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Antibodies against Plasmodium falciparum malaria at the molecular level

Abstract

Malaria is a vector-borne disease of global importance, with the vast majority of its life-threatening cases caused by infection with Plasmodium falciparum parasites. Repeated exposure to P. falciparum leads to naturally occurring immunity, but this is not sterilizing and is relatively short-lived. However, antibodies can protect from the disease, as has been shown by serum transfer studies in humans and in animal models. Recent advances in single-cell antibody cloning technologies have enabled the characterization of recombinant monoclonal antibodies against parasite antigens at the molecular level. This work has significantly advanced our understanding of how protective antibodies against P. falciparum are generated, what their molecular features are, their epitope specificity and binding modes, and the formation of memory B cell responses. Here we review these recent advances, with a particular emphasis on human antibody responses. We discuss how these discoveries have laid the foundation for the development of novel intervention strategies, as well as having conceptual implications beyond the malaria field.

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Fig. 1: Domain organization of Plasmodium falciparum circumsporozoite protein and its recognition by human monoclonal antibodies.
Fig. 2: Affinity maturation for homotypic antibody–antibody interactions has been observed in humans to optimize recognition of Plasmodium falciparum.
Fig. 3: Molecular basis of erythrocytic-stage inhibition of Plasmodium falciparum by monoclonal antibodies.
Fig. 4: Antibody diversification through gene insertions for the recognition of Plasmodium falciparum.
Fig. 5: Molecular basis of transmission-blocking antibodies against Plasmodium falciparum.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Keeling, P. J. & Rayner, J. C. The origins of malaria: there are more things in heaven and earth. Parasitology 142, S16–S25 (2015).

    Article  PubMed  Google Scholar 

  3. Loy, D. E. et al. Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Int. J. Parasitol. 47, 87–97 (2017).

    Article  PubMed  Google Scholar 

  4. World Health Organization. World Malaria Report. WHO https://www.who.int/malaria/publications/world-malaria-report-2018/en/ (2018).

  5. De Niz, M. & Heussler, V. T. Rodent malaria models: insights into human disease and parasite biology. Curr. Opin. Microbiol. 46, 46–93 (2018).

    Google Scholar 

  6. Schofield, L. & Grau, G. E. Immunological processes in malaria pathogenesis. Nat. Rev. Immunol. 5, 722–735 (2005).

    Article  PubMed  CAS  Google Scholar 

  7. Kwong, P. D. What are the most powerful immunogen design vaccine strategies? Cold Spring Harb. Perspect. Biol. 9, a029470 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Burton, D. R. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2, 706–713 (2002).

    Article  PubMed  CAS  Google Scholar 

  9. Burton, D. R. What are the most powerful immunogen design vaccine strategies? Cold Spring Harb. Perspect. Biol. 9, a030262 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Rappuoli, R., Bottomley, M. J., D’Oro, U., Finco, O. & De Gregorio, E. Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design. J. Exp. Med. 213, 469–481 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Witney, A. A. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520 (2002).

    Article  PubMed  CAS  Google Scholar 

  12. Lasonder, E. et al. Analysis of the Plasmodium falciparum proteome by high-accuracy mass spedrometry. Nature 419, 537–542 (2002).

    Article  PubMed  CAS  Google Scholar 

  13. Roch, K. G. Le et al. Discovery of gene function by expression. Science 301, 1503–1508 (2003).

    Article  PubMed  Google Scholar 

  14. Bozdech, Z. et al. The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLOS Biol. 1, 85–100 (2003).

    Article  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Orjih, A. U. & Nussenzweig, R. S. Plasmodium berghei: suppression of antibody response to sporozoite stage by acute blood stage infection. Clin. Exp. Immunol. 38, 1–8 (1979).

    PubMed  PubMed Central  CAS  Google Scholar 

  17. McCall, M. B. B., Kremsner, P. G. & Mordmüller, B. Correlating efficacy and immunogenicity in malaria vaccine trials. Semin. Immunol. 39, 52–64 (2018).

    Article  PubMed  CAS  Google Scholar 

  18. Hoffman, S. L. et al. Naturally acquired antibodies to sporozoites do not prevent malaria: Vaccine development implications. Science 237, 639–642 (1987).

    Article  PubMed  CAS  Google Scholar 

  19. Clyde, D. F., McCarthy, V. C., Miller, R. M. & Hornick, R. B. Specificity of protection of man immunized against sporozoite-induced falciparum malaria. Am. J. Med. Sci. 266, 398–404 (1973).

    Article  PubMed  CAS  Google Scholar 

  20. 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  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Sauerwein, R. W., Roestenberg, M. & Moorthy, V. S. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat. Rev. Immunol. 11, 57–64 (2011).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Stanisic, D. I., McCarthy, J. S. & Good, M. F. Controlled human malaria infection: applications, advances, and challenges. Infect. Immun. 86, 1–17 (2017).

