Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Erythrocyte invasion in malaria: from molecular mechanisms to rational vaccines

Nature Reviews Microbiology (2025)Cite this article

Subjects

Abstract

Plasmodium parasites, which cause malaria, invade and remodel our red blood cells, creating niches in which they replicate. If erythrocyte invasion is blocked during the blood stage of infection, malaria can be prevented. Indeed, a vaccine that targets a component of the erythrocyte invasion machinery has recently shown efficacy against malaria. Erythrocyte invasion occurs through a sequence of temporally organized molecular processes, such as bridging of the erythrocyte and parasite membranes during invasion by the Plasmodium falciparum PCRCR complex. Structural investigations of human antibodies that target invasion machinery, induced by vaccination or natural infection, have revealed neutralizing epitopes and uncovered mechanisms by which antibodies can potentiate the activity of other antibodies. Using rational, structure-guided protein design, these insights are being leveraged to develop targeted vaccine components, with the first rationally designed blood-stage malaria vaccine immunogen now entering clinical trials.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Stages in the active invasion of human red blood cells by Plasmodium parasites.
Fig. 2: From merozoite gliding to host cell selection.
Fig. 3: From triggering of rhoptry release to formation of the moving junction.
Fig. 4: Understanding how antibodies inhibit PfPCRCR complex function.
Fig. 5: Structure-guided vaccine design for PfRH5.

Similar content being viewed by others

References

  1. World Health Organization. World Malaria Report: Addressing Inequity in the Global Malaria Response (WHO, 2024).

  2. Cowman, A. F., Healer, J., Marapana, D. & Marsh, K. Malaria: biology and disease. Cell 167, 610–624 (2016).

    Article  PubMed  Google Scholar 

  3. Duffy, P. E., Gorres, J. P., Healy, S. A. & Fried, M. Malaria vaccines: a new era of prevention and control. Nat. Rev. Microbiol. 22, 756–772 (2024).

    Article  PubMed  Google Scholar 

  4. Koch, M. & Baum, J. The mechanics of malaria parasite invasion of the human erythrocyte — towards a reassessment of the host cell contribution. Cell Microbiol. 18, 319–329 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Moreau, A. et al. Physical mechanisms of red blood cell splenic filtration. Proc. Natl Acad. Sci. USA 120, e2300095120 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Martinez, M. et al. Rhoptry secretion system structure and priming in Plasmodium falciparum revealed using in situ cryo-electron tomography. Nat. Microbiol. 7, 1230–1238 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kadekoppala, M. & Holder, A. A. Merozoite surface proteins of the malaria parasite: the MSP1 complex and the MSP7 family. Int. J. Parasitol. 40, 1155–1161 (2010).

    Article  PubMed  Google Scholar 

  8. Zuccala, E. S. et al. Subcompartmentalisation of proteins in the rhoptries correlates with ordered events of erythrocyte invasion by the blood stage malaria parasite. PLoS ONE 7, e46160 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Riglar, D. T. et al. Super-resolution dissection of coordinated events during malaria parasite invasion of the human erythrocyte. Cell Host Microbe 9, 9–20 (2011). This paper provides a powerful demonstration through super-resolution microscopy of the stages of invasion.

    Article  PubMed  Google Scholar 

  10. Bannister, L. H. & Mitchell, G. H. The fine structure of secretion by Plasmodium knowlesi merozoites during red cell invasion. J. Protozool. 36, 362–367 (1989).

    Article  PubMed  Google Scholar 

  11. Frenal, K., Dubremetz, J. F., Lebrun, M. & Soldati-Favre, D. Gliding motility powers invasion and egress in apicomplexa. Nat. Rev. Microbiol. 15, 645–660 (2017).

