TY - JOUR
T1 - A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein
AU - Tan, Joshua
AU - Sack, Brandon K.
AU - Oyen, David
AU - Zenklusen, Isabelle
AU - Piccoli, Luca
AU - Barbieri, Sonia
AU - Foglierini, Mathilde
AU - Fregni, Chiara Silacci
AU - Marcandalli, Jessica
AU - Jongo, Said
AU - Abdulla, Salim
AU - Perez, Laurent
AU - Corradin, Giampietro
AU - Varani, Luca
AU - Sallusto, Federica
AU - Sim, Betty Kim Lee
AU - Hoffman, Stephen L.
AU - Kappe, Stefan H.I.
AU - Daubenberger, Claudia
AU - Wilson, Ian A.
AU - Lanzavecchia, Antonio
N1 - Funding Information:
We would like to thank M. Nussenzweig (Rockefeller University) and H. Wardemann (German Cancer Research Center) for providing reagents for antibody cloning and expression. This work was supported in part by the Swiss Vaccine Research Institute, by the European Research Council (grant no. 670955 BROADimmune) and by the Fondazione Aldo e Cele Daccò. J.T. is funded by the Wellcome Trust (grant no. 204689/Z/16/Z). B.S. is funded by the National Institutes of Health (grant no. F32 AI 114113). The authors would like to thank first and foremost the study volunteers for their participation in the study. We also thank the entire study team at the Bagamoyo branch of the Ifakara Health Institute and the manufacturing, quality control, regulatory and clinical teams at Sanaria, Inc. for their contributions to the conduct of the trial. We would like to thank M. Tanner (former director of the Swiss Tropical and Public Health Institute, Basel) for his vision and support of the development of the clinical trial platform enabling whole sporozoite-based malaria vaccine trials in Bagamoyo, Tanzania. D.O. and I.A.W. are funded by PATH's Malaria Vaccine Initiative under a collaborative agreement with The Scripps Research Institute and by the Bill and Melinda Gates Foundation. A.L. and F.S. are supported by the Helmut Horten Foundation. This research used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231. The Tanzanian Commission on Science and Technology (COSTECH), the Ifakara Health Institute, and the Swiss Tropical Public Health Institute provided funding for the clinical trial. The functional assays were supported by the Bill and Melinda Gates foundation (Investment ID: 24922). The development, manufacturing, and quality control release and stability studies of PfSPZ Vaccine and PfSPZ Challenge were supported in part by National Institute of Allergy and Infectious Diseases (NIAID) Small Business Innovation Research grant 5R44AI055229. Sanaria supported transport of PfSPZ Vaccine and PfSPZ Challenge to the study site and syringe preparation.
Funding Information:
We would like to thank M. Nussenzweig (Rockefeller University) and H. Wardemann (German Cancer Research Center) for providing reagents for antibody cloning and expression. This work was supported in part by the Swiss Vaccine Research Institute, by the European Research Council (grant no. 670955 BROADimmune) and by the Fondazione Aldo e Cele Daccò. J.T. is funded by the Wellcome Trust (grant no. 204689/Z/16/Z). B.S. is funded by the National Institutes of Health (grant no. F32 AI 114113). The authors would like to thank first and foremost the study volunteers for their participation in the study. We also thank the entire study team at the Bagamoyo branch of the Ifakara Health Institute and the manufacturing, quality control, regulatory and clinical teams at Sanaria, Inc. for their contributions to the conduct of the trial. We would like to thank M. Tanner (former director of the Swiss Tropical and Public Health Institute, Basel) for his vision and support of the development of the clinical trial platform enabling whole sporozoite–based malaria vaccine trials in Bagamoyo, Tanzania. D.O. and I.A.W. are funded by PATH’s Malaria Vaccine Initiative under a collaborative agreement with The Scripps Research Institute and by the Bill and Melinda Gates Foundation. A.L. and F.S. are supported by the Helmut Horten Foundation. This research used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231. The Tanzanian Commission on Science and Technology (COSTECH), the Ifakara Health Institute, and the Swiss Tropical Public Health Institute provided funding for the clinical trial. The functional assays were supported by the Bill and Melinda Gates foundation (Investment ID: 24922). The development, manufacturing, and quality control release and stability studies of PfSPZ Vaccine and PfSPZ Challenge were supported in part by National Institute of Allergy and Infectious Diseases (NIAID) Small Business Innovation Research grant 5R44AI055229. Sanaria supported transport of PfSPZ Vaccine and PfSPZ Challenge to the study site and syringe preparation.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.
AB - Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.
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U2 - 10.1038/nm.4513
DO - 10.1038/nm.4513
M3 - Article
C2 - 29554084
AN - SCOPUS:85045284082
VL - 24
SP - 401
EP - 407
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 4
ER -