Development and characterization of Epstein-Barr virus (EBV) antibodies and testing their efficacy in a humanized mouse model

Abstract

Epstein-Barr virus (EBV) is one of the most prevalent human viruses with more than 90% of the adult population infected with EBV. EBV is well-known to cause infectious mononucleosis, but also is associated with several B cell lymphomas and epithelial cell carcinomas. In bone marrow or solid organ transplant patients and individuals with X-linked lymphoproliferative disease, primary EBV infection can lead to life-threatening complications. There is no licensed vaccine and even if one is available, these immunocompromised individuals might not respond well to the vaccine. Thus, an effective vaccine and therapeutic are both needed. Here, I have evaluated the efficacy of (a) EBV hyperimmune globulin isolated from healthy plasma donors with high EBV gp350 antibody and EBV B cell neutralizing titers, (b) several EBV gp350, gH/gL and gp42 monoclonal antibodies (mAbs) isolated from human plasma or vaccinated monkeys, (c) a bispecific antibody targeting both gH/gL and gp42, and (d) gH/gL and gH/gL/gp42 nanoparticle vaccines in a humanized mouse model. Animals that received hyperimmune globulin showed protection from EBV infection at a similar level as that seen in animals receiving intravenous immunoglobulin. However, humanized mice that received gH/gL mAb B10 or gp42 mAb A10 showed increased survival and reduced viremia compared to animals that received other gH/gL or gp42 mAbs. These two mAbs also demonstrated protection from development of EBV B cell lymphomas in animals. Humanized mice that received bispecific antibody derived from gH/gL mAb B10 and gp42 mAb A10 showed similar protection against EBV as animals that received the combination of the two antibodies. Passive transfer of IgG isolated from mice immunized with a gH/gL or gH/gL/gp42 nanoparticle vaccine showed reduction in viremia and no development of EBV lymphomas compared to mice that received IgG from naïve mice. These findings suggest that development of vaccines or therapeutics targeting gH/gL and/or gp42 may provide protection in healthy individuals and severely immunocompromised individuals from EBV infection and B cell lymphoma.