Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genetically modified Plasmodium parasites as a protective experimental malaria vaccine

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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

References

  1. Kappe, S. H., Kaiser, K. & Matuschewski, K. The Plasmodium sporozoite journey: a rite of passage. Trends Parasitol. 19, 135–143 (2003)

    Article  Google Scholar 

  2. Shortt, H. E. & Garnham, P. C. C. Pre-erythrocytic stage in mammalian malaria parasites. Nature 161, 126 (1948)

    ADS  CAS  Article  Google Scholar 

  3. Hoffman, S. L. & Doolan, D. L. Malaria vaccines-targeting infected hepatocytes. Nature Med. 6, 1218–1219 (2000)

    CAS  Article  Google Scholar 

  4. Matuschewski, K. et al. Infectivity-associated changes in the transcriptional repertoire of the malaria parasite sporozoite stage. J. Biol. Chem. 277, 41948–41953 (2002)

    CAS  Article  Google Scholar 

  5. Kaiser, K., Matuschewski, K., Camargo, N., Ross, J. & Kappe, S. H. Differential transcriptome profiling identifies Plasmodium genes encoding pre-erythrocytic stage-specific proteins. Mol. Microbiol. 51, 1221–1232 (2004)

    CAS  Article  Google Scholar 

  6. Sachs, J. & Malaney, P. The economic and social burden of malaria. Nature 415, 680–685 (2002)

    CAS  Article  Google Scholar 

  7. Hoffman, S. L. Save the children. Nature 430, 940–941 (2004)

    ADS  CAS  Article  Google Scholar 

  8. Nussenzweig, R. S., Vanderberg, J., Most, H. & Orton, C. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei . Nature 216, 160–162 (1967)

    ADS  CAS  Article  Google Scholar 

  9. Hoffman, S. L. et al. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J. Infect. Dis. 185, 1155–1164 (2002)

    Article  Google Scholar 

  10. Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum . Nature 419, 498–511 (2002)

    ADS  CAS  Article  Google Scholar 

  11. Carlton, J. M. et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii . Nature 419, 512–519 (2002)

    ADS  CAS  Article  Google Scholar 

  12. Thathy, V. & Menard, R. Gene targeting in Plasmodium berghei . Methods Mol. Med. 72, 317–331 (2002)

    CAS  PubMed  Google Scholar 

  13. Sibley, L. D. Intracellular parasite invasion strategies. Science 304, 248–253 (2004)

    ADS  CAS  Article  Google Scholar 

  14. Meis, J. F., Verhave, J. P., Jap, P. H., Sinden, R. E. & Meuwissen, J. H. Malaria parasites–discovery of the early liver form. Nature 302, 424–426 (1983)

    ADS  CAS  Article  Google Scholar 

  15. Meis, J. F., Verhave, J. P., Jap, P. H. & Meuwissen, J. H. Transformation of sporozoites of Plasmodium berghei into exoerythrocytic forms in the liver of its mammalian host. Cell Tissue Res. 241, 353–360 (1985)

    CAS  Article  Google Scholar 

  16. Potocnjak, P., Yoshida, N., Nussenzweig, R. S. & Nussenzweig, V. Monovalent fragments (Fab) of monoclonal antibodies to a sporozoite surface antigen (Pb44) protect mice against malarial infection. J. Exp. Med. 151, 1504–1513 (1980)

    CAS  Article  Google Scholar 

  17. Tsuji, M. et al. Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites. Parasitol. Res. 80, 16–21 (1994)

    CAS  Article  Google Scholar 

  18. Renia, L. et al. Malaria sporozoite penetration. A new approach by double staining. J. Immunol. Methods 112, 201–205 (1988)

    CAS  Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03188

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing