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Programming Durable Immune Responses To Vaccination

Award Number: U01AI141990
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/18/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Programming Durable Immune Responses To Vaccination - ABSTRACT mRNA-based vaccines use lipid nanoparticles to transport mRNA-encoding antigens to the host cells. We have recently shown that SARS-CoV-2 mRNA vaccination in humans induces a robust plasmablast response in blood and a persistent GC reaction in the draining lymph nodes. This corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity and neutralization capacity of bone marrow plasma cell (BMPC)-derived monoclonal antibodies (mAbs). mRNA-based influenza vaccines could be a promising alternative to conventional influenza vaccine platforms because of their high immunogenicity. The following questions, however, are yet to be addressed: (1) does an mRNA-based influenza vaccination induce a robust and persistent GC reaction in humans? (2) if yes, what drives such persistence, and how different is that from the GC response induced by conventional influenza vaccines? (3) can an mRNA-based influenza vaccination induce a robust GC response in the elderly (>65 years old)? (4) does robust GC response to influenza vaccination in humans correlate with a more durable antibody response? (5) does an mRNA-based influenza vaccination induce a more sustained increase in the frequency of long-lived BMPCs compared to conventional vaccines? (6) can a vaccine-induced robust GC response overcome influenza antigenic imprinting in humans? (7) what are the molecular determinants that dictate the persistence of BMPCs? Addressing these questions will allow us to discern the cellular and molecular determinants associated with durable antibody responses to vaccination in humans. We will directly examine antigen-specific GC and long-lived BMPC responses induced after mRNA-based and conventional influenza vaccination in humans in the proposed studies. These responses will be examined in 18- 50 year-old and 65-80 year-old human adults. We will assess the persistence of the vaccine antigen in draining lymph nodes as a potential mechanism for driving GC longevity in humans. We will examine how robust GC B cell responses to influenza vaccination in humans could overcome antigenic imprinting and if that correlates with a more durable antibody response. Finally, we will genetically analyze the mechanisms of action of the transcriptional determinants that are preferentially expressed in plasma cells destined for longevity. Our findings will potentially reveal the cellular and molecular determinants dictating the longevity and the breadth of elicited antibody responses to influenza – and potentially other – vaccination in humans.


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: 2025 ( Subtotal = $659,699 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	7	1/16/2025	NON-COMPETING CONTINUATION	$659,699
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	002	6	1/21/2025	COMPETING CONTINUATION	$44,783
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	5	1/21/2025	NON-COMPETING CONTINUATION	-$44,783
														Subtotal = $659,699

Issue Date FY: 2024 ( Subtotal = $593,729 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	6	2/1/2024	COMPETING CONTINUATION	$593,729
														Subtotal = $593,729

Issue Date FY: 2023 ( Subtotal = $654,858 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	5	2/24/2023	NON-COMPETING CONTINUATION	$0
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	5	11/7/2022	NON-COMPETING CONTINUATION	$654,858
														Subtotal = $654,858

Issue Date FY: 2022 ( Subtotal = $667,595 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	4	12/10/2021	NON-COMPETING CONTINUATION	$667,595
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	10/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $667,595

Issue Date FY: 2021 ( Subtotal = $679,996 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	3	12/16/2020	NON-COMPETING CONTINUATION	$679,996
2021	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	10/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $679,996

Issue Date FY: 2020 ( Subtotal = $693,502 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	11/26/2019	NON-COMPETING CONTINUATION	$693,502
														Subtotal = $693,502

Issue Date FY: 2019 ( Subtotal = $719,857 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	1	6/5/2019	NEW	$0
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	12/18/2018	NEW	$719,857
														Subtotal = $719,857

Grand Total All Awards = $4,669,236

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Programming Durable Immune Responses To Vaccination

Award Number: U01AI141990

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 12/18/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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