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Cohen, S., McGregor, I. A. & Carrington, S. Gamma-globulin and acquired immunity to human malaria. Nature 192, 733–737 (1961).

    Article  PubMed  CAS  Google Scholar 

  30. Edozien, J. C., Gilles, H. M. & Udeozo, I. O. K. Adult and cord-blood gamma-globulin and immunity to malaria in Nigerians. Lancet 280, 951–955 (1962).

    Article  Google Scholar 

  31. Doolan, D. L., Dobaño, C. & Baird, J. K. Acquired immunity to malaria. Clin. Microbiol. Rev. 22, 13–36 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Stone, W. J. R. et al. Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity. Nat. Commun. 9, 558 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Graves, P. M., Carters, R., Burkot, T. R., Quakyi, I. A. & Kumar, Ni. Antibodies to Plasmodium falciparum gamete surface antigens in papua new guinea sera. Parasite Immunol. 10, 209–218 (1988).

    Article  PubMed  CAS  Google Scholar 

  34. van der Kolk, M., de Vlas, S. J. & Sauerwein, R. W. Reduction and enhancement of Plasmodium falciparum transmission by endemic human sera. Int. J. Parasitol. 36, 1091–1095 (2006).

    Article  PubMed  Google Scholar 

  35. Mulder, B. et al. Plasmodium falciparum: Membrane feeding assays and competition ELISAs for the measurement of transmission reduction in sera from Cameroon. Exp. Parasitol. 92, 81–86 (1999).

    Article  PubMed  CAS  Google Scholar 

  36. Bousema, T. et al. Human immune responses that reduce the transmission of Plasmodium falciparum in African populations. Int. J. Parasitol. 41, 293–300 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Carter, R. & Chen, D. H. Malaria transmission blocked by immunisation with gametes of the malaria parasite. Nature 263, 57–60 (1976).

    Article  PubMed  CAS  Google Scholar 

  38. Gwadz, R. W. & Green, I. Malaria immunization in Rhesus monkeys. A vaccine effective against both the sexual and asexual stages of Plasmodium knowlesi. J. Exp. Med. 148, 1311–1323 (1978).

    Article  PubMed  CAS  Google Scholar 

  39. Mendis, K. N. & Targett, G. A. T. Immunisation against gametes and asexual erythrocytic stages of a rodent malaria parasite. Nature 277, 389–391 (1979).

    Article  PubMed  CAS  Google Scholar 

  40. Rener, J. Target antigens of transmission-blocking immunity on gametes of Plasmodium falciparum. J. Exp. Med. 158, 976–981 (1983).

    Article  PubMed  CAS  Google Scholar 

  41. Nikolaeva, D., Draper, S. J. & Biswas, S. Toward the development of effective transmission-blocking vaccines for malaria. Expert. Rev. Vaccines 14, 653–680 (2015).

    Article  PubMed  CAS  Google Scholar 

  42. Sauerwein, R. W. & Bousema, T. Transmission blocking malaria vaccines: assays and candidates in clinical development. Vaccine 33, 7476–7482 (2015).

    Article  PubMed  CAS  Google Scholar 

  43. Kurup, S. P., Butler, N. S. & Harty, J. T. T cell-mediated immunity to malaria. Nat. Rev. Immunol. 19, 457–471 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Vanderberg, J. P. & Frevert, U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes. Int. J. Parasitol. 34, 991–996 (2004).

    Article  PubMed  Google Scholar 

  45. Hopp, C. S. & Sinnis, P. The innate and adaptive response to mosquito saliva and Plasmodium sporozoites in the skin. Ann. NY Acad. Sci. 1342, 37–43 (2015).

    Article  PubMed  CAS  Google Scholar 

  46. Aliprandini, E. et al. Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin. Nat. Microbiol. 3, 1224–1233 (2018).

    Article  PubMed  CAS  Google Scholar 

  47. Portugal, S. et al. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function. eLife 4, e07218 (2015).

    Article  PubMed Central  Google Scholar 

  48. Portugal, S., Obeng-Adjei, N., Moir, S., Crompton, P. D. & Pierce, S. K. Atypical memory B cells in human chronic infectious diseases: an interim report. Cell. Immunol. 321, 18–25 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Weiss, G. E. et al. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area. J. Immunol. 183, 2176–2182 (2009).

    Article  PubMed  CAS  Google Scholar 

  50. Muellenbeck, M. F. et al. Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies. J. Exp. Med. 210, 389–399 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Wahlgren, M., Goel, S. & Akhouri, R. R. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria. Nat. Rev. Microbiol. 15, 479–491 (2017).

