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

• Published in: Cell Vol. 162; no. 5; pp. 1090 - 1100
• Main Authors: Kanekiyo, Masaru, Bu, Wei, Joyce, M. Gordon, Meng, Geng, Whittle, James R.R., Baxa, Ulrich, Yamamoto, Takuya, Narpala, Sandeep, Todd, John-Paul, Rao, Srinivas S., McDermott, Adrian B., Koup, Richard A., Rossmann, Michael G., Mascola, John R., Graham, Barney S., Cohen, Jeffrey I., Nabel, Gary J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.08.2015
• Subjects: Animals; Antibodies, Neutralizing - immunology; Crystallography, X-Ray; Drug Design; Female; Herpesvirus 4, Human; Herpesvirus Vaccines - chemistry; Herpesvirus Vaccines - genetics; Herpesvirus Vaccines - immunology; Herpesvirus Vaccines - isolation & purification; Macaca fascicularis; Mice; Mice, Inbred BALB C; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Receptors, Complement 3d - chemistry; Receptors, Complement 3d - immunology; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - isolation & purification
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.07.043

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. [Display omitted] [Display omitted] •Self-assembling nanoparticles present the conserved gp350 receptor-binding domain•The nanoparticles elicit more potent neutralizing antibodies than soluble gp350•These neutralizing antibodies predominantly target the CR2-binding site on gp350•The nanoparticles elicit potent neutralizing antibodies in mice and non-human primates Structurally designed EBV vaccine candidates based on self-assembling nanoparticles elicit potent and durable virus-neutralizing antibodies that target the receptor-binding site on the viral envelope protein gp350, a site of vulnerability, serving as a template to develop an EBV vaccine and providing a basis for immunofocusing through rational vaccine design.