Herpesvirus Pathogenesis and Vaccine Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with a number of cancers including Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. EBV infects B cells and 95% of adults are infected. Human cytomegalovirus (HCMV) infects over half of the human population and is the most common infectious cause of birth defects. The virus is the most important infection occurring in transplant recipients. A human cytomegalovirus (HCMV) vaccine to prevent infection and/or reduce disease associated with congenital infection or visceral disease in transplant recipients is a high priority, but has remained elusive. An effective EBV vaccine is not available. The virus primarily infects B cells in the blood, where it establishes latency, and epithelial cells in the oropharynx where the virus replicates and is shed. The virus expresses several glycoproteins including gp350 which is important for attachment of the virus to B cells, gp42 which is required for the virus to fuse to B cells, and the gH/gL complex which is necessary for the virus to fuse to B cells and epithelial cells. We found that antibodies to EBV gp350 are the major components in human plasma that prevent EBV infection of B cells. Antibodies in plasma to EBV gH/gL and gp42 also prevent virus infection of B cells. Antibodies to EBV gH/gL are the principal components in human plasma that prevent virus infection of epithelial cells. We produced nanoparticle vaccines containing EBV gH/gL or EBV gH/gL/gp42. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial cell and B cell infection. Serum from the vaccinated nonhuman primates inhibited EBV glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, EBV gH/gL and EBV gH/gL/gp42 nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell type-independent protection from virus infection. These vaccines are currently being manufactured for clinical trials.