Review Article | Published:

Malaria prevention: from immunological concepts to effective vaccines and protective antibodies

Nature Immunologyvolume 19pages11991211 (2018) | Download Citation



Development of a malaria vaccine remains a critical priority to decrease clinical disease and mortality and facilitate eradication. Accordingly, RTS,S, a protein-subunit vaccine, has completed phase III clinical trials and confers ~30% protection against clinical infection over 4 years. Whole-attenuated-sporozoite and viral-subunit vaccines induce between 20% and 100% protection against controlled human malaria infection, but there is limited published evidence to date for durable, high-level efficacy (>50%) against natural exposure. Importantly, fundamental scientific advances related to the potency, durability, breadth and location of immune responses will be required for improving vaccine efficacy with these and other vaccine approaches. In this Review, we focus on the current understanding of immunological mechanisms of protection from animal models and human vaccine studies, and on how these data should inform the development of next-generation vaccines. Furthermore, we introduce the concept of using passive immunization with monoclonal antibodies as a new approach to prevent and eliminate malaria.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Yamauchi, L. M., Coppi, A., Snounou, G. & Sinnis, P. Plasmodium sporozoites trickle out of the injection site. Cell. Microbiol. 9, 1215–1222 (2007).

  2. 2.

    Langhorne, J., Ndungu, F. M., Sponaas, A. M. & Marsh, K. Immunity to malaria: more questions than answers. Nat. Immunol. 9, 725–732 (2008).

  3. 3.

    Tran, T. M. et al. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin. Infect. Dis. 57, 40–47 (2013).

  4. 4.

    Owusu-Agyei, S. et al. Incidence of symptomatic and asymptomatic Plasmodium falciparum infection following curative therapy in adult residents of northern Ghana. Am. J. Trop. Med. Hyg. 65, 197–203 (2001).

  5. 5.

    Sagara, I. et al. A high malaria reinfection rate in children and young adults living under a low entomological inoculation rate in a periurban area of Bamako, Mali. Am. J. Trop. Med. Hyg. 66, 310–313 (2002).

  6. 6.

    Sokhna, C. S., Faye, F. B. K., Dieng, H. & Trape, J. F. Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission. Am. J. Trop. Med. Hyg. 65, 167–170 (2001).

  7. 7.

    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).

  8. 8.

    Chan, J. A. et al. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J. Clin. Invest. 122, 3227–3238 (2012).

  9. 9.

    Fowkes, F. J., Richards, J. S., Simpson, J. A. & Beeson, J. G. The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: a systematic review and meta-analysis. PLoS Med. 7, e1000218 (2010).

  10. 10.

    Pinzon-Charry, A. et al. Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice. J. Clin. Invest. 120, 2967–2978 (2010).

  11. 11.

    Süss, G., Eichmann, K., Kury, E., Linke, A. & Langhorne, J. Roles of CD4- and CD8-bearing T lymphocytes in the immune response to the erythrocytic stages of Plasmodium chabaudi. Infect. Immun. 56, 3081–3088 (1988).

  12. 12.

    Horne-Debets, J. M. et al. PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep. 5, 1204–1213 (2013).

  13. 13.

    Imai, T. et al. Involvement of CD8+ T cells in protective immunity against murine blood-stage infection with Plasmodium yoelii 17XL strain. Eur. J. Immunol. 40, 1053–1061 (2010).

  14. 14.

    Richards, W. H. Active immunization of chicks against Plasmodium gallinaceum by inactivated homologous sporozoites and erythrocytic parasites. Nature 212, 1492–1494 (1966).

  15. 15.

    Mulligan, H. W., Russell, P. F. & Mohan, B. N. Active immunization of fowls against Plasmodium gallinacemn by injections of killed homologous sporozoites. J. Malar. Inst. India 4, 25–34 (1941).

  16. 16.

    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).

  17. 17.

    Clyde, D. F. Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am. J. Trop. Med. Hyg. 24, 397–401 (1975).

  18. 18.

    Luke, T. C. & Hoffman, S. L. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J. Exp. Biol. 206, 3803–3808 (2003).

  19. 19.

    Rodrigues, M., Nussenzweig, R. S. & Zavala, F. The relative contribution of antibodies, CD4+ and CD8+ T cells to sporozoite-induced protection against malaria. Immunology 80, 1–5 (1993).

