A Pentavalent Epstein-Barr Virus-Like Particle Vaccine Elicits High Titers of Neutralizing Antibodies against Epstein-Barr Virus Infection in Immunized Rabbits

Abstract

Primary infection with Epstein-Barr virus (EBV) is associated with acute infectious mononucleosis, whereas persistent infection is associated with chronic diseases such as autoimmune diseases and various types of cancer. Indeed, approximately 2% of all new cancer cases occurring annually worldwide are EBV-associated. Currently, there is no licensed EBV prophylactic vaccine. Selection of appropriate viral protein subunits is critical for development of an effective vaccine. Although the major EBV surface glycoprotein gp350/220 (gp350) has been proposed as an important prophylactic vaccine target, attempts to develop a potent vaccine based on gp350 alone have shown limited success in the clinic. We provide data showing that five EBV glycoproteins (gp350, gB, gp42, gH, and gL) involved in viral entry and infection can successfully be incorporated on the surface of EBV-like particles (EBV-LPs). These EBV-LPs, when administered together with aluminum hydroxide and monophosphoryl lipid A as adjuvants to New Zealand white rabbits, elicited EBV glycoprotein-specific antibodies capable of neutralizing viral infection in vitro in both B cells and epithelial cells, better than soluble gp350 ectodomain. Our findings suggest that a pentavalent EBV-LP formulation might be an ideal candidate for development as a safe and immunogenic EBV vaccine.

A bivalent EBV vaccine induces neutralizing antibodies that block B and epithelial cell infection and confer immunity in humanized mice

“…An effective vaccine could reduce the burden of a variety of diseases associated with EBV infection, including infectious mononucleosis and a wide range of B cell and epithelial cell cancers. A previous phase 2 trial with an EBV gp350 vaccine reduced rate of infectious mononucleosis, but failed to induce sterilizing immunity in clinic (10), suggesting that additional immunogens that target viral entry to epithelial cells may be required for a successful prophylactic vaccine (15,22). While EBV gp350 is important for attachment of the virus to B cells, it is not required for infection in vitro; in contrast, EBV gH, gL and gp42 are all essential for infection and EBV fusion to host cells.…”

The Status and Prospects of Epstein–Barr Virus Prophylactic Vaccine Development

“…A humanized mouse model was also used to evaluate the protective efficacy of AMMO1 (63), and the results showed that the AMMO1 antibody could inhibit EBV infection. Some studies also used rabbits as animal models for EBV vaccine evaluation (22,27,28,51,56,155,156). The anti-EBV VCA titer and EBV DNA level could be detected in the blood of most rabbits after intravenous, intranasal, or peroral inoculation.…”

“…However, the possibility of repacking of EBV DNA would bring safety concerns to such designs. In addition to the construction of VLPs based on EBV itself, a Newcastle disease virus-like particle (ND VLP) platform was also used for the presentation of EBV antigens such as gp350/gp220, combinations of gHgL-EBNA1 or gB/LMP2, and even pentavalent gp350/gH/gL/gp42/gB ( 47 , 56 ). It may be easier to produce VLPs by additional co-transfection of NDV-F for particle assembly, benefiting the rapid development of safe VLP vaccines.…”

Main Targets of Interest for the Development of a Prophylactic or Therapeutic Epstein-Barr Virus Vaccine

“… Optimization of prophylactic vaccine strategies. 1a, Cui et al, 2013 ; 1b, Kanekiyo et al, 2015 ; 1c, Zhao et al, 2018 ; 1d, Zhang et al, 2020 ; 1e, Kang et al, 2021 ; 2a,2b, Cui et al, 2016 ; 2c, Cui et al, 2021 ; 2d, Bu et al, 2019 ; 2e, Escalante et al, 2020 ; 3, Elliott et al, 2008 ; 4a,4b, Perez et al, 2017 ; 4c, van Zyl et al, 2018 . …”

“…This pentavalent (5-in-1) vaccine stimulated production of antibodies specific to the five glycoproteins capable of neutralizing EBV infection of the B cells as well as the epithelial cells. The IgG anti-gp350/220 and anti-gB levels were markedly higher than the IgG anti-gp42 and anti-gH/gL levels ( Escalante et al, 2020 ).…”