title: A chimeric EBV gp350/220-based VLP replicates the virion B-cell attachment mechanism and elicits long-lasting neutralizing antibodies in mice.
abstract: Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, causes acute infectious mononucleosis (AIM) and is linked to the development of several human malignancies. There is an urgent need for a vaccine that is safe, prevents infection and/or limits disease. Unique among human herpesviruses, glycoprotein (gp)350/220, which initiates EBV attachment to susceptible host cells, is the major ligand on the EBV envelope and is highly conserved. Interaction between gp350/220 and complement receptor type 2 (CR2)/CD21 and/or (CR1)/CD35 on B-cells is required for infection. Potent antibody responses to gp350/220 occur in animal models and humans. Thus, gp350/220 provides an attractive candidate for prophylactic subunit vaccine development. However, in a recent Phase II clinical trial immunization with soluble recombinant gp350 reduced the incidence of AIM, but did not prevent infection. Despite various attempts to produce an EBV vaccine, no vaccine is licensed. Herein we describe a sub-unit vaccine against EBV based on a novel Newcastle disease virus (NDV)-virus-like particle (VLP) platform consisting of EBVgp350/220 ectodomain fused to NDV-fusion (F) protein. The chimeric protein EBVgp350/220-F is incorporated into the membrane of a VLP composed of the NDV matrix and nucleoprotein. The particles resemble native EBV in diameter and shape and bind CD21 and CD35. Immunization of BALB/c mice with EBVgp350/220-F VLPs elicited strong, long-lasting neutralizing antibody responses when assessed in vitro. This chimeric VLP is predicted to provide a superior safety profile as it is efficiently produced in Chinese hamster ovary (CHO) cells using a platform devoid of human nucleic acid and EBV-transforming genes.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester, MA, 01605, USA. javier.ogembo@umassmed.edu.
authors.forename: Javier Gordon
authors.initials: JG
authors.lastname: Ogembo
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK. mrmurawsk@gmail.com.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Muraswki
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA. lori.mcginnes@umassmed.edu.
authors.forename: Lori W
authors.initials: LW
authors.lastname: McGinnes
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK. agapi.parcharidou@bedfordhospital.nhs.uk.
authors.forename: Agapi
authors.initials: A
authors.lastname: Parcharidou
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester, MA, 01605, USA. rujapak.sutiwisesak@umassmed.edu.
authors.forename: Rujapak
authors.initials: R
authors.lastname: Sutiwisesak
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester, MA, 01605, USA. timelia.tison@umassmed.edu.
authors.forename: Timelia
authors.initials: T
authors.lastname: Tison
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK. juanmanuelavendano@icloud.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Avendano
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK. dagnani@gmail.com.
authors.forename: Deep
authors.initials: D
authors.lastname: Agnani
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester, MA, 01605, USA. robert.finberg@umassmed.edu.|Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA. robert.finberg@umassmed.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA. trudy.morrison@umassmed.edu.|Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA. trudy.morrison@umassmed.edu.
authors.forename: Trudy G
authors.initials: TG
authors.lastname: Morrison
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester, MA, 01605, USA. joyce.fingeroth@umassmed.edu.|Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK. joyce.fingeroth@umassmed.edu.|Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA. joyce.fingeroth@umassmed.edu.
authors.forename: Joyce D
authors.initials: JD
authors.lastname: Fingeroth
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis*; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology*; D002448:Cell Adhesion; D002460:Cell Line; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000276:immunology*; D014771:Virion / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins