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    High-Definition Mapping of Four Spatially Distinct Neutralizing Epitope Clusters on RiVax, a Candidate Ricin Toxin Subunit Vaccine

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    Issue Date
    2017-10-18
    Author
    Toth, Ronald T., IV
    Angalakurthi, Siva Krishna
    Van Slyke, Greta
    Vance, David J.
    Hickey, John M.
    Josh, Sangeeta B.
    Middaugh, C. Russell
    Volkin, David B.
    Weis, David D.
    Mantis, Nicholas J.
    Publisher
    American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Rights
    © 2017 American Society for Microbiology. All Rights Reserved.
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    Abstract
    RiVax is a promising recombinant ricin toxin A subunit (RTA) vaccine antigen that has been shown to be safe and immunogenic in humans and effective at protecting rhesus macaques against lethal-dose aerosolized toxin exposure. We previously used a panel of RTA-specific monoclonal antibodies (MAbs) to demonstrate, by competition enzyme-linked immunosorbent assay (ELISA), that RiVax elicits similar serum antibody profiles in humans and macaques. However, the MAb binding sites on RiVax have yet to be defined. In this study, we employed hydrogen exchange-mass spectrometry (HX-MS) to localize the epitopes on RiVax recognized by nine toxin-neutralizing MAbs and one nonneutralizing MAb. Based on strong protection from hydrogen exchange, the nine MAbs grouped into four spatially distinct epitope clusters (namely, clusters I to IV). Cluster I MAbs protected RiVax's α-helix B (residues 94 to 107), a protruding immunodominant secondary structure element known to be a target of potent toxin-neutralizing antibodies. Cluster II consisted of two subclusters located on the “back side” (relative to the active site pocket) of RiVax. One subcluster involved α-helix A (residues 14 to 24) and α-helices F-G (residues 184 to 207); the other encompassed β-strand d (residues 62 to 69) and parts of α-helices D-E (154 to 164) and the intervening loop. Cluster III involved α-helices C and G on the front side of RiVax, while cluster IV formed a sash from the front to back of RiVax, spanning strands b, c, and d (residues 35 to 59). Having a high-resolution B cell epitope map of RiVax will enable the development and optimization of competitive serum profiling assays to examine vaccine-induced antibody responses across species.
    URI
    http://hdl.handle.net/1808/27395
    DOI
    https://doi.org/10.1128/CVI.00237-17
    Collections
    • Chemistry Scholarly Works [587]
    Citation
    Toth RT, IV, Angalakurthi SK, Van Slyke G, Vance DJ, Hickey JM, Joshi SB, Middaugh CR, Volkin DB, Weis DD, Mantis NJ. 2017. Highdefinition mapping of four spatially distinct neutralizing epitope clusters on RiVax, a candidate ricin toxin subunit vaccine. Clin Vaccine Immunol 24:e00237-17. https://doi.org/10.1128/CVI.00237-17.

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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