  20. 20.

    Schofield, L. et al. Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature 330, 664–666 (1987).

  21. 21.

    Weiss, W. R., Sedegah, M., Beaudoin, R. L., Miller, L. H. & Good, M. F . CD8+ T cells(cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc. Natl. Acad. Sci. USA 85, 573–576 (1988).

  22. 22.

    Hafalla, J. C., Sano, G., Carvalho, L. H., Morrot, A. & Zavala, F. Short-term antigen presentation and single clonal burst limit the magnitude of the CD8+ T cell responses to malaria liver stages. Proc. Natl. Acad. Sci. USA 99, 11819–11824 (2002).

  23. 23.

    Keitany, G. J. et al. Blood stage malaria disrupts humoral immunity to the pre-erythrocytic stage circumsporozoite protein. Cell Rep. 17, 3193–3205 (2016).

  24. 24.

    Ocaña-Morgner, C., Mota, M. M. & Rodriguez, A. Malaria blood stage suppression of liver stage immunity by dendritic cells. J. Exp. Med. 197, 143–151 (2003).

  25. 25.

    Casares, S., Brumeanu, T. D. & Richie, T. L. The RTS,S malaria vaccine. Vaccine 28, 4880–4894 (2010).

  26. 26.

    Belnoue, E. et al. Vaccination with live Plasmodium yoelii blood stage parasites under chloroquine cover induces cross-stage immunity against malaria liver stage. J. Immunol. 181, 8552–8558 (2008).

  27. 27.

    Mordmüller, B. et al. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature 542, 445–449 (2017).

  28. 28.

    Roestenberg, M. et al. Protection against a malaria challenge by sporozoite inoculation. N. Engl. J. Med. 361, 468–477 (2009).

  29. 29.

    Wu, Y., Sinden, R. E., Churcher, T. S., Tsuboi, T. & Yusibov, V. Development of malaria transmission-blocking vaccines: from concept to product. Adv. Parasitol. 89, 109–152 (2015).

  30. 30.

    Weiss, W. R. & Jiang, C. G. Protective CD8+ T lymphocytes in primates immunized with malaria sporozoites. PLoS One 7, e31247 (2012).

  31. 31.

    Cockburn, I. A. et al. In vivo imaging of CD8+ T cell-mediated elimination of malaria liver stages. Proc. Natl. Acad. Sci. USA 110, 9090–9095 (2013).

  32. 32.

    Kimura, K. et al. CD8+ T cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection. Infect. Immun. 81, 3825–3834 (2013).

  33. 33.

    Rodrigues, M., Nussenzweig, R. S., Romero, P. & Zavala, F. The in vivo cytotoxic activity of CD8+ T cell clones correlates with their levels of expression of adhesion molecules. J. Exp. Med. 175, 895–905 (1992).

  34. 34.

    Butler, N. S., Schmidt, N. W. & Harty, J. T. Differential effector pathways regulate memory CD8 T cell immunity against Plasmodium berghei versus P. yoelii sporozoites. J. Immunol. 184, 2528–2538 (2010).

  35. 35.

    Chakravarty, S., Baldeviano, G. C., Overstreet, M. G. & Zavala, F. Effector CD8+ T lymphocytes against liver stages of Plasmodium yoelii do not require gamma interferon for antiparasite activity. Infect. Immun. 76, 3628–3631 (2008).

  36. 36.

    Oliveira, G. A. et al. Class II-restricted protective immunity induced by malaria sporozoites. Infect. Immun. 76, 1200–1206 (2008).

  37. 37.

    Carvalho, L. H. et al. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nat. Med. 8, 166–170 (2002).

  38. 38.

    Tsuji, M. et al. Gamma delta T cells contribute to immunity against the liver stages of malaria in alpha beta T-cell-deficient mice. Proc. Natl. Acad. Sci. USA 91, 345–349 (1994).

  39. 39.

    Rénia, L. et al. Effector functions of circumsporozoite peptide-primed CD4+ T cell clones against Plasmodium yoelii liver stages. J. Immunol. 150, 1471–1478 (1993).

  40. 40.

    Ishizuka, A. S. et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat. Med. 22, 614–623 (2016).

  41. 41.

    Seder, R. A. et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341, 1359–1365 (2013).

  42. 42.

