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A Phase 1/2a, randomized study of a Tfh-targeting genetic vaccine adjuvant designed to induce broad, durable immune responses

Award Number: U01AI172800
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: 05/07/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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A Phase 1/2a, randomized study of a Tfh-targeting genetic vaccine adjuvant designed to induce broad, durable immune responses - PROJECT SUMMARY/ABSTRACT This U01-supported clinical trial will test a unique T follicular helper (Tfh)-targeting vaccine approach, “s3”, that we predict will generate exceptionally broad and long-lived antigen-specific antibody responses, characteristics likely to result in resilient vaccines that maintain protection over long periods. The “s3” adjuvant moiety is an anti- CD3 antibody fragment (scFv) that safely induces a potent Tfh and B-cell response to an immunogen to which it is fused. The combined immunogen simultaneously targets immunogen-specific B cells and local Tfh cells, thus accelerating and expanding B-cell development. Using the RBD immunogen in a low dose Ad35 vector, we showed in macaques that s3 safely stimulates high NAb titers that are stable for >10 months. The major deficiencies of current SARS-COV-2 and other vaccines (such as influenza) are limited durability and breadth of protection, even with booster vaccination. Over the course of 6 months, serum antibodies in COVID- naïve vaccine recipients decline by one order of magnitude. Booster vaccination confers greater durability but notable declines in serum NAb titers occur by 4-6 months. Limited mucosal IgA responses is another major deficit that may underlie failure of current vaccine options to prevent acquisition at the site of virus entry. Finally, the breadth of responses is limited, even with bivalent vaccines. These vaccine deficiencies have been linked repeatedly to inadequate T-cell help. Thus, new approaches that provide abundant T-cell help, such as the proposed s3 approach, are needed to deliver more effective SARS-CoV-2 as well as pancoronavirus, influenza, and other vaccines. We will test the safety and immunogenicity of the s3 adjuvant using Ad35 as the vector and the SARS-CoV-2 BA.5 receptor-binding domain (RBD) as the immunogen. We will compare a vaccine with s3 (CoTend-s3B) against one lacking s3 (CoTend-B). The vaccines will be given as a “booster” vaccine on the background of prior SARS-CoV-2 spike mRNA vaccination. This approach will allow us to evaluate the ability of CoTend-s3B to (i) boost pre-existing antibodies and (ii) recruit new naïve B cells with new specificity for BA.5 RBD. Aim 1. Test safety of s3-adjuvanted/Tfh-targeted (CoTend-s3B) and unadjuvanted (CoTend-B) SARS- CoV-2 RBD vaccines. The primary safety readouts are local and systemic reactions, grade 3+ adverse events (AEs), serious adverse events, AEs of special interest (including thrombotic events), and anti-PF4 antibodies. Aim 2. Evaluate intensity, breadth, and durability of adaptive immune responses to CoTend-s3B compared to CoTend-B in blood and saliva. We hypothesize that Tfh responses to CoTend-s3B will support NAb responses of sufficient breadth and potency for long-lived protection against SARS-CoV-2 variants. Aim 3. Examine the mechanisms of s3 adjuvant activity in germinal centers. Tfh targeting via s3 is predicted to generate robust germinal-center reactions that democratize recruitment of naïve B cells and spur development of long-lived plasma cells.


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 = $1,429,199 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	5/1/2026	NON-COMPETING CONTINUATION	$1,429,199
2026	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/15/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,429,199

Issue Date FY: 2025 ( Subtotal = $1,417,453 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	2	5/14/2025	NON-COMPETING CONTINUATION	$1,417,453
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	11/29/2024	NEW	$0
														Subtotal = $1,417,453

Issue Date FY: 2024 ( Subtotal = $1,435,214 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	5/7/2024	NEW	$1,435,214
														Subtotal = $1,435,214

Grand Total All Awards = $4,281,866

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A Phase 1/2a, randomized study of a Tfh-targeting genetic vaccine adjuvant designed to induce broad, durable immune responses

Award Number: U01AI172800

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: 05/07/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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