TY - JOUR
T1 - Neutralizing antibodies protect mice against Venezuelan equine encephalitis virus aerosol challenge
AU - Kafai, Natasha M.
AU - Williamson, Lauren E.
AU - Binshtein, Elad
AU - Sukupolvi-Petty, Soila
AU - Gardner, Christina L.
AU - Liu, Jaclyn
AU - Mackin, Samantha
AU - Kim, Arthur S.
AU - Kose, Nurgun
AU - Carnahan, Robert H.
AU - Jung, Ana
AU - Droit, Lindsay
AU - Reed, Douglas S.
AU - Handley, Scott A.
AU - Klimstra, William B.
AU - Crowe, James E.
AU - Diamond, Michael S.
N1 - Funding Information:
This study was supported by National Institutes of Health grants R01 AI095436 (W.B. Klimstra), U19 AI142790 (J.E. Crowe and M.S. Diamond), T32 AI007172 (N.M. Kafai), T32 HL069765 (L.E. Williamson), F31 AI145189 (L.E. Williamson), and U01 AI151810 (M.S. Diamond, S.A. Handley); the Defense Threat Reduction Agency grants HDTRA1-15-1-0013 (M.S. Diamond, W.B. Klimstra, and D.S. Reed) and HDTRA1-13-1-0034 (J.E. Crowe); and the 2019 Future Insight Prize from Merck (J.E. Crowe). Data collection was performed at the Stanford-SLAC National Accelerator Laboratory Cryo-EM Center (S2C2) supported by the National Institutes of Health Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129541).
Funding Information:
Disclosures: M.S. Diamond is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Washington University has licensed murine anti-VEEV mAbs, and M.S. Diamond, S. Sukupolvi-Petty, and N.M. Kafai are inventors. J.E. Crowe has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Boards of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory has received unrelated sponsored research agreements from Takeda, AstraZeneca, and IDBiologics. J.E. Crowe reported grants from NIH during the conduct of the study and from GSK and Merck and grants from IDBiologics outside the submitted work; in addition, J. Crowe had a patent app for human antibodies for VEEV pending. The Klimstra laboratory has received unrelated research support from SAB Biotherapeutics and Tiba Biotechnology. The other authors have no additional conflicts of interest to declare. No other disclosures were reported.
Publisher Copyright:
© 2022 Kafai et al.
PY - 2022/4/4
Y1 - 2022/4/4
N2 - Venezuelan equine encephalitis virus (VEEV) remains a risk for epidemic emergence or use as an aerosolized bioweapon. To develop possible countermeasures, we isolated VEEV-specific neutralizing monoclonal antibodies (mAbs) from mice and a human immunized with attenuated VEEV strains. Functional assays and epitope mapping established that potently inhibitory anti-VEEV mAbs bind distinct antigenic sites in the A or B domains of the E2 glycoprotein and block multiple steps in the viral replication cycle including attachment, fusion, and egress. A 3.2-Å cryo-electron microscopy reconstruction of VEEV virus-like particles bound by a human Fab suggests that antibody engagement of the B domain may result in cross-linking of neighboring spikes to prevent conformational requirements for viral fusion. Prophylaxis or postexposure therapy with these mAbs protected mice against lethal aerosol challenge with VEEV. Our study defines functional and structural mechanisms of mAb protection and suggests that multiple antigenic determinants on VEEV can be targeted for vaccine or antibody-based therapeutic development.
AB - Venezuelan equine encephalitis virus (VEEV) remains a risk for epidemic emergence or use as an aerosolized bioweapon. To develop possible countermeasures, we isolated VEEV-specific neutralizing monoclonal antibodies (mAbs) from mice and a human immunized with attenuated VEEV strains. Functional assays and epitope mapping established that potently inhibitory anti-VEEV mAbs bind distinct antigenic sites in the A or B domains of the E2 glycoprotein and block multiple steps in the viral replication cycle including attachment, fusion, and egress. A 3.2-Å cryo-electron microscopy reconstruction of VEEV virus-like particles bound by a human Fab suggests that antibody engagement of the B domain may result in cross-linking of neighboring spikes to prevent conformational requirements for viral fusion. Prophylaxis or postexposure therapy with these mAbs protected mice against lethal aerosol challenge with VEEV. Our study defines functional and structural mechanisms of mAb protection and suggests that multiple antigenic determinants on VEEV can be targeted for vaccine or antibody-based therapeutic development.
UR - http://www.scopus.com/inward/record.url?scp=85126723728&partnerID=8YFLogxK
U2 - 10.1084/jem.20212532
DO - 10.1084/jem.20212532
M3 - Article
C2 - 35297953
AN - SCOPUS:85126723728
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
M1 - e20212532
ER -