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A CD4+ T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease

Nature Medicine volume 10, pages 406–410 (2004)Cite this article

Abstract

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection1. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-γ-secreting CD4+ T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types2. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells3,4. These findings provide direct evidence for a protective role for CD4+ T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.

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Figure 1: Cultured ELISPOT response to peptide 22, measured at start of malaria season (2 weeks after vaccine dose 3), correlates with time to parasitemia in pooled cohorts.
Figure 2: T-cell immune responses.

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References

  1. Aidoo, M. & Udhayakumar, V. Field studies of cytotoxic T lymphocytes in malaria infections: implications for malaria vaccine development. Parasitol. Today 16, 50–56 (2000).

    Article  CAS  Google Scholar 

  2. Sinigaglia, F. et al. A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules. Nature 336, 778–780 (1988).

    Article  CAS  Google Scholar 

  3. Flanagan, K.L. et al. Unique T cell effector functions elicited by Plasmodium falciparum epitopes in malaria-exposed Africans tested by three T cell assays. J. Immunol. 167, 4729–4737 (2001).

    Article  CAS  Google Scholar 

  4. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  5. Wang, R. et al. Protection against malaria by Plasmodium yoelii sporozoite surface protein 2 linear peptide induction of CD4+ T cell- and IFN-γ-dependent elimination of infected hepatocytes. J. Immunol. 157, 4061–4067 (1996).

    CAS  Google Scholar 

  6. Zavala, F. et al. Synthetic peptide vaccine confers protection against murine malaria. J. Exp. Med. 166, 1591–1596 (1987).

    Article  CAS  Google Scholar 

  7. Wizel, B. et al. Irradiated sporozoite vaccine induces HLA-B8-restricted cytotoxic T lymphocyte responses against two overlapping epitopes of the Plasmodium falciparum sporozoite surface protein 2. J. Exp. Med. 182, 1435–1445 (1995).

    Article  CAS  Google Scholar 

  8. Stoute, J.A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. N. Engl. J. Med. 336, 86–91 (1997).

    Article  CAS  Google Scholar 

  9. Stoute, J.A. et al. Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine. J. Infect. Dis. 178, 1139–1144 (1998).

    Article  CAS  Google Scholar 

  10. Sinigaglia, F. et al. Epitopes recognized by human T lymphocytes on malaria circumsporozoite protein. Eur. J. Immunol. 18, 633–636 (1988).

    Article  CAS  Google Scholar 

  11. Riley, E.M. et al. Recognition of dominant T cell-stimulating epitopes from the circumsporozoite protein of Plasmodium falciparum and relationship to malaria morbidity in Gambian children. Trans. Roy. Soc. Trop. Med. Hyg. 84, 648–657 (1990).

    Article  CAS  Google Scholar 

  12. Romero, P. et al. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341, 323–326 (1989).

    Article  CAS  Google Scholar 

  13. Bojang, K.A. et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciaprum infection in semi-immune adult men in The Gambia: a randomized trial. Lancet 358, 1927–1934 (2001).

    Article  CAS  Google Scholar 

  14. Pinder, M. et al. Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia. Clin. Exp. Immunol. 135, 286–293 (2004).

    Article  CAS  Google Scholar 

  15. Lalvani, A. et al. Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. J. Infect. Dis. 180, 1656–1664 (1999).

    Article  CAS  Google Scholar 

  16. McConkey, S.J. et al. Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat. Med. 9, 729–735 (2003).

    Article  CAS  Google Scholar 

  17. Flanagan, K.F. et al. Ex vivo interferon-γ immune response to thrombospondin-related adhesive protein in coastal Kenyans: longevity and risk of Plasmodium falciparum infection. Am. J. Trop. Med. Hyg. 68, 421–430 (2003).

    Article  CAS  Google Scholar 

  18. Kester, K.E. et al. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J. Infect. Dis. 183, 640–647 (2001).

    Article  CAS  Google Scholar 

  19. Schwenk, R. et al. Opsonization by antigen-specific antibodies as a mechanism of protective immunity induced by Plasmodium falciparum circumsporozoite protein-based vaccine. Parasite Immunol. 25, 17–25 (2003).

    Article  CAS  Google Scholar 

  20. Sun, P. et al. Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-γ. J. Immunol. 171 6961–6967 (2003).

    Article  CAS  Google Scholar 

  21. Harrell, F.E., Califf, R.M., Pryor, D.B., Lee, K.L. & Rosati, R.A. Evaluating the yield of medical tests. JAMA 247, 2543–2546 (1982).

    Article  Google Scholar 

  22. Hoffman, S.L. et al. Human lymphocyte proliferative response to a sporozoite T cell epitope correlates with resistance to falciparum malaria. J. Immunol. 142, 1299–1303 (1989).

    CAS  Google Scholar 

  23. Alloueche, A. et al. Protective efficacy of the RTS,S/AS02 Plasmodium falciparum malaria vaccine is not strain specific. Am. J. Trop. Med. Hyg. 68, 97–101 (2003).

    Article  Google Scholar 

  24. Baron, V. et al. The repertoires of circulating human CD8+ central and effector memory T cell subsets are largely distinct. Immunity 18, 193–204 (2003).

    Article  Google Scholar 

  25. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  26. Wu, C.Y. et al. Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo. Nat. Immunol. 3, 852–858 (2002).

    Article  CAS  Google Scholar 

  27. Godkin, A., Thomas, H.C. & Openshaw, P.J. Evolution of epitope-specific memory CD4+ T cells after clearance of hepatitis C virus. J. Immunol. 169, 2210–2214 (2002).

    Article  CAS  Google Scholar 

  28. Bull, P.C. et al. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat. Med. 4, 358–360 (1998).

    Article  CAS  Google Scholar 

  29. Polley, S.D. et al. Repeat sequences in block 2 of Plasmodium falciparum merozoite surface protein 1 are targets of antibodies associated with protection from malaria. Infect. Immun. 71, 1833–1842 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the volunteers who participated in this study; the malaria field and laboratory staff, the Local Safety Monitor (T. Corrah), the Data Safety Monitoring Committee (chair, P. Smith); the WHO Independent Monitors (M. Molyneux and F. Binka); and C. Holland and H. Whittle for help and advice. A.V.S.H. is a Wellcome Trust Principal Research Fellow. This study was supported by an EC Demonstration Project Grant (PL962164) and by the Wellcome Trust.

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Authors and Affiliations

  1. Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    William H H Reece, Philip K Gothard, Magdalena Plebanski, Simone Everaere, Katherine R Watkins & Adrian V S Hill

  2. MRC Laboratories, PO Box 273, Fajara, The Gambia, West Africa

    Margaret Pinder, Paul Milligan, Kalifa Bojang, Tom Doherty, Peter Akinwunmi & Keith P W J McAdam

  3. GlaxoSmithKline Biologicals, Rue de l'Institut 89, B-1330 Rixensart, Belgium

    Gerald Voss, Nadia Tornieporth & Joe Cohen

  4. London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Ali Alloueche & Brian M Greenwood

  5. Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, 20910, Maryland, USA

    Kent E Kester

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Correspondence to Adrian V S Hill.

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Competing interests

A.V.S.H. is a consultant to and cofounder of Oxxon Pharmaccines Ltd., Oxford, UK. G.V., N.T. and J.C. are employees of GlaxoSmithKline Biologicals, Rixensart, Belgium.

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Reece, W., Pinder, M., Gothard, P. et al. A CD4+ T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease. Nat Med 10, 406–410 (2004). https://doi.org/10.1038/nm1009

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