MANUFACTURE OF CLINICAL GRADE EPSTEIN-BARR VIRUS VACCINE

About This Grant

Epstein-Barr virus (EBV), also known as human herpesvirus 4, is an oncogenic gamma-herpesvirus etiologically linked to post-transplant lymphoproliferative disease (PTLD), Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma (NPC), gastric (GC) and other epithelial cancers. EBV is responsible for over 350,000 new cancer cases and approximately 200,000 deaths annually. More than 90% of adults are believed to be EBV-seropositive, as primary EBV infection occurs during childhood. While primary EBV infection remains asymptomatic in most cases, there are individuals who develop symptomatic infectious mononucleosis (IM), especially if infected as young adults. Some studies have also demonstrated that the severity of IM symptoms correlated with EBV load in blood. People with a history of IM are known to have an elevated risk of EBV-associated cancers. Major targets of EBV infection are B cells and epithelial cells. EBV glycoproteins, gp350/220, gB, gp42, and the gH/gL complex, are known to play a key role in EBV cell entry. Depending on the cell type, different EBV glycoproteins facilitate EBV infection. Of these glycoproteins, however, the gH/gL complex has been identified as a key target of EBV-neutralizing antibodies irrespective of cell type. After primary infection, EBV establishes latency, which allows EBV genome to remain dormant and persist for life in human cells as episomes. EBV latency can transition to lytic replication cycle with the production of infectious virions, when host immune system is compromised such as by chemotherapy and radiation for bone marrow transplant conditioning or HIV co-infection. Reactivation of EBV lytic replication is associated with the increased risk of EBV-associated lymphomas and other cancers in immunocompromised hosts. The critical role of anti-EBV immunity in controlling EBV infection and reducing the risk of EBV-associated cancers has been studied over the years. One approach to elicit anti-EBV immunity is through vaccination. Various EBV vaccines have been developed over the last decades without much success. Although five candidate EBV vaccines reached clinical trials, none of them prevented EBV infection and replication in human subjects. In more recent years, newer vaccination strategies have been explored for the development of next-gen EBV vaccines, including the use of RNA vaccine platforms and targeting multiple EBV glycoprotein antigens, such as gH, gL, gp42, and gp350. There are currently two major RNA-based vaccine technologies available, non-replicating mRNA-based and self-replicating RNA-based vaccines. Conventional LNP-mRNA-based EBV vaccines targeting gH, gL gp42, and gp220 with/without latency antigens are currently being developed by Moderna (NCT05164094 and NCT05831111). In contrast to conventional mRNA-based vaccines, vaccines based on a self-amplifying RNA platform can intracellularly amplify the encoding transcripts, resulting in significantly higher expression levels of vaccine antigens. A self-amplifying replicon RNA (repRNA) derived from alphavirus Venezuelan equine encephalitis TC83 strain has been used to construct vaccines that encode the EBV gH/gL complex alone or in combination with other EBV glycoproteins. These EBV vaccines have been preclinically evaluated for anti-EBV immune responses and inhibition of EBV replication. The repRNA-gH/gL vaccine elicited EBV-neutralizing antibodies (neut Ab) that protected both B cells and epithelial cells from EBV infection. Neut Ab persisted in circulation for more than 8 months in vaccinated mice. The repRNA-gH/gL vaccine also elicited Ag-specific CD8+ T cell response. Moreover, passive transfer of the repRNA-gH/gL vaccine-induced immune sera protected humanized mice from splenomegaly and lethality after high-dose EBV challenge. Thus, this specific repRNA-gH/gL vaccine is considered a clinical candidate for immunoprevention of EBV-associated cancers.