1. Human Biology and Medicine
  2. Microbiology and Infectious Disease
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A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites

  1. Ben C L van Schaijk
  2. Ivo H J Ploemen
  3. Takeshi Annoura
  4. Martijn W Vos
  5. Foquet Lander
  6. Geert-Jan van Gemert
  7. Severine Chevalley-Maurel
  8. Marga van de Vegte-Bolmer
  9. Mohammed Sajid
  10. Jean-Francois Franetich
  11. Audrey Lorthiois
  12. Geert Leroux-Roels
  13. Philip Meuleman
  14. Cornelius C Hermsen
  15. Dominique Mazier
  16. Stephen L Hoffman
  17. Chris J Janse
  18. Shahid M Khan
  19. Robert W Sauerwein  Is a corresponding author
  1. Radboud University Nijmegen Medical Center, Netherlands
  2. Institute for Translational Vaccinology, Netherlands
  3. Jikei University School of Medicine, Japan
  4. Ghent University and University Hospital, Belgium
  5. Leiden University Medical Center, Netherlands
  6. Université Pierre et Marie Curie-Paris 6, France
  7. Sanaria Inc., United States
Research Article
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Cite this article as: eLife 2014;3:e03582 doi: 10.7554/eLife.03582

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.

Article and author information

Author details

  1. Ben C L van Schaijk

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  2. Ivo H J Ploemen

    Institute for Translational Vaccinology, Bilthoven, Netherlands
    Competing interests
    No competing interests declared.
  3. Takeshi Annoura

    Jikei University School of Medicine, Tokyo, Japan
    Competing interests
    No competing interests declared.
  4. Martijn W Vos

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  5. Foquet Lander

    Ghent University and University Hospital, Ghent, Belgium
    Competing interests
    No competing interests declared.
  6. Geert-Jan van Gemert

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  7. Severine Chevalley-Maurel

    Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  8. Marga van de Vegte-Bolmer

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  9. Mohammed Sajid

    Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  10. Jean-Francois Franetich

    Université Pierre et Marie Curie-Paris 6, Paris, France
    Competing interests
    No competing interests declared.
  11. Audrey Lorthiois

    Université Pierre et Marie Curie-Paris 6, Paris, France
    Competing interests
    No competing interests declared.
  12. Geert Leroux-Roels

    Ghent University and University Hospital, Ghent, Belgium
    Competing interests
    No competing interests declared.
  13. Philip Meuleman

    Ghent University and University Hospital, Ghent, Belgium
    Competing interests
    No competing interests declared.
  14. Cornelius C Hermsen

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  15. Dominique Mazier

    Université Pierre et Marie Curie-Paris 6, Paris, France
    Competing interests
    No competing interests declared.
  16. Stephen L Hoffman

    Sanaria Inc., Rockville, United States
    Competing interests
    Stephen L Hoffman, CEO of Sanaria Inc, biotechnology company focused on whole sporozoite malaria vaccines.
  17. Chris J Janse

    Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  18. Shahid M Khan

    Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  19. Robert W Sauerwein

    Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
    For correspondence
    Robert.Sauerwein@radboudumc.nl
    Competing interests
    No competing interests declared.

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

Reviewing Editor

  1. Nicholas J White, Mahidol University, Thailand

Publication history

  1. Received: June 4, 2014
  2. Accepted: November 19, 2014
  3. Accepted Manuscript published: November 19, 2014 (version 1)
  4. Accepted Manuscript updated: November 21, 2014 (version 2)
  5. Version of Record published: December 23, 2014 (version 3)

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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