Candidate vaccines for Epstein-Barr virusBMJ 1998; 317 doi: http://dx.doi.org/10.1136/bmj.317.7156.423 (Published 15 August 1998) Cite this as: BMJ 1998;317:423
Several promising approaches for vaccines against primary infection
- D J Moss, Senior principal research fellow,
- A Suhrbier, Senior research fellow,
- S L Elliott, Senior research officer
Owing to our increased understanding of the immune variables that control Epstein-Barr virus infection, detailed planning can now be given to developing a vaccine. 1 2 Commercial and scientific considerations are likely to focus on a vaccine directed towards minimising the clinical consequences of primary infection with Epstein-Barr virus (infectious mononucleosis and post-transplant lymphoproliferative disease) rather than towards malignancies associated with the virus (such as Hodgkin's disease, nasopharyngeal carcinoma, and Burkitt's lymphoma). Several trials are now under way with candidate vaccines against primary infection.
It might be argued that Epstein-Barr virus has evolved to generate an asymptomatic seroconversion as clinical symptoms of infectious mononucleosis are rare in developing countries, where primary infection typically occurs in the first few years of life. In contrast, in Western communities primary infection is delayed until adolescence in 10-20% of individuals, and after infection about half of these will develop infectious mononucleosis, the symptoms of which include pharyngitis, fever, and cervical lymphadenopathy. These observations are important in developing strategies for vaccination against Epstein-Barr virus since they suggest that a vaccine generating a minimal immune response might limit the clinical symptoms of infectious mononucleosis.
Given the potential oncogenicity of Epstein-Barr virus, it is generally assumed that an attenuated virus vaccine would not meet the stringent licensing requirements for a vaccine administered prophylactically to healthy adolescents. This consideration has resulted in the adoption of two separate approaches, both based on subunit vaccines.
The first seeks to exploit the major envelope glycoprotein of the virus, gp340.3 Impetus for this approach arose from the observation that this protein includes the major neutralising determinants of the virus and that various gp340-based vaccines protect cottontop tamarins from lymphoproliferative disease induced by Epstein-Barr virus. 4 5 Indeed, a clinical trial in China showed that a proportion (6/9) children negative for Epstein-Barr virus who were given recombinant vaccinia virus encoding gp340 gained protection from subsequent infection.6
This important observation suggests that neutralising or cell mediated determinants within gp340 might induce sterile immunity against Epstein-Barr virus infection. Despite this promising result, a delivery system using live recombinant vaccinia virus is unlikely to find application as a vaccine against infectious mononucleosis. Nevertheless, SmithKline Beecham in association with Aviron, has announced its intention to initiate a phase I randomised, double-blind clinical trial with a single adjuvanted surface antigen responsible for most of the neutralising antibodies stimulated by Epstein-Barr virus infection. 3 7
An alternative strategy for a vaccine against infectious mononucleosis is based on the induction of cytotoxic T cells specific to Epstein-Barr virus. 1 2 This approach relies on reducing the clinical symptoms of infectious mononucleosis rather than preventing primary infection. The importance of cytotoxic T cells in controlling disease associated with Epstein-Barr virus has been shown in the case of bone marrow derived post-transplant lymphoproliferative disease, where the lymphomas were successfully resolved by adoptive transfer of uncloned cytotoxic T cell lines stimulated by Epstein-Barr virus cultured in vitro.8
This established the important principle that specific cytotoxic T cells are capable of recognising these Epstein-Barr virus-infected B cell expansions in vivo (which also occur in infectious mononucleosis) and gave impetus to efforts to design a vaccine based on cytotoxic T cells. Indeed, the early recipients of an Epstein-Barr virus vaccine might well be Epstein-Barr virus seronegative graft recipients who are at risk of developing post-transplant lymphoproliferative disease.9 Currently, a phase I clinical trial designed to determine the safety and immunogenicity of Epstein-Barr virus cytotoxic T cell epitope vaccines is in progress in our institute. Healthy volunteers negative for Epstein-Barr virus and who are HLA B8 have been vaccinated with a formulation consisting of a synthetic peptide, FLRGRAYGL (an HLA B8 restricted epitope from Epstein-Barr virus nuclear antigen 3), and tetanus toxoid emulsified in the water in oil adjuvant Montanide ISA 720.2 To date the vaccine has been well tolerated with no significant adverse reactions.
Since each HLA class I allele presents a different epitope and there is a diversity of HLA alleles in the human population, multiple cytotoxic T cell epitopes will need to be delivered. One approach is to formulate a cocktail of defined epitopes in a single vaccine. Of the current Epstein-Barr virus epitopes identified, five would probably span >80% of the white population. Another approach might be to make use of a recent technical advance in which multiple, minimal cytotoxic T cells epitopes were genetically conjoined so that the vaccine codes for a synthetic polyepitope protein.10 Such a “polytope” vaccine will, however, need to be delivered using a vector or naked DNA based modality.
Epstein-Barr virus vaccines directed against Hodgkin's disease, nasopharyngeal carcinoma, and Burkitt's lymphoma are conceptually distinct from those directed against infectious mononucleosis. In general, these tumours have evoked a variety of escape mechanisms enabling them to expand despite an existing Epstein-Barr virus specific response which primarily controls the lifelong latent infection in B lymphocytes.1 The most potent of these mechanisms is likely to be down regulated Epstein-Barr virus antigen expression. Immunological strategies against these malignancies are thus likely to be therapeutic and could exploit the presence of Epstein-Barr virus in the tumour cells or could focus on tumour antigens not encoded by Epstein-Barr virus.
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