Epstein Barr Virus: Development of Vaccines and Immune Cell Therapy for EBV-Associated Diseases

Abstract

Epstein-Barr virus (EBV) is the first human tumor virus discovered and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. Each year EBV associated cancers account for over 200,000 new cases of cancer and cause 150,000 deaths world-wide. EBV is also the primary cause of infectious mononucleosis, and up to 70% of adolescents and young adults in developed countries suffer from infectious mononucleosis. In addition, EBV has been shown to play a critical role in the pathogenesis of multiple sclerosis. An EBV prophylactic vaccine that induces neutralizing antibodies holds great promise for prevention of EBV associated diseases. EBV envelope proteins including gH/gL, gB and gp350 play key roles in EBV entry and infection of target cells, and neutralizing antibodies elicited by each of these proteins have shown to prevent EBV infection of target cells and markedly decrease EBV titers in the peripheral blood of humanized mice challenged with lethal dose EBV. Recent studies demonstrated that immunization with the combination of gH/gL, gB and/or gp350 induced markedly increased synergistic EBV neutralizing activity compared to immunization with individual proteins. As previous clinical trials focused on gp350 alone were partially successful, the inclusion of gH/gL and gB in a vaccine formulation with gp350 represents a promising approach of EBV prophylactic vaccine development. Therapeutic EBV vaccines have also been tested clinically with encouraging results. Immunization with various vaccine platforms expressing the EBV latent proteins EBNA1, LMP1, and/or LMP2 promoted specific CD4+ and CD8+ cytotoxic responses with anti-tumor activity. The addition of EBV envelope proteins gH/gL, gB and gp350 has the potential to increase the efficacy of a therapeutic EBV vaccine. The immune system plays a critical role in the control of tumors, and immune cell therapy has emerged as a promising treatment of cancers. Adoptive T-cell therapy has been successfully used in the prevention and treatment of post-transplant lymphoproliferative disorder. Chimeric antigen receptor T cell therapy and T cell receptor engineered T cell therapy targeting EBV latent proteins LMP1, LMP2 and/or EBNA1 have been in development, with the goal to increase the specificity and efficacy of treatment of EBV associated cancers.

Identification of useful genes from multiple microarrays for ulcerative colitis diagnosis based on machine learning methods

“…The prognosis of Epstein–Barr virus infection in UC was less paid attention to 45 . In this study, the KEGG pathways results indicated that more studies of the Epstein–Barr virus infection pathway in UC could be conducted 46 . Particularly, IBD patients have a higher risk to develop autoimmune and inflammatory diseases, such as rheumatoid arthritis 47 .…”

Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

“…Adoptive T cell therapy has been successfully applied for treating patients with EBV-associated PTLD by reconstituting host cellular immunity against the disease. The first clinical trial of adoptive T cell therapy showed that infusion of donor-derived EBV-specific T cells (EBVSTs) into patients with allogeneic hematopoietic stem cell transplantation (HSCT) induced complete regression in all five patients, but graft-versus-host disease developed [ 153 ]. Later, in vitro expanded donor-derived or autologous EBVSTs in phase I clinical trials were proven effective in the prevention and treatment of PTLD in HSCT or solid organ transplantation patients with minimal alloreactivity [ 154 , 155 ].…”

“…In addition, most therapeutic EBV vaccines have been focused on patients with NPC, and early clinical trials were done with DC-based EBV vaccines and recombinant viral vector vaccines [ 192 , 193 ]. Although the therapeutic EBV vaccines have shown increasing T cell responses in patients with NPC, future studies remain to be done to overcome the limited antigen epitopes delivered by DC-based EBV vaccines and the decreased antiviral vector immune responses after repeated immunizations [ 153 , 194 ].…”

“…Immune-based tumor-specific therapy is under evaluation in clinical studies because it is highly effective with limited adverse effects [ 225 ]. Therapeutic EBV vaccines are designed to stimulate the existing or trigger novel antiviral immune responses in patients with EBV-associated malignancies [ 153 , 194 ]. The targets of EBV therapeutic vaccines are mainly the latent proteins of EBV, such as EBNA1, LMP1, and LMP2.…”

Promising Role of Emodin as Therapeutics to Against Viral Infections

“…A small proportion of people infected with EBV present with infectious mononucleosis, which can cause persistent fatigue for up to 6 months and lead to serious neurological, hematological or hepatic complications. EBV was also the first human oncovirus to be identified and it is closely associated with several lymphomas and epithelial cancers especially in immunocompromised individuals, such as Burkitt’s lymphoma, Hodgkin’s lymphoma and nasopharyngeal carcinoma (NPC) ( Cui and Snapper, 2021 ). In general, the utilizing of existing antiviral compounds is limited by toxic side effects, poor oral bioavailability and the risk of the emergence of resistant viral strains.…”