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Genetically modified Plasmodium parasites as a protective experimental malaria vaccine

Nature volume 433, pages 164–167 (2005)Cite this article

A Corrigendum to this article was published on 01 March 2007

Abstract

Malaria is a mosquito-borne disease that is transmitted by inoculation of the Plasmodium parasite sporozoite stage. Sporozoites invade hepatocytes1, transform into liver stages, and subsequent liver-stage development ultimately results in release of pathogenic merozoites2. Liver stages of the parasite are a prime target for malaria vaccines because they can be completely eliminated by sterilizing immune responses, thereby preventing malarial infection3. Using expression profiling, we previously identified genes that are only expressed in the pre-erythrocytic stages of the parasite4,5. Here, we show by reverse genetics that one identified gene, UIS3 (upregulated in infective sporozoites gene 3), is essential for early liver-stage development. uis3-deficient sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, and thus do not lead to disease. Immunization with uis3-deficient sporozoites confers complete protection against infectious sporozoite challenge in a rodent malaria model. This protection is sustained and stage specific. Our findings demonstrate that a safe and effective, genetically attenuated whole-organism malaria vaccine is possible.

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Figure 1: Targeted gene disruption of P. berghei UIS3.
Figure 2: Arrested liver-stage development in uis3(-) parasites.

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Acknowledgements

We thank A. Kunze and J. Whisler for technical assistance. This work was supported by grants from the National Institutes of Health and the Bill and Melinda Gates foundation to S.H.I.K., and the research focus ‘Tropical Medicine Heidelberg’ of the Medical Faculty of Heidelberg University and the Deutsche Forschungsgemeinschaft to K.M.

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Author notes

  1. Stefan H. I. Kappe and Kai Matuschewski: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Parasitology, Heidelberg University School of Medicine, Heidelberg, 69120, Germany

    Ann-Kristin Mueller & Kai Matuschewski

  2. Seattle Biomedical Research Institute, Seattle, Washington, 98109, USA

    Mehdi Labaied & Stefan H. I. Kappe

  3. Department of Pathobiology, University of Washington, Seattle, Washington, 98195, USA

    Stefan H. I. Kappe

Authors
  1. Ann-Kristin Mueller
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  2. Mehdi Labaied
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  3. Stefan H. I. Kappe
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  4. Kai Matuschewski
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Corresponding authors

Correspondence to Stefan H. I. Kappe or Kai Matuschewski.

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The authors declare that they have no competing financial interests.

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Mueller, AK., Labaied, M., Kappe, S. et al. Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature 433, 164–167 (2005). https://doi.org/10.1038/nature03188

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