Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein

Arthur S. Kim, S. Kyle Austin, Christina L. Gardner, Adam Zuiani, Douglas S. Reed, Derek W. Trobaugh, Chengqun Sun, Katherine Basore, Lauren E. Williamson, James E. Crowe, Mark Slifka, Daved H. Fremont, William B. Klimstra, Michael S. Diamond

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high case mortality rate in humans. EEEV is a biodefence concern because of its potential for aerosol spread and the lack of existing countermeasures. Here, we identify a panel of 18 neutralizing murine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein, several of which have ‘elite’ activity with 50 and 99% effective inhibitory concentrations (EC50 and EC99) of less than 10 and 100 ng ml−1, respectively. Alanine-scanning mutagenesis and neutralization escape mapping analysis revealed epitopes for these mAbs in domains A or B of the E2 glycoprotein. A majority of the neutralizing mAbs blocked infection at a post-attachment stage, with several inhibiting viral membrane fusion. Administration of one dose of anti-EEEV mAb protected mice from lethal subcutaneous or aerosol challenge. These experiments define the mechanistic basis for neutralization by protective anti-EEEV mAbs and suggest a path forward for treatment and vaccine design.

    Original languageEnglish (US)
    JournalNature Microbiology
    DOIs
    StateAccepted/In press - Jan 1 2018

    Fingerprint

    Eastern equine encephalitis virus
    Epitopes
    Glycoproteins
    Monoclonal Antibodies
    Antibodies
    Aerosols
    Alphavirus
    Virus Internalization
    Neutralizing Antibodies
    Culicidae
    Mutagenesis
    Alanine
    Vaccines
    Mortality
    Infection

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Applied Microbiology and Biotechnology
    • Genetics
    • Microbiology (medical)
    • Cell Biology

    Cite this

    Kim, A. S., Austin, S. K., Gardner, C. L., Zuiani, A., Reed, D. S., Trobaugh, D. W., ... Diamond, M. S. (Accepted/In press). Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. Nature Microbiology. https://doi.org/10.1038/s41564-018-0286-4

    Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. / Kim, Arthur S.; Austin, S. Kyle; Gardner, Christina L.; Zuiani, Adam; Reed, Douglas S.; Trobaugh, Derek W.; Sun, Chengqun; Basore, Katherine; Williamson, Lauren E.; Crowe, James E.; Slifka, Mark; Fremont, Daved H.; Klimstra, William B.; Diamond, Michael S.

    In: Nature Microbiology, 01.01.2018.

    Research output: Contribution to journalArticle

    Kim, AS, Austin, SK, Gardner, CL, Zuiani, A, Reed, DS, Trobaugh, DW, Sun, C, Basore, K, Williamson, LE, Crowe, JE, Slifka, M, Fremont, DH, Klimstra, WB & Diamond, MS 2018, 'Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein', Nature Microbiology. https://doi.org/10.1038/s41564-018-0286-4
    Kim, Arthur S. ; Austin, S. Kyle ; Gardner, Christina L. ; Zuiani, Adam ; Reed, Douglas S. ; Trobaugh, Derek W. ; Sun, Chengqun ; Basore, Katherine ; Williamson, Lauren E. ; Crowe, James E. ; Slifka, Mark ; Fremont, Daved H. ; Klimstra, William B. ; Diamond, Michael S. / Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. In: Nature Microbiology. 2018.
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    abstract = "Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high case mortality rate in humans. EEEV is a biodefence concern because of its potential for aerosol spread and the lack of existing countermeasures. Here, we identify a panel of 18 neutralizing murine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein, several of which have ‘elite’ activity with 50 and 99{\%} effective inhibitory concentrations (EC50 and EC99) of less than 10 and 100 ng ml−1, respectively. Alanine-scanning mutagenesis and neutralization escape mapping analysis revealed epitopes for these mAbs in domains A or B of the E2 glycoprotein. A majority of the neutralizing mAbs blocked infection at a post-attachment stage, with several inhibiting viral membrane fusion. Administration of one dose of anti-EEEV mAb protected mice from lethal subcutaneous or aerosol challenge. These experiments define the mechanistic basis for neutralization by protective anti-EEEV mAbs and suggest a path forward for treatment and vaccine design.",
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