A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity
A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity
Abstract Malaria is a global health concern and research efforts are ongoing to develop a superior vaccine to RTS,S/AS01. To guide immunogen design, we seek a comprehensive understanding of the protective humoral response against Plasmodium falciparum circumsporozoite protein (PfCSP). In contrast to the well-studied responses to the repeat region and the C-terminus, the antibody response against the N-terminal domain of PfCSP (N-CSP) remains obscure. Here, we characterized the molecular recognition and functional efficacy of the N-CSP-specific monoclonal antibody 5D5. The crystal structure at 1.85 ? resolution revealed that 5D5 binds an α-helical epitope in N-CSP with high affinity through extensive shape and charge complementarity, and the unusual utilization of an N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites, and lack of sporozoite inhibition in vitro and in mosquitoes. Overall, our data on low recognition and inhibition of sporozoites do not support the inclusion of the 5D5 epitope into the next generation of CSP-based vaccines. Summary StatementThe Plasmodium falciparum sporozoite surface protein, PfCSP, is an attractive vaccine target, but the antibody response against the CSP N-terminal domain has remained understudied. Here, to guide immunogen design, Thai et al. provide insights into the binding motif and functional efficacy of the N-terminal domain-specific monoclonal antibody, 5D5.
Scally Stephen W.、Costa Giulia、Weyrich Anna、Prieto Katherine、Wu Nicholas C.、Wardemann Hedda、Oyen David、Wilson Ian A.、Murugan Rajagopal、Valleriani Angelo、Thai Elaine、Pholcharee Tossapol、Julien Jean-Philippe、Bosch Alexandre、Levashina Elena A.
Program in Molecular Medicine, The Hospital for Sick Children Research InstituteVector Biology Unit, Max Planck Institute for Infection BiologyVector Biology Unit, Max Planck Institute for Infection BiologyDepartment of Biochemistry, University of TorontoDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteB Cell Immunology, German Cancer Research Institute (DKFZ)Department of Integrative Structural and Computational Biology, The Scripps Research InstituteDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute||The Skaggs Institute for Chemical Biology, The Scripps Research InstituteB Cell Immunology, German Cancer Research Institute (DKFZ)Vector Biology Unit, Max Planck Institute for Infection Biology||Department of Theory and Biosystems, Max Planck Institute of Colloids and InterfacesProgram in Molecular Medicine, The Hospital for Sick Children Research Institute||Department of Biochemistry, University of TorontoDepartment of Integrative Structural and Computational Biology, The Scripps Research InstituteProgram in Molecular Medicine, The Hospital for Sick Children Research Institute||Department of Biochemistry, University of Toronto||Department of Immunology, University of TorontoDepartment of Biochemistry, University of TorontoVector Biology Unit, Max Planck Institute for Infection Biology
基础医学分子生物学预防医学
Scally Stephen W.,Costa Giulia,Weyrich Anna,Prieto Katherine,Wu Nicholas C.,Wardemann Hedda,Oyen David,Wilson Ian A.,Murugan Rajagopal,Valleriani Angelo,Thai Elaine,Pholcharee Tossapol,Julien Jean-Philippe,Bosch Alexandre,Levashina Elena A..A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2020.01.13.904425.点此复制
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