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    Identification and characterization of human monoclonal antibodies for immunoprophylaxis against enterotoxigenic Escherichia coli infection

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    Author
    Giuntini, Serena
    Stoppato, Matteo
    Barry, Eileen M.
    Date
    2018-08-01
    Journal
    Infection and Immunity
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.1128/IAI.00355-18
    https://www.doi.org/10.1128/IAI.00713-18
    Abstract
    Enterotoxigenic Escherichia coli (ETEC) causes diarrheal illness in infants in the developing world and travelers to countries where the disease is endemic, including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion, leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC infection. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have the potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea. Mice transgenic for human immunoglobulin genes were immunized with CfaE to generate a panel of human monoclonal IgG1 antibodies (HuMAbs). The most potent IgG1 antibodies identified in the in vitro functional assays were selected and isotype switched to secretory IgA (sIgA) and tested in animal colonization assays via oral administration. Over 300 unique anti-CfaE IgG1 HuMAbs were identified. The lead IgG1 anti-CfaE HuMAbs completely inhibited hemagglutination and blocked adhesion of ETEC to Caco-2 cells. Epitope mapping studies revealed that HuMAbs recognized epitopes in the N-terminal domain of CfaE near the putative receptor binding site. Oral administration of anti-CfaE antibodies in either IgG or sIgA isotypes inhibited intestinal colonization in mice challenged with ETEC. A 2- to 4-log decrease in CFU was observed in comparison to mice challenged with irrelevant isotype controls. We identified fully human monoclonal antibodies against the CfaE adhesion domain that can be potentially employed as an immunoprophylactic to prevent ETEC-related diarrhea.
    Description
    Correction for this article is at https://www.doi.org/10.1128/IAI.00713-18
    Sponsors
    This work was supported by the Defense Advanced Research Project Agency (DARPA-BAA-13-03) and the Bill & Melinda Gates Foundation (OPP1173647).
    Keyword
    Adhesins
    CfaE
    ETEC
    Fimbriae
    HuMAb
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054936549&origin=inward; http://hdl.handle.net/10713/9860
    ae974a485f413a2113503eed53cd6c53
    10.1128/IAI.00355-18
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