Development of a Listeria monocytogenes - based therapeutic HBV vaccine
Department of Health and Human Services
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626 BANCROFT WAY, 3C, BERKELEY, CA, -
Socially and Economically Disadvantaged:
AbstractDESCRIPTION (provided by applicant): Despite the availability of a safe and effective prophylactic vaccine for hepatitis B virus (HBV), each year a significant number of new infections are reported to the CDC in the United States. Worldwide more than 2 billion people have been infected with HBV, and more than 350 million have developed chronic infections, which frequently lead to liver cirrhosis and liver cancer. None of the currently available antiviral therapies result in clearance of HBV infection whichcomplicates the goal of eradicating HBV in the US. Clearly, new treatments of chronic HBV infections are needed. Notably, studies in chronically infected chimpanzees and liver transplant patients demonstrated a causal role for T cells during HBV viral clearance. This suggests that active immunotherapies which induce potent T cell immunity may be effective for the treatment of chronic hepatitis B. Recent advances in the field of bacterial-based vaccine vectors have shown promising results for infectious disease-targeted immunotherapy. One such example is the use of live-attenuated and killed strains of the intracellular bacterium Listeria monocytogenes (Lm). Lm represents an attractive platform for therapeutic HBV vaccines due to its ability to induce robustinnate immunity as well as acquired CD4+ and CD8+ T-cell immunity. T cells represent the immune system's most potent weapon against chronic viral infections such as HBV. However, Lm is a pathogenic infectious agent in man, and in order to provide an appropriate therapeutic window, we have developed two highly attenuated vaccine platforms. The first is live- attenuated Lm in which two virulence genes have been completely deleted from the bacterial chromosome (Lm actA inlB). The second platform is based onLm that is inactivated in such a way to prevent its replication while retaining its metabolic activity. These killed but metabolically active (KBMA) Lm are still able to induce robust cellular immunity and therefore provide a promising approach for therapeutic vaccine development. The live-attenuated Lm platform has already been tested clinically under three separate U.S. Investigational New Drug Applications (INDs), and is therefore the more advanced of the two approaches. Our proposal will help to define an Lm-based clinical vaccine candidate in the setting of chronic hepatitis B virus infection. The overall goal of this NIH SBIR Phase 1 proposal is to establish proof-of-concept (POC) to support the initiation of a development program for a KBMA Lm-basedhepatitis B therapeutic vaccine expressing several HBV antigens (HBsAg, HBcAg, and HBV Pol), that ultimately results in safety and efficacy testing in human clinical trials. To this end, we propose the following aims: (1) Construct a panel of recombinantHBV antigen-expressing Lm strains; (2) Select the best monovalent configuration for each HBV Ag based ability to stimulate a reporter T cell line, expression of HBV antigens in cell culture, and immunogenicity in mice; and (3) Select a polyvalent KBMA Lm HBV clinical vaccine strain candidate for further development. PUBLIC HEALTH RELEVANCE: An effective treatment for hepatitis B virus infection remains a significant unmet medical need in the United States and worldwide, despite the availability of a safeand effective prophylactic vaccine. Current small molecule-based treatments suppress viral gene expression, but fail to induce viral clearance. Recent findings in chronically infected chimpanzees and liver transplant patients suggest that therapeutic vaccines which induce multifunctional T cell immunity may be effective for the treatment of chronic hepatitis B.
* information listed above is at the time of submission.