    Lyke, K. E. et al. Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. Proc. Natl. Acad. Sci. USA 114, 2711–2716 (2017).

  43. 43.

    Epstein, J. E. et al. Protection against Plasmodium falciparum malaria by PfSPZ Vaccine. JCI Insight 2, e89154 (2017).

  44. 44.

    Sissoko, M. S. et al. Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect. Dis. 17, 498–509 (2017).

  45. 45.

    Chakravarty, S. et al. CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nat. Med. 13, 1035–1041 (2007).

  46. 46.

    Lau, L. S. et al. CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria. PLoS Pathog. 10, e1004135 (2014).

  47. 47.

    Bijker, E. M. et al. Cytotoxic markers associate with protection against malaria in human volunteers immunized with Plasmodium falciparum sporozoites. J. Infect. Dis. 210, 1605–1615 (2014).

  48. 48.

    Zaidi, I. et al. γδ T cells are required for the induction of sterile immunity during irradiated sporozoite vaccinations. J. Immunol. 199, 3781–3788 (2017).

  49. 49.

    Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40, 490–500 (2014).

  50. 50.

    De Rosa, S. C. et al. Ontogeny of gamma delta T cells in humans. J. Immunol. 172, 1637–1645 (2004).

  51. 51.

    Jagannathan, P. et al. Loss and dysfunction of Vδ2+ γδ T cells are associated with clinical tolerance to malaria. Sci. Transl. Med. 6, 251ra117 (2014).

  52. 52.

    Kazmin, D. et al. Systems analysis of protective immune responses to RTS,S malaria vaccination in humans. Proc. Natl. Acad. Sci. USA 114, 2425–2430 (2017).

  53. 53.

    Li, S. et al. Priming with recombinant influenza virus followed by administration of recombinant vaccinia virus induces CD8+ T-cell-mediated protective immunity against malaria. Proc. Natl. Acad. Sci. USA 90, 5214–5218 (1993).

  54. 54.

    Chuang, I. et al. DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity. PLoS One 8, e55571 (2013).

  55. 55.

    Ewer, K. J. et al. Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation. Nat. Commun. 4, 2836 (2013).

  56. 56.

    Mensah, V. A. et al. Safety and immunogenicity of malaria vectored vaccines given with routine expanded program on immunization vaccines in Gambian infants and neonates: a randomized controlled trial. Front. Immunol. 8, 1551 (2017).

  57. 57.

    Ogwang, C. et al. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci. Transl. Med. 7, 286re5 (2015).

  58. 58.

    Cockburn, I. A., Tse, S. W. & Zavala, F. CD8+ T cells eliminate liver-stage Plasmodium berghei parasites without detectable bystander effect. Infect. Immun. 82, 1460–1464 (2014).

  59. 59.

    Fernandez-Ruiz, D. et al. Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. Immunity 45, 889–902 (2016).

  60. 60.

    Schmidt, N. W. et al. Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria. Proc. Natl. Acad. Sci. USA 105, 14017–14022 (2008).

  61. 61.

    Gillespie, G. M. et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8+ T lymphocytes in healthy seropositive donors. J. Virol. 74, 8140–8150 (2000).

  62. 62.

    Hansen, S. G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011).

  63. 63.

    Hansen, S. G. et al. Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nat. Med. 24, 130–143 (2018).

  64. 64.

    Gebhardt, T., Palendira, U., Tscharke, D. C. & Bedoui, S. Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance. Immunol. Rev. 283, 54–76 (2018).

  65. 65.

    Tse, S. W., Radtke, A. J., Espinosa, D. A., Cockburn, I. A. & Zavala, F. The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8+ T cells specific for infectious pathogens. J. Infect. Dis. 210, 1508–1516 (2014).

  66. 66.

    McNamara, H. A. et al. Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids. Sci. Immunol. 2, eaa1996 (2017).

  67. 67.

    Epstein, J. E. et al. Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science 334, 475–480 (2011).

  68. 68.

    Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absenceof persisting local antigen presentation. Proc. Proc. Natl. Acad. Sci. USA 109, 7037–7042 (2012).

  69. 69.

    Slutter, B. et al. Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci. Immunol. 2, eaag2031 (2017).

  70. 70.

    Wu, T. et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95, 215–224 (2014).

  71. 71.

