Epstein-Barr Virus Vaccination of Transplant Candidates: Light at the End of the Tunnel?

Is there light at the end of the tunnel leading to a safe and effective Epstein-Barr Virus (EBV) vaccine for use in specific groups at risk of EBV diseases? In this issue of the Journal, Rees et al. (1) report the results of a phase 1 study using a gp350 EBV vaccine aimed at preventing EBV-related posttransplant lymphoproliferative disorder (PTLD) among pediatric organ transplant recipients. The EBV is a gamma herpesvirus that was first isolated in 1964 from Burkitt lymphoma tissue. Like other herpesviruses, EBV has the ability to cause lytic infections and to remain latent within the host. In addition, EBV is able to transform and immortalize B- lymphocytes, leading to the potential for uncontrolled proliferation of these transformed cells—a potential that is often realized in immunodeficient individuals, including organ transplant recipients. Primary EBV infection is often asymptomatic when it occurs in early childhood. In this regard, infection is often acquired within the first decade of life for individuals living in developing countries, in contrast to the 3rd or 4th decade of life for individuals living in developed countries. Infection in adolescence often results in symptomatic infectious mononucleosis. After primary infection, EBV may be associated with several important diseases, including undifferentiated nasopharyngeal carcinoma, endemic Burkitt lymphoma, some forms of Hodgkin lymphoma, and PTLD. Currently, there is a general consensus that while EBV vaccination may be an achievable goal, the aim of vaccination is the prevention of EBV-associated diseases and not infection. Attempts at development of an EBV vaccine have occurred within an atmosphere characterized by some challenges or unknowns. For example, the limited understanding of the biology and immunology of the virus has impeded progress in vaccine development. Indeed, the virus has developed sophisticated mechanisms to evade the defenses posed by the adaptive and innate immune responses in humans. In addition, there are unknown consequences of vaccinating populations at risk of EBV diseases (e.g., immuncompromised patients) given that these populations might well be the groups that are most likely to have aberrant responses to EBV antigens. EBV is regarded as a grade 1 carcinogen (i.e., carincogenic to human). Thus, the composition of an EBV vaccine can only contain viral elements that are nontransforming, which limits the composition of vaccine candidates. Vaccine development is also influenced by economic considerations, taking into account the relative burden of the EBV-diseases that could be targeted in different regions of the world. Another challenge in developing an EBV vaccine is the lack of an animal model of EBV that reproduces the virus-host interaction that occurs in EBV infection or EBV-associated diseases. This notwithstanding, there are now murine and primate animal models that provide a useful experimental basis for vaccine testing to support human trials. To this end, there are two main approaches that are being considered, relating to the development of an EBV vaccine (2, 3). One approach involves a vaccine capable of producing protective immunity using the major envelope glycoprotein, gp350, whereas another involves a cytotoxic T lymphocyte (CTL)-based vaccine formulation capable of modifying clinical symptoms or disease. The major EBV glycoprotein gp350 has been identified as a candidate subunit vaccine due to the observation that antibodies against gp350 are neutralizing. However, it has been shown that if the gp350 gene is deleted, EBV infection can still occur in vitro, though with decreased efficiency. Thus, neutralizing antibodies against gp350 are unlikely to uniformly prevent EBV infection. Although not necessarily preventing infection, such a vaccine could ameliorate infection and thereby influence the likelihood of EBV diseases, including PTLD. This candidate vaccine has been the subject of trials in humans (4, 5). In the study by Rees et al., subjects were EBV-seronegative children with chronic kidney disease who were awaiting renal transplantation. These subjects were vaccinated using two successive cohorts, each receiving three injections of 12.5 μg (n=6) and 25 μg (n=10) of recombinant gp350 per alhydrogel vaccine for a period of 6 to 8 weeks. A fourth vaccine dose was offered at week 30 to 32 for children who were not transplanted, but who remained negative for EBV infection and who had a total anti-gp350 antibody level at week 26 to 28 that was less than a target level of 300 units of reference standard. In addition to assessing adverse events related to vaccination, the investigators documented EBV-related events and measured total gp350 antibody concentrations. Neutralizing antibody titers were also assessed. The investigators observed that both doses had similar immunogenicity and induced IgG responses in all evaluable subjects (n=13). Neutralizing antibodies were detected in four recipients (1 of 4 in the 12.5 μg and 3 of 9 in the 25 μg cohort). However, the antibody titers declined rapidly and thus were not likely to have an effect in the posttransplant period. The results of this study offer promise by demonstrating that neurtralizing antibodies could be safely generated, albeit transiently. Further research could then be directed at strategies to enhance the sustainability of the immune response and the most appropriate vaccine schedule leading up to the point of transplantation. Short-term protection in the posttransplant period could still be of value to transplant recipients, if such protection spans the period when they are most vulnerable to PTLD. Autologous CD8+ T cells against ENBA3, that were propagated ex vivo and administered to immunosuppressed patients at risk of PTLD, were able to prevent PTLD and cause regression of lesions in some patients (6). The strategy is the subject of ongoing research (7). This demonstrates the potential efficacy of a CTL-based approach to vaccination against EBV. This strategy is based on the hypothesis that CTLs that are specific for EBV latent proteins can be generated to control EBV-infected B cells in vivo. This has led to a focus on development of HLA-resricted peptides that illicit an epitope-specific CTL response. However, in order for an effective vaccine for all population groups of patients to be developed, it would be necessary to deliver a relatively larger number of CTL epitopes that cover the major histocompatibility complex spectrum in humans. In summary, the improved understanding of the biology, immunology, and virology of EBV for the past decade has advanced progress in EBV vaccine development. A focus on vaccines that target EBV diseases, including PTLD, is of immense importance to the transplant recipient, given that to date there are no established effective strategies to prevent PTLD. Thus, while the conclusions that can be drawn from the study by Rees et al. are limited, it does provide useful information as this relates to the potential role for a candidate gp350 vaccine in the prevention of PTLD. The information from this work will help to guide further research in this area, notably targeting transplant recipients. Optimistically speaking, this could indeed represent light at the end of the tunnel for transplant patients at risk of PTLD.

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