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Adjuvant, mimicry and booster requirements for shepherding the development of neutralizing antibodies to the high-mannose patch on HIV-1

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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PROJECT SUMMARY The HIV-1 envelope spike (Env) bears a cluster of oligomannose-type glycans that is a target for broadly neutralizing antibodies (bnAbs). However, while nAbs to this cluster, dubbed the high-mannose patch (HMP), are known to develop in at least some HIV-infected individuals, past attempts to elicit similar antibodies by immunization have been largely unsuccessful. Most previous approaches have involved presenting clusters of natural or synthetic high-mannose glycans on the surface of carrier proteins. The difficulty in eliciting high-mannose-targeting nAbs by immunization is believed to relate, at least in part, to the ‘self’ nature of the targeted glycans; naïve B cells bearing Ig receptors of the desired fine specificity or affinity might be anergic or at relatively low frequency due to tolerance mechanisms. The approach that we are pursuing is based on the scientific premise that antigenic mimicry of mammalian host structures can stimulate cross-reactive antibodies if such mimics are presented in the proper ‘foreign’ milieu. Our overarching hypothesis is that, upon immunization, an antigenic mimic of mammalian oligomannose will more readily elicit antibodies that bind the HMP than native or synthetic oligomannose. In our progress report, we show that a CRM197-conjugate of our lead oligomannose mimetic, the design of which is inspired by a bacterial polysaccharide with resemblance to mammalian oligomannose, is bound with high avidity by various HMP-specific bnAbs as well as their germline precursors. Furthermore, human antibody transgenic mice immunized with this neoglycoconjugate yield antibodies that bind recombinant HIV-1 SOSIP trimers, albeit only when the conjugate is formulated in the TLR4-stimulating Th1-adjuvant GLA-SE; not when formulated in Th2- or mixed Th1/2-adjuvants. Based on our findings so far, we propose in this renewal application to extend our investigations. A first step (Aim 1) will be to probe the relevance of Th1 stimulation further, by assessing immunogenicity of our lead glycoconjugate when formulated with other Th1-directing adjuvants. These additional adjuvants will not be agonistic for TLR4, thus helping to reveal whether stimulating TLR4 is relevant. We will assess also (Aim 2) the significance of antigenic mimicry for triggering high mannose-specific antibodies, by comparing the immunogenicity of our lead mimetic to synthetic oligomannose. We will evaluate also whether incorporating an archetypical component of gram-negative bacterial LPS –Kdo and lipid A—into our lead glycoside is immunologically beneficial. Our third step (Aim 3) will be to investigate whether injecting glycoconjugate-primed transgenic mice at specific time points with select SOSIP trimers boosts nAb titers. We expect our findings to help sharpen our strategy and critically inform the pursuit of future preclinical studies. Results from this research could inform other HIV vaccine design strategies also.


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 = $487,746 )
2024	2024	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DRIVE	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	001	7	8/2/2024	NON-COMPETING CONTINUATION	$487,746
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 = $487,746

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 = $3,279,722

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Adjuvant, mimicry and booster requirements for shepherding the development of neutralizing antibodies to the high-mannose patch on HIV-1

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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