My career goal as a cancer researcher is to develop preventive and therapeutic vaccines to both prevent and treat Epstein-Barr virus (EBV)-driven lymphomas. Through the Department of Defense Peer Reviewed Cancer Research Program (PRCRP) Horizon Award, I seek to reduce the burden of EBV-driven infection and lymphomas for military Service members, their families, and the general population by developing and characterizing a protective vaccine against EBV infection.

EBV infects more than 90% of the human population and is considered a cancer-causing virus. Indeed, EBV infection is associated with the development of about 200,000 new cancer cases every year, which include various lymphomas and related post-transplant disorders. In addition, EBV is the causative agent behind infectious mononucleosis (mono) which, while not life-threatening, can lead to debilitating and severe complications. Due to the sometimes-crowded living conditions associated with military settings, military Service members and trainees are particularly at risk of acquiring EBV and developing mono, which not only results in more than 2,797 weeks of lost duty per year, but also increases the risk of developing EBV-driven lymphomas and other cancers later in life.

Military Service conditions (such as exposure to additional infectious agents, training, or battle wounds) may also result in the need for tissue or organ transplantation. Indeed, from 2003 to 2014, more than 55,000 U.S. soldiers and Veterans were classified as potentially eligible for stem cell or solid organ transplants. Transplantation success is highly dependent on sufficient suppression of the immune system to prevent tissue/organ rejection. However, suppression of the immune system also increases the risk of development of EBV-driven post-transplant proliferative disorders (transplant-related lymphomas), which have reported mortality rates of up to 80%. Despite the health and economic burdens posed by EBV, a preventive vaccine against EBV infection is currently lacking. Previous EBV vaccine candidates tested in the clinic targeted a single protein used by the virus to mediate infection, but they were unsuccessful in reducing infection in four clinical trials. Research has shown that although this protein enhances infection, it is not necessary for infection. Furthermore, EBV uses four additional proteins to infect the host. A successful protective vaccine might thus require targeting of all five viral proteins important for infection. Therefore, the objective of this application is to: (1) develop and characterize a vaccine candidate that targets these five proteins, and (2) test the vaccine’s ability to prevent EBV infection in cells grown in the laboratory and to prevent EBV infection and lymphoproliferative disorders in a mouse model.

To attain the necessary skills to complete this project successfully, my Researcher Development Plan includes technical training at my institution for pre-clinical animal testing, particularly on the mouse model of EBV infection and lymphoma I will use in this project. I will also take courses in areas relevant to my proposed research and career interests. I plan to present the results of my research in peer-reviewed publications and at several local and international scientific meetings, which will further support my professional development.

Successful completion of this project will advance my career toward becoming an independent cancer researcher, inform future EBV vaccine development studies, and lay the necessary groundwork for translating such a vaccine into the clinic. In the short-term (two years, the duration of the proposed project), to address the Fiscal Year 2019 (FY19) PRCRP Topic Area of lymphoma and the FY19 PRCRP Military Health Focus Area of environmental/exposure risk factors associated with cancer, I will develop and characterize a preventive EBV vaccine candidate and validate it in an animal model relevant to human EBV infection and disease. In the medium-term (5 years), I expect the results from the proposed experiments to support a U.S. Food and Drug Administration Investigational New Drug application. This will lead to clinical trials in healthy individuals that can establish the safety and protective ability of the vaccine candidate in the clinic. In the long-term (10 to 20 years), if successful, I expect the vaccine candidate to become a licensed EBV protective vaccine that will effectively prevent EBV infection and its associated diseases. This vaccine would impact military health directly by providing protection against EBV infection and mono, effectively reducing lost-duty time associated with this disease. Importantly, the vaccine would reduce the risk of developing lymphoma in both military members, their beneficiaries, and the general population, and significantly reduce the risk of developing post-transplant lymphoproliferative disorders in transplant recipients. Overall, successful completion of the proposed research and subsequent translation of the proposed vaccine candidate into the clinic would reduce the health and economic burden associated with EBV infection and EBV-driven lymphoma for military members, their families, and the general population.