    Article  PubMed  CAS  Google Scholar 

  52. McGregor, I. A., Carrington, S. P. & Cohen, S. Treatment of east African P. falciparum malaria with west African human γ-globulin. Trans. R. Soc. Trop. Med. Hyg. 57, 170–175 (1963).

    Article  Google Scholar 

  53. Vermeulen, A. N. et al. Sequential expression of antigens on sexual stages of Plasmodium falciparum accessible to transmission-blocking antibodies in the mosquito. J. Exp. Med. 162, 1460–1476 (1985).

    Article  PubMed  CAS  Google Scholar 

  54. Roeffen, W. et al. Association between anti-Pfs48/45 reactivity and P. falciparum transmission-blocking activity in sera from Cameroon. Parasite Immunol. 18, 103–109 (1996).

    Article  PubMed  CAS  Google Scholar 

  55. Quakyi, I. A. et al. The 230-kDa gamete surface protein of Plasmodium falciparum is also a target for transmission-blocking antibodies. J. Immunol. 139, 4213–4217 (1987).

    PubMed  CAS  Google Scholar 

  56. 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).

    Article  PubMed  CAS  Google Scholar 

  57. Cochrane, A. H., Aikawa, M., Jeng, M. & Nussenzweig, R. S. Antibody-induced ultrastructural changes of malarial sporozoites. J. Immunol. 116, 859–867 (1976).

    PubMed  CAS  Google Scholar 

  58. Nardin, E. H. et al. Circumsporozoite proteins of human malaria parasites Plasmodium falciparum and Plasmodium vivax. J. Exp. Med. 156, 20–30 (1982).

    Article  PubMed  CAS  Google Scholar 

  59. Zavala, F., Cochrane, A. H., Nardin, E. H., Nussenzweig, R. S. & Nussenzweig, V. Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes. J. Exp. Med. 157, 1947–1957 (1983).

    Article  PubMed  CAS  Google Scholar 

  60. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Freeman, R. R., Trejdosiewicz, A. J. & Cross, G. A. M. Protective monoclonal antibodies recognising stage-specific merozoite antigens of a rodent malaria parasite. Nature 284, 366–368 (1980).

    Article  PubMed  CAS  Google Scholar 

  62. Cox, F. E. Hybridoma technology identifies protective malaria antigens. Nature 294, 612 (1981).

    Article  PubMed  CAS  Google Scholar 

  63. Perrin, L. H., Ramirez, E., Lambert, P. H. & Miescher, P. A. Inhibition of P. falciparum growth in human erythrocytes by monoclonal antibodies. Nature 289, 301–303 (1981).

    Article  PubMed  CAS  Google Scholar 

  64. Rener, J., Carter, R., Rosenberg, Y. & Miller, L. H. Anti-gamete monoclonal antibodies synergistically block transmission of malaria by preventing fertilization in the mosquito. Proc. Natl Acad. Sci. USA 77, 6797–6799 (1980).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Herrington, D. A. et al. Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 328, 257–259 (1987).

    Article  PubMed  CAS  Google Scholar 

  66. Ballou, W. R. et al. Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1, 1277–1281 (1987).

    Article  PubMed  CAS  Google Scholar 

  67. Draper, S. J. et al. Malaria vaccines: recent advances and new horizons. Cell Host Microbe 24, 43–56 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Adepoju, P. RTS,S malaria vaccine pilots in three African countries. Lancet 393, 1685 (2019).

    Article  PubMed  Google Scholar 

  69. The RTS,S Clinical Trial Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012).

    Article  CAS  Google Scholar 

  70. The RTS,S Clinical Trial 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).

    Article  CAS  Google Scholar 

  71. The RTS,S Clinical Trial Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N. Engl. J. Med. 365, 1863–1875 (2011).

    Article  Google Scholar 

  72. Doolan, D. L. Plasmodium immunomics. Int. J. Parasitol. 41, 3–20 (2011).

    Article  PubMed  CAS  Google Scholar 

  73. Davies, D. H., Duffy, P., Bodmer, J. L., Felgner, P. L. & Doolan, D. L. Large screen approaches to identify novel malaria vaccine candidates. Vaccine 33, 7496–7505 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Illingworth, J. J. et al. Functional comparison of blood-stage Plasmodium falciparum malaria vaccine candidate antigens. Front. Immunol. 10, 1254 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Hoffman, S. L., Vekemans, J., Richie, T. L. & Duffy, P. E. The march toward malaria vaccines. Vaccine 33, D13–D23 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Triller, G. et al. Natural parasite exposure induces protective human anti-malarial antibodies. Immunity 47, 1197–1209.e10 (2017). Triller et al. give the first molecular characterization of human parasite-inhibitory PfCSP-specific antibodies induced by natural parasite exposure that differ in their NANP-binding mode.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 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). This study reports the identification of potent human PfCSP-specific antibodies targeting different epitopes in the N-terminal junction and the NANP after repeated immunization with radiation-attenuated sporozoites and low-dose sporozoite challenge in donors naturally exposed to P. falciparum.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Murugan, R. et al. Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci. Immunol. 3, eaap8029 (2018). This study describes a clonal evolution analysis and functional characterization of more than 200 recombinant monoclonal human PfCSP-specific antibodies induced by repeated exposure of naive donors to live sporozoites under chemoprophylaxis, which identified potent high-affinity IGHV3-33, IGKV1-5-encoded germline NANP-binding antibodies.

