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.
Highlights
Epstein-Barr virus (EBV) is an oncogenic human herpesvirus [1]
It was demonstrated that the ability to form virus-like particle (VLP) is preserved when the ED of F is substituted with an ED derived from unrelated viral envelope type 1 proteins as long as the TM and CT of F remain intact [35]
To assess whether the expressed chimera appropriately localized to the plasma membrane, pCAGGS-EBVgp350/220-F and pCAGGS-EBVgp350/220 WT plasmids were individually transfected into cell lines from four different species (CHO, ELL-0, Vero and 293A)
Summary
Epstein-Barr virus (EBV) is an oncogenic human herpesvirus [1]. By adulthood, EBV has infected >95% of the global population. EBV persists for life due to a complex life cycle consisting of alternate latent and lytic phases [1]. Primary EBV infection typically occurs during early childhood and is asymptomatic. EBV+ Burkitt’s lymphoma [1,2]. AIM is normally self-limited, illness can be prolonged. Catastrophic sequelae such as splenic rupture and hemophagocytosis may be life threatening, and AIM increases the risk of developing EBV+ Hodgkin lymphoma [1,2]. Lytic EBV replication is limited and the pool of latently infected cells remains stable [5]. Under conditions of immunosuppression, replication can accelerate, leading to expansion of EBV-infected cells
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