A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite

  • 1.

    Ménard, R. et al. Circumsporozoite protein is required for development of malaria sporozoites in mosquitoes. Nature 385, 336–340 (1997).

  • 2.

    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).

  • 3.

    Ancsin, J.B. & Kisilevsky, R. A binding site for highly sulfated heparan sulfate is identified in the N terminus of the circumsporozoite protein: significance for malarial sporozoite attachment to hepatocytes. J. Biol. Chem. 279, 21824–21832 (2004).

  • 4.

    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).

  • 5.

    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).

  • 6.

    Enea, V. et al. DNA cloning of Plasmodium falciparum circumsporozoite gene: amino acid sequence of repetitive epitope. Science 225, 628–630 (1984).

  • 7.

    Nussenzweig, R.S. & Nussenzweig, V. Antisporozoite vaccine for malaria: experimental basis and current status. Rev. Infect. Dis. 11 (Suppl. 3), S579–S585 (1989).

  • 8.

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

  • 9.

    White, M.T. et al. The relationship between RTS,S vaccine-induced antibodies, CD4+ T cell responses and protection against Plasmodium falciparum infection. PLoS One 8, e61395 (2013).

  • 10.

    Stoute, J.A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N. Engl. J. Med. 336, 86–91 (1997).

  • 11.

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

  • 12.

    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).

  • 13.

    Olotu, A. et al. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N. Engl. J. Med. 368, 1111–1120 (2013).

  • 14.

    Olotu, A. et al. Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N. Engl. J. Med. 374, 2519–2529 (2016).

  • 15.

    Triller, G. et al. Natural parasite exposure induces protective human anti-malarial antibodies. Immunity 47, 1197–1209.e10 (2017).

  • 16.

    Hoffman, S.L. et al. Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria. Hum. Vaccin 6, 974–106 (2010).

  • 17.

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

  • 18.

    Briney, B.S., Willis, J.R., Hicar, M.D., Thomas, J.W. II & Crowe, J.E. Jr. Frequency and genetic characterization of V(DD)J recombinants in the human peripheral blood antibody repertoire. Immunology 137, 56–64 (2012).

  • 19.

    March, S. et al. A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax. Cell Host Microbe 14, 104–115 (2013).

  • 20.

    March, S. et al. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. Nat. Protoc. 10, 2027–2053 (2015).

  • 21.

    Espinosa, D.A. et al. Robust antibody and CD8+ T-cell responses induced by P. falciparum CSP adsorbed to cationic liposomal adjuvant CAF09 confer sterilizing immunity against experimental rodent malaria infection. NPJ. Vaccines 2, 10 (2017).

  • 22.

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

  • 23.

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

  • 24.

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

  • 25.

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

  • 26.

    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).

  • 27.

    Sack, B.K. et al. Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum. Infect. Immun. 82, 808–817 (2014).

  • 28.

    Epstein, J.E. et al. Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum–infected mosquitoes: an update. J. Infect. Dis. 196, 145–154 (2007).

  • 29.

    Rickman, L.S. et al. Plasmodium falciparum–infected Anopheles stephensi inconsistently transmit malaria to humans. Am. J. Trop. Med. Hyg. 43, 441–445 (1990).

  • 30.

    Freire, E., Schön, A. & Velazquez-Campoy, A. Isothermal titration calorimetry: general formalism using binding polynomials. Methods Enzymol. 455, 127–155 (2009).

  • 31.

    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).

  • 32.

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

  • 33.

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

  • 34.

    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).

  • 35.

    Topchiy, E. et al. T1BT* structural study of an anti-plasmodial peptide through NMR and molecular dynamics. Malar. J. 12, 104 (2013).

  • 36.

    Coppi, A., Pinzon-Ortiz, C., Hutter, C. & Sinnis, P. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J. Exp. Med. 201, 27–33 (2005).

  • 37.

    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).

  • 38.

    Aurrecoechea, C. et al. PlasmoDB: a functional genomic database for malaria parasites. Nucleic Acids Res. 37, D539–D543 (2009).

  • 39.