    Article  PubMed  Google Scholar 

  79. 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). In this report, Kisalu et al. identify and provide molecular and functional characterization of a potent human monoclonal antibody, CIS43, which has a unique binding profile and high affinity to the PfCSP junction, induced by exposure of naive donors to radiation-attenuated sporozoites.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  81. 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). This report is the first molecular characterization of the binding modes of two potent antibodies obtained from RTS,S/AS01-immunized donors to NANP and recombinant PfCSP.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Wardemann, H. & Murugan, R. From human antibody structure and function towards the design of a novel Plasmodium falciparum circumsporozoite protein malaria vaccine. Curr. Opin. Immunol. 53, 119–123 (2018).

    Article  PubMed  CAS  Google Scholar 

  83. Plassmeyer, M. L. et al. Structure of the Plasmodium falciparum circumsporozoite protein, a leading malaria vaccine candidate. J. Biol. Chem. 284, 26951–26963 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Dame, J. B. et al. Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum. Science 225, 593–599 (1984).

    Article  PubMed  CAS  Google Scholar 

  85. Doud, M. B. et al. Unexpected fold in the circumsporozoite protein target of malaria vaccines. Proc. Natl Acad. Sci. USA 109, 7817–7822 (2012).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. 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). Scally et al. give a molecular characterization of the target epitope of a human antibody against the PfCSP C-terminal α-TSR domain that fails to bind to live sporozoites and lacks parasite-inhibitory activity, presumably due to inaccessibility of the PfCSP C terminus.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kidgell, C. et al. A systematic map of genetic variation in Plasmodium falciparum. PLOS Pathog. 2, e57 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Rathore, D., Sacci, J. B., de la Vega, P. & McCutchan, T. F. Binding and invasion of liver cells by Plasmodium falciparum sporozoites. Essential involvement of the amino terminus of circumsporozoite protein. J. Biol. Chem. 277, 7092–7098 (2002).

    Article  PubMed  CAS  Google Scholar 

  90. Aldrich, C. et al. Roles of the amino terminal region and repeat region of the Plasmodium berghei circumsporozoite protein in parasite infectivity. PLOS ONE 7, e32524 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Bongfen, S. E. et al. The N-terminal domain of Plasmodium falciparum circumsporozoite protein represents a target of protective immunity. Vaccine 27, 328–335 (2009).

    Article  PubMed  CAS  Google Scholar 

  92. Herrera, R. et al. Reversible conformational change in the Plasmodium falciparum circumsporozoite protein masks its adhesion domains. Infect. Immun. 83, 3771–3780 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Cerami, C. et al. The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of Plasmodium falciparum sporozoites. Cell 70, 1021–1033 (1992).

    Article  PubMed  CAS  Google Scholar 

  94. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Coppi, A. et al. Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells. Cell Host Microbe 2, 316–327 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Dyson, H. J., Satterthwait, A. C., Lerner, R. A. & Wright, P. E. Conformational preferences of synthetic peptides derived from the immunodominant site of the circumsporozoite protein of Plasmodium falciparum by 1H NMR. Biochemistry 29, 7828–7837 (1990).

    Article  PubMed  CAS  Google Scholar 

  97. Ghasparian, A., Moehle, K., Linden, A. & Robinson, J. A. Crystal structure of an NPNA-repeat motif from the circumsporozoite protein of the malaria parasite Plasmodium falciparum. Chem. Commun. 3, 174–176 (2006).

    Article  Google Scholar 

  98. Imkeller, K. et al. Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360, 1358–1362 (2018). Ghasparian et al. (reference 97) and Imkeller et al. identify a novel mechanism to indirectly increase the antigen affinity of antibodies that bind to PfCSP NANP, through the selection of somatic mutations that mediate direct homotypic interactions between two NANP-bound Fab molecules.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Oyen, D. et al. Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts. Sci. Adv. 4, eaau8529 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Marsh, K. & Howard, R. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science 231, 150–153 (1986).

