David Milich, Ph.D.
Director/Chairman of the Board, Vaccine Research Institute of San Diego
The Milich lab has developed a transgenic mouse model focusing on the immune response to HBV nucleoproteins as well as a vaccine platform for developing vaccines to problem diseases which as yet have not yielded to more standard vaccine design.
Dr. Milich as been studying the immune response to Hepatitis B for many years. The clinical consequences of HBV infection are extremely variable. It has been suggested that variation in immune responsiveness to HBV infection may, at least partially, account for the diversity of clinical syndromes associated with HBV infection (Lancet 1972; 723-725; Dudley, F, J., et al). After clinically apparent acute hepatitis B infection, approximately 90% of affected adults recover without sequelae, and develop immunity to the virus; however, the clinical course can be quite variable. In another 0.1-0.5% of cases a fulminant hepatitis results in which cell death in the liver is so extensive that fewer that 20-30% of these patients survive. Finally, 5-10% of adults exposed to HBV develop a chronic infection. The nature of the chronic infection is also variable, ranging from continuous hepatocellular necrosis and inflammation to an asymptomatic carrier state. Chronic HBV infection is also associated with hepatocellular carcinoma. Exposure to the virus during the first year of life often results in chronic infection and represents the major route of infection of the 350 million chronically infected individuals worldwide.
In order to address questions related to this variation in the immune response to HBV infection, the Milich lab in collaboration with the Chisari lab at The Scripps Research Institute has developed an experimental mouse model including HBV T-cell receptor and HBV nucleocapsid transgenic mice. This model offers a unique opportunity to study the genetic, cellular and molecular basis for variable immune responsiveness to HBV-encoded antigens. The on-going research in this area focuses on: 1) HBV nucleocapsid T-cell tolerance at the cellular and molecular levels, 2) the relationships between HBV nucleocapsid-specific CD4+/- and CD8 +/- T cells, 3) reasons for ‘split tolerance' between the secreted versus intracellular form of the HBV nucleocapsid at the cellular and molecular levels and 4) development of strategies to reverse or bypass HBV nucleocapsid tolerance as a possible immunotherapy for chronic HBV infection. In the course of developing such an immunotherapy it is hoped that a greater understanding of the basic nature of immune regulation will be gained.
The particulate hepatitis core protein (HBcAg) represents an efficient carrier platform with many of the characteristics uniquely required for the delivery of weak immunogens to the immune system. Although the HBcAg is highly immunogenic, the existing HBcAg-based platform technology has a number of theoretical and practical limitations including the issues of "preexisting immunity" and "assembly". Investigators at the VRISD hope to resolve the problems inherent in the existing hepadnaviral core vaccine platform technology and to optimize the next generation platform. Because native woodchuck hepadnavirus core protein (WHcAg) is extremely protease resistant and equal in immunogenicity to or more immunogenic than HBcAg at the B-cell and T-cell levels, the strategy will be to recapitulate these qualities in hybrid-WHcAg particles. This research will focus on two main areas: 1) the role and implications of B cells as antigen presenting cells (APC) for HBc/WHcAg core particles and 2) identifying a post-assembly degradation pathway that may represent core particle "disassembly".
Looking forward, the intention is to develop optimized therapeutic and/or prophylactic vaccines for pathogens such as HBV, HCV, influenza and Malaria. Additionally, this platform will be used to develop vaccines for cancer, allergies and cholesterolemia.
1. Frelin L, Wahlstrom T, Tucker, AE, Jones J, Hughes J, Lee BO, Billaud JN, Peters C, Whitacre D Peterson D Milich DR. A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J of Virol. 2009; 83:1379-1392.
Dr. Milich is an immunologist who has enjoyed a very productive career studying the immune response to the hepatitis B and C viruses. Having published in excess of 150 peer reviewed articles, he is regarded internationally as an outstanding investigator who seeks innovative approaches to answer significant questions. Over the course of his career he has been awarded multiple grants from the private sector as well as the NIH. His expertise in the areas of virology, cellular immunology, immune tolerance and transgenic murine systems will be pivotal to the success of VRISD's quest to solve the problems inherent in vaccine development. He founded the Vaccine Research Institute of San Diego in 2000.
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