    Rich, S.M., Hudson, R.R. & Ayala, F.J. Plasmodium falciparum antigenic diversity: evidence of clonal population structure. Proc. Natl. Acad. Sci. USA 94, 13040–13045 (1997).

  • 40.

    Zeeshan, M. et al. Genetic variation in the Plasmodium falciparum circumsporozoite protein in India and its relevance to RTS,S malaria vaccine. PLoS One 7, e43430 (2012).

  • 41.

    Zakeri, S., Avazalipoor, M., Mehrizi, A.A., Djadid, N.D. & Snounou, G. Restricted T-cell epitope diversity in the circumsporozoite protein from Plasmodium falciparum populations prevalent in Iran. Am. J. Trop. Med. Hyg. 76, 1046–1051 (2007).

  • 42.

    Tanabe, K. et al. Within-population genetic diversity of Plasmodium falciparum vaccine candidate antigens reveals geographic distance from a Central sub-Saharan African origin. Vaccine 31, 1334–1339 (2013).

  • 43.

    Gaudinski, M.R. et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med. 15, e1002493 (2018).

  • 44.

    Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010).

  • 45.

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

  • 46.

    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).

  • 47.

    Wheatley, A.K. et al. H5N1 vaccine–elicited memory B cells are genetically constrained by the IGHV locus in the recognition of a neutralizing epitope in the hemagglutinin stem. J. Immunol. 195, 602–610 (2015).

  • 48.

    Kanekiyo, M. et al. Rational design of an Epstein–Barr virus vaccine targeting the receptor-binding site. Cell 162, 1090–1100 (2015).

  • 49.

    Liao, H.X. et al. High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies.
    J. Virol. Methods
    158, 171–179 (2009).

  • 50.

    Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008).

  • 51.

    Lefranc, M.P. et al. IMGT, the international immunogenetics information system. Nucleic Acids Res. 37, D1006–D1012 (2009).

  • 52.

    Bonsignori, M. et al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J. Virol. 85, 9998–10009 (2011).

  • 53.

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

  • 54.

    Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

  • 55.

    Bruña-Romero, O. et al. Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. Int. J. Parasitol. 31, 1499–1502 (2001).

  • 56.

    Vaughan, A.M. et al. A transgenic Plasmodium falciparum NF54 strain that expresses GFP-luciferase throughout the parasite life cycle. Mol. Biochem. Parasitol. 186, 143–147 (2012).

  • 57.

    Miller, J.L. et al. Quantitative bioluminescent imaging of pre-erythrocytic malaria parasite infection using luciferase-expressing Plasmodium yoelii. PLoS One 8, e60820 (2013).

  • 58.

    Murphy, S.C. et al. Real-time quantitative reverse transcription PCR for monitoring of blood-stage Plasmodium falciparum infections in malaria human challenge trials. Am. J. Trop. Med. Hyg. 86, 383–394 (2012).

  • 59.

    Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

  • 60.

    Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  • 61.

    Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

  • 62.

    Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

  • 63.

    Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph 14, 33–38, 27–28 (1996).

  • 64.

    Phillips, J.C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).

  • 65.

    Huang, J. & MacKerell, A.D. Jr. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput. Chem. 34, 2135–2145 (2013).

  • 66.

    Páll, S. et al. Tackling exascale software challenges in molecular dynamics simulations with GROMACS. In Solving Software Challenges for Exascale (eds. Markadis, S. & Laure, E.) 3–27 (Springer, Cham, 2015).

  • 67.

    McGibbon, R.T. et al. MDTraj: a modern open library for the analysis of molecular dynamics trajectories. Biophys. J. 109, 1528–1532 (2015).

  • 68.

    Pedregosa, F. et al. Scikit-learn: machine learning in Python. J. Mach. Learn. Res. 12, 2825–2830 (2011).

  • 69.

    Hunter, J.D. Matplotlib: a 2D graphics environment. Comput. Sci. Eng. 9, 90–95 (2007).

  • 70.

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

  • 71.

    Guerois, R., Nielsen, J.E. & Serrano, L. Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J. Mol. Biol. 320, 369–387 (2002).

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