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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aidoo, M. & Udhayakumar, V. Field studies of cytotoxic T lymphocytes in malaria infections: implications for malaria vaccine development. Parasitol. Today 16, 50–56 (2000).
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).
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).
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).
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).
Zavala, F. et al. Synthetic peptide vaccine confers protection against murine malaria. J. Exp. Med. 166, 1591–1596 (1987).
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).
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).
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).
Sinigaglia, F. et al. Epitopes recognized by human T lymphocytes on malaria circumsporozoite protein. Eur. J. Immunol. 18, 633–636 (1988).
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).
Romero, P. et al. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341, 323–326 (1989).
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).
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).
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).
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).
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).
Kester, K.E. et al. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J. Infect. Dis. 183, 640–647 (2001).
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).
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).
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).
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).
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).
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).
Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).
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).
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).
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).
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).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1009
This article is cited by
-
Analysis of sequence diversity in Plasmodium falciparum glutamic acid-rich protein (PfGARP), an asexual blood stage vaccine candidate
Scientific Reports (2023)
-
Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial
npj Vaccines (2020)
-
Changing plasma cytokine, chemokine and growth factor profiles upon differing malaria transmission intensities
Malaria Journal (2019)
-
T cell-mediated immunity to malaria
Nature Reviews Immunology (2019)
-
On-chip structure-switching aptamer-modified magnetic nanobeads for the continuous monitoring of interferon-gamma ex vivo
Microsystems & Nanoengineering (2019)