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Synthetic bacterial analogs of mammalian oligomannose for eliciting neutralizing antibodies to the high-mannose patch on HIV Env

Award Number: R01AI134299
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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In recent years there have been an increasing number of reports on broadly cross-reactive neutralizing antibodies (nAbs) with specificity for oligomannose-type glycans on the HIV envelope spike (Env). Immunization strategies that could yield such nAbs would therefore be desirable. One of the challenges faced by efforts to elicit oligomannose-specific nAbs is the host origin of the glycans, with immune tolerance mechanisms possibly limiting the frequency or development of B cells capable of producing Abs with specificity for mammalian oligomannose. For example, Abs elicited in typical experimental animals by glycoconjugate immunogens presenting oligomannosides are generally unable to bind oligomannose on Env and even when Env-binding Abs have been obtained, such as with recombinant yeast, they appear to bind insufficiently avid to the virus and fail to exert meaningful neutralizing activity. Here, we propose to utilize bacterially derived oligosaccharide analogs of oligomannose to overcome these challenges. We focus in this application on a fairly conserved patch of high-mannose glycans at and surrounding Asn301 and Asn332 on HIV gp120. Prototypic for Abs targeting these oligomannose-type glycans is the PGT128 family of Abs, which exhibit potent neutralizing activity. A vaccine component capable of eliciting similar nAbs could thus offer protection at even modest serum Ab titers. We not long ago discovered a bacterial oligosaccharide that closely resembles the D1 arm of mammalian oligomannose and subsequently made synthetic analogs of it with a D3 arm-like extension. One of these analogs, in the form of a neoglycoconjugate, is bound avidly by members of the PGT128 Ab family and their predicted germline predecessor. More crucially, preliminary data show that immunization of transgenic animals expressing an unarranged human Ab repertoire with this conjugate results in glycan- specific Abs with HIV tier 2 cross-neutralizing activity. Here, we propose to expand on these encouraging first results. Specifically, we seek to elaborate on our conjugate design and utilize transgenic animals to identify an optimal adjuvant+conjugate combination to maximize nAb responses. We also seek to dissect Ab responses at the serum and repertoire levels to compare similarities between the elicited and existing nAbs, which may inform boosting strategies. Finally, we propose to test our strategy in macaques to assess the extent to which it may work in outbred systems. In sum, this project will investigate whether glycan mimicry can serve to readily trigger the development of cross-reactive nAbs to the highly vulnerable oligomannose patch on HIV Env. If so, this work could inform strategies for targeting other glyco-epitopes on HIV-1.


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: 2024 ( Subtotal = $0 )
2024	2020	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DRIVE	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	4	2/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $539,999 )
2023	2023	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DRIVE	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	001	6	7/26/2023	NON-COMPETING CONTINUATION	$539,999
2023	2022	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	5	2/1/2023	COMPETING CONTINUATION	$0
														Subtotal = $539,999

Issue Date FY: 2022 ( Subtotal = $545,999 )
2022	2022	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	001	5	8/23/2022	COMPETING CONTINUATION	$545,999
2022	2020	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	4	8/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $545,999

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	4	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $539,341 )
2020	2020	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	000	4	8/12/2020	NON-COMPETING CONTINUATION	$539,341
														Subtotal = $539,341

Issue Date FY: 2019 ( Subtotal = $505,735 )
2019	2019	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	002	3	8/26/2019	NON-COMPETING CONTINUATION	$505,735
2019	2018	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	001	2	8/5/2019	NON-COMPETING CONTINUATION	$0
2019	2017	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	000	1	8/5/2019	NEW	$0
														Subtotal = $505,735

Issue Date FY: 2018 ( Subtotal = $330,451 )
2018	2018	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	000	2	8/9/2018	NON-COMPETING CONTINUATION	$330,451
														Subtotal = $330,451

Issue Date FY: 2017 ( Subtotal = $330,451 )
2017	2017	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR	BURNABY	BC	V5A 1S6		CAN	Allergy and Infectious Diseases Research	000	1	8/30/2017	NEW	$330,451
														Subtotal = $330,451

Grand Total All Awards = $2,791,976

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Synthetic bacterial analogs of mammalian oligomannose for eliciting neutralizing antibodies to the high-mannose patch on HIV Env

Award Number: R01AI134299

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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