A gH/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge

• Published in: npj Vaccines
• Main Authors: Kristina R. Edwards, Harman Malhi, Karina Schmidt, Amelia R. Davis, Leah J. Homad, Nikole L. Warner, Crystal B. Chhan, Samuel C. Scharffenberger, Karen Gaffney, Troy Hinkley, Nicole B. Potchen, Jing Yang Wang, Jason Price, M. Juliana McElrath, James Olson, Neil P. King, Jennifer M. Lund, Zoe Moodie, Jesse H. Erasmus, Andrew T. McGuire
• Format: Article
• Language: English
• Published: Nature Portfolio 2024-06-01
• Online Access: https://doi.org/10.1038/s41541-024-00907-y

Abstract Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH/gL, gH/gL/gp42 or gp350 delivered by a cationic nanocarrier termed LION™. The lead candidate, encoding full-length gH/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8+ T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION/repRNA-gH/gL is an ideal candidate vaccine for preventing EBV infection and/or related malignancies in humans.