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Synthetic DNA-launched and adjuvanted Env immunogens for HIV

Award Number: U19AI166916
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: 12/08/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Synthetic DNA-launched and adjuvanted Env immunogens for HIV - Overall Summary A protective vaccine for HIV is arguably the most important prevention strategy to end the global HIV pandemic. The RV144 trial demonstrated a correlation between protection and envelope (Env) specific serum IgG antibodies. However, there was a notable lack of HIV-specific neutralizing antibodies (nAbs) and T cell responses. The DNA platform has several advantages, it is (1) simple to design, (2) can co-deliver molecular adjuvants, (3) can deliver complex structural antigens, and (4) is safe and well tolerated, even after numerous boosts. In our previous IPCAVD program we developed DNA-launched nanoparticle (DLNP) vaccines targeting Env which induced potent and neutralizing immunity in vivo. We have also developed DNA-launched native-like trimer (DL-NLT) immunogens including the clinically relevant BG505 MD39 trimer (Xu et al. Nat. Comm 2022). Protein nanoparticles are difficult to manufacture and poorly stimulate CD8+ T cells. We reported that in vivo assembled nanoparticles drive extremely rapid and strong B and T cell immunity. Functional antibody responses require help from germinal center (GC) follicular helper T cells (TFH). In previous clinical trials with HIV antigens, we observed increased B and T cell responses in the presence of plasmid-encoded IL-12 (pIL-12). Work from members of this team has demonstrated that co-delivery of adenosine deaminase (ADA-1) and plasmid-encoded IL-21 (pIL-21) can enhance antibody induction in mice in a GC-dependent fashion. Here, we combine the DLNP and DL-NLT platforms to generate DNLPs bearing stabilized NLTs focusing immune responses on apex and CD4bs B cell lineage-targeting Envs (DNLP-ACE). We will characterize humoral and cellular immunity to these constructs in the presence of molecular IL-12 with and without additional GC-targeting adjuvants, in mouse and non-human primate vaccination studies. The overarching hypothesis of this project is that DLNP-ACE immunogen technology combined with the co-delivery of genetic adjuvants is a novel approach for the development of HIV-1 vaccines that promotes robust, durable, broad, and neutralizing antibody responses, and supports effector T cell function in vivo A key innovation of this project will be to integrate the selected DNLP-ACE HIV vaccine constructs in a dual expressing plasmid construct with next generation noninvasive intradermal skin electroporation (EP) devices which promote functional CTL and humoral immune responses. The clinical development plan for this IPCAVD is directed by a leading HIV vaccine development organization, Inovio Pharmaceuticals (INO), which has expertise in development of synthetic DNA vaccines and in vivo electroporation delivery. Inovio will oversee clinical grade production of 2 plasmid constructs at a state- of-the-art cGMP plasmid manufacturing facility. Inovio’s processes have passed rigorous international regulatory reviews and have been used in dozens of human clinical trials in the U.S., Europe and Asia, including multiple Phase II and in Phase III studies.


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 = $6,319,573 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	4	4/10/2026	NON-COMPETING CONTINUATION	$0
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	1/9/2026	NON-COMPETING CONTINUATION	$6,319,573
														Subtotal = $6,319,573

Issue Date FY: 2025 ( Subtotal = $2,424,072 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	12/19/2024	NON-COMPETING CONTINUATION	$2,424,072
														Subtotal = $2,424,072

Issue Date FY: 2024 ( Subtotal = $4,420,687 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	2	4/24/2024	NON-COMPETING CONTINUATION	$442,068
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	1/12/2024	NON-COMPETING CONTINUATION	$3,978,619
														Subtotal = $4,420,687

Issue Date FY: 2023 ( Subtotal = $4,497,948 )
2023	2023	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	12/8/2022	NEW	$4,497,948
														Subtotal = $4,497,948

Grand Total All Awards = $17,662,280

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Synthetic DNA-launched and adjuvanted Env immunogens for HIV

Award Number: U19AI166916

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: 12/08/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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