Prophylactic and Therapeutic EBV Vaccines: Major Scientific Obstacles, Historical Progress, and Future Direction

Abstract

The Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is associated with various malignant tumors and immune diseases, imparting a huge disease burden on the human population. Available EBV vaccines are imminent. Prophylactic vaccines can effectively prevent the spread of infection, whereas therapeutic vaccines mainly stimulate cell-mediated immunity and kill infected cells, thus curbing the development of malignant tumors. Nevertheless, there are still no approved EBV vaccines after decades of effort. The complexity of the EBV life cycle, the lack of appropriate animal models, and the limited reports on adjuvant selection and immune responses are gravely impeding progress in EBV vaccines. The soluble gp350 vaccine could reduce the incidence of infectious mononucleosis (IM), which seemed to offer hope, but could not prevent EBV infection. Continuous research and vaccine trials provide deep insights into the structural biology of viruses, the designs for immunogenicity, and the evolving vaccine platforms. Moreover, the new vaccine candidates are expected to achieve further success via combined immunization to elicit both a dual protection of B cells and epithelial cells, and sustainable immunization against infected cells at several phases of infection.

Progress in Prophylactic and Therapeutic EBV Vaccine Development Based on Molecular Characteristics of EBV Target Antigens

“…Those proteins are the main vaccine targets, as they are necessary for virus entry and, therefore, its primary infection [18]. Besides envelope glycoproteins and CR2, successful infection of B lymphocytes requires two additional cellular proteins: HLA and integrin [19]. HLA class II proteins on the host cell bind to the gHgL/gp42 complex, which activates membrane fusion during primary infection, while integrin triggers entry of EBV into epithelial cells with binding to gHgL [8].…”

“…B lymphocytes present viral peptides on their HLA class I molecules, which CD8+ lymphocytes recognize, and they consequently destroy the infected cells. Moreover, B lymphocytes produce IgG/IgA antibodies against gp350/220, which prevents EBV attachment to CR2 [19]. The latent state is the stage of EBV replication cycle when the virus is the most difficult to detect by the immune system owing to the reduced number of proteins expressed.…”

“…The complexity of the EBV replication cycle as well as its high number of envelope proteins make vaccine development a demanding task. EBV can infect T lymphocytes as well as NK cells through still unknown mechanisms, which makes the development of a vaccine that would prevent the infection of all EBV-target cells currently not possible [19]. In addition, EBV lacks a true animal model as its infection was observed only among humans.…”

“…Some vaccines contain an adjuvant, substances that increase the response of the immune system to target antigens, with the most common one being aluminum hydroxide, sometimes combined with monophosphoryl lipid A. Freund's adjuvant and immune-stimulating complexes have also been used in order to enhance the defense against primary infection and later reactivation from the latent state. The choice of adjuvant has been shown to lead to significant differences in vaccine production [19].…”

How Does Epstein–Barr Virus Interact With Other Microbiomes in EBV-Driven Cancers?

“…However, limit progressions have been made by targeting the deregulated signal pathway in EBV infection or focusing on the drugs targeting EBV antigens, such as EBNA1 ( Thompson et al., 2010 ; Messick et al., 2019 ). Up to now, no vaccine against EBV has been made successfully ( Dugan et al., 2019 ; Cai et al., 2021 ). The application of nucleoside analogs which could act during the lytic phase of EBV, such as ganciclovir and zidovudine, in addition to IL-2 and CAR-T treatment, worked well in EBV-positive PCNSL ( Aboulafia et al., 2006 ; Dugan et al., 2019 ).…”