    Article  PubMed  Google Scholar 

  12. Yahata, K. et al. Gliding motility of Plasmodium merozoites. Proc. Natl Acad. Sci. USA 118, e2114442118 (2021). This article demonstrates that merozoites glide.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hart, M. N. et al. Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites. Nat. Commun. 14, 4619 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Scally, S. W. et al. PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum. Nat. Microbiol. 7, 2039–2053 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Weiss, G. E. et al. Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes. PLoS Pathog. 11, e1004670 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ben Chaabene, R., Lentini, G. & Soldati-Favre, D. Biogenesis and discharge of the rhoptries: key organelles for entry and hijack of host cells by the apicomplexa. Mol. Microbiol. 115, 453–465 (2021).

    Article  PubMed  Google Scholar 

  17. Cova, M. M., Lamarque, M. H. & Lebrun, M. How apicomplexa parasites secrete and build their invasion machinery. Annu. Rev. Microbiol. 76, 619–640 (2022).

    Article  PubMed  Google Scholar 

  18. Besteiro, S., Dubremetz, J. F. & Lebrun, M. The moving junction of apicomplexan parasites: a key structure for invasion. Cell Microbiol. 13, 797–805 (2011).

    Article  PubMed  Google Scholar 

  19. Harris, P. K. et al. Molecular identification of a malaria merozoite surface sheddase. PLoS Pathog. 1, 241–251 (2005).

    Article  PubMed  Google Scholar 

  20. Pavlou, G. et al. Toxoplasma parasite twisting motion mechanically induces host cell membrane fission to complete invasion within a protective vacuole. Cell Host Microbe 24, 81–96.e5 (2018).

    Article  PubMed  Google Scholar 

  21. Bisio, H. & Soldati-Favre, D. Signaling cascades governing entry into and exit from host cells by Toxoplasma gondii. Annu. Rev. Microbiol. 73, 579–599 (2019).

    Article  PubMed  Google Scholar 

  22. Singh, S., Alam, M. M., Pal-Bhowmick, I., Brzostowski, J. A. & Chitnis, C. E. Distinct external signals trigger sequential release of apical organelles during erythrocyte invasion by malaria parasites. PLoS Pathog. 6, e1000746 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tham, W. H., Healer, J. & Cowman, A. F. Erythrocyte and reticulocyte binding-like proteins of Plasmodium falciparum. Trends Parasitol. 28, 23–30 (2012).

    Article  PubMed  Google Scholar 

  24. Iyer, J., Gruner, A. C., Renia, L., Snounou, G. & Preiser, P. R. Invasion of host cells by malaria parasites: a tale of two protein families. Mol. Microbiol. 65, 231–249 (2007).

    Article  PubMed  Google Scholar 

  25. Sim, B. K., Chitnis, C. E., Wasniowska, K., Hadley, T. J. & Miller, L. H. Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264, 1941–1944 (1994).

    Article  PubMed  Google Scholar 

  26. Orlandi, P. A., Klotz, F. W. & Haynes, J. D. A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2-3)Gal- sequences of glycophorin A. J. Cell Biol. 116, 901–909 (1992).

    Article  PubMed  Google Scholar 

  27. Tolia, N. H., Enemark, E. J., Sim, B. K. & Joshua-Tor, L. Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell 122, 183–193 (2005).

    Article  PubMed  Google Scholar 

  28. Tham, W. H. et al. Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand. Proc. Natl Acad. Sci. USA 107, 17327–17332 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Duraisingh, M. T., Maier, A. G., Triglia, T. & Cowman, A. F. Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 100, 4796–4801 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stubbs, J. et al. Molecular mechanism for switching of P. falciparum invasion pathways into human erythrocytes. Science 309, 1384–1387 (2005). This paper shows that merozoites can switch between different invasion pathways that use different EBL and RBL proteins.

    Article  PubMed  Google Scholar 

  31. Gruszczyk, J. et al. Cryo-EM structure of an essential Plasmodium vivax invasion complex. Nature 559, 135–139 (2018).

