Herpesvirus Pathogenesis and Vaccine Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Over 90% of adults are infected with EBV. Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with a number of B cell and epithelial cell cancers including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. EBV is also associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Human cytomegalovirus (HCMV) infects over half of the human population and is the most common infectious cause of birth defects. At present there are no licensed vaccines for either EBV or HCMV and hyperimmune globulin to HCMV has been of limited usefulness for prophylaxis or therapy of HCMV infections, while no such antibody product exists for EBV. Previously we designed a nanoparticle vaccines EBV glycoprotein 350 (gp350) or EBV glycoprotein H (gH), glycoprotein L (gL), and glycoprotein 42 (gp42) as a heterotrimer fused to bacterial ferritin to form a self-assembling nanoparticle. These vaccines elicited neutralizing antibodies in mice and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. We have a phase 1 trial of our EBV gp350 nanoparticle vaccine currently being completed at the NIH Clinical Center and a phase 1/2 trial of the same vaccine being tested at both the NIH Clinical Center and the University of Minnesota. Recently, we started a phase 1 trial of our EBV gH/gL/gp42 nanoparticle vaccine either alone or in combination with gp350 nanoparticles. We have also developed monoclonal antibodies to several EBV glycoproteins and have shown that some of them can protect humanized mice from viremia and EBV lymphomas after they are challenged with EBV. More recently, we have we determined the structure of gp350 in complex with its cellular receptor, CR2, at high resolution. CR2 binding of gp350 uses the same set of arginine residues required for recognition of its natural ligand, complement component C3d. In addition, we isolated several potent neutralizing antibodies to gp350 from humans and nonhuman primates and determined the structures of gp350 in complex with three neutralizing antibodies. Like the CR2 interaction, these neutralizing antibodies targeted an acidic region in the CR2-binding site on gp350 using arginine residues. These results suggest that these neutralizing antibodies might be useful as therapeutics to prevent EBV disease.