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Asian doctor wearing anti-virus clothing taking a COVID-19 test for a man

Influence of host HLA variation on COVID-19 disease severity

Long term immunity against viral pathogens, such as SARS-CoV-2 and Influenzas, requires identification of T cell epitopes affecting host immunogenicity. Our central hypothesis is that differences in T cell epitopes, mediated by host HLAs and mutations of viral gene products, contribute to differential clinical severity of disease outcomes of COVID-19. 

3MT Slide - Winner of LSUHSC 3MT 2023

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Bioinformatic analysis of T cell epitope diversity in SARS-CoV-2 variants

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Figure Graphical abstract of our manuscript. Click the image or below to read more about our work.

Approach

  • Computational analysis of estimated CD8+ epitope diversity in 27 of the most common HLA-A and -B alleles, utilizing NIH's TepiTools.

  • 16 SARS-CoV-2 variants 1 Pre-Alpha, 1 Alpha, 5 Delta, and 9 Omicron variants

Key Findings​

  • CD8+ epitope conservation was estimated at 87.6-96.5% in spike (S), 92.5-99.6% in membrane (M), and 94.6-99% for nucleocapsid (N).

  • As the virus mutated, an increasing proportion of S epitopes experienced reduced predicted binding affinity: 70% of Omicron BQ.1- XBB.1.5 S  as compared to ~ 3% and ~15% in earlier strains Delta AY.100-AY.44 and Omicron BA.1-BA.5, respectively.

  • Identification of several novel candidate HLA alleles that may be more susceptible to severe disease, notably HLA-A*32:01, -A*26:01, and -B*53:01, and relatively protected from disease, such as -A*31:01, -B*40:01, -B*44:03, and -B*57:01. 

Outputs​

  • First-author manuscript, including mentored student co-authorship

  • Several awards, including but not limited to: TL1 award, 2023 Association for Clinical Translational Science Blue Ribbon Award 

Long COVID incidence across SARS-CoV-2 lineages and identification of conserved spike targets for multivalent vaccines

Approach

  • 4789 SARS-CoV-2 sequences linked to 3090 de-identified patient electronic health record information. The base population was defined as any patient with an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) based definitions of Long COVID presentation developed by the N3C consortium.

Key Findings​

  • Long COVID-positive patients were older (mean age 43.1 years) than negative patients (35.9 years; p = 0.0054) and were more likely to be female (p = 0.0001).

  • Among unvaccinated patients, those with Long COVID were significantly younger than their vaccinated counterparts (p < 0.00001).

  • Long COVID incidence varied by PANGO lineage, ranging between 14% in AY.13 to 67.8% in B.1.1.7.

  • Analysis of spike protein diversity revealed eight conserved amino acid regions (Shannon entropy < 0.43), representing potential targets for vaccine design. 

Outputs​

  • First-author manuscript

  • Several awards, including but not limited to: T32 award, 2024 Association for Clinical Translational Science Blue Ribbon Award, 1st Place winner of the Nathan Solomon & Irene Oransky-Solomon Medical Student Award of the 2024 Southern Society for Clinical Investigation Southern Regional Meeting 

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Figure 3 from our manuscript. Click the image or below to read more about our work.

HLA allelic variation shapes risk of severe SARS-CoV-2 infection and long COVID

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Approach

  • The objective of this study is to investigate the relationship between imputed human leukocyte antigen (HLA) alleles to COVID-19 clinical severity within the NIH funded All of Us dataset, which integrates electronic health records and genomic sequences of enrolled participants. The base population was defined as any participant who had been administered a SARS-CoV-2 test and provided genomic sequencing data (n=113,015). Cohorts were refined by COVID-19 conditions:  (1) a positive COVID-19 test (n=20,872), (2) a negative COVID-19 test (n= 88,680), (3) both a positive test and an ICD-10 diagnosis code for pneumonia due to COVID-19 or lower respiratory infection caused by SARS-CoV-2 (n= 1,079), (4) a positive test and a diagnosis code for Long COVID (n= 509), and (5) ONLY and at least 3 positive COVID-19 tests (n= 1,298), and (6) ONLY and at least 3 negative COVID-19 tests (n=4,884). Through this approach, we found several alleles significantly associated with increased risk of severe COVID-19 infection. 

Method

  • HLA Class I and Class II allele imputation utilized a global diversity reference panel utilizing the HIBAG “R” package with a median posterior probability rate greater than 92.7% for the 6 HLA alleles. Logistic regression analysis controlled for sex, age, comorbidities, PCA for genetic ancestry.  

Outputs​

  • First-author manuscript in preparation

  • Several awards, including but not limited to: podium presentation at 2026 American Association of Immunologists Conference 

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