    Article  PubMed  Google Scholar 

  32. Gruszczyk, J. et al. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science 359, 48–55 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Moon, R. W. et al. Normocyte-binding protein required for human erythrocyte invasion by the zoonotic malaria parasite Plasmodium knowlesi. Proc. Natl Acad. Sci. USA 113, 7231–7236 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tham, W. H. et al. Plasmodium falciparum adhesins play an essential role in signalling and activation of invasion into human erythrocytes. PLoS Pathog. 11, e1005343 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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  Google Scholar 

  36. Farrell, B. et al. The PfRCR complex bridges malaria parasite and erythrocyte during invasion. Nature 625, 578–584 (2024). Using cryoEM, this paper visualises the bridge between merozoite and erythrocyte formed by the PfPCRCR complex.

    Article  PubMed  Google Scholar 

  37. 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  Google Scholar 

  38. Crosnier, C. et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480, 534–537 (2011). This article presents the discovery that basigin is the erythrocyte ligand for PfRH5.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wright, K. E. et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature 515, 427–430 (2014). This paper shows how PfRH5 binds to basigin and inhibitory antibodies.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zenonos, Z. A. et al. Basigin is a druggable target for host-oriented antimalarial interventions. J. Exp. Med. 212, 1145–1151 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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  Google Scholar 

  42. Patel, S. D. et al. Plasmodium falciparum merozoite surface antigen, PfRH5, elicits detectable levels of invasion-inhibiting antibodies in humans. J. Infect. Dis. 208, 1679–1687 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tran, T. M. et al. Naturally acquired antibodies specific for Plasmodium falciparum reticulocyte-binding protein homologue 5 inhibit parasite growth and predict protection from malaria. J. Infect. Dis. 209, 789–798 (2014).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  45. Alanine, D. G. W. et al. Human antibodies that slow erythrocyte invasion potentiate malaria-neutralizing antibodies. Cell 178, 216–228 (2019). This article characterizes human antibodies that target PfRH5.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wang, L. T. et al. Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5. Cell 187, 4981–4995 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  48. Aniweh, Y. et al. P. falciparum RH5-Basigin interaction induces changes in the cytoskeleton of the host RBC. Cell Microbiol. 19, e12747 (2017).

    Article  Google Scholar 

  49. Schmidt, N. et al. Neuroplastin and basigin are essential auxiliary subunits of plasma membrane Ca2+-ATPases and key regulators of Ca2+ clearance. Neuron 96, 827–838 (2017).

    Article  PubMed  Google Scholar 

  50. Jamwal, A. et al. Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes. eLife 12, e83681 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 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  PubMed Central  Google Scholar 

  52. 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  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  54. 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 

  55. Knuepfer, E. et al. Divergent roles for the RH5 complex components, CyRPA and RIPR in human-infective malaria parasites. PLoS Pathog. 15, e1007809 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Thompson, J. et al. PTRAMP; a conserved Plasmodium thrombospondin-related apical merozoite protein. Mol. Biochem. Parasitol. 134, 225–232 (2004).

    Article  PubMed  Google Scholar 

  57. Siddiqui, F. A. et al. A thrombospondin structural repeat containing rhoptry protein from Plasmodium falciparum mediates erythrocyte invasion. Cell Microbiol. 15, 1341–1356 (2013).

    Article  PubMed  Google Scholar 

  58. Triglia, T. et al. Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion. Nat. Commun. 14, 2219 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Moskovitz, R. et al. Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax. Nat. Commun. 14, 3637 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Horuk, R. et al. A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science 261, 1182–1184 (1993).

    Article  PubMed  Google Scholar 

  61. Alexander, D. L., Mital, J., Ward, G. E., Bradley, P. & Boothroyd, J. C. Identification of the moving junction complex of Toxoplasma gondii: a collaboration between distinct secretory organelles. PLoS Pathog. 1, e17 (2005). This study identifies the RON complexes as a binding partner of AMA1.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lamarque, M. et al. The RON2-AMA1 interaction is a critical step in moving junction-dependent invasion by apicomplexan parasites. PLoS Pathog. 7, e1001276 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Vulliez-Le Normand, B. et al. Structural and functional insights into the malaria parasite moving junction complex. PLoS Pathog. 8, e1002755 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tonkin, M. L. et al. Host cell invasion by apicomplexan parasites: insights from the co-structure of AMA1 with a RON2 peptide. Science 333, 463–467 (2011).