    Article  PubMed  CAS  Google Scholar 

  101. 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  PubMed  PubMed Central  CAS  Google Scholar 

  102. Leech, James,H., Barnwell, J. W., Aikawa, M., Miller, L. H. & Howard, R. Plasmodium falciparum malaria: Association of knobs on the surface of infected erythrocytes with a histidine-rich protein and the erythrocyte skeleton. J. Cell Biol. 98, 1256–1264 (1984).

    Article  PubMed  CAS  Google Scholar 

  103. Tan, J., Piccoli, L. & Lanzavecchia, A. The antibody response to Plasmodium falciparum: cues for vaccine design and the discovery of receptor-based antibodies. Annu. Rev. Immunol. 37, 225–246 (2019).

    Article  PubMed  CAS  Google Scholar 

  104. Hill, D. L. et al. Opsonising antibodies to P. falciparum merozoites associated with immunity to clinical malaria. PLOS ONE 8, e74627 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Reiling, L. et al. Targets of complement-fixing antibodies in protective immunity against malaria in children. Nat. Commun. 10, 610 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Fried, M., Nosten, F., Brockman, A., Brabin, B. J. & Duffy, P. E. Maternal antibodies block malaria. Nature 395, 851–852 (1998).

    Article  PubMed  CAS  Google Scholar 

  108. Staalsoe, T. et al. Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria. Lancet 363, 283–289 (2004).

    Article  PubMed  CAS  Google Scholar 

  109. Fowkes, F. J. I., 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Manske, M. et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 487, 375–379 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Baum, J. et al. Reticulocyte-binding protein homologue 5 — an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum. Int. J. Parasitol. 39, 371–380 (2009).

    Article  PubMed  CAS  Google Scholar 

  113. 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).

    Article  PubMed  CAS  Google Scholar 

  114. Wong, W. et al. Structure of Plasmodium falciparum Rh5–CyRPA–Ripr invasion complex. Nature 565, 118–121 (2019).

    Article  PubMed  CAS  Google Scholar 

  115. Chen, L. et al. An EGF-like protein forms a complex with PfRh5 and is required for invasion of human erythrocytes by Plasmodium falciparum. PLOS Pathog. 7, e1002199 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Reddy, K. S. et al. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc. Natl Acad. Sci. USA 112, 1179–1184 (2015).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Favuzza, P. et al. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody. eLife 6, e20383 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Douglas, A. D. et al. The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody. Nat. Commun. 2, 601 (2011).

    Article  PubMed  CAS  Google Scholar 

  119. Healer, J. et al. Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes. Cell Microbiol. 21, e13030 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Wright, K. E. et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature 515, 427–430 (2014). This study provides a structural delineation of the crucial interaction between merozoite protein PfRH5 and the erythrocyte surface protein basigin and of the molecular basis of how antibody-binding to PfRH5 can efficiently block parasite invasion.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Payne, R. O. et al. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions. JCI Insight 2, 1–19 (2017).

    CAS  Google Scholar 

  122. Alanine, D. G. W. et al. Human antibodies that slow erythrocyte invasion potentiate malaria-neutralizing antibodies. Cell 178, 216–228.e21 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Baruch, D. I. et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87 (1995).

    Article  PubMed  CAS  Google Scholar 

  124. Smith, J. D. et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Su, X. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100 (1995).

    Article  PubMed  CAS  Google Scholar 

  126. Chen, Q. et al. Developmental selection of var gene expression in Plasmodium falciparum. Nature 394, 392–395 (1998).

    Article  PubMed  CAS  Google Scholar 

  127. Fernandez, V., Hommel, M., Chen, Q., Hagblom, P. & Wahlgren, M. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum-infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. J. Exp. Med. 190, 1393–1404 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Saito, F. et al. Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors. Nature 552, 101–105 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Tan, J. et al. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature 529, 105–109 (2016). Tan et al. identify a novel antibody diversification mechanism in humans based on the templated insertion of DNA fragments into antibody genes that generates broadly reactive antibodies against P. falciparum-infected erythrocytes.

    Article  PubMed  CAS  Google Scholar 

  130. Pieper, K. et al. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature 548, 597–601 (2017). This study provides mechanistic insights into the generation of LAIR1 antibodies through insertions in the IGHV–DJ joint or the hinge region between the IGH variable and constant regions, likely during germinal centre reactions, or by replacing the IGH variable region, which generates camel-like antibodies.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Pradel, G. Proteins of the malaria parasite sexual stages: expression, function and potential for transmission blocking strategies. Parasitology 134, 1911–1929 (2007).

