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Vaccine Assembly from Surface Proteins of Staphylococcus aureus

Award Number: R01AI052474
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: 06/01/2002
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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View Award Description

Vaccine Assembly from Surface Proteins of Staphylococcus aureus - ABSTRACT Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. Nasal colonization is observed in the first weeks of life and persists despite the development of serum IgG against staphylococcal antigens. S. aureus is also an invasive pathogen, causing soft tissue, wound, lung, skeletal and bloodstream infections in community- and hospital-settings. Infection with antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), is associated with treatment failure and poor disease outcomes. MRSA and methicillin-sensitive (MSSA) strains are frequent causes of infectious disease morbidity and mortality in the United States. It is not always clear why colonization progresses to infection but such transition indicates that antibody responses elicited upon colonization are not protective. The surface of S. aureus is coated with over 10,000 molecules of Staphylococcal protein A (SpA) linked to peptidoglycan by the Sortase A enzyme. Using genetic and biochemical schemes, we found that peptidoglycan-modified SpA diverts antibodies away from their intended targets by interacting with the Fcg domain of IgG and by blocking complement activation. Thus, surface exposed SpA neutralizes the effector functions of pathogen-specific antibodies, including antibodies elicited by candidate vaccines. SpA is also released from the bacterial envelope and binds the variant heavy chains of VH3-IgM that serves as the B cell receptor (BCR) in approximately half of human B cells. SpA-BCR interactions prevent the development of neutralizing anti-SpA antibodies and instead trigger B cell proliferation and the secretion of VH3-rearranged antibodies with no specificity toward S. aureus. Carefully applied molecular engineering yielded the non-toxigenic SpA* vaccine that elicits SpA-neutralizing antibodies. When tested in our mouse model of colonization that takes advantage of the mouse-adapted strain WU1, we found that SpA* immunization leads to broad spectrum anti-S. aureus immune responses. We presume that some of these antibodies target the colonization factors of S. aureus that we seek to identify in this proposal. We also presume that during colonization SpA diffuses into nasal- associated lymphoid tissues to reprogram their B cell repertoire. Lastly, we will evaluate mechanisms of protection against colonization by examining the contribution of serum opsonophagocytic antibodies and luminal IgA for the nasopharyngeal clearance of S. aureus.


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: 2026 ( Subtotal = $410,000 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	22	4/8/2026	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2025 ( Subtotal = $410,000 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	21	4/1/2025	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2024 ( Subtotal = $410,000 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	20	5/24/2024	NON-COMPETING CONTINUATION	$41,000
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	20	3/1/2024	NON-COMPETING CONTINUATION	$369,000
2024	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	004	19	7/31/2024	COMPETING CONTINUATION	$17
2024	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	19	10/19/2023	COMPETING CONTINUATION	$0
2024	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	003	18	7/31/2024	NON-COMPETING CONTINUATION	-$17
														Subtotal = $410,000

Issue Date FY: 2023 ( Subtotal = $410,000 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	19	2/22/2023	COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2022 ( Subtotal = $445,500 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	18	4/7/2022	NON-COMPETING CONTINUATION	$445,500
														Subtotal = $445,500

Issue Date FY: 2021 ( Subtotal = $445,500 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	17	3/15/2021	NON-COMPETING CONTINUATION	$445,500
														Subtotal = $445,500

Issue Date FY: 2020 ( Subtotal = $445,500 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	16	3/11/2020	NON-COMPETING CONTINUATION	$445,500
														Subtotal = $445,500

Issue Date FY: 2019 ( Subtotal = $445,494 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	15	7/23/2019	COMPETING CONTINUATION	$0
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	15	4/3/2019	COMPETING CONTINUATION	$445,500
2019	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	14	12/17/2018	NON-COMPETING CONTINUATION	-$6
														Subtotal = $445,494

Issue Date FY: 2017 ( Subtotal = $395,000 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	14	6/20/2017	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2016 ( Subtotal = $395,000 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	13	6/13/2016	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2015 ( Subtotal = $395,000 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	12	6/29/2015	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2014 ( Subtotal = $395,000 )
2014	2014	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	11	7/15/2014	COMPETING CONTINUATION	$395,000
2014	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	10	6/13/2014	NON-COMPETING CONTINUATION	$0
2014	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	10	7/15/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $395,000

Issue Date FY: 2013 ( Subtotal = $354,352 )
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	10	1/15/2013	NON-COMPETING CONTINUATION	$0
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	10	11/19/2012	NON-COMPETING CONTINUATION	$339,273
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	10	5/28/2013	NON-COMPETING CONTINUATION	$15,079
														Subtotal = $354,352

Issue Date FY: 2012 ( Subtotal = $376,970 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	9	5/30/2012	NON-COMPETING CONTINUATION	$37,697
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	9	11/25/2011	NON-COMPETING CONTINUATION	$339,273
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	9	9/13/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,970

Issue Date FY: 2011 ( Subtotal = $376,970 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	8	6/15/2011	NON-COMPETING CONTINUATION	$34,270
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	8	11/11/2010	NON-COMPETING CONTINUATION	$342,700
														Subtotal = $376,970

Issue Date FY: 2010 ( Subtotal = $380,778 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	7	5/10/2010	NON-COMPETING CONTINUATION	$34,616
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	7	11/20/2009	NON-COMPETING CONTINUATION	$346,162
														Subtotal = $380,778

Issue Date FY: 2009 ( Subtotal = $384,624 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	6	12/5/2008	COMPETING CONTINUATION	$384,624
														Subtotal = $384,624

Issue Date FY: 2006 ( Subtotal = $372,291 )
2006	2006	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	4/21/2006	NON-COMPETING CONTINUATION	$372,291
														Subtotal = $372,291

Grand Total All Awards = $8,772,667

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Vaccine Assembly from Surface Proteins of Staphylococcus aureus

Award Number: R01AI052474

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: 06/01/2002

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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