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Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Agudelo, Marianna and Palus, Martin and Keeffe, Jennifer R. and Bianchini, Filippo and Svoboda, Pavel and Salát, Jiří and Peace, Avery and Gazumyan, Anna and Cipolla, Melissa and Kapoor, Tania and Guidetti, Francesca and Yao, Kai-Hui and Elsterová, Jana and Teislerová, Dana and Chrdle, Aleš and Hönig, Václav and Oliveira, Thiago and West, Anthony P. and Lee, Yu E. and Rice, Charles M. and MacDonald, Margaret R. and Bjorkman, Pamela J. and Růžek, Daniel and Robbiani, Davide F. and Nussenzweig, Michel C. (2021) Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease. Journal of Experimental Medicine, 218 (5). Art. No. e20210236. ISSN 0022-1007. PMCID PMC8040517. doi:10.1084/jem.20210236.

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Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC₅₀s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

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URLURL TypeDescription CentralArticle
Agudelo, Marianna0000-0003-3924-6449
Palus, Martin0000-0002-4279-7092
Keeffe, Jennifer R.0000-0002-5317-6398
Bianchini, Filippo0000-0002-0746-7629
Svoboda, Pavel0000-0002-2180-3174
Salát, Jiří0000-0002-9915-8953
Peace, Avery0000-0003-3074-1662
Gazumyan, Anna0000-0002-5976-9717
Cipolla, Melissa0000-0001-8156-2512
Kapoor, Tania0000-0002-0396-4476
Guidetti, Francesca0000-0001-7962-1501
Yao, Kai-Hui0000-0001-7912-5516
Elsterová, Jana0000-0001-5921-3092
Teislerová, Dana0000-0002-5207-1885
Chrdle, Aleš0000-0003-4572-745X
Hönig, Václav0000-0003-0469-4604
Oliveira, Thiago0000-0002-2654-0879
West, Anthony P.0000-0003-4213-5184
Lee, Yu E.0000-0001-5989-326X
Rice, Charles M.0000-0003-3087-8079
MacDonald, Margaret R.0000-0001-5177-2068
Bjorkman, Pamela J.0000-0002-2277-3990
Růžek, Daniel0000-0003-4655-2380
Robbiani, Davide F.0000-0001-7379-3484
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:© 2021 Agudelo et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at Submitted: 28 January 2021; Revised: 17 February 2021; Accepted: 19 February 2021. We especially thank the study participants of České Budějovice and Brno who agreed to take part in this study, as well as the staff of the Hospital České Budějovice for their assistance with the clinical protocols, and all members of the Nussenzweig laboratory for discussions. We are grateful to Mary Ellen Castillo and Andrea Jurado for facilitating work with reporter viruses and Zoran Jankovic and Masa Jankovic for laboratory support. We thank Pauline Hoffman, Jost Vielmetter, and the Caltech Beckman Institute Protein Expression Center for expression and purification of Fabs and Harry B. Gristick and Christopher O. Barnes for assistance with crystallographic methods and helpful discussions. We also thank Jens Kaiser from the Molecular Observatory at the Beckman Institute at the California Institute of Technology and the staff at Beamline 12–2, Stanford Synchrotron Radiation Lightsource for their assistance with crystallographic data collection and processing. This work was supported by National Institutes of Health pilot award U19AI111825 and Swiss National Science Foundation grant IRB startup funds (to D.F. Robbiani) and grants R01AI037526, UM1AI100663, U19AI111825, and UL1TR001866 (to M.C. Nussenzweig), P01AI138938 (to M.C. Nussenzweig, P.J. Bjorkman, and C.M. Rice), R01AI124690 (to C.M. Rice), and U19AI057229 (CCHI Opportunity Fund Project to C.M. Rice and M.R. MacDonald). This work was also supported by Czech Science Foundation grants 20-14325S and 20-30500S (to D. Růžek and M. Palus), Czech Academy of Sciences grant MSM200962002 (to M. Palus), and Ministry of Health of the Czech Republic grant NV19-05-00457 (to D. Růžek). Operations at the Stanford Synchrotron Radiation Lightsource are supported by the U.S. Department of Energy and the National Institutes of Health. M.C. Nussenzweig is an investigator of the Howard Hughes Medical Institute. Author contributions: M. Agudelo conducted experiments, supervised and designed experiments, interpreted data, and wrote the paper. M. Palus, J. Salát, and P. Svoboda designed and conducted experiments with viruses, interpreted data, edited the paper, and together with J. Elsterová and V. Hönig coordinated and assisted in blood collection. A. Chrdle and D. Teislerová were responsible for the recruitment of the participants and blood collection. J.R. Keeffe solved and analyzed crystal structures with Y.E. Lee, and wrote structural portions of the paper with P.J. Bjorkman. F. Bianchini, A. Gazumyan, M. Cipolla, T. Kapoor, A. Peace, F. Guidetti, and K-H. Yao conducted experiments. T. Oliveira and A.P. West, Jr. performed statistical and computational analysis. C.M. Rice and M.R. MacDonald supervised and interpreted experimental results. D. Růžek coordinated clinical cohorts, supervised and designed experiments with viruses, interpreted data, and edited the paper. D.F. Robbiani and M.C. Nussenzweig supervised, designed, and interpreted experiments and wrote the paper. Competing Interests: Disclosures: M. Agudelo, D.F. Robbiani, and M.C. Nussenzweig reported a patent to Broadly Neutralizing Antibodies to Tick-Borne Encephalitis and Related Viruses (US 63/118,461) pending. M.C. Nussenzweig reported personal fees from Celldex outside the submitted work. Additionally, M.C. Nussenzweig is a Frontier Bioscience SAB member. No other disclosures were reported.
Funding AgencyGrant Number
Swiss National Science Foundation (SNSF)UNSPECIFIED
Grantová Agentura České Republiky (GACR)20-14325S
Grantová Agentura České Republiky (GACR)20-30500S
Akademie věd České republikyMSM200962002
Ministerstvo zdravotnictví České republikyNV19-05-00457
Department of Energy (DOE)UNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Infectious disease and host defense
Issue or Number:5
PubMed Central ID:PMC8040517
Record Number:CaltechAUTHORS:20210415-152506780
Persistent URL:
Official Citation:Marianna Agudelo, Martin Palus, Jennifer R. Keeffe, Filippo Bianchini, Pavel Svoboda, Jiří Salát, Avery Peace, Anna Gazumyan, Melissa Cipolla, Tania Kapoor, Francesca Guidetti, Kai-Hui Yao, Jana Elsterová, Dana Teislerová, Aleš Chrdle, Václav Hönig, Thiago Oliveira, Anthony P. West, Yu E. Lee, Charles M. Rice, Margaret R. MacDonald, Pamela J. Bjorkman, Daniel Růžek, Davide F. Robbiani, Michel C. Nussenzweig; Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease. J Exp Med 3 May 2021; 218 (5): e20210236. doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108747
Deposited By: Tony Diaz
Deposited On:19 Apr 2021 16:43
Last Modified:02 Jun 2021 21:36

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