An EBV vaccine to prevent cancers and MS?

Project Overview

Most humans are infected with Epstein-Barr virus. The virus has the ability to establish latency in B cells and pre-malignant epithelial cells, and, via expression of viral oncogenes, is responsible for c. 120,000 cases of cancer each year. Less well-known is the existence of evidence linking EBV to a number of auto-immune diseases, including the observation that multiple sclerosis (MS) is exceptionally rare in individuals uninfected with EBV. It has thus been suggested that most cases of MS could be prevented by an effective EBV vaccine.

This project would seek to develop such a vaccine, based upon the induction of antibodies against viral glycoproteins essential for cell entry. The student would design recombinant protein antigens, characterise their ability to induce neutralising antibody after vaccination of mice, and assess their ability to protect against EBV in vivo (using ‘humanised’ mice bearing human cells susceptible to infection). We would also seek to identify and characterise mouse and human monoclonal antibodies against the critical viral glycoprotein ‘gB’, which is required for virus-cell membrane fusion. Polyclonal antibody against gB is known neutralise the virus, but at present there is little understanding of the antibody-sensitive epitopes or the protein’s pre-fusion structure, and hence poor understanding of how to produce an optimal gB vaccine antigen.

The ubiquity of EBV in human populations offers outstanding opportunities for small and yet informative clinical trials and experimental medicine. The project would be truly translational, and a core aim would be rapid progression of the tools developed towards human studies.

Training Opportunities

Dr Douglas aims to offer high-quality supervision to his students and to allow them to make the most of the opportunities afforded by an Oxford DPhil, working within a stimulating, supportive and enjoyable environment. Prospective applicants are encouraged to contact Sandy (sandy.douglas@ndm.ox.ac.uk) for further information and/or to be put in touch with current lab members.

All students are expected to present their research internally and at relevant conferences, and to work towards publications. A student pursuing this project could expect to learn a broad range of transferable practical techniques in molecular biology, virology, and immunology.

The Jenner Institute is Europe’s largest academic translational vaccinology research centre, with activity extending from basic microbiological and immunological research into first-time-in-human clinical trials and subsequent international field trials. The Institute’s close integration of pre-clinical and clinical activities offers near-unique opportunities for students to be involved throughout this process. With other active programmes within the Institute targeting diseases including HIV, TB, dengue, cancer and influenza, DPhil students have the opportunity to interact with senior researchers with a wide variety of expertise, and to develop a broad skill-set to support a career in 21st century translational medicine.

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 987

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Alexander (Sandy) D Douglas MRCP Jenner Institute Oxford University, Henry Wellcome Building for Molecular Physiology GBR sandy.douglas@ndm.ox.ac.uk
Professor Simon J Draper Jenner Institute Oxford University, Old Road Campus Research Building GBR simon.draper@ndm.ox.ac.uk

Cohen JI. 2015. Epstein-barr virus vaccines. Clin Transl Immunology, 4 (1), pp. e32. Read abstract | Read more

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis (IM) and is associated with epithelial cell malignancies such as nasopharyngeal carcinoma and gastric carcinoma, as well as lymphoid malignancies including Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. EBV vaccines to prevent primary infection or disease, or therapeutic vaccines to treat EBV malignancies have not been licensed. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which is the major target of neutralizing antibody. A single phase 2 trial of an EBV gp350 vaccine has been reported; the vaccine reduced the rate of IM but not virus infection. The observation that infusion of EBV-specific T cells can reduce disease due to Hodgkin lymphoma and nasopharyngeal carcinoma provides a proof of principle that a therapeutic vaccine for these and other EBV-associated malignancies might be effective. Most therapeutic vaccines have targeted EBV LMP2 and EBV nuclear antigen-1. As EBV is associated with nearly 200 000 new malignancies each year worldwide, an EBV vaccine to prevent these diseases is needed. Hide abstract

Pender MP, Burrows SR. 2014. Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy. Clin Transl Immunology, 3 (10), pp. e27. Read abstract | Read more

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8(+) T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8(+) T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4(+) T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8(+) T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. Hide abstract

Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. 2016. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health, 4 (9), pp. e609-16. Read abstract | Read more

BACKGROUND: Infections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012. METHODS: We considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses. FINDINGS: Of 14 million new cancer cases in 2012, 2·2 million (15·4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status-from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa. INTERPRETATION: A large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available. FUNDING: Fondation de France. Hide abstract