    Article  PubMed  CAS  Google Scholar 

  132. Canepa, G. E. et al. Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission. NPJ Vaccines 3, 26 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Espinosa, D. A. et al. The Plasmodium falciparum cell-traversal protein for ookinetes and sporozoites as a candidate for preerythrocytic and transmission-blocking vaccines. Infect. Immun. 85, e00498–16 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Williamson, K. C., Criscio, M. D. & Kaslow, D. C. Cloning and expression of the gene for Plasmodium falciparum transmission-blocking target antigen, Pfs230. Mol. Biochem. Parasitol. 58, 355–358 (1993).

    Article  PubMed  CAS  Google Scholar 

  135. Kocken, C. H. M. et al. Cloning and expression of the gene coding for the transmission blocking target antigen Pfs48/45 of Plasmodium falciparum. Mol. Biochem. Parasitol. 61, 59–68 (1993).

    Article  PubMed  CAS  Google Scholar 

  136. Kumar, N. & Carter, R. Biosynthesis of the target antigens of antibodies blocking transmission of Plasmodium falciparum. Mol. Biochem. Parasitol. 13, 333–342 (1984).

    Article  PubMed  CAS  Google Scholar 

  137. van Dijk, M. R. et al. A central role for P48/45 in malaria parasite male gamete fertility. Cell 104, 153–164 (2001).

    Article  PubMed  Google Scholar 

  138. Kumar, N. Target antigens of malaria transmission blocking immunity exist as a stable membrane bound complex. Parasite Immunol. 9, 321–335 (1987).

    Article  PubMed  CAS  Google Scholar 

  139. Outchkourov, N. et al. Epitope analysis of the malaria surface antigen Pfs48/45 identifies a subdomain that elicits transmission blocking antibodies. J. Biol. Chem. 282, 17148–17156 (2007).

    Article  PubMed  CAS  Google Scholar 

  140. Carter, R., Graves, P. M., Keister, D. B. & Quakyi, I. A. Properties of epitopes of Pfs 48/45, a target of transmission blocking monoclonal antibodies, on gametes of different isolates of Plasmodium falciparum. Parasite Immunol. 12, 587–603 (1990).

    Article  PubMed  CAS  Google Scholar 

  141. Roeffen, W. et al. Plasmodium falciparum: Production and characterization of rat monoclonal antibodies specific for the sexual-stage Pfs48/45 antigen. Exp. Parasitol. 97, 45–49 (2001).

    Article  PubMed  CAS  Google Scholar 

  142. Kundu, P. et al. Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45. Nat. Commun. 9, 4458 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Lennartz, F. et al. Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody. Nat. Commun. 9, 3822 (2018). Lennartz et al. uncover the antibody-binding regions on Pfs48/45 that correlate with transmission-blocking activity. Both Kundu et al. and Lennartz et al. reveal that a conformational epitope in the C-terminal domain of Pfs48/45 is recognized by the most potent transmission-blocking antibody, thus providing key molecular insights for structure-guided immunogen design. In addition, Kundu et al. describe humanization of the most potent rat-derived monoclonal antibody against Pfs48/45, thus paving the way for passive immunization studies in humans.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. MacDonald, N. J. et al. Structural and immunological characterization of recombinant 6-cysteine domains of the Plasmodium falciparum sexual stage protein Pfs230. J. Biol. Chem. 291, 19913–19922 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Tachibana, M. et al. Identification of domains within Pfs230 that elicit transmission blocking antibody responses. Vaccine 37, 1799–1806 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Coelho, C. H., Doritchamou, J. Y. A., Zaidi, I. & Duffy, P. E. Advances in malaria vaccine development: report from the 2017 Malaria Vaccine Symposium. NPJ Vaccines 2, 34 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Kaslow, D. C. et al. A vaccine candidate from the sexual stage of human malaria that contains EGF-like domains. Nature 333, 74–76 (1988).

    Article  PubMed  CAS  Google Scholar 

  148. Barr, P. J. et al. Recombinant Pfs25 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in experimental animals. J. Exp. Med. 174, 1203–1208 (1991).

    Article  PubMed  CAS  Google Scholar 

  149. Gozar, M. M., Price, V. L. & Kaslow, D. C. Saccharomyces cerevisiae-secreted fusion proteins Pfs25 and Pfs28 elicit potent Plasmodium falciparum transmission-blocking antibodies in mice. Infect. Immun. 66, 59–64 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Chichester, J. A. et al. Safety and immunogenicity of a plant-produced Pfs25 virus-like particle as a transmission blocking vaccine against malaria: a Phase 1 dose-escalation study in healthy adults. Vaccine 36, 5865–5871 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Scally, S. W. et al. Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25. Nat. Commun. 8, 1568 (2017). This study describes the first crystal structure of Pfs25, a leading transmission-blocking antigen, in complex with crystal structures of six antibodies derived from immunizations in transgenic mice that possess the human immunoglobulin repertoire (Kymice). Two predominant immunogenic sites are defined on Pfs25, with a site located on the EGF3 domain being associated with recognition by the most potent antibodies for inhibiting parasite transmission to the mosquito vector.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Talaat, K. R. et al. Safety and immunogenicity of Pfs25-EPA/alhydrogel®, a transmission blocking vaccine against Plasmodium falciparum: an open label study in malaria naïve adults. PLOS ONE 11, e0163144 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. McLeod, B. et al. Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25. Nat. Commun. (in the press).

