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.

Expression and immunogenic characterization of recombinant gp350 for developing a subunit vaccine against Epstein-Barr virus

“…It has been reported that gp350 DNA vaccine induced effective immune responses against the antigen, and the major isotype of the gp350-specific antibodies was IgG1 (Jung et al 2001). The chimeric gp350 virus-like particles also induced a dominant IgG1 subclass response (Ogembo et al 2015). In the present study, the recombinant gp350 1-443 induced significant IgG1 and IgG2a antibody responses, demonstrating that gp350 1-443 elicited a systemic Th1/Th2 immune response.…”

“…Options for developing safe prophylactic EBV vaccines have been limited due to the oncogenic potential of EBV (Ogembo et al 2015). As the most abundant glycoprotein on the surface of EBV and virus-infected cells, gp350 is an attractive candidate for development of a prophylactic subunit vaccine.…”

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Presently, there is no available vaccine to protect against EBV infection. One possible approach to developing such a vaccine would be to target gp350 or other viral proteins [73]. A small trial evaluating a vaccine against EBV showed limited results in MS [74].…”

Novel Epstein-Barr virus-like particles incorporating gH/gL-EBNA1 or gB-LMP2 induce high neutralizing antibody titers and EBV-specific T-cell responses in immunized mice

“…Flow cytometric analysis was performed on an LSRII benchtop FC (Becton-Dickinson, B-D) and data was analyzed using CellQuest Pro Version 4.0.1 (BD Biosciences) and/or FlowJo Cytometry Analysis software (FlowJo, LLC) as described [20]. All the experiments were independently repeated at least three times unless otherwise specified.…”