Developing Vaccines Against EBV-Associated Diseases
Developing Vaccines Against EBV-Associated DiseasesDeveloping Vaccines Against EBV-Associated Diseases: The past ten years have seen a dramatic accumulation of insights into the biology, immunology and virology of EBV so that for the first time rational vaccine development can begin. Thus the targets molecules present on latency I, II and III diseases have been well defined and the relative importance of both the cellular and the humoral responses are understood at least in the broad sense. Several vaccine trials towards infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD) have been conducted and others are planned. While formulating vaccines for nasopharyngeal carcinoma (NPC) and Hodgkin's lymphoma (HL) are more speculative, there is good reason to believe that formulations encompassing cytotoxic T cell (CTL) epitopes encoded by LMP1 and LMP2 should have therapeutic benefit. On the other hand, there is little prospect for a vaccine to reverse the rapid growth of Burkitt's lymphoma.
There is a strong scientific and commercial focus on developing vaccines and immunotherapeutic strategies for the treatment of EBV-associated diseases. However, it is unlikely that a single vaccine that is applicable to all EBV-associated diseases will be developed. Given the variety of potential EBV targets in latency III diseases and the problems of immune recognition of latency II and latency I diseases, vaccines against infectious mononucleosis (IM) and post transplant lymphoproliferative disease (PTLD) would seem to offer the best opportunity for early development. However, in spite of this caveat, early human trials aimed at nasopharyngeal carcinoma (NPC) and Hodgkin's lymphoma (HL) deserve serious consideration while there remain significant obstacles towards the reality of a therapeutic vaccine against Burkitt's lymphoma (BL).
M.A. Epstein first proposed the concept of the development of EBV vaccines as long ago as 1976. These original proposals were based on the notion that vaccination might prevent EBV infection and break the link in the complex chains of events that lead to EBV-associated disease. Since that time, a better understanding of EBV biology has led to the postulation of more sophisticated but, as yet, untested vaccination strategies. Presently, it seems most unlikely that vaccination of any kind will achieve sterilizing immunity against herpesviruses. The murine gamma-herpesvirus, MHV68, establishes the same steady-state levels of lytic and latent infection whatever the route of infection or dose. It may be that a single virus particle successfully infecting a single target cell will be enough to establish persistent infection in a susceptible subject. There is a general consensus that the goal of EBV vaccination is the prevention of disease and not of infection. Vaccination that could modify infection, or at least the subsequent immunological status of the infected person with respect to EBV, may minimize disease or reverse the expansion of EBV-associated tumors.
It is unlikely that EBV has evolved to avoid immune recognition. On the contrary, it is likely that there may well be selection towards immune recognition since this is likely to favor host and viral survival. An important precedent for herpesvirus vaccination is the attenuated varicella zoster virus (VZV) Oka strain vaccine that does not prevent infection but is able to prevent disease. More recently the concept of therapeutic vaccination to treat EBV-associated tumors themselves has begun to emerge.
The lack of a complete understanding of the biology of EBV in vivo remains an unfortunate reality and the various approaches to EBV vaccine design discussed below are, of necessity, based on a number of unproven assumptions. The virus is an orally transmitted infection of B-cells both peripherally and in lymphoid tissue in the oropharyngeal region. Although it has not been possible to convincingly demonstrate the presence of EBV in oropharyngeal epithelial, it has been shown recently, using polarized tongue and oropharyngeal epithelial cells in vitro, that EBV-infected donor cells in saliva are very efficient at infecting recipient epithelial cells at their apical surface by cell-cell contact. However, these same epithelial cells are refractory to infection with free virus at their apical surface. It has also been shown that neighboring epithelial cells are infected by cell-cell transmission and free virus is produced at both the apical and basolateral epithelial surfaces. Presumably, it is the latter cell-free virus that subsequently infects B-cells circulating within the oropharyngeal epithelium and oropharyngeal lymphoid tissues.
Current knowledge of the immune control of EBV infection has reached a level where vaccine trials aimed at controlling IM, PTLD, NPC and HL are justified, particularly in light of the recent success with adoptive immunotherapy to a number of these conditions. Recent advances in characterizing the T cell response to the EBNA1 gene suggest that it may also be possible to treat BL with a vaccine derived from this antigen; however it would be advisable to attempt adoptive immunotherapy before vaccine trials are considered. One of the key challenges facing researchers attempting pioneering vaccine trials are the increasingly stringent regulatory issues involved. Too often, regulatory authorities apply restrictive criteria based on a model of product development which is better suited to the drug industry than to the academic research institute. For the future benefit of patients with EBV-associated malignancies, it is vital that regulatory authorities do not apply stringent controls on small-scale trials applied to patients with late stage malignancies, so that academic-led interventional research can advance rapidly.
Developing Vaccines Against EBV-Associated Diseases .
(adapted from Denis J. Moss in Epstein-Barr Virus)
Developing Vaccines Against EBV-Associated Diseases
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