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Development of vaccination strategies to elicit broadly protective immunity against influenza

Award Number: R01AI145870
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Development of vaccination strategies to elicit broadly protective immunity against influenza - ABSTRACT Licensed influenza vaccines commonly elicit strain-specific immunity, failing to provide protection against antigenically distinct strains with the capacity to cause pandemic outbreaks. Therefore, the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains is critically needed to prevent future influenza pandemics. Influenza hemagglutinin (HA) represents a key vaccine target, as it is the major glycoprotein expressed on the surface of influenza virions and mediates viral entry and fusion. HA comprises two distinct functional domains: (i) the globular head, which is highly variable due to antigenic drift, and (ii) the stalk domain, which is structurally conserved among diverse influenza strains. Influenza infection or vaccination commonly elicits immune responses against immunodominant, strain-specific epitopes on the HA head. By contrast, immune responses against highly conserved epitopes are limited and short-lived, despite conferring broad and heterologous protection. Refocusing the immune response towards conserved, immunosubdominant HA epitopes, while avoiding eliciting strain-specific immunity, represents a promising strategy for the development of a universal influenza vaccine that would confer broad protection against diverse influenza strains. To achieve this, the proposed studies aim to develop and evaluate novel HA immunogens, termed mosaic HAs (mHA), in which the immunodominant, strain-specific epitopes at the head domain have been replaced from those of exotic HAs which humans are naïve, while immunosubdominant, conserved epitopes have been retained. In previous studies, we have dissected the mechanisms by which antibodies, through specific interactions of their Fc domains with activating Type I Fcγ receptors (FcγRs), such as FcγRIIa on dendritic cells and with the Type II FcγR, CD23, on B cells modulate cellular and humoral immunity against influenza, respectively. Given the immunomodulatory consequences of Fc-FcγR interactions, the proposed studies will develop Fc-engineered mHA immunogens that will engage and activate specific FcγR pathways on defined effector cell populations to elicit broad and long-lasting immunity against diverse influenza strains. We anticipate that the proposed studies will lead to the design, selection, and pre-clinical evaluation of innovative immunogens with the capacity to confer durable and heterologous protection against influenza. These studies are expected to have important implications not only for our efforts towards the development of a universal influenza vaccine, but also provide the framework for the design of vaccines with long-lasting and broad protection against other viral pathogens, such as SARS-CoV-2.


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 = -$6,060 )
2025	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	6	12/4/2024	COMPETING CONTINUATION	$0
2025	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	12/4/2024	NON-COMPETING CONTINUATION	$0
2025	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	12/4/2024	SUPPLEMENT FOR EXPANSION	-$6,060
														Subtotal = -$6,060

Issue Date FY: 2024 ( Subtotal = $862,508 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	7/16/2024	COMPETING CONTINUATION	$862,508
2024	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	7/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $862,508

Issue Date FY: 2023 ( Subtotal = $847,458 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	5/19/2023	NON-COMPETING CONTINUATION	$847,458
														Subtotal = $847,458

Issue Date FY: 2022 ( Subtotal = $978,281 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	5/24/2022	SUPPLEMENT FOR EXPANSION	$130,823
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	5/10/2022	NON-COMPETING CONTINUATION	$847,458
														Subtotal = $978,281

Issue Date FY: 2021 ( Subtotal = $1,632,399 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	5/11/2021	NON-COMPETING CONTINUATION	$847,458
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	6/1/2021	NON-COMPETING CONTINUATION	$0
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	3	6/10/2021	SUPPLEMENT FOR EXPANSION	$784,941
														Subtotal = $1,632,399

Issue Date FY: 2020 ( Subtotal = $1,501,574 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	2	8/10/2020	SUPPLEMENT FOR EXPANSION	$654,116
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	2	8/3/2020	NON-COMPETING CONTINUATION	$0
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	5/21/2020	NON-COMPETING CONTINUATION	$847,458
														Subtotal = $1,501,574

Issue Date FY: 2019 ( Subtotal = $864,833 )
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	6/19/2019	NEW	$864,833
														Subtotal = $864,833

Grand Total All Awards = $6,680,993

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Development of vaccination strategies to elicit broadly protective immunity against influenza

Award Number: R01AI145870

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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