Progress in EBV Vaccines

Abstract

The Epstein-Barr virus (EBV) is a ubiquitous pathogen that imparts a significant burden of disease on the human population. EBV is the primary cause of infectious mononucleosis and is etiologically linked to the development of numerous malignancies. In recent years, evidence has also been amassed that strongly implicate EBV in the development of several autoimmune diseases, including multiple sclerosis. Prophylactic and therapeutic vaccination has been touted as a possible means of preventing EBV infection and controlling EBV-associated diseases. However, despite several decades of research, no licensed EBV vaccine is available. The majority of EBV vaccination studies over the last two decades have focused on the major envelope protein gp350, culminating in a phase II clinical trial that showed soluble gp350 reduced the incidence of IM, although it was unable to protect against EBV infection. Recently, novel vaccine candidates with increased structural complexity and antigenic content have been developed. The ability of next generation vaccines to safeguard against B-cell and epithelial cell infection, as well as to target infected cells during all phases of infection, is likely to decrease the negative impact of EBV infection on the human population.

Keywords: EBV (Epstein-Barr virus); lympho proliferative disorder; oncogenic; vaccine; γ-herpesvirus.

Figure 1

The targeting of EBV virions and EBV-infected cells by the adaptive immune system. Humoral immunity respectively targets EBV virions and EBV-infected cells through neutralizing antibodies (1) and antibody dependent-cellular cytotoxicity (ADCC) (2). The targeting of virions by neutralizing antibodies prevents the infection of host cells, while the binding of antibodies to glycoproteins at the surface of lytically replicating cells enable their recognition and elimination by natural killer (NK) cells. Vaccines geared toward stimulating humoral immunity against the major envelope glycoprotein gp350 have previously been tested in several clinical studies (–22). (3) EBV-infected cells that display viral antigens on major histocompatibility (MHC) molecules are recognized by cytolytic T cells, which release cytotoxic granules (e.g., perforin and granzymes) and trigger apoptosis in infected cells. A vaccine that elicits EBNA3A-specific T cells responses has previously been investigated in a clinical trial (23). The ability of future EBV vaccines to stimulate potent humoral and cellular immune responses are likely to provide optimal protection against EBV infection.

Figure 2

The antigenicity of EBV during a single infection cycle. (Top panel) Incoming virions target permissive cells within the oropharynx, lytic replication ensues and amplifies the number of virions within newly infected hosts (not shown). Virions subsequently infect naïve B cells within underlying lymphoid tissues. The presence of numerous glycoproteins at the surface of virions renders them vulnerable to neutralizing bodies (humoral immunity). Newly infected naïve B cells, also referred to as pre-latent, express a handful of lytic and latent antigens. Infected B cells subsequently transition through several latency stages (III → II → 0), gradually reducing the number of EBV antigens that are expressed, eventually resulting in the establishment of latency 0 in quiescent memory B cells. Since no EBV antigens are expressed during latency 0, it enables infected cells to evade immune recognition. However, EBV-infected memory B cells are maintained through normal B-cell homeostatic mechanisms and express EBNA1 when they divide (latency I). The expression of viral antigens during pre-latency, latency I, II, and III renders the infected cells vulnerable to EBV-specific T cells (cellular immunity). Circulating B cells that re-enter the nasopharyngeal lymphoid system differentiate into plasma cells that support lytic replication. The expression of approximately 80 viral proteins, several of which are displayed at the surface of infected cells, exposes these cells to EBV-specific T cells (cellular immunity), and ADCC (humoral immunity). Virions released from lytically replicating cells can initiate another cycle of infection if they are not targeted by neutralizing antibodies (humoral immunity). (Bottom panel) The number and nature of EBV antigens fluctuates throughout a single infection cycle and these proteins are targeted by humoral immunity and/or cellular immunity.

Figure 3

Prophylactic EBV vaccine candidates vary in their structural complexity and antigenic content. (A) An epitope peptide from EBNA3A. (B) Recombinant gp350 expressed as a monomeric protein. (C) EBV latent antigens (red) conjugated to dendritic cell- or B-cell-specific antibodies. (D) Multimeric forms of EBV structural proteins can be generated through the use of multimerization domains (black). (E) Self-assembling ferritin nanoparticles presenting gp350. (F) Chimeric NDV VLPs containing lytic (green) and latent (red) EBV antigens. Several EBV antigens (viz. gp350, gH/gL, g, EBNA1, and LMP2) have been targeted using this platform. (G) EBV VLPs comprise numerous envelope (green), tegument (blue), and capsid (gray) proteins. (H) The tegument of EBV VLPs can be modified to contain latent antigens (red).