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"Extended dosing" immunization to enhance humoral immunity to next-generation vaccines

Award Number: R01AI175489
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: 02/14/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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"Extended dosing" immunization to enhance humoral immunity to next-generation vaccines - Project Summary/Abstract The majority of licensed vaccines are thought to elicit protection mediated by humoral immunity. A key determinant of the specificity and affinity of the antibody response is the germinal center (GC) response elicited by immunization, wherein B cells enter GCs to undergo cyclic rounds of proliferation and somatic hypermutation to evolve higher-affinity antibodies, followed by exit from the GC to become long-lived plasma cells or memory B cells. Effective GC responses are thought to be critical for difficult pathogens such as HIV, and even for easily- neutralized viruses such as SARS-CoV-2, effective and long-lived GC responses are associated with more effective cross-neutralization of viral variants. Hence, optimizing GC responses is fundamental to vaccines broadly. In recent work, we have studied how vaccine kinetics– the temporal pattern of antigen and adjuvant exposure during immunization– impact humoral immunity and GC reaction in particular. Our preliminary studies have revealed that prolonged delivery of antigen to draining lymph nodes over a period of 2-3 weeks substantially alters the immune response. One particularly effective immunization approach, which we term “extended dosing” (ext-dosing) immunization, involves administering a given total dose of vaccine antigen and adjuvant as a half-dozen injections over two weeks in an escalating-dose pattern. Ext-dosing enhances the magnitude of the GC response in both small and large animal models and increases the clonality (number of distinct B cell clones participating in the GC), leading to enhanced neutralizing antibody production. These dramatic effects of ext-dosing vaccination warrant close study to understand how and why this strategy is so effective. As ext-dosing through repeat injections is not practical for human immunization, we are also highly motivated to develop alternate strategies to achieve the same immunologic effects without the need for 6 or more injections. To address these goals, our specific aims are (1) define how antigen exposure kinetics govern the immune response elicited by ext-dosing immunization, (2) determine how adjuvant exposure kinetics impact the immune response in ext-dosing, (3) test strategies to achieve “extended-dosing” effects using bolus subunit vaccine administration, and (4) to evaluate the potential for ext-dosing-like effects in mRNA vaccines. Altogether, these studies will both clarify fundamental concepts underlying effective primary immune responses and develop new translationally-relevant approaches to enhance immune responses elicited by subunit and mRNA vaccines. We test-bed these concepts using clinically-relevant antigens and adjuvants, and aim to pursue strategies we expect to be broadly applicable to vaccines independent of disease target.


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 = $477,610 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	1/15/2026	NON-COMPETING CONTINUATION	$477,610
														Subtotal = $477,610

Issue Date FY: 2025 ( Subtotal = $454,147 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	1/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$454,147
2025	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	1/7/2025	NON-COMPETING CONTINUATION	$0
2025	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	2	5/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $454,147

Issue Date FY: 2024 ( Subtotal = $469,443 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$46,944
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	1/31/2024	NON-COMPETING CONTINUATION	$422,499
														Subtotal = $469,443

Issue Date FY: 2023 ( Subtotal = $469,443 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	2/14/2023	NEW	$469,443
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	1	7/24/2023	NEW	$0
														Subtotal = $469,443

Grand Total All Awards = $1,870,643

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"Extended dosing" immunization to enhance humoral immunity to next-generation vaccines

Award Number: R01AI175489

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: 02/14/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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