Immunologic Research

, Volume 59, Issue 1–3, pp 166–176 | Cite as

Correlates of protective immunity following whole sporozoite vaccination against malaria

  • Katherine L. Doll
  • John T. HartyEmail author


Human infection with Plasmodium parasites remains a serious global health crisis, leading to more than 600,000 deaths annually. Currently, no licensed vaccine is available to alleviate this malaria disease burden and vaccination with the most advanced antimalarial vaccine candidate, RTS,S, provides limited protection that wanes over time. To date, the only vaccination strategy capable of inducing complete, long-lasting protection in human subjects is administration of attenuated whole sporozoites. Several approaches for vaccination with attenuated whole sporozoites have been clinically tested in humans and include vaccination with radiation or genetically attenuated sporozoites or with virulent sporozoites concurrent with administration of antimalarial drug cover. Rodent studies with these three attenuated whole sporozoite vaccination (WSV) approaches provide insights into the immune correlates of vaccine-induced protection. The majority of these studies have identified a critical role for liver-stage parasite-directed CD8 T cells in providing protection with possible contributions from Plasmodium-specific CD4 T cells or antibodies. Together, rodent and human vaccination studies with attenuated WSV may lead to an understanding of the correlates of protective immunity against malarial disease, and the development of new, highly efficacious vaccines.


Malaria Plasmodium infections Sporozoite Genetically attenuated parasites Infection–treatment vaccination Radiation-attenuated sporozoites 



The authors would like to thank members of the Harty Laboratory for critical insights during preparation of this review. We also thank the many investigators who contributed to the research discussed in this review and apologize to those who’s work we were unable to cite due to space considerations.


