TY - JOUR
T1 - A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity
AU - Thai, Elaine
AU - Costa, Giulia
AU - Weyrich, Anna
AU - Murugan, Rajagopal
AU - Oyen, David
AU - Flores-Garcia, Yevel
AU - Prieto, Katherine
AU - Bosch, Alexandre
AU - Valleriani, Angelo
AU - Wu, Nicholas C.
AU - Pholcharee, Tossapol
AU - Scally, Stephen W.
AU - Wilson, Ian A.
AU - Wardemann, Hedda
AU - Julien, Jean Philippe
AU - Levashina, Elena A.
N1 - Funding Information:
We thank C. Kreschel for her support in Pf sporozoite production and cell culture, as well as H. Ahmed, L. Spohr, M. Andres, and D. Eyermann (Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin, Germany) for mosquito rearing and infections. The following reagents were obtained from BEI Resources, National Institute of Allergy and Infectious Diseases, National Institutes of Health: HC-04, hepatocyte (human), and MRA-975, contributed by Jetsumon Sattabongkot Prachumsri (Mahidol University, Bangkok, Thailand). E. Thai is currently supported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship, and N.C. Wu by National Institutes of Health grant K99 AI139445. S.W. Scally was supported by a Hospital for Sick Children Lap-Chee Tsui Postdoctoral Fellowship and a CIHR fellowship. The mouse liver burden experiments were performed in a Reference Laboratory supported by the Bill and Melinda Gates Foundation and led by Prof. Fidel Zavala at the Johns Hopkins School of Public Health, Baltimore, MD. This work was undertaken in part thanks to funding from the Bill and Melinda Gates Foundation (OPP1179906 to J.-P. Julien, H. Wardemann, and E.A. Levashina and OPP1170236 to I.A. Wilson), the Canadian Institute for Advanced Research Azrieli Global Scholar program (to J.-P. Julien), and the Canada Research Chairs program (950-231604 to J.-P. Julien). X-ray diffraction experiments were performed using beamline 08ID-1 at the Canadian Light Source, which is supported by the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, the Western Economic Diversification Canada, the National Research Council Canada, and the CIHR.
Funding Information:
E. Thai is currently supported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship, and N.C. Wu by National Institutes of Health grant K99 AI139445. S.W. Scally was supported by a Hospital for Sick Children Lap-Chee Tsui Postdoctoral Fellowship and a CIHR fellowship. The mouse liver burden experiments were performed in a Reference Laboratory supported by the Bill and Melinda Gates Foundation and led by Prof. Fidel Zavala at the Johns Hopkins School of Public Health, Baltimore, MD. This work was undertaken in part thanks to funding from the Bill and Melinda Gates Foundation (OPP1179906 to J.-P. Julien, H. Wardemann, and E.A. Levashina and OPP1170236 to I.A. Wilson), the Canadian Institute for Advanced Research Azrieli Global Scholar program (to J.-P. Julien), and the Canada Research Chairs program (950-231604 to J.-P. Julien). X-ray diffraction experiments were performed using beamline 08ID-1 at the Canadian Light Source, which is supported by the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, the Western Economic Diversification Canada, the National Research Council Canada, and the CIHR.
Publisher Copyright:
© 2020 Thai et al.
PY - 2020/8
Y1 - 2020/8
N2 - 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 (Pf) 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-°A 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 antibody N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites and lack of sporozoite inhibition in vitro and in vivo. Overall, our data do not support the inclusion of the 5D5 N-CSP epitope into the next generation of CSP-based vaccines.
AB - 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 (Pf) 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-°A 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 antibody N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites and lack of sporozoite inhibition in vitro and in vivo. Overall, our data do not support the inclusion of the 5D5 N-CSP epitope into the next generation of CSP-based vaccines.
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U2 - 10.1084/JEM.20200061
DO - 10.1084/JEM.20200061
M3 - Article
C2 - 32790871
AN - SCOPUS:85089472949
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20200061
ER -