    Tarun, A. S. et al. A combined transcriptome and proteome survey of malaria parasite liver stages. Proc. Natl. Acad. Sci. USA 105, 305–310 (2008).

  72. 72.

    Roestenberg, M. et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377, 1770–1776 (2011).

  73. 73.

    Schats, R. et al. Heterologous protection against malaria after immunization with Plasmodium falciparum sporozoites. PLoS One 10, e0124243 (2015).

  74. 74.

    Walk, J. et al. Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial. BMC Med. 15, 168 (2017).

  75. 75.

    Butler, N. S. et al. Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites. Cell Host Microbe 9, 451–462 (2011).

  76. 76.

    Nahrendorf, W. et al. Blood-stage immunity to Plasmodium chabaudi malaria following chemoprophylaxis and sporozoite immunization. eLife 4, e05165 (2015).

  77. 77.

    Bijker, E. M. et al. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc. Natl. Acad. Sci. USA 110, 7862–7867 (2013).

  78. 78.

    Peters, J. et al. High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Proc. Natl. Acad. Sci. USA 99, 10689–10694 (2002).

  79. 79.

    Vaughan, A. M. et al. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell. Microbiol. 11, 506–520 (2009).

  80. 80.

    Spring, M. et al. First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers. Vaccine 31, 4975–4983 (2013).

  81. 81.

    Kublin, J. G. et al. Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects. Sci. Transl. Med. 9, eaad9099 (2017).

  82. 82.

    Doll, K. L., Pewe, L. L., Kurup, S. P. & Harty, J. T. Discriminating protective from nonprotective Plasmodium-specific CD8+ T cell responses. J. Immunol. 196, 4253–4262 (2016).

  83. 83.

    Cockburn, I. A. et al. Dendritic cells and hepatocytes use distinct pathways to process protective antigen from plasmodium in vivo. PLoS Pathog. 7, e1001318 (2011).

  84. 84.

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

  85. 85.

    Hafalla, J. C. et al. Identification of targets of CD8+ T cell responses to malaria liver stages by genome-wide epitope profiling. PLoS Pathog. 9, e1003303 (2013).

  86. 86.

    Kumar, K. A. et al. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature 444, 937–940 (2006).

  87. 87.

    Grüner, A. C. et al. Sterile protection against malaria is independent of immune responses to the circumsporozoite protein. PLoS One 2, e1371 (2007).

  88. 88.

    Doolan, D. L. et al. Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data. Proc. Natl. Acad. Sci. USA 100, 9952–9957 (2003).

  89. 89.

    Draper, S. J. et al. Recent advances in recombinant protein-based malaria vaccines. Vaccine 33, 7433–7443 (2015).

  90. 90.

    Schussek, S. et al. Novel Plasmodium antigens identified via genome-based antibody screen induce protection associated with polyfunctional T cell responses. Sci. Rep. 7, 15053 (2017).

  91. 91.

    Speake, C. et al. Identification of novel pre-erythrocytic malaria antigen candidates for combination vaccines with circumsporozoite protein. PLoS One 11, e0159449 (2016).

  92. 92.

    Longley, R. J. et al. Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates. Sci. Rep. 5, 11820 (2015).

  93. 93.

    Shao, W. et al. The SysteMHC Atlas project. Nucleic Acids Res. 46, D1237–D1247 (2018).

  94. 94.

    Plotkin, S. A. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47, 401–409 (2008).

  95. 95.

    Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).

  96. 96.

    Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 17, 1055–1065 (2010).

  97. 97.

    Nussenzweig, R. S., Vanderberg, J. P., Sanabria, Y. & Most, H. Plasmodium berghei: accelerated clearance of sporozoites from blood as part of immune-mechanism in mice. Exp. Parasitol. 31, 88–97 (1972).

  98. 98.

    Behet, M. C. et al. Sporozoite immunization of human volunteers under chemoprophylaxis induces functional antibodies against pre-erythrocytic stages of Plasmodium falciparum. Malar. J. 13, 136 (2014).

  99. 99.

    Peng, K. et al. Breadth of humoral response and antigenic targets of sporozoite-inhibitory antibodies associated with sterile protection induced by controlled human malaria infection. Cell. Microbiol. 18, 1739–1750 (2016).

  100. 100.

    Sack, B. K. et al. Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice. NPJ Vaccines 2, 27 (2017).

  101. 101.

