Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.
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.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Masaru
M
Kanekiyo
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Wei
W
Bu
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
M Gordon
MG
Joyce
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Geng
G
Meng
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
James R R
JR
Whittle
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Ulrich
U
Baxa
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Takuya
T
Yamamoto
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sandeep
S
Narpala
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
John-Paul
JP
Todd
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Srinivas S
SS
Rao
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Adrian B
AB
McDermott
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Richard A
RA
Koup
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Michael G
MG
Rossmann
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
John R
JR
Mascola
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Barney S
BS
Graham
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jcohen@niaid.nih.gov.
Jeffrey I
JI
Cohen
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gary.nabel@sanofi.com.
Gary J
GJ
Nabel
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D004854:Herpesvirus 4, Human; D022283:Herpesvirus Vaccines / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D017464:Receptors, Complement 3d / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
D057134:Antibodies, Neutralizing; D022283:Herpesvirus Vaccines; D017464:Receptors, Complement 3d; D011994:Recombinant Proteins