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

Neville K. Kisalu; Azza H. Idris; Connor Weidle; Yevel Flores-Garcia; Barbara J. Flynn; Brandon K. Sack; Sean Murphy; Arne Schön; Ernesto Freire; Joseph R. Francica; Alex B. Miller; Jason Gregory; Sandra March; Hua Xin Liao; Barton F. Haynes; Kevin Wiehe; Ashley M. Trama; Kevin O. Saunders; Morgan A. Gladden; Anthony Monroe; Mattia Bonsignori; Masaru Kanekiyo; Adam K. Wheatley; Adrian B. McDermott; S. Katie Farney; Gwo Yu Chuang; Baoshan Zhang; Natasha Kc; Sumana Chakravarty; Peter D. Kwong; Photini Sinnis; Sangeeta N. Bhatia; Stefan H.I. Kappe; B. Kim Lee Sim; Stephen L. Hoffman; Fidel Zavala; Marie Pancera; Robert A. Seder

doi:10.1038/nm.4512

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

Neville K. Kisalu, Azza H. Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J. Flynn, Brandon K. Sack, Sean Murphy, Arne Schön, Ernesto Freire, Joseph R. Francica, Alex B. Miller, Jason Gregory, Sandra March, Hua Xin Liao, Barton F. Haynes, Kevin Wiehe, Ashley M. Trama, Kevin O. Saunders, Morgan A. Gladden, Anthony MonroeMattia Bonsignori, Masaru Kanekiyo, Adam K. Wheatley, Adrian B. McDermott, S. Katie Farney, Gwo Yu Chuang, Baoshan Zhang, Natasha Kc, Sumana Chakravarty, Peter D. Kwong, Photini Sinnis, Sangeeta N. Bhatia, Stefan H.I. Kappe, B. Kim Lee Sim, Stephen L. Hoffman, Fidel Zavala, Marie Pancera, Robert A. Seder

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93 Scopus citations

Abstract

Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

Original language	English (US)
Pages (from-to)	408-416
Number of pages	9
Journal	Nature medicine
Volume	24
Issue number	4
DOIs	https://doi.org/10.1038/nm.4512
State	Published - May 1 2018

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.4512

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Kisalu, N. K., Idris, A. H., Weidle, C., Flores-Garcia, Y., Flynn, B. J., Sack, B. K., Murphy, S., Schön, A., Freire, E., Francica, J. R., Miller, A. B., Gregory, J., March, S., Liao, H. X., Haynes, B. F., Wiehe, K., Trama, A. M., Saunders, K. O., Gladden, M. A., ... Seder, R. A. (2018). A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nature medicine, 24(4), 408-416. https://doi.org/10.1038/nm.4512

Kisalu, NK, Idris, AH, Weidle, C, Flores-Garcia, Y, Flynn, BJ, Sack, BK, Murphy, S, Schön, A, Freire, E, Francica, JR, Miller, AB, Gregory, J, March, S, Liao, HX, Haynes, BF, Wiehe, K, Trama, AM, Saunders, KO, Gladden, MA, Monroe, A, Bonsignori, M, Kanekiyo, M, Wheatley, AK, McDermott, AB, Farney, SK, Chuang, GY, Zhang, B, Kc, N, Chakravarty, S, Kwong, PD, Sinnis, P, Bhatia, SN, Kappe, SHI, Sim, BKL, Hoffman, SL, Zavala, F, Pancera, M & Seder, RA 2018, 'A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite', Nature medicine, vol. 24, no. 4, pp. 408-416. https://doi.org/10.1038/nm.4512

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

abstract = "Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.",

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AU - Kisalu, Neville K.

AU - Idris, Azza H.

AU - Weidle, Connor

AU - Flores-Garcia, Yevel

AU - Flynn, Barbara J.

AU - Sack, Brandon K.

AU - Murphy, Sean

AU - Schön, Arne

AU - Freire, Ernesto

AU - Francica, Joseph R.

AU - Miller, Alex B.

AU - Gregory, Jason

AU - March, Sandra

AU - Liao, Hua Xin

AU - Haynes, Barton F.

AU - Wiehe, Kevin

AU - Trama, Ashley M.

AU - Saunders, Kevin O.

AU - Gladden, Morgan A.

AU - Monroe, Anthony

AU - Bonsignori, Mattia

AU - Kanekiyo, Masaru

AU - Wheatley, Adam K.

AU - McDermott, Adrian B.

AU - Farney, S. Katie

AU - Chuang, Gwo Yu

AU - Zhang, Baoshan

AU - Kc, Natasha

AU - Chakravarty, Sumana

AU - Kwong, Peter D.

AU - Sinnis, Photini

AU - Bhatia, Sangeeta N.

AU - Kappe, Stefan H.I.

AU - Sim, B. Kim Lee

AU - Hoffman, Stephen L.

AU - Zavala, Fidel

AU - Pancera, Marie

AU - Seder, Robert A.

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

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