A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites
- Radboud University Nijmegen Medical Center, Netherlands
- Institute for Translational Vaccinology, Netherlands
- Jikei University School of Medicine, Japan
- Ghent University and University Hospital, Belgium
- Leiden University Medical Center, Netherlands
- Université Pierre et Marie Curie-Paris 6, France
- Sanaria Inc., United States
Abstract
A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. Here we present data on safety and protective efficacy using sporozoites with deletions of two genes i.e. the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high level protection. The human PfΔb9ΔslarpGAP generated without drug-resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a PfΔb9ΔslarpSPZ vaccine.
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Ethics
Animal experimentation: All animal experiments with rodent parasites performed at the LUMC (Netherlands) were approved by the Animal Experiments Committee of the Leiden University Medical Center (DEC 07171; DEC 10099) and at the RUNMC (Netherlands) by the Radboud University Experimental Animal Ethical Committee (RUDEC 2008-123, RUDEC 2008-148, RUDEC 2010-250, RUDEC 2011-022, RUDEC 2011-208). The Dutch Experiments on Animal Act is established under European guidelines (EU directive 86/609/CEE) regarding the Protection of Animals used for Experimental and Other Scientific Purposes.Human liver-uPA-SCID mice (chimeric mice) were produced as described before. The study protocol for infecting these mice with P. falciparum sporozoites was approved by the animal ethics committee of the Faculty of Medicine and Health Sciences of the Ghent University.The study protocol was approved by the animal ethics committee of the Faculty of Medicine and Health Sciences of the Ghent University.
Human subjects: Primary human hepatocytes were isolated from healthy parts of human liver fragments which were collected during unrelated surgery in agreement with French national ethical regulations and after oral informed consent from adult patients undergoing partial hepatectomy as part of their medical treatment (Service de Chirurgie Digestive, H�pato-Bilio-Pancr�atique et Transplantation H�patique, H�pital Piti�-Salp�tri�re, Paris, France). The collection and use of this material for the purposes of the study presented here were undertaken in accordance with French national ethical guidelines under Article L. 1121-1 and article L. 1211-2
Copyright
© 2014, van Schaijk et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites
eLife 3:e03582.
https://doi.org/10.7554/eLife.03582
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