  1. 1.
    W.M.R. World Malaria Report 2013. World Health Organization. 2013.Google Scholar
  2. 2.
    Gordon DM, McGovern TW, Krzych U, Cohen JC, Schneider I, LaChance R, et al. Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine. J Infect Dis. 1995;171(6):1576–85.CrossRefPubMedGoogle Scholar
  3. 3.
    Cohen J, Nussenzweig V, Nussenzweig R, Vekemans J, Leach A. From the circumsporozoite protein to the RTS, S/AS candidate vaccine. Hum Vaccin. 2010;6(1):90–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, et al. First results of phase 3 trial of RTS, S/AS01 malaria vaccine in African children. N Engl J Med. 2011;365(20):1863–75.CrossRefPubMedGoogle Scholar
  5. 5.
    White NJ. A vaccine for malaria. N Engl J Med. 2011;365(20):1926–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Baer K, Klotz C, Kappe SH, Schnieder T, Frevert U. Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature. PLoS Pathog. 2007;3(11):e171.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet. 2014;383(9918):723–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Kaiser K, Matuschewski K, Camargo N, Ross J, Kappe SH. Differential transcriptome profiling identifies Plasmodium genes encoding pre-erythrocytic stage-specific proteins. Mol Microbiol. 2004;51(5):1221–32.CrossRefPubMedGoogle Scholar
  9. 9.
    Belnoue E, Voza T, Costa FT, Gruner AC, Mauduit M, Rosa DS, et al. Vaccination with live Plasmodium yoelii blood stage parasites under chloroquine cover induces cross-stage immunity against malaria liver stage. J Immunol. 2008;181(12):8552–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Butler NS, Schmidt NW, Vaughan AM, Aly AS, Kappe SH, Harty JT. Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites. Cell Host Microbe. 2011;9(6):451–62.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Nussenzweig RS, Vanderberg J, Most H, Orton C. Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei. Nature. 1967;216(5111):160–2.CrossRefPubMedGoogle Scholar
  12. 12.
    Clyde DF. Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg. 1975;24(3):397–401.PubMedGoogle Scholar
  13. 13.
    Mellouk S, Lunel F, Sedegah M, Beaudoin RL, Druilhe P. Protection against malaria induced by irradiated sporozoites. Lancet. 1990;335(8691):721.CrossRefPubMedGoogle Scholar
  14. 14.
    Hoffman SL, Billingsley PF, James E, Richman A, Loyevsky M, Li T, et al. Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria. Hum Vaccin. 2010;6(1):97–106.CrossRefPubMedGoogle Scholar
  15. 15.
    Roestenberg M, Bijker EM, Sim BK, Billingsley PF, James ER, Bastiaens GJ, et al. Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2013;88(1):5–13.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, Gordon IJ, et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013;341(6152):1359–65.CrossRefPubMedGoogle Scholar
  17. 17.
    Sheehy SH, Spencer AJ, Douglas AD, Sim BK, Longley RJ, Edwards NJ, et al. Optimising controlled human malaria infection studies using cryopreserved parasites administered by needle and syringe. PLoS One. 2013;8(6):e65960.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Spring M, Murphy J, Nielsen R, Dowler M, Bennett JW, Zarling S, et al. First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers. Vaccine. 2013;31(43):4975–83.CrossRefPubMedGoogle Scholar
  19. 19.
    Labaied M, Harupa A, Dumpit RF, Coppens I, Mikolajczak SA, Kappe SH. Plasmodium yoelii sporozoites with simultaneous deletion of P52 and P36 are completely attenuated and confer sterile immunity against infection. Infect Immun. 2007;75(8):3758–68.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Bijker EM, Bastiaens GJ, Teirlinck AC, van Gemert GJ, Graumans W, van de Vegte-Bolmer M, et al. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci USA. 2013;10(19):7862–7.CrossRefGoogle Scholar
  21. 21.
    Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, et al. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009;361(5):468–77.CrossRefPubMedGoogle Scholar
  22. 22.
    Belnoue E, Costa FT, Frankenberg T, Vigario AM, Voza T, Leroy N, et al. Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatment. J Immunol. 2004;172(4):2487–95.CrossRefPubMedGoogle Scholar
  23. 23.
    Doll KL, Butler NS, Harty JT. CD8 T cell independent immunity after single dose infection-treatment- vaccination (ITV) against Plasmodium yoelii. Vaccine. 2014;32(4):483–91.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Fink E. Assessment of causal prophylactic activity in Plasmodium berghei yoelii and its value for the development of new antimalarial drugs. Bull World Health Organ. 1974;50(3–4):213–22.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Schofield L, Villaquiran J, Ferreira A, Schellekens H, Nussenzweig R, Nussenzweig V. Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature. 1987;330(6149):664–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Weiss WR, Sedegah M, Beaudoin RL, Miller LH, Good MF. CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc Natl Acad Sci USA. 1988;85(2):573–6.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Rodrigues MM, Cordey AS, Arreaza G, Corradin G, Romero P, Maryanski JL, et al. CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria. Int Immunol. 1991;3(6):579–85.CrossRefPubMedGoogle Scholar
  28. 28.
    Romero P, Maryanski JL, Corradin G, Nussenzweig RS, Nussenzweig V, Zavala F. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature. 1989;341(6240):323–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Doolan DL, Hoffman SL. The complexity of protective immunity against liver-stage malaria. J Immunol. 2000;165(3):1453–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Schmidt NW, Butler NS, Badovinac VP, Harty JT. Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. PLoS Pathog. 2010;6(7):e1000998.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Chen DH, Tigelaar RE, Weinbaum FI. Immunity to sporozoite-induced malaria infection in mice. I. The effect of immunization of T and B cell-deficient mice. J Immunol. 1977;118(4):1322–7.PubMedGoogle Scholar
  32. 32.
    Seguin MC, Klotz FW, Schneider I, Weir JP, Goodbary M, Slayter M, et al. Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells. J Exp Med. 1994;180(1):353–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Epstein JE, Tewari K, Lyke KE, Sim BK, Billingsley PF, Laurens MB, et al. Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science. 2011;334(6055):475–80.CrossRefPubMedGoogle Scholar
