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MECHANISMS OF CHRONIC HEPATITIS B INFECTION AND THERAPEUTIC VACCINES

Award Number: R01AI020720
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/1984
PERIOD OF PERFORMANCE END DATE: 06/30/2012

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MECHANISMS OF CHRONIC HEPATITIS B INFECTION AND THERAPEUTIC VACCINES - The he'patitiS'Bvirus (HBV) is a major cause of infectious liver disease throughout the world. There are 1.2 million carriers of HBV in the U.S. and approximately 400 million worldwide. Neonatal HBV infection is rarely cleared and as many as 90% of perinatally infected children become chronically infected. Therefore, in addition to worldwide vaccine programs to prevent new infections, methods for treating HBV chronic carriers will be necessary to eradicate this disease. This proposal is focused on understanding the mechanisms responsible for inducing and maintaining chronic HBV infection and more specifically the role of HBV nucleoprotein antigens, the nueleocapsid (HBcAg) and the secreted non-particulate HBeAg. Armed with this information we are designing immunotherapeutic vaccine candidates for the treatment of chronic hepatitis B infection. The specific aims are addressed through the use of HBc/HBeAg-expressing and HBV replicating tra'nsgehic(Tg) mice and three recently developed HBc/HBeAg-specific T cell receptor (TCR)-Tg lineages and the Various combinations of "double and triple-Tg" hybrids. The specific aims are: (1) determine mechanisms of HBeAg-induced t cell tolerance at the cellular and molecular levels; (2) examine the relationship between HBc/HBeAg-specific CD4+ and CD8+ T cells; (3) explore the reasons for "split tolerance" between the HBcAg and the HBeAg at the cellular and molecular levels; and (4) develop strategies to reverse or bypass HBeAg-induced T cell tolerance as possible immunotherapies for chronic HBV infection. During the previous years of this project we have developed a number of Tg model systems that will facilitate the pursuit of the current specific aims. For example, four in vivo models of HBeAg-induced T cell tolerance mediate'd by clohal deletion, clonal anergy, clonal ignorance and T regulatory (Treg) cells have been developed. Furthermore, models of in vivo anti-HBc and anti-HBe seroconversion and CD4+ T cell-mediated liver injury have been developed. These model systems should be very useful in elucidating the mechanisms of T cell tolerance that play an important role in promoting viral persistence during chronic HBV infection and in designing candidate vaccines for treating chronic HBV infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	28	1/18/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $777,154 )
2011	2011	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	28	5/26/2011	NON-COMPETING CONTINUATION	$49,479
2011	2011	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	28	12/9/2010	NON-COMPETING CONTINUATION	$727,675
														Subtotal = $777,154

Issue Date FY: 2010 ( Subtotal = $784,979 )
2010	2010	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	27	5/12/2010	NON-COMPETING CONTINUATION	$71,360
2010	2010	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	27	12/21/2009	NON-COMPETING CONTINUATION	$713,619
														Subtotal = $784,979

Issue Date FY: 2009 ( Subtotal = $769,814 )
2009	2009	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	26	12/18/2008	NON-COMPETING CONTINUATION	$692,832
2009	2009	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	26	5/21/2009	NON-COMPETING CONTINUATION	$76,982
														Subtotal = $769,814

Issue Date FY: 2008 ( Subtotal = $747,395 )
2008	2008	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	25	12/17/2007	NON-COMPETING CONTINUATION	$747,395
														Subtotal = $747,395

Issue Date FY: 2007 ( Subtotal = $739,678 )
2007	2007	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	24	12/26/2006	COMPETING CONTINUATION	$739,678
														Subtotal = $739,678

Issue Date FY: 2005 ( Subtotal = $703,710 )
2005	2005	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	23	3/9/2005	NON-COMPETING CONTINUATION	$703,710
														Subtotal = $703,710

Issue Date FY: 2004 ( Subtotal = $683,213 )
2004	2004	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	22	3/8/2004	NON-COMPETING CONTINUATION	$683,213
														Subtotal = $683,213

Issue Date FY: 2003 ( Subtotal = $663,313 )
2003	2003	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	21		NON-COMPETING CONTINUATION	$663,313
														Subtotal = $663,313

Issue Date FY: 2002 ( Subtotal = $643,993 )
2002	2002	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	20	8/2/2002	NON-COMPETING CONTINUATION	$643,993
														Subtotal = $643,993

Issue Date FY: 2001 ( Subtotal = $558,374 )
2001	2001	VACCINE RESEARCH INSTITUTE OF SAN DIEGO	3030 SCIENCE PARK ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	19	9/13/2001	COMPETING CONTINUATION	$558,374
														Subtotal = $558,374

Issue Date FY: 2000 ( Subtotal = $598,886 )
2000	2000	IMMUNE COMPLEX CORPORATION	PO BOX 910564	SAN DIEGO	CA	92191	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	17	7/30/2000	NON-COMPETING CONTINUATION	$598,886
														Subtotal = $598,886

Issue Date FY: 1999 ( Subtotal = $534,513 )
1999	1999	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	15	3/10/1999	NON-COMPETING CONTINUATION	$534,513
														Subtotal = $534,513

Issue Date FY: 1998 ( Subtotal = $513,956 )
1998	1998	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Microbiology and Infectious Diseases Research	000	14	3/23/1998	NON-COMPETING CONTINUATION	$513,956
														Subtotal = $513,956

Grand Total All Awards = $8,718,978

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MECHANISMS OF CHRONIC HEPATITIS B INFECTION AND THERAPEUTIC VACCINES

Award Number: R01AI020720

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/1984

PERIOD OF PERFORMANCE END DATE: 06/30/2012

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