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Assessing T-cell cross-reactivity to SARS-CoV-2 variants

Govinda Rajan Ravi, Subeksha (2023) Assessing T-cell cross-reactivity to SARS-CoV-2 variants. Master's Thesis, University of Pittsburgh. (Unpublished)

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The coronavirus pandemic is a major, ongoing public health crisis. COVID-19 has resulted in over 6 million deaths as of April 2023 according to WHO. The COVID-19 mRNA vaccine widely administered in the United States was based on the spike protein of the Washington strain of SARS-CoV-2. Several new studies have indicated that a phenomenon like original antigenic sin (where prior exposure to an antigen leads to an ineffective immune response against related antigens) might be occurring in COVID. In this study, we wanted to determine if a COVID-19 mRNA vaccine-induced memory CTLs cross-react with Delta/Omicron variant epitopes without target cell killing. To test this, we identified HLA-A2 restricted, CD8+ T-cell epitopes in the spike protein that differ between the Washington strain Vs the Delta and/or Omicron variants. We collected T-cells from HLA-A2 positive, MWCCS donors who were vaccinated but not naturally exposed to any variant of SARS-CoV-2 and expanded the antigen-specific T-cells ex-vivo. We then assessed the cross-reactive potential of these Washington variant spike-specific CD8+ T-cells (readout was optimized to detect CD8+ T-cells) against the variant peptides generated using IFN-gamma ELISpot assay. We tested 14 peptide pairs and found that vaccine-induced CD8+ T-cells can cross-react with epitope variants. We also observed a decreased T-cell reactivity to the variant epitopes compared to the Washington epitopes in some cases and an increased T-cell reactivity to the variant epitopes compared to the Washington epitopes in some other cases. Another interesting observation was that MHC binding affinity and T-cell binding affinity did not always correlate with the T-cell responses (IFN-g production) observed. Our future efforts will be aimed at testing the killing capacity of the CTLs when exposed to variant-antigen expressing target cells. The findings from this study has laid a groundwork in determining the efficacy of the COVID vaccine and to determine if there is need for the development of a more efficacious COVID vaccine.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Govinda Rajan Ravi, Subekshasug49@pitt.edusug49
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMailliard, Robbierbm19@pitt.edurbm19
Committee MemberRinaldo,
Committee MemberMarques, Ernesto
Date: 9 May 2023
Date Type: Publication
Defense Date: 13 April 2023
Approval Date: 9 May 2023
Submission Date: 27 April 2023
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 42
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: T-cells, SARS-CoV-2, spike protein
Date Deposited: 10 May 2023 03:01
Last Modified: 10 May 2023 03:01


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