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Immune Mechanisms of Protection in S. Typhi Infection and Vaccination in Humans

Award Number: R01AI036525
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: 09/01/1994
PERIOD OF PERFORMANCE END DATE: 05/31/2024

Group Awards By:

View Award Description

Immune Mechanisms of Protection in S. Typhi Infection and Vaccination in Humans - Project Summary Limited understanding of the immunological mechanisms underlying protective immunity hampers the development of novel vaccines, particularly against human-restricted enteric bacteria such as Salmonella Typhi. The near exclusive reliance on circulating immune cells, which do not necessarily reflect the responses of “resident” immune cells present in the gut, is another major limitation. Over the past 25 years, in studies largely supported by this R01, and particularly during the last funding period (2013-2018), the PI reported major advances in our understanding the B, T and innate immune responses elicited by the licensed Ty21a oral typhoid and other candidate attenuated S. Typhi vaccines and, more recently, using specimens obtained from a wild type (wt) S. Typhi human challenge model. The latter studies examined, among other key immune cell types, the induction and activation of memory T (TM) subsets and regulatory T cells (TREG), demonstrating, for the first time, an association between defined multifunctional CD8+ subsets and regulatory T cell (TREG) responses and clinical outcome upon challenge. However, many key questions regarding whether the same T subsets are elicited following Ty21a immunization and are associated with protection from challenge with wt S. Typhi and the induction and persistence of gut and systemic immunity following vaccination remain unexplored. These major gaps should be addressed before we can apply this knowledge to the development of more effective oral vaccines. To directly address these major gaps, we propose to continue and greatly expand our findings during the current funding period by evaluating the hypotheses that the characteristics of CD4 and CD8 T-CMI S. Typhi- specific responses, including TM subsets (e.g., TM, T effector (TEFF), T stem-cell like memory (TSCM), and TREG at baseline and at the early stages after immunization and/or challenge with wt S. Typhi play critical roles in protection from infection and persistence of immunity in humans. To this end we will use unique specimens from adults vaccinated and/or challenged with wt S. Typhi, and gut biopsies from participants vaccinated with Ty21a to: Aim 1. Evaluate the hypothesis that defined T cell subsets with gut-homing potential present at baseline and those elicited during the early stages following Ty21a vaccination and/or wt S. Typhi challenge are associated with robust immunity, protection from clinical disease and persistent immunity. Aim 2. Evaluate the hypothesis that protection from infection following wt S. Typhi challenge and robust effector and memory immunity following vaccination is associated with defined regulatory T cell (TREG) responses and depends on a balanced TEFF / TM / TSCM / and TREG responses at baseline and after immunization. Aim 3. Evaluate the hypothesis that robust terminal ileum (TI) CD4 and CD8 TEFF, TM, and T resident/memory (TRM) responses in the absence of TREG cells is associated with long-term maintenance of mucosal and systemic responses (TEFF, TM, TSCM) after oral immunization of volunteers with the Ty21a typhoid vaccine.


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 = $2,783,014 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	25	3/27/2026	COMPETING CONTINUATION	$2,783,014
														Subtotal = $2,783,014

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	24	7/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $567,403 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	24	5/12/2023	NON-COMPETING CONTINUATION	$567,403
														Subtotal = $567,403

Issue Date FY: 2022 ( Subtotal = $567,403 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	23	5/19/2022	NON-COMPETING CONTINUATION	$567,403
														Subtotal = $567,403

Issue Date FY: 2021 ( Subtotal = $567,403 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	22	5/28/2021	NON-COMPETING CONTINUATION	$567,403
														Subtotal = $567,403

Issue Date FY: 2020 ( Subtotal = $567,403 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	21	6/11/2020	NON-COMPETING CONTINUATION	$567,403
2020	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	19	2/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $567,403

Issue Date FY: 2019 ( Subtotal = $567,403 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	20	6/12/2019	COMPETING CONTINUATION	$567,403
2019	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	19	3/1/2019	NON-COMPETING CONTINUATION	$0
2019	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	19	6/7/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $567,403

Issue Date FY: 2017 ( Subtotal = $469,830 )
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	19	2/6/2017	NON-COMPETING CONTINUATION	$469,830
														Subtotal = $469,830

Issue Date FY: 2016 ( Subtotal = $469,830 )
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	18	2/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$469,830
														Subtotal = $469,830

Issue Date FY: 2015 ( Subtotal = $469,830 )
2015	2015	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	17	2/23/2015	NON-COMPETING CONTINUATION	$469,830
														Subtotal = $469,830

Issue Date FY: 2014 ( Subtotal = $558,993 )
2014	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	16	3/5/2014	NON-COMPETING CONTINUATION	$555,790
2014	2013	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	15	4/23/2014	SUPPLEMENT FOR EXPANSION	$3,203
														Subtotal = $558,993

Issue Date FY: 2013 ( Subtotal = $502,375 )
2013	2013	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	003	15	6/19/2013	COMPETING CONTINUATION	$19,105
2013	2013	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	15	3/19/2013	COMPETING CONTINUATION	$429,866
2013	2013	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	004	15	8/15/2013	SUPPLEMENT FOR EXPANSION	$50,201
2013	2013	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	005	15	4/23/2014	SUPPLEMENT FOR EXPANSION	$3,203
2013	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	14	3/14/2013	NON-COMPETING CONTINUATION	$0
2013	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	14	10/19/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $502,375

Issue Date FY: 2011 ( Subtotal = $449,163 )
2011	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	14	11/16/2010	NON-COMPETING CONTINUATION	$420,564
2011	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	14	5/26/2011	NON-COMPETING CONTINUATION	$28,599
2011	2011	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	14	9/27/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $449,163

Issue Date FY: 2010 ( Subtotal = $456,230 )
2010	2010	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	13	5/24/2010	NON-COMPETING CONTINUATION	$41,475
2010	2010	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	13	11/18/2009	NON-COMPETING CONTINUATION	$414,755
														Subtotal = $456,230

Issue Date FY: 2009 ( Subtotal = $449,991 )
2009	2009	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	12	6/2/2009	NON-COMPETING CONTINUATION	$44,999
2009	2009	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	12	11/18/2008	NON-COMPETING CONTINUATION	$404,992
														Subtotal = $449,991

Issue Date FY: 2008 ( Subtotal = $439,396 )
2008	2008	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	11	2/8/2008	NON-COMPETING CONTINUATION	$439,396
														Subtotal = $439,396

Issue Date FY: 2007 ( Subtotal = $419,872 )
2007	2007	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	10	12/11/2006	COMPETING CONTINUATION	$419,872
														Subtotal = $419,872

Issue Date FY: 2004 ( Subtotal = $350,196 )
2004	2004	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	737 WEST LOMBARD STREET	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Microbiology and Infectious Diseases Research	000	9	5/24/2004	NON-COMPETING CONTINUATION	$350,196
														Subtotal = $350,196

Issue Date FY: 2003 ( Subtotal = $467,431 ) (Continued on the next page)
Grand Total All Awards = $12,157,737

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Immune Mechanisms of Protection in S. Typhi Infection and Vaccination in Humans

Award Number: R01AI036525

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: 09/01/1994

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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