    Zavala, F. et al. Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria. Science 228, 1436–1440 (1985).

  102. 102.

    Kisalu, N. K. et al. A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat. Med. 24, 408–416 (2018).

  103. 103.

    Tan, J. et al. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat. Med. 24, 401–407 (2018).

  104. 104.

    Espinosa, D. A. et al. Proteolytic cleavage of the Plasmodium falciparum circumsporozoite protein is a target of protective antibodies. J. Infect. Dis. 212, 1111–1119 (2015).

  105. 105.

    RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015).

  106. 106.

    White, M. T. et al. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect. Dis. 15, 1450–1458 (2015).

  107. 107.

    Dups, J. N., Pepper, M. & Cockburn, I. A. Antibody and B cell responses to Plasmodium sporozoites. Front. Microbiol. 5, 625 (2014).

  108. 108.

    Douglas, A. D. et al. A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus monkeys. Cell Host Microbe 17, 130–139 (2015).

  109. 109.

    Thera, M. A. et al. A field trial to assess a blood-stage malaria vaccine. N. Engl. J. Med. 365, 1004–1013 (2011).

  110. 110.

    Dvorak, J. A., Miller, L. H., Whitehouse, W. C. & Shiroishi, T. Invasion of erythrocytes by malaria merozoites. Science 187, 748–750 (1975).

  111. 111.

    Gilson, P. R. & Crabb, B. S. Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites. Int. J. Parasitol. 39, 91–96 (2009).

  112. 112.

    Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

  113. 113.

    Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).

  114. 114.

    Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

  115. 115.

    Clutterbuck, E. A. et al. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J. Infect. Dis. 205, 1408–1416 (2012).

  116. 116.

    Fisher, C. R. et al. T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein. PLoS Pathog. 13, e1006469 (2017).

  117. 117.

    Oyen, D. et al. Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. Proc. Natl. Acad. Sci. USA 114, E10438–E10445 (2017).

  118. 118.

    Imkeller, K. et al. Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360, 1358–1362 (2018).

  119. 119.

    Murugan, R. et al. Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci. Immunol. 3, eaap8029 (2018).

  120. 120.

    Regules, J. A. et al. Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite infection and immunogenicity study. J. Infect. Dis. 214, 762–771 (2016).

  121. 121.

    RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 11, e1001685 (2014).

  122. 122.

    Ryg-Cornejo, V. et al. Severe malaria infections impair germinal center responses by inhibiting T follicular helper cell differentiation. Cell Rep. 14, 68–81 (2016).

  123. 123.

    Obeng-Adjei, N. et al. Circulating Th1-cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children. Cell Rep. 13, 425–439 (2015).

  124. 124.

    Portugal, S. et al. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. eLife 4, 07218 (2015).

  125. 125.

    Weiss, G. E. et al. The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. 6, e1000912 (2010).

  126. 126.

    Kurtovic, L. et al. Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children. BMC Med. 16, 61 (2018).

  127. 127.

    Boyle, M. J. et al. Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity 42, 580–590 (2015).

  128. 128.

    Krishnamurty, A. T. et al. Somatically hypermutated Plasmodium-specific IgM+ memory B cells are rapid, plastic, early responders upon malaria rechallenge. Immunity 45, 402–414 (2016).

  129. 129.

    Zenklusen, I. et al. Immunization of malaria-preexposed volunteers with PfSPZ Vaccine elicits long-lived IgM invasion-inhibitory and complement-fixing antibodies. J. Infect. Dis. 217, 1569–1578 (2018).

  130. 130.

    Kwong, P. D. What are the most powerful immunogen design vaccine strategies? A structural biologist’s perspective. Cold Spring Harb. Perspect. Biol. 9, a029470 (2017).

  131. 131.

    Foquet, L. et al. Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. J. Clin. Invest. 124, 140–144 (2014).

  132. 132.

    Triller, G. et al. Natural parasite exposure induces protective human anti-malarial antibodies. Immunity 47, 1197–1209.e1110 (2017).

  133. 133.

    Coppi, A. et al. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. J. Exp. Med. 208, 341–356 (2011).

  134. 134.

    Scally, S. W. et al. Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection. J. Exp. Med. 215, 63–75 (2018).

  135. 135.