  34. 34.
    Schmidt NW, Butler NS, Harty JT. Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity. J Immunol. 2011;186(10):5873–84.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL, et al. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis. 2002;185(8):1155–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Mueller AK, Deckert M, Heiss K, Goetz K, Matuschewski K, Schluter D. Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cells. Am J Pathol. 2007;171(1):107–15.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Jobe O, Lumsden J, Mueller AK, Williams J, Silva-Rivera H, Kappe SH, et al. Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells. J Infect Dis. 2007;196(4):599–607.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Tarun AS, Dumpit RF, Camargo N, Labaied M, Liu P, Takagi A, et al. Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cells. J Infect Dis. 2007;196(4):608–16.CrossRefPubMedGoogle Scholar
  39. 39.
    Trimnell A, Takagi A, Gupta M, Richie TL, Kappe SH, Wang R. Genetically attenuated parasite vaccines induce contact-dependent CD8+ T cell killing of Plasmodium yoelii liver stage-infected hepatocytes. J Immunol. 2009;183(9):5870–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Vaughan AM, Wang R, Kappe SH. Genetically engineered, attenuated whole-cell vaccine approaches for malaria. Hum Vaccin. 2010;6(1):107–13.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Doll KL, Butler NS, Harty JT. Tracking the total CD8 T cell response following whole Plasmodium vaccination. Methods Mol Biol. 2013;923:493–504.CrossRefPubMedGoogle Scholar
  42. 42.
    Nganou-Makamdop K, Ploemen I, Behet M, Vang GJ, Hermsen C, Roestenberg M, et al. Reduced Plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization. Parasite Immunol. 2012;34(12):562–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Nganou-Makamdop K, van Gemert GJ, Arens T, Hermsen CC, Sauerwein RW. Long term protection after immunization with P. berghei sporozoites correlates with sustained IFNgamma responses of hepatic CD8+ memory T cells. PLoS One. 2012;7(5):e36508.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Butler NS, Vaughan AM, Harty JT, Kappe SH. Whole parasite vaccination approaches for prevention of malaria infection. Trends Immunol. 2012;33(5):247–54.CrossRefPubMedGoogle Scholar
  45. 45.
    Roestenberg M, Teirlinck AC, McCall MB, Teelen K, Makamdop KN, Wiersma J, et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet. 2011;377(9779):1770–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Kaech SM, Hemby S, Kersh E, Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell. 2002;111(6):837–51.CrossRefPubMedGoogle Scholar
  47. 47.
    van der Heyde HC, Huszar D, Woodhouse C, Manning DD, Weidanz WP. The resolution of acute malaria in a definitive model of B cell deficiency, the JHD mouse. J Immunol. 1994;152(9):4557–62.PubMedGoogle Scholar
  48. 48.
    Langhorne J, Cross C, Seixas E, Li C, von der Weid T. A role for B cells in the development of T cell helper function in a malaria infection in mice. Proc Natl Acad Sci USA. 1998;95(4):1730–4.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M. Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science. 1980;207(4426):71–3.CrossRefPubMedGoogle Scholar
  50. 50.
    Potocnjak P, Yoshida N, Nussenzweig RS, Nussenzweig V. Monovalent fragments (Fab) of monoclonal antibodies to a sporozoite surface antigen (Pb44) protect mice against malarial infection. J Exp Med. 1980;151(6):1504–13.CrossRefPubMedGoogle Scholar
  51. 51.
    Lewis MD, Pfeil J, Heiss K, Mueller AK. CD8(+) T cells mediate robust stage-specific immunity to P. berghei under chemoprophylaxis and this protective environment is not downregulated by the presence of blood-stage infection. PLoS One. 2014;9(2):e88117.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Felgner PL, Roestenberg M, Liang L, Hung C, Jain A, Pablo J, et al. Pre-erythrocytic antibody profiles induced by controlled human malaria infections in healthy volunteers under chloroquine prophylaxis. Sci Rep. 2013;3:3549.CrossRefPubMedGoogle Scholar
  53. 53.
    Stewart MJ, Nawrot RJ, Schulman S, Vanderberg JP. Plasmodium berghei sporozoite invasion is blocked in vitro by sporozoite-immobilizing antibodies. Infect Immun. 1986;51(3):859–64.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Vanderberg JP, Frevert U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes. Int J Parasitol. 2004;34(9):991–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Foquet L, Hermsen CC, van Gemert GJ, Van Braeckel E, Weening KE, Sauerwein R, et al. Vaccine- induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. J Clin Invest. 2014;124(1):140–4.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Trieu A, Kayala MA, Burk C, Molina DM, Freilich DA, Richie TL, et al. Sterile protective immunity to malaria is associated with a panel of novel P. falciparum antigens. Mol Cell Proteomics. 2011;10(9):M111-007948.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Finney OC, Keitany GJ, Smithers H, Kappe S, Wang R. Immunization with genetically attenuated P. falciparum parasites induces long-lived antibodies that efficiently block hepatocyte invasion by sporozoites. Vaccine. 2014;32(19):2135–8.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Doolan DL, Dobano C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev. 2009;22(1):13–36.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Harty JT, Badovinac VP. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. 2008;8(2):107–19.CrossRefPubMedGoogle Scholar
  60. 60.
    Butler NS, Schmidt NW, Harty JT. Differential effector pathways regulate memory CD8 T cell immunity against Plasmodium berghei versus P. yoelii sporozoites. J Immunol. 2010;184(5):2528–38.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Schmidt NW, Podyminogin RL, Butler NS, Badovinac VP, Tucker BJ, Bahjat KS, et al. Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria. Proc Natl Acad Sci USA. 2008;105(37):14017–22.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of MicrobiologyUniversity of IowaIowa CityUSA
  2. 2.Interdisciplinary Program in ImmunologyUniversity of IowaIowa CityUSA
  3. 3.Department of PathologyUniversity of IowaIowa CityUSA

Personalised recommendations