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Epitope focusing using structure-based immunogen design approaches

Award Number: F30AI160908
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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Epitope focusing using structure-based immunogen design approaches - Project Summary/Abstract Since the emergence of the novel severe acute respiratory syndrome virus 2 (SARS-CoV-2) coronavirus, the need for better frameworks to rapidly develop vaccines in response to emerging viral threats, including other coronaviruses of potential pandemic concern, is clear. One approach is to develop an immunogen design platform that leverages the often-conserved interface between viral surface glycoproteins and their host cellular receptor(s). For SARS-CoV-2, elicited antibodies would target the interaction between its “spike” glycoprotein and the human angiotensin-converting enzyme 2 (ACE-2) receptor. Other coronaviruses like SARS-CoV-1 and the common cold-causing NL63 also use ACE-2, thus antibodies that interfere with this conserved interaction might also protect against future novel coronaviruses that also use this receptor. The goal of this proposed work is to use structure-guided, rational design of novel immunogens to focus the immune response to the ACE-2 receptor binding interface of SARS-CoV-2. This may provide a generalizable framework of immunogen design strategies that can be rapidly used to combat novel emerging viruses in the future. I will use the following two design approaches: 1) I will use molecular scaffolds that are structurally homologous to the SARS-CoV-2 receptor binding domain (RBD) and “resurface” them with the ACE-2 receptor binding motif (RBM) from SARS- CoV-2. As a result, the antigenically distinct scaffolds will uniformly present the conserved SARS-CoV-2 RBM and will focus the immune response to the conserved interface. 2) I will use hyperglycosylation to mask immunodominant, non-protective epitopes on the SARS-CoV-2 RBD to direct the immune response to the SARS-CoV-2 RBM. For both approaches, I will analyze the elicited immune response to determine the extent of immune focusing to the SARS-CoV-2 RBM, obtain neutralization profiles and structurally characterize down- selected elicited antibodies. Collectively, these data will provide insight into how masking and resurfacing can determinatively direct the immune response to a conserved viral epitope. While I use SARS-CoV-2 as a model virus, this could provide a vaccine design framework for future viral pathogens with the potential for rapid deployment.


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	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	8/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	10/21/2022	NON-COMPETING CONTINUATION	$51,752
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	2/24/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $52,694

Issue Date FY: 2021 ( Subtotal = $37,980 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	8/23/2021	NEW	$0
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/23/2021	NEW	$37,980
														Subtotal = $37,980

Grand Total All Awards = $90,674

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Epitope focusing using structure-based immunogen design approaches

Award Number: F30AI160908

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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