Immunization with Epstein–Barr Virus Core Fusion Machinery Envelope Proteins Elicit High Titers of Neutralizing Activities and Protect Humanized Mice from Lethal Dose EBV Challenge

Xinle Cui,Zhouhong Cao,Yuriko Ishikawa,Clifford M Snapper,Ken-Ichi Imadome,Sara Cui

doi:10.3390/vaccines9030285

Abstract

Epstein–Barr virus (EBV) is the primary cause of infectious mononucleosis and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. EBV core fusion machinery envelope proteins gH/gL and gB coordinately mediate EBV fusion and entry into its target cells, B lymphocytes and epithelial cells, suggesting these proteins could induce antibodies that prevent EBV infection. We previously reported that the immunization of rabbits with recombinant EBV gH/gL or trimeric gB each induced markedly higher serum EBV-neutralizing titers for B lymphocytes than that of the leading EBV vaccine candidate gp350. In this study, we demonstrated that immunization of rabbits with EBV core fusion machinery proteins induced high titer EBV neutralizing antibodies for both B lymphocytes and epithelial cells, and EBV gH/gL in combination with EBV trimeric gB elicited strong synergistic EBV neutralizing activities. Furthermore, the immune sera from rabbits immunized with EBV gH/gL or trimeric gB demonstrated strong passive immune protection of humanized mice from lethal dose EBV challenge, partially or completely prevented death respectively, and markedly decreased the EBV load in peripheral blood of humanized mice. These data strongly suggest the combination of EBV core fusion machinery envelope proteins gH/gL and trimeric gB is a promising EBV prophylactic vaccine.

Highlights

Epstein–Barr virus (EBV) is a gamma human herpesvirus that primarily infects B cells and epithelial cells
EBV is the first human tumor virus discovered, and it has been strongly implicated in the etiology of multiple lymphoid and epithelial cancers, such as Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, nasopharyngeal carcinoma, and gastric carcinoma [8,9,10,11]
Induced by immunization with compared to the immune sera from rabbits immunized with EBV gH/gL or trimeric gB

Summary

Introduction

Epstein–Barr virus (EBV) is a gamma human herpesvirus that primarily infects B cells and epithelial cells. EBV is the primary cause of infectious mononucleosis [1,2]. ~125,000 new cases of infectious mononucleosis each year in the United States, and it is the most common cause of lost time for new army recruits [3,4,5]. EBV is the first human tumor virus discovered, and it has been strongly implicated in the etiology of multiple lymphoid and epithelial cancers, such as Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, post-transplant lymphoproliferative disorder, nasopharyngeal carcinoma, and gastric carcinoma [8,9,10,11]. EBV-associated cancers account for over 200,000 new cases of cancer and cause

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Conclusion