Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease
- Creators
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Agudelo, Marianna
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Palus, Martin
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Keeffe, Jennifer R.
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Bianchini, Filippo
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Svoboda, Pavel
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Salát, Jiří
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Peace, Avery
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Gazumyan, Anna
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Cipolla, Melissa
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Kapoor, Tania
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Guidetti, Francesca
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Yao, Kai-Hui
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Elsterová, Jana
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Teislerová, Dana
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Chrdle, Aleš
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Hönig, Václav
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Oliveira, Thiago
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West, Anthony P.
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Lee, Yu E.
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Rice, Charles M.
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MacDonald, Margaret R.
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Bjorkman, Pamela J.
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Růžek, Daniel
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Robbiani, Davide F.
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Nussenzweig, Michel C.
Abstract
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.
Additional Information
© 2021 Agudelo et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). 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.Attached Files
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Supplemental Material - jem_20210236_tables1.xlsx
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Supplemental Material - jem_20210236_tables6.docx
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Additional details
- PMCID
- PMC8040517
- Eprint ID
- 108747
- Resolver ID
- CaltechAUTHORS:20210415-152506780
- NIH
- U19AI111825
- Swiss National Science Foundation (SNSF)
- NIH
- R01AI037526
- NIH
- UM1AI100663
- NIH
- U19AI111825
- NIH
- UL1TR001866
- NIH
- P01AI138938
- NIH
- R01AI124690
- NIH
- U19AI057229
- Grantová Agentura České Republiky (GACR)
- 20-14325S
- Grantová Agentura České Republiky (GACR)
- 20-30500S
- Akademie věd České republiky
- MSM200962002
- Ministerstvo zdravotnictví České republiky
- NV19-05-00457
- Department of Energy (DOE)
- Howard Hughes Medical Institute (HHMI)
- Created
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2021-04-19Created from EPrint's datestamp field
- Updated
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2021-06-02Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering (BBE)