    Article  PubMed  Google Scholar 

  65. Richard, D. et al. Interaction between Plasmodium falciparum apical membrane antigen 1 and the rhoptry neck protein complex defines a key step in the erythrocyte invasion process of malaria parasites. J. Biol. Chem. 285, 14815–14822 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Srinivasan, P. et al. Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion. Proc. Natl Acad. Sci. USA 108, 13275–13280 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Soldati, D., Foth, B. J. & Cowman, A. F. Molecular and functional aspects of parasite invasion. Trends Parasitol. 20, 567–574 (2004).

    Article  PubMed  Google Scholar 

  68. Gonzalez, V. et al. Host cell entry by apicomplexa parasites requires actin polymerization in the host cell. Cell Host Microbe 5, 259–272 (2009).

    Article  PubMed  Google Scholar 

  69. Dobrowolski, J. M. & Sibley, L. D. Toxoplasma invasion of mammalian cells is powered by the actin cytoskeleton of the parasite. Cell 84, 933–939 (1996).

    Article  PubMed  Google Scholar 

  70. Angrisano, F. et al. Spatial localisation of actin filaments across developmental stages of the malaria parasite. PLoS ONE 7, e32188 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Guerin, A. et al. Efficient invasion by Toxoplasma depends on the subversion of host protein networks. Nat. Microbiol. 2, 1358–1366 (2017).

    Article  PubMed  Google Scholar 

  72. Bargieri, D. et al. Host cell invasion by apicomplexan parasites: the junction conundrum. PLoS Pathog. 10, e1004273 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dasgupta, S. et al. Membrane-wrapping contributions to malaria parasite invasion of the human erythrocyte. Biophys. J. 107, 43–54 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  75. Siddiqui, W. A. An effective immunization of experimental monkeys against a human malaria parasite, Plasmodium falciparum. Science 197, 388–389 (1977).

    Article  PubMed  Google Scholar 

  76. Chauhan, V. S., Yazdani, S. S. & Gaur, D. Malaria vaccine development based on merozoite surface proteins of Plasmodium falciparum. Hum. Vaccin. 6, 757–762 (2010).

    Article  Google Scholar 

  77. Siddiqui, W. A. et al. Merozoite surface coat precursor protein completely protects Aotus monkeys against Plasmodium falciparum malaria. Proc. Natl Acad. Sci. USA 84, 3014–3018 (1987).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Stowers, A. W. et al. Vaccination of monkeys with recombinant Plasmodium falciparum apical membrane antigen 1 confers protection against blood-stage malaria. Infect. Immun. 70, 6961–6967 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ogutu, B. R. et al. Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya. PLoS ONE 4, e4708 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Patel, P. N. et al. Structure-based design of a strain transcending AMA1-RON2L malaria vaccine. Nat. Commun. 14, 5345 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Blank, A. et al. Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial. npj Vaccines 5, 10 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Natama, H. M. et al. Safety and efficacy of the blood-stage malaria vaccine RH5.1/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled, phase 2b trial in children. Lancet Infect. Dis. 25, 495–506 (2024). This trial demonstrates efficacy from a blood stage malaria vaccine in humans.

    Article  PubMed  Google Scholar 

  84. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Stowers, A. W. & Miller, L. H. Are trials in new world monkeys on the critical path for blood-stage malaria vaccine development? Trends Parasitol. 17, 415–419 (2001).