  154. Sherrard-Smith, E. et al. Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density. eLife 7, e35213 (2018). Sherrard-Smith et al. provide evidence that the coexistence of antibodies against two parasite life stages (the pre-erythrocytic and sexual stages) can function synergistically to enhance the efficacy of these antibodies across a range of transmission intensities. These findings are particularly relevant for designing multi-combinatorial approaches towards malaria elimination in the context of vaccines that may only confer partial protection when used alone.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Pleass, R. J. & Holder, A. A. Opinion: antibody-based therapies for malaria. Nat. Rev. Microbiol. 3, 893–899 (2005).

    Article  PubMed  CAS  Google Scholar 

  156. Wang, Y., Tian, Z., Thirumalai, D. & Zhang, X. Neonatal Fc receptor (FcRn): a novel target for therapeutic antibodies and antibody engineering. J. Drug Target. 22, 269–278 (2014).

    Article  PubMed  CAS  Google Scholar 

  157. Eldering, M. et al. Comparative assessment of An. gambiae and An. stephensi mosquitoes to determine transmission-reducing activity of antibodies against P. falciparum sexual stage antigens. Parasit. Vectors 10, 489 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Vanderberg, J. P. Imaging mosquito transmission of Plasmodium sporozoites into the mammalian host: Immunological implications. Parasitol. Int. 63, 150–164 (2014).

    Article  PubMed  Google Scholar 

  159. Aly, A. S. I., Vaughan, A. M. & Kappe, S. H. I. Malaria parasite development in the mosquito and infection of the mammalian host. Annu. Rev. Microbiol. 63, 195–221 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Matsuoka, H., Yoshida, S., Hirai, M. & Ishii, A. A rodent malaria, Plasmodium berghei, is experimentally transmitted to mice by merely probing of infective mosquito, Anopheles stephensi. Parasitol. Int. 51, 17–23 (2002).

    Article  PubMed  Google Scholar 

  161. Frischknecht, F. et al. Imaging movement of malaria parasites during transmission by Anopheles mosquitoes. Cell. Microbiol. 6, 687–694 (2004).

    Article  PubMed  CAS  Google Scholar 

  162. Churcher, T. S. et al. Probability of transmission of malaria from mosquito to human is regulated by mosquito parasite density in naïve and vaccinated hosts. PLOS Pathog. 13, e1006108 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Beier, J. C. et al. Quantitation of Plasmodium falciparum sporozoites transmitted in vitro by experimentally infected Anopheles gambiae and Anopheles stephensi. Am. J. Trop. Med. Hyg. 44, 564–570 (1991).

    Article  PubMed  CAS  Google Scholar 

  164. Mota, M. M. et al. Migration of Plasmodium sporozoites through cells before infection. Science 291, 141–144 (2001).

    Article  PubMed  CAS  Google Scholar 

  165. Amino, R. et al. Host cell traversal is important for progression of the malaria parasite through the dermis to the liver. Cell Host Microbe 3, 88–96 (2008).

    Article  PubMed  CAS  Google Scholar 

  166. Yang, A. S. P. et al. Cell traversal activity is important for Plasmodium falciparum liver infection in humanized mice. Cell Rep. 18, 3105–3116 (2017).

    Article  PubMed  CAS  Google Scholar 

  167. Amino, R. et al. Quantitative imaging of Plasmodium transmission from mosquito to mammal. Nat. Med. 12, 220–224 (2006).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Sturm, A. et al. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313, 1287–1290 (2006).

    Article  PubMed  CAS  Google Scholar 

  170. Vaughan, A. M. et al. Complete Plasmodium falciparum liver-stage development in liver-chimeric mice. J. Clin. Invest. 122, 3618–3628 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Joice, R. et al. Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci. Transl. Med. 6, 244re5 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Dantzler, K. W., Ravel, D. B., Brancucci, N. M. & Marti, M. Ensuring transmission through dynamic host environments: host–pathogen interactions in Plasmodium sexual development. Curr. Opin. Microbiol. 26, 17–23 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Whitten, M. M. A., Shiao, S. H. & Levashina, E. A. Mosquito midguts and malaria: cell biology, compartmentalization and immunology. Parasite Immunol. 28, 121–130 (2006).

