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Development of computational tools for accounting for host variability in predicting T-cell epitopes

Award Number: R35GM147164
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Development of computational tools for accounting for host variability in predicting T-cell epitopes - PROJECT SUMMARY The processing of antigens through proteolytic degradation and the recognition of epitopes is central to the body’s ability to combat pathogens, like viruses, through discriminating self from non-self. As a result, there has been substantial research effort aimed at determining the outcomes of these processes for novel pathogens to enable epitope-driven vaccine design. There has also been great interest at the intersection of immunology and personalized medicine in identifying subject (host) specific epitopes, as these have great promise in the treatment of allergies and cancer where the distinction between self vs. non-self becomes blurred. Computational methods have emerged as promising approaches for identifying (predicting) epitopes that elicit a robust immune response given genetic information for an antigen. This is a very challenging task, which is compounded further due to the existence of uncertainty caused by genetic variability between pathogen strains, as well as, from individual to individual. Following this logic, it is also clear that using animal models in evaluating the immune response elicited by epitopes can often have limited predictive value, since sequence differences between a model species and humans can result in significantly different outcomes in terms of the peptides formed during antigen processing and epitopes recognized by immune cell receptors. Accordingly, there is an unmet need for computational tools that can predict the outcomes of antigen processing and epitope recognition in a host-dependent fashion, where the models take as input both antigen and host-specific genetic data. We propose the development of computational tools in three related areas to meet these needs: i) Prediction of peptides formed through antigen processing; ii) Prediction of epitope recognition by MHC molecules and T-cell receptors; and iii) Probabilistic analysis of epitopes most likely to elicit an immune response. In the proposed work, molecular modeling and machine learning will be used to develop accurate models of antigen processing and epitope binding to MHC molecules and T-cell receptors. Molecular models will first allow us to identify key interactions between the antigen and immune system proteins, which when coupled with statistical data can allow us to understand how mutations would affect those interactions. The statistical analysis of the effects of mutations will be applied to large publicly available datasets to sufficiently capture the effects of mutations on antigen processing and epitope recognition and will ultimately be incorporated into machine learning models. The proposed probabilistic models will apply a scenario-driven approach for capturing uncertainty in epitope generation and recognition. We will sample potential antigen and human sequences based on known distributions of mutation prevalence to measure the likelihood that an identified epitope will be generated and elicit a robust immune response. The proposed computational tools, if successful, could have substantial impact on the areas of epitope-driven vaccine design, including personalized cancer vaccines, and the identification of allergy related epitopes.


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: 2025 ( Subtotal = $375,826 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	002	5	9/2/2025	NON-COMPETING CONTINUATION	$370,854
2025	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	001	4	8/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$277,464
2025	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	3	8/1/2025	NON-COMPETING CONTINUATION	-$272,492
														Subtotal = $375,826

Issue Date FY: 2024 ( Subtotal = $372,451 )
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	3	8/19/2024	NON-COMPETING CONTINUATION	$372,451
														Subtotal = $372,451

Issue Date FY: 2023 ( Subtotal = $372,451 )
2023	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	2	9/8/2023	NON-COMPETING CONTINUATION	$372,451
														Subtotal = $372,451

Issue Date FY: 2022 ( Subtotal = $372,451 )
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Biomedical Research and Research Training	000	1	8/26/2022	NEW	$372,451
														Subtotal = $372,451

Grand Total All Awards = $1,493,179

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Development of computational tools for accounting for host variability in predicting T-cell epitopes

Award Number: R35GM147164

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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