Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site

Masaru Kanekiyo; Wei Bu; M. Gordon Joyce; Geng Meng; James R.R. Whittle; Ulrich Baxa; Takuya Yamamoto; Sandeep Narpala; John Paul Todd; Srinivas S. Rao; Adrian B. McDermott; Richard A. Koup; Michael G. Rossmann; John R. Mascola; Barney S. Graham; Jeffrey I. Cohen; Gary J. Nabel

doi:10.1016/j.cell.2015.07.043

Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site

Masaru Kanekiyo, Wei Bu, M. Gordon Joyce, Geng Meng, James R.R. Whittle, Ulrich Baxa, Takuya Yamamoto, Sandeep Narpala, John Paul Todd, Srinivas S. Rao, Adrian B. McDermott, Richard A. Koup, Michael G. Rossmann, John R. Mascola, Barney S. Graham, Jeffrey I. Cohen, Gary J. Nabel

School of Medicine

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

Summary Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses.

Original language	English (US)
Pages (from-to)	1090-1100
Number of pages	11
Journal	Cell
Volume	162
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2015.07.043
State	Published - Aug 27 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Kanekiyo, M., Bu, W., Joyce, M. G., Meng, G., Whittle, J. R. R., Baxa, U., Yamamoto, T., Narpala, S., Todd, J. P., Rao, S. S., McDermott, A. B., Koup, R. A., Rossmann, M. G., Mascola, J. R., Graham, B. S., Cohen, J. I., & Nabel, G. J. (2015). Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site. Cell, 162(5), 1090-1100. https://doi.org/10.1016/j.cell.2015.07.043

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title = "Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site",

abstract = "Summary Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses.",

author = "Masaru Kanekiyo and Wei Bu and Joyce, {M. Gordon} and Geng Meng and Whittle, {James R.R.} and Ulrich Baxa and Takuya Yamamoto and Sandeep Narpala and Todd, {John Paul} and Rao, {Srinivas S.} and McDermott, {Adrian B.} and Koup, {Richard A.} and Rossmann, {Michael G.} and Mascola, {John R.} and Graham, {Barney S.} and Cohen, {Jeffrey I.} and Nabel, {Gary J.}",

note = "Funding Information: We thank B. Hartman (VRC) for help with manuscript preparation; S.-Y. Ko, H. Bao, C. Chiedi, M. Dillon, and K. Wuddie (VRC) for help with animal studies; K. Foulds and V. Letukas (VRC) for monkey sample processing; P. Radecki (LID) for help with serum analyses; A. Wheatley, S. Andrews, T. Zhou, and H. Yassine (VRC) for technical advice; Y. Okuno (Osaka University) for providing C179 antibody; and X. Chen (VRC) for help with transfections. This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. M.K., W.B., J.I.C., and G.J.N. are named as inventors on a patent application describing the data presented in this paper, which has been filed by the National Institutes of Health. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

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doi = "10.1016/j.cell.2015.07.043",

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AU - Kanekiyo, Masaru

AU - Bu, Wei

AU - Joyce, M. Gordon

AU - Meng, Geng

AU - Whittle, James R.R.

AU - Baxa, Ulrich

AU - Yamamoto, Takuya

AU - Narpala, Sandeep

AU - Todd, John Paul

AU - Rao, Srinivas S.

AU - McDermott, Adrian B.

AU - Koup, Richard A.

AU - Rossmann, Michael G.

AU - Mascola, John R.

AU - Graham, Barney S.

AU - Cohen, Jeffrey I.

AU - Nabel, Gary J.

N1 - Funding Information: We thank B. Hartman (VRC) for help with manuscript preparation; S.-Y. Ko, H. Bao, C. Chiedi, M. Dillon, and K. Wuddie (VRC) for help with animal studies; K. Foulds and V. Letukas (VRC) for monkey sample processing; P. Radecki (LID) for help with serum analyses; A. Wheatley, S. Andrews, T. Zhou, and H. Yassine (VRC) for technical advice; Y. Okuno (Osaka University) for providing C179 antibody; and X. Chen (VRC) for help with transfections. This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. M.K., W.B., J.I.C., and G.J.N. are named as inventors on a patent application describing the data presented in this paper, which has been filed by the National Institutes of Health. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/8/27

Y1 - 2015/8/27

N2 - Summary Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses.

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JO - Cell

JF - Cell

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ER -

Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site

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