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Harnessing oral mucosa vaccination to drive protective HIV antibody responses

Award Number: R01DE026336
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Harnessing oral mucosa vaccination to drive protective HIV antibody responses - Developing an effective vaccine against HIV/AIDS remains an important global health target to inhibit and reverse the high level of HIV-1 transmission currently ongoing around the world. To date, there have been four large HIV-1 vaccine trials, of these only RV144 exhibited a limited, but significant protection (31.2%) from HIV- 1 acquisition. The assessment of the results from this study has revealed a number of key correlates of protection, including antibodies that target a conformational epitope in the V1V2 region of Env. It is clear that new vaccination methodologies are needed to improve upon the findings in the RV144 trial by generating high titers of V1-V2 and functional antibodies, creating long lived B cell memory, and driving antibody maturation toward broadly neutralizing activity. The oral mucosal tissues provide a unique environment in which to vaccinate, owing to its accessible lymphoid organs, high density of immune cells and increased potential for generating a mucosal response that is able to prevent HIV-1 acquisition at a mucosal surface. We propose a vaccination strategy to deliver recombinant HIV-1 trimeric Envelope (Env) protein vaccines directly to the oral mucosa (buccal mucosa of the cheek) by intra-epithelial (IEp) vaccination. Vaccines will be tested with two adjuvant formulations designed to stimulate strong innate induction through TLR4 and TLR7/8 pathways. The goal of this proposal is to optimize oral mucosal vaccination of the HIV-1 Env protein in order to enhance Env- specific antibody responses, and to characterize the effect of oral vaccination with Env by conducting a thorough multi-parametric assessment of vaccine-elicited immunity. The first Specific Aim will assess the innate immune response to the vaccine, with a focus on the influence of the vaccine at the buccal mucosa where the vaccine is administered by IEp injection. Innate immune changes are interesting for their potential to reveal a biomolecular signature that we believe will correspond to superior HIV-1 ENV antibody responses. The second and third Specific Aims will evaluate whether supplying Env to the oral mucosa drives superior antibody responses at mucosal sites and systemically. An assessment of the neutralization and ADCVI activity will provide a functional assessment that can be correlated with the findings from studies of the innate immune response. Aims 2 and 3 will also involve a mechanistic assessment of the anti-Env antibody response through an assessment of both CD4 T Follicular Helper cell responses and antibody maturation in these macaques. In addition to the optimization of oral mucosal IEp vaccination and the exhaustive multi-parametric analyses, the combined expertise of the Sodora and Sather laboratories is one of the major strengths of this application. The experiments outlined in this proposal utilize an oral mucosal IEp delivery of next-generation HIV-1 Env antigens, as well as an assessment of both innate and adaptive immune responses. This comprehensive approach results in a high degree of confidence that undertaking these studies will make a significant contribution to HIV-1 vaccine development and advance efforts toward reversing the ongoing HIV-1 pandemic.


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 = -$11,257 )
2023	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Oral Diseases and Disorders Research	000	6	1/20/2023	NON-COMPETING CONTINUATION	-$11,257
														Subtotal = -$11,257

Issue Date FY: 2022 ( Subtotal = $6 )
2022	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	000	3	9/26/2022	NON-COMPETING CONTINUATION	$6
														Subtotal = $6

Issue Date FY: 2020 ( Subtotal = $718,084 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Oral Diseases and Disorders Research	000	6	4/24/2020	NON-COMPETING CONTINUATION	$718,084
														Subtotal = $718,084

Issue Date FY: 2019 ( Subtotal = $828,617 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Oral Diseases and Disorders Research	002	5	5/21/2019	NON-COMPETING CONTINUATION	$828,617
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	003	3	7/18/2019	NON-COMPETING CONTINUATION	$0
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Oral Diseases and Disorders Research	001	4	3/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$685,700
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	000	3	3/7/2019	NON-COMPETING CONTINUATION	-$685,700
														Subtotal = $828,617

Issue Date FY: 2018 ( Subtotal = $855,888 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	000	3	5/14/2018	NON-COMPETING CONTINUATION	$855,888
														Subtotal = $855,888

Issue Date FY: 2017 ( Subtotal = $855,888 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	000	2	5/31/2017	NON-COMPETING CONTINUATION	$855,888
														Subtotal = $855,888

Issue Date FY: 2016 ( Subtotal = $853,346 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	000	1	6/14/2016	NEW	$732,231
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Oral Diseases and Disorders Research	001	1	8/11/2016	NEW	$121,115
														Subtotal = $853,346

Grand Total All Awards = $4,100,572

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Harnessing oral mucosa vaccination to drive protective HIV antibody responses

Award Number: R01DE026336

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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