News: QIMR researchers aim for EBV vaccine

Researchers at the Queensland Institute for Medical Research (QIMR) in Brisbane hope to begin human trials late this year of a vaccine that could prevent three different forms of cancer associated with infection by Epstein-Barr virus.

Dr Rajiv Kanna's research group at the Clive Berghofer Cancer Research Centre at QIMR has just won a US$400,000 grant from the US National Institutes of Health (NIH) to continue developing its prototype Epstein-Barr virus (EBV) vaccine -- the first NIH grant for an EBV vaccine.

In Western nations, Epstein-Barr virus (EBV) is notorious as the agent of glandular fever -- so-called 'kissing disease'. A member of the herpesvirus family, it targets antibody-producing B-cells.I

n Australia, glandular fever is almost a rite of passage among secondary and university students. Many recover rapidly, but some individuals develop chronic symptoms including fatigue and depression, that may persist for up to six months.

Danish researchers recently reported that young people with a history of glandular fever are at increased risk of Hodgkin's disease, a form of lymphoma. About 50 per cent of Hodgkin's disease is EBV-associated.

Hodgkin's disease usually responds well to chemotherapy. Australia's best-known Hodgkin's patient, pop star Delta Goodrem, is among those recovering after successful therapy.

But Kanna says 20 to 30 per cent of Hodgkin's patients relapse, because of an inadequate immune response against EBV antigens. Their prognosis is usually poor, because their cancer no longer responds to standard radiotherapy or chemotherapy.

The new EBV vaccine could be a lifesaver for relapsed patients. Kanna's team recently reported that transgenic laboratory mice with a 'humanised' immune system cleared their Hodgkin's-like cancers after being immunised with the prototype EBV vaccine.

But the Australian-developed vaccine's promise as a therapeutic for cancer is much broader.

In developing nations, chronic EBV infection can lead to two other, highly lethal forms of cancer. Nasopharyngeal carcinoma (NPC) is a leading cause of cancer-related mortality in China and south-east Asia, while EBV-induced Burkitt's lymphoma is common in African populations.

Kanna's QIMR team has shown that many Hodgkin's disease patients mount a poor T-cell response against cancerous cells chronically infected by Epstein-Barr virus. T-cells are the body's front-line defence against cancer, seeking and destroying cells displaying alien or mutant antigens. Cancerous, EBV-infected cells, known as Reed-Sternberg cells, display EBV antigens on their surface, but do not elicit a strong T-cell response.

The QIMR's prototype vaccine elicits a strong T-cell response that destroys Reed-Sternberg cells in vitro, and in its mouse model.

The new vaccine was developed with a powerful new technique called PolyTope, developed by the Cooperative Research Centre for Vaccine Technology, in which QIMR is a partner.

Kanna said PolyTope linked key immunogenic domains, or epitopes, of multiple viral proteins, to create a single, 'designer' antigen that elicits a powerful T-cell response.

It also offers potential for combining immunogenic epitopes from several unrelated viruses in a single, synthetic antigen that would immunise patients against multiple pathogenic viruses.

Another advantage of the Polytope system, Kanna said, is that some viral proteins, such as EBV's latent membrane protein number 1 (LMP1), are oncogenic -- their mere presence in a cell can turn it cancerous.

By separating the immunogenic epitopes from non-immunogenic 'junk', researchers can avoid the risks inherent in using the intact, active protein in a vaccine.

The QIMR vaccine is being developed primarily as an immunotherapeutic, rather than to prevent EBV infection.

Kanna said more than 100,000 new cases of nasopharyngeal cancer were diagnosed in Asia every year, and the incidence is rising in Australia and other Western nations with large, immigrant populations from Asia.

Burkitt's lymphoma is problematic, because infected B-cells express only a single EBV antigen, and shut down their antigen-processing machinery -- they would not respond even to a Polytope vaccine.

Some 90 to 100 per cent of Asians carry latent, lifetime infections of EBV virus. In Western nations, the figure is around 80 per cent. But Kanna believes it may be neither feasible nor desirable to mass-vaccinate populations against EBV to prevent glandular fever and its associated cancers.

The presence of latent, EBV-like viruses in distant primate cousins of humans like macaques and baboons suggests they are not only benign, but may be positively beneficial. In its normal role as a harmless commensal, EBV may prevent other infections by boosting the body's immune defences.

In an immunotherapeutic role, the EBV vaccine could be used to prevent a type of lymphoma that develops in organ-transplant recipients, called post-transplantation lymphoproliferative disease (PTLD).

Because a large percentage of the population is latently infected with EBV, donor organs often carry the virus, which causes infected B-cells to proliferate when the recipient's immune system is suppressed to prevent organ rejection.

Organ-transplant recipients could be immunised with the new vaccine to prevent PTLD.