    Article  PubMed  CAS  Google Scholar 

  174. Prudêncio, M., Mota, M. M. & Mendes, A. M. A toolbox to study liver stage malaria. Trends Parasitol. 27, 565–574 (2011).

    Article  PubMed  Google Scholar 

  175. Siciliano, G. & Alano, P. Enlightening the malaria parasite life cycle: bioluminescent Plasmodium in fundamental and applied research. Front. Microbiol. 6, 1–8 (2015).

    Article  Google Scholar 

  176. Richie, T. L. et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines. Vaccine 33, 7452–7461 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Trager, W. & Jensen, J. Human malaria parasites in continuous culture. Science 193, 673–675 (1976).

    Article  PubMed  CAS  Google Scholar 

  178. Ifediba, T. & Vanderberg, J. P. Complete in vitro maturation of Plasmodium falciparum gametocytes. Nature 294, 364–366 (1981).

    Article  PubMed  CAS  Google Scholar 

  179. van der Kolk, M. et al. Evaluation of the standard membrane feeding assay (SMFA) for the determination of malaria transmission-reducing activity using empirical data. Parasitology 130, 13–22 (2005).

    Article  PubMed  Google Scholar 

  180. Minkah, N. K., Schafer, C. & Kappe, S. H. I. Humanized mouse models for the study of human malaria parasite biology, pathogenesis, and immunity. Front. Immunol. 9, 807 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Othman, A. S. et al. The use of transgenic parasites in malaria vaccine research. Expert. Rev. Vaccines 16, 685–697 (2017).

    Article  CAS  Google Scholar 

  182. Vanderberg, J. et al. Assessment of antibody protection against malaria sporozoites must be done by mosquito injection of sporozoites. Am. J. Pathol. 171, 1405–1406 (2007).

    Article  PubMed  Google Scholar 

  183. Ashkenazy, H., Erez, E., Martz, E., Pupko, T. & Ben-Tal, N. ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res. 38, W529–W533 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Chen, E., Paing, M. M., Salinas, N., Sim, B. K. L. & Tolia, N. H. Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175. PLOS Pathog. 9, e1003390 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Coley, A. M. et al. Structure of the malaria antigen AMA1 in complex with a growth-inhibitory antibody. PLOS Pathog. 3, e138 (2007).

    Article  PubMed Central  CAS  Google Scholar 

  186. Chen, L. et al. Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA. eLife 6, 21347 (2017). This study describes a molecular mechanism for how antibody binding can block the interaction between CyRPA and PfRh5 to inhibit merozoite invasion of erythrocytes during the asexual erythrocyte stage.

    Article  Google Scholar 

  187. Douglas, A. D. et al. Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5. J. Immunol. 192, 245–258 (2013).

    Article  PubMed  CAS  Google Scholar 

  188. Pettersen, E. F. et al. UCSF Chimera — a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  189. Hsieh, F.-L. & Higgins, M. K. The structure of a LAIR1-containing human antibody reveals a novel mechanism of antigen recognition. eLife 6, e27311 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank E. A. Levashina for discussions and critical reading of the manuscript. This Review was undertaken, in part, thanks to funding from the Canada Research Chairs program (to J.-P.J.).

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Glossary

Sterilizing immunity

An immune response that prevents the establishment of the infection or the development of erythrocytic-stage parasites.

Controlled human malaria infection

Deliberate infection of humans with Plasmodium parasites by either mosquito bite or injection of sporozoites or infected erythrocytes. This model is widely used to investigate the potency of drug and vaccine candidates.

Chemoprophylaxis

Drug-mediated attenuation of parasite development in the liver or blood to prevent malaria disease.

Circumsporozoite precipitation reaction

Antibody-mediated precipitation of circumsporozoite protein from the surface of Plasmodium sporozoites, which leads to parasite immobilization associated with impaired infectivity.

RTS,S/AS01

The first human PfCSP-based vaccine against the pre-erythrocytic stage of malaria.

Complementarity-determining region 3

(CDR3). A hypervariable region of membrane-bound and soluble B cell receptors that is involved in antigen binding.

Fab molecules

The antigen-binding fragments of immunoglobulin molecules.

Variant surface antigens

Proteins encoded by Plasmodium gene families in sub-telomeric regions; they have functions in virulence and immune evasion.

Activation-induced cytidine deaminase

(AID). An enzyme expressed in germinal centre B cells that has a crucial function in somatic hypermutation and class-switch recombination.

Structure-guided vaccine design

Rational engineering of vaccine immunogens based on structural analysis of potent antibodies and their target epitopes.

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Julien, JP., Wardemann, H. Antibodies against Plasmodium falciparum malaria at the molecular level. Nat Rev Immunol 19, 761–775 (2019). https://doi.org/10.1038/s41577-019-0209-5

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