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 K. Slifka; Daved H. Fremont; William B. Klimstra; Michael S. Diamond

doi: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

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 K. Slifka, Daved H. Fremont, William B. Klimstra, Michael S. Diamond

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30 Scopus citations

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 language	English (US)
Pages (from-to)	187-197
Number of pages	11
Journal	Nature Microbiology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s41564-018-0286-4
State	Published - Jan 1 2019

ASJC Scopus subject areas

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

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Kim, A. S., Austin, S. K., Gardner, C. L., Zuiani, A., Reed, D. S., Trobaugh, D. W., Sun, C., Basore, K., Williamson, L. E., Crowe, J. E., Slifka, M. K., Fremont, D. H., Klimstra, W. B., & Diamond, M. S. (2019). Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. Nature Microbiology, 4(1), 187-197. https://doi.org/10.1038/s41564-018-0286-4

Kim, AS, Austin, SK, Gardner, CL, Zuiani, A, Reed, DS, Trobaugh, DW, Sun, C, Basore, K, Williamson, LE, Crowe, JE, Slifka, MK, Fremont, DH, Klimstra, WB & Diamond, MS 2019, 'Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein', Nature Microbiology, vol. 4, no. 1, pp. 187-197. https://doi.org/10.1038/s41564-018-0286-4

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

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 {\textquoteleft}elite{\textquoteright} 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.",

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

note = "Funding Information: This work was supported by the Defense Threat Reduction Agency (grant no. HDTRA1-15-1-0013 to M.S.D. and W.B.K. and grant no. HDTRA1-13-1-0034 to J.E.C) and National Institutes of Health grant no. R01 AI095436 to W.B.K. Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature Limited.",

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AU - Reed, Douglas S.

AU - Trobaugh, Derek W.

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AU - Slifka, Mark K.

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AU - Klimstra, William B.

AU - Diamond, Michael S.

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N2 - 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.

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

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