    Chaudhury, S. et al. The biological function of antibodies induced by the RTS,S/AS01 malaria vaccine candidate is determined by their fine specificity. Malar. J. 15, 301 (2016).

  136. 136.

    Chaudhury, S. et al. Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis. Sci. Rep. 7, 7998 (2017).

  137. 137.

    Srinivasan, P. et al. Disrupting malaria parasite AMA1-RON2 interaction with a small molecule prevents erythrocyte invasion. Nat. Commun. 4, 2261 (2013).

  138. 138.

    Srinivasan, P. et al. A malaria vaccine protects Aotus monkeys against virulent Plasmodium falciparum infection. NPJ Vaccines 2, 14 (2017).

  139. 139.

    Crosnier, C. et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480, 534–537 (2011).

  140. 140.

    Volz, J. C. et al. Essential role of the PfRh5/PfRipr/CyRPA complex during Plasmodium falciparum invasion of erythrocytes. Cell Host Microbe 20, 60–71 (2016).

  141. 141.

    Payne, R. O. et al. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions. JCI Insight 2, 96381 (2017).

  142. 142.

    Douglas, A. D. et al. Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5. J. Immunol. 192, 245–258 (2014).

  143. 143.

    Chen, L. et al. Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA. eLife 6, e21347 (2017).

  144. 144.

    Favuzza, P. et al. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody. eLife 6, 20383 (2017).

  145. 145.

    Wright, K. E. et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature 515, 427–430 (2014).

  146. 146.

    Foquet, L. et al. Plasmodium falciparum liver stage infection and transition to stable blood stage infection in liver-humanized and blood-humanized FRGN KO mice enables testing of blood stage inhibitory antibodies (reticulocyte-binding protein homolog 5) in vivo. Front. Immunol. 9, 524 (2018).

  147. 147.

    Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).

  148. 148.

    Lynch, R. M. et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206 (2015).

  149. 149.

    Deal, C. et al. Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice. Proc. Natl. Acad. Sci. USA 111, 12528–12532 (2014).

  150. 150.

    Olotu, A. et al. Advancing global health through development and clinical trials partnerships: a randomized, placebo-controlled, double-blind assessment of safety, tolerability, and immunogenicity of PfSPZ vaccine for malaria in healthy Equatoguinean men. Am. J. Trop. Med. Hyg. 98, 308–318 (2018).

  151. 151.

    Bergmann-Leitner, E. S. et al. Immunization with pre-erythrocytic antigen CelTOS from Plasmodium falciparum elicits cross-species protection against heterologous challenge with Plasmodium berghei. PLoS One 5, e12294 (2010).

  152. 152.

    de Barra, E. et al. A phase Ia study to assess the safety and immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and with MVA CS. PLoS One 9, e115161 (2014).

  153. 153.

    Collins, K. A., Snaith, R., Cottingham, M. G., Gilbert, S. C. & Hill, A. V. S. Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine. Sci. Rep. 7, 46621 (2017).

  154. 154.

    Esen, M. et al. Safety and immunogenicity of GMZ2: a MSP3-GLURP fusion protein malaria vaccine candidate. Vaccine 27, 6862–6868 (2009).

  155. 155.

    Remarque, E. J., Faber, B. W., Kocken, C. H. & Thomas, A. W. A diversity-covering approach to immunization with Plasmodium falciparum apical membrane antigen 1 induces broader allelic recognition and growth inhibition responses in rabbits. Infect. Immun. 76, 2660–2670 (2008).

  156. 156.

    Olugbile, S. et al. Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c. Infect. Immun. 77, 5701–5709 (2009).

  157. 157.

    Lusingu, J. P. et al. Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months. Malar. J. 8, 163 (2009).

  158. 158.

    Palacpac, N. M. et al. Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36. PLoS One 8, e64073 (2013).

  159. 159.

    Nielsen, M. A. et al. The influence of sub-unit composition and expression system on the functional antibody response in the development of a VAR2CSA based Plasmodium falciparum placental malaria vaccine. PLoS One 10, e0135406 (2015).

  160. 160.

    Li, Y. et al. Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology. Sci. Rep. 6, 18848 (2016).

Download references

Author information


  1. Department of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

    • Ian A. Cockburn
  2. Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA

    • Robert A. Seder


  1. Search for Ian A. Cockburn in:

  2. Search for Robert A. Seder in:

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Robert A. Seder.

About this article

Publication history