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Pushing the envelope: Optimizing vaccine display of flexibly linked HIV Env trimer immunogens

Award Number: P01AI124337
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Pushing the envelope: Optimizing vaccine display of flexibly linked HIV Env trimer immunogens - DESCRIPTION (provided by applicant): The overall goal of this HIVRAD consortium is to develop and compare four novel vaccine candidates designed to deliver HIV envelope (Env) trimers mimicking the presentation of Env by HIV infection and ultimately generating broadly neutralizing antibodies (bNAbs) against the AIDS virus. The team will work towards this goal by completing objectives in four Specific Aims. Aim 1 intends to design, develop, and characterize vaccine candidates that deliver stabilized, membrane-anchored Clade C 1086 spikes adapted from the well-ordered native flexibly linked (NFL) trimer design (EnvNFL). Aim 2 will conduct initial immunogenicity studies comparing the candidates in inbred mice including analysis of gene expression profiles, cellular and humoral immune responses, and Env-specific antibodies and B-cells guiding iterative improvement of the candidates. Aim 3 will further test the optimized candidates in small animal models that enable evaluation of HIV-neutralization activity elicited by vaccination including rabbits and novel, genetically-modified mice (VelocImmune(r)) that express antibodies with human VH and Vk domains. Aim 4 will prioritize two vaccine regimens for evaluation in macaques based on accumulated comparative data from small animal studies in Aims 2 and 3, ultimately conducting mucosal SHIV challenge experiments to correlate vaccine performance with degree of resistance to SHIV infection. Compared to previous HIV vaccine trials, this program hypothesizes that performance gains can be achieved if an Env vaccine is designed to deliver authentic spikes arrayed on enveloped particles, and if a trimer delivery platform can be identified that provides immunostimulatory signals promoting polyclonal responses of greater epitope breadth encompassing Abs with bNAb specificities. To this end, four novel Env trimer vaccines based on different delivery technologies that will evoke unique immune response profiles will be developed and compared. Each vaccine will deliver clade C trimers based on the EnvNFL design to promote efficient assembly of well-ordered complexes of greater uniformity and increased stability. The four vaccine platforms are: 1) RNActive(r) technology, an innovative mRNA vector and adjuvant delivery system; 2) EnvNFL trimers assembled on liposome-based VLPs; 3) EnvNFL trimers displayed on inactivated vesicular stomatitis virus (VSV) particles; and 4) EnvNFL delivered with a live VSV vector that incorporates Env in its viral envelope. Three projects supported by three cores will undertake the above experimental plan. Project 1 will design and develop the vectors in concert with Project 2, which will provide the Env trimers and develop a liposome-based vaccine, while Project 3 will evaluate the HIV Env-specific B cell repertoire in the small animal and NHP studies. Core C will provide gene signature analysis of the vaccine platforms and Core B will carry out the small animal and NHP studies. Administrative Core A will provide overall management of the program. Overall, the program will develop four new Env vaccines delivering stabilized trimers, and generate a comprehensive database on their performance in multiple animal models including nonhuman primates.


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: 2023 ( Subtotal = -$3,290 )
2023	2020	INTERNATIONAL AIDS VACCINE INITIATIVE INC	125 BROAD ST	NEW YORK	NY	10004	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	7/26/2023	NON-COMPETING CONTINUATION	-$3,290
														Subtotal = -$3,290

Issue Date FY: 2020 ( Subtotal = $2,249,057 )
2020	2020	INTERNATIONAL AIDS VACCINE INITATIVE INC.	125 BROAD ST FL 9TH	NEW YORK	NY	10004	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	6/24/2020	NON-COMPETING CONTINUATION	$2,249,057
														Subtotal = $2,249,057

Issue Date FY: 2019 ( Subtotal = $2,353,868 )
2019	2019	INTERNATIONAL AIDS VACCINE INITATIVE INC	125 BROAD ST FL 9TH	NEW YORK	NY	10004	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	7/2/2019	NON-COMPETING CONTINUATION	$2,353,868
														Subtotal = $2,353,868

Issue Date FY: 2018 ( Subtotal = $2,635,377 )
2018	2018	INTERNATIONAL AIDS VACCINE INITATIVE INC	125 BROAD ST FL 9TH	NEW YORK	NY	10004	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	6/22/2018	NON-COMPETING CONTINUATION	$2,635,377
														Subtotal = $2,635,377

Issue Date FY: 2017 ( Subtotal = $2,445,841 )
2017	2017	INTERNATIONAL AIDS VACCINE INITATIVE INC	125 BROAD ST FL 9TH	NEW YORK	NY	10004	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	8/7/2017	NON-COMPETING CONTINUATION	$2,445,841
														Subtotal = $2,445,841

Issue Date FY: 2016 ( Subtotal = $2,525,443 )
2016	2016	INTERNATIONAL AIDS VACCINE INITIATIVE	110 WILLIAM STREET	NEW YORK	NY	10038	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	8/12/2016	NEW	$91,244
2016	2016	INTERNATIONAL AIDS VACCINE INITIATIVE	110 WILLIAM STREET	NEW YORK	NY	10038	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	7/19/2016	NEW	$2,434,199
														Subtotal = $2,525,443

Grand Total All Awards = $12,206,296

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Pushing the envelope: Optimizing vaccine display of flexibly linked HIV Env trimer immunogens

Award Number: P01AI124337

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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