    Article  PubMed  Google Scholar 

  86. Douglas, A. D. et al. A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates. Nat. Commun. 10, 1953 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Cooper, M. M., Loiseau, C., McCarthy, J. S. & Doolan, D. L. Human challenge models: tools to accelerate the development of malaria vaccines. Expert Rev. Vaccines 18, 241–251 (2019).

    Article  PubMed  Google Scholar 

  88. Miura, K. et al. Assessment of precision in growth inhibition assay (GIA) using human anti-PfRH5 antibodies. Malar. J. 22, 159 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Payne, R. O. et al. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions. JCI Insight 2, e96381 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Minassian, A. M. et al. Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination. Med 2, 701–719 (2021).

    Article  PubMed  Google Scholar 

  91. Silk, S. E. et al. Superior antibody immunogenicity of a viral-vectored RH5 blood-stage malaria vaccine in Tanzanian infants as compared to adults. Med 4, 668–686 (2023).

    Article  PubMed  Google Scholar 

  92. Silk, S. E. et al. Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial. Lancet Infect. Dis. 24, 1105–1117 (2024).

    Article  PubMed  Google Scholar 

  93. Barrett, J. R. et al. Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype. Cell 187, 4964–4980 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Harrison, T. E. et al. Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5. EMBO Mol. Med. 16, 2539–2559 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang, N. et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 184, 370–383 (2021).

    Article  PubMed  Google Scholar 

  96. Gong, D. et al. Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin. Nat. Commun. 9, 3623 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ragotte, R. J. et al. Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Nat. Commun. 13, 933 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Campeotto, I. et al. One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen. Proc. Natl Acad. Sci. USA 114, 998–1002 (2017). This paper reports the design of RH5.2 vaccine.

    Article  PubMed  PubMed Central  Google Scholar 

  99. King, L. D. W. et al. Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies. Cell Rep. Med. 5, 101654 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Andrews, M., Baum, J., Gilson, P. R. & Wilson, D. W. Bottoms up! Malaria parasite invasion the right way around. Trends Parasitol. 39, 1004–1013 (2023).

    Article  PubMed  Google Scholar 

  101. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Varadi, M. et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439–D444 (2021).

    Article  PubMed Central  Google Scholar 

  103. Rts, S. C. T. P. 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  Google Scholar 

  104. Datoo, M. S. et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet 403, 533–544 (2024).

    Article  PubMed  Google Scholar 

  105. Kappe, S. H., Vaughan, A. M., Boddey, J. A. & Cowman, A. F. That was then but this is now: malaria research in the time of an eradication agenda. Science 328, 862–866 (2010).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

For the studies of erythrocyte invasion, the authors are grateful for funding in the form of an Investigator Award from Wellcome (220797/Z/20/Z). For the structural studies of inhibitory monoclonal antibodies and structure-guided vaccine design projects, the authors are grateful for funding from the Medical Research Council (APP22787 and APP36549) and the Gates Foundation.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, UK

    Nawsad Alam, Brendan Farrell, Abhishek Jamwal & Matthew K. Higgins

  2. Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, UK

    Nawsad Alam, Brendan Farrell, Abhishek Jamwal & Matthew K. Higgins

Authors
  1. Nawsad Alam
    View author publications

    Search author on:PubMed Google Scholar

  2. Brendan Farrell
    View author publications

    Search author on:PubMed Google Scholar

  3. Abhishek Jamwal
    View author publications

    Search author on:PubMed Google Scholar

  4. Matthew K. Higgins
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Matthew K. Higgins.

Ethics declarations

Competing interests

M.K.H. and N.A. are named inventors on patents relating to antibodies targeting PfRH5 and structure-guided design of PfRH5-based and PfCyRPA-based vaccine immunogens. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Alan Cowman, who co-reviewed with Stephen Scally, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alam, N., Farrell, B., Jamwal, A. et al. Erythrocyte invasion in malaria: from molecular mechanisms to rational vaccines. Nat Rev Microbiol (2025). https://doi.org/10.1038/s41579-025-01235-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41579-025-01235-1

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology