Although Powassan virus (POWV) is an emerging tick-transmitted flavivirus that causes severe or fatal neuroinvasive disease in humans, medical countermeasures have not yet been developed. Here, we developed a panel of neutralizing anti-POWV mAbs recognizing six distinct antigenic sites. The most potent of these mAbs bind sites within domain II or III of the envelope (E) protein and inhibit postattachment viral entry steps. A subset of these mAbs cross-react with other flaviviruses. Both POWV type–specific and cross-reactive neutralizing mAbs confer protection in mice against POWV infection when given as prophylaxis or postexposure therapy. Several cross-reactive mAbs mapping to either domain II or III also protect in vivo against heterologous tick-transmitted flaviviruses including Langat and tick-borne encephalitis virus. Our experiments define structural and functional correlates of antibody protection against POWV infection and identify epitopes targeted by broadly neutralizing antibodies with therapeutic potential against multiple tick-borne flaviviruses.
Broadly neutralizing monoclonal antibodies protect against multiple tick-borne flaviviruses
Disclosures: S. Himansu reported a patent to Moderna issued. M.L. Gross reported other from ProteinMetrics outside the submitted work, and serves as an unpaid member of the scientific advisory boards of ProteinMetrics, a software company specializing in structural mass spectrometry, and GenNext, a startup seeking to commercialize protein footprinting for biotechnology. D.H. Fremont reported grants from Emergent BioSolutions, other from Abbvie, and other from Courier Therapeutics outside the submitted work. M.S. Diamond reported personal fees from Inbios, personal fees from Vir Biotechnology, personal fees from NGM Biopharmaceuticals, personal fees from Carnival Corporation, grants from Vir Biotechnology, grants from Emergent BioSolutions, grants from Moderna, other from Moderna, and other from Immunome during the conduct of the study. No other disclosures were reported.
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Laura A. VanBlargan, John M. Errico, Natasha M. Kafai, Katherine E. Burgomaster, Prashant N. Jethva, Rebecca M. Broeckel, Kimberly Meade-White, Christopher A. Nelson, Sunny Himansu, David Wang, Scott A. Handley, Michael L. Gross, Sonja M. Best, Theodore C. Pierson, Daved H. Fremont, Michael S. Diamond; Broadly neutralizing monoclonal antibodies protect against multiple tick-borne flaviviruses. J Exp Med 3 May 2021; 218 (5): e20210174. doi: https://doi.org/10.1084/jem.20210174
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