., Hotez, P. J., Loukas, A. An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.

Key Words: vaccine • protease • hemoglobin • neglected tropical disease