The use of DNA for the development of novel prophylactic and therapeutic vaccines against the hepatitis B virus

by Payette, Paul J.

The prevention and control of new and existing hepatitis B virus (HBV) infections remains an important global health concem. Despite current global immunization efforts, new HBV infection continues to occur. It is estimated that about 350 million people worldwide are currently afflicted by viral persistence. This body of work explores the possibility of developing improved prophylactic and possibly therapeutic vaccines against HBV using DNA technology. It has become well established that the effective control of HBV infection requires the development of strong humoral and cell mediated immunity (CMI) including the production of the pro-in fiammatory cytokines interferon (1 FN) y and tumor necrosis factor (TNF) a that are associated with a CM1 response. In the absence of these responses infection is not resolved and persistence ensues. The ability of DNA (either in the form of a DNA vaccine or as immunostirnulatory DNA sequences in combination with protein antigens) to stimulate both humoral and cellular immune responses that include the production of lFNy and TNFa, makes them attractive candidates for development of novel prophylactic and therapeutic agents in the struggle against HBV infection. This work demonstrates that immunization strategies that include DNA technology were capable of controlling HBV gene expression in a hepatitis B surface antigen transgenic mouse model as well as provide protection against infectious HBV challenge in chimpanzees. The quality of the immune responses induced in the chimpanzees suggests that the therapeutic potential of these immunization strategies observed in the mouse model may also extend to higher primates. First and foremost I would like to thank my supervisor, Dr. Heather L. Davis. Her faith, guidance, and support have allowed me to becorne a better scientist. I would like to thank the University of Ottawa, Medical Research Council of Canada, the govemment of Ontario, and Coley Phannaceutical Group Inc. for their support of this work. Iwould like to thank our collaborators, Dr. Marie-Louise Michel of the Pasteur Institute, and Or. Robert Purcell of the National lnstitute of Health for the wonderful opportunities and experiences. Iwould like to thank Dr. R Bradbury, Max Shapiro and their team at Bioqual Inc. for their expertise and assistance with the chimpanzee immunizations. Iwould like to thank the members of my thesis advisory cornmittee, Dr. Kathryn Wright, Dr. Ken Dimdc, and Dr. Ken Rosenthal, for their valuable and much appreciated input. I would like to thank rny colleagues, Dr. Risini D Weeratna, Dr. Michael J McCluskie, and the whole research team at Coley Pharrnaceutical Group Inc. for continual encouragement and support. I would like to thank the staff of the animal Gare facility at the LOEB Health Research lnstitute for their guidance and support. I would like to thank Dr. Wallace Lauzon for our continual and stimulating immunological discussions. Iwould like to thank my parents for giving me the drive to succeed. Finally I would Iike to thank my wife Genny Giroux, whose love and support have been, and will continue to be, the foundation of my career. She is my partner, my confidant, and most of all, my very best friend. iii