EBV vaccine could reduce the risk of EBV-associated diseases

Jeffrey Cohen, National Institute of Allergy and Infectious Diseases, USA, reported on the current developments pertaining to the development of vaccine options against the Epstein-Barr virus.

EBV glycoprotein, a potential vaccine candidate

So far, no vaccine against the Epstein-Barr virus has been approved. Jeffrey Cohen, National Institute of Allergy and Infectious Diseases, NIH; Bethesda, MD, USA, reported at the CROI 2019 on 6 March 2019 in Seattle, Washington, on the current developments of his working group and the road leading to the EBV vaccine.

The Epstein-Barr virus (EBV) causes about 125,000 cases of infectious mononucleosis per year in the USA. The disease is considered benign, but for some of those affected, it is very unpleasant, with fatigue lasting up to 6 months, which can lead to long absences from school or work.

However, EBV is of great importance primarily because of its association with malignant diseases. Worldwide, approximately 200,000 EBV-associated cancers and 140,000 deaths occur every year. Most common are gastric carcinomas with 84,000 cases annually and nasopharyngeal carcinomas with 78,000 cases. In both cases, epithelial cells are affected. EBV is also associated with Hodgkin's lymphoma (29,000 cases/year), Burkitt's lymphoma (7,000 cases/year) and lymphoma in transplant patients. EBV also plays a role in other diseases such as multiple sclerosis.

The association between malignant disease and EBV is characterized by the fact that the virus in the malignant cell "is not just a passenger, but contributes to oncogenesis," explained Cohen. In the case of an association between virus and cancer, the viral genome must be detected in each tumor cell, viral gene expression takes place and EBV is clonal or oligoclonal in the tumor cell.

Two groups of EBV-associated cancers

EBV-associated malignancies can be divided into two groups. In group 1 (e.g. Hodgkin's lymphoma, primary CNS lymphoma) EBV is found in over 90% of cases and cellular mutations are not common. The virus "fires" these tumors. It produces three or more so-called latency proteins that lead to type 2 or type 3 EBV latency. The tumors also occur late in the course of the infection, when the organism is strongly immunosuppressed. In the second group (e.g. plasmablastic lymphoma, Burkitt's lymphoma) EBV can be detected in 30% to 80% and cellular mutations such as Bcl-6, c-MYC or p53 occur.

EBV mainly affects epithelial cells, primarily through droplet infection (keyword: Kissing Disease), as well as B cells. These are therefore also the two target cells of vaccines. Cohen and his team have developed two EBV vaccines that attack these cells.

EBV glycoprotein as a vaccine candidate

A target for a vaccine may be glycoproteins on the surface of the virus and virus-infected cells. EBV-gp350 is important for the attachment of the virus to B cells. EBVgp350 binds there to the receptor CD21 or CD35. The virus is then absorbed into the B cell by endocytosis. Gp350 is the principal target of neutralizing antibodies, it is a target of antibody-dependent cytotoxicity and a target of CD4 and CD8 cells. This could make gp350 useful for an EBV vaccine as a target.

A vaccine with soluble EBVgp350 was tested in a double-blind Phase II study in Belgian EBV seronegative volunteers aged 16 to 25 years compared to placebo. The rate of infectious mononucleosis was 78% lower in the vaccinated group than in the placebo group. However, the vaccine did not affect the EBV infection. "This was probably the reason GSK did not develop this vaccine further," said Cohen.

Cohen and his team have developed a vaccine based on self-organizing nanoparticles that provide a multivalent, symmetrical and repetitive antigen array, thereby enhancing immunogenicity. They use ferritin as nanoparticles. In studies in mice and monkeys, the ferritin nanoparticle-based vaccine achieved a much higher titer of neutralizing antibodies than the soluble gp350 vaccine. In addition, the higher titer lasted for more than 100 days.

However, it is not gp350 that plays the most important role in the binding of EBV to epithelial cells, but gH/gL (viral glycoprotein H and its chaperone gL). The infection takes place on the cell surface. For the vaccine to induce antibodies against infection of B cells and epithelial cells, it should be multivalent and contain gp350, gH/gL and possibly gp42. Cohen and his colleagues designed ferritin nanoparticles with gH/gL alone or with gp42. In animal experiments, these vaccines also proved to be more effective than soluble vaccines. The vaccines will now be investigated in clinical trials.

Possible advantages of a vaccine

Cohen hopes that the vaccine will help to limit the proliferation of T cells during initial infection, thereby reducing EBV-induced infectious mononucleosis (IM). The prevention of IM could, in turn, reduce the incidence of EBV-induced Hodgkin's lymphoma. Another hope is that the vaccine will reduce the viral load after infection. The viral load correlates with the risk of EBV posttransplant lymphoproliferative disease (PTLD), this risk could possibly be reduced by vaccination. Lowering the viral load could also reduce the risk of EBV-induced cancer in non-immunocompromised patients.

Cohen J. EBV: Immunopathogenesis and the path to an EBV vaccine. CROI 2019, Seattle, Washington, March 5, 209, Abstract 56. http://www.croiconference.org/sessions/ebv-immunopathogenesis-and-path-ebv-vaccine

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