Severe Acute Respiratory Syndrome Coronavirus 2 Delta Variant Genomic Variation Associated With Breakthrough Infection in Northern California: A Retrospective Cohort Study

• Published in: The Journal of infectious diseases Vol. 228; no. 7; pp. 878 - 888
• Main Authors: Skarbinski, Jacek, Nugent, Joshua R, Wood, Mariah S, Liu, Liyan, Bullick, Teal, Schapiro, Jeffrey M, Arunleung, Phacharee, Morales, Christina, Amsden, Laura B, Hsiao, Crystal A, Wadford, Debra A, Chai, Shua J, Reingold, Arthur, Wyman, Stacia K
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 03-10-2023
• Subjects: Breakthrough Infections; California - epidemiology; Coronaviruses; COVID-19; COVID-19 - epidemiology; COVID-19 Vaccines; Gene frequency; Genomics; Humans; Infections; Mutation; Prediction models; Retrospective Studies; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Single-nucleotide polymorphism; Variation; California; immune evasion; genomic variation; SARS-CoV-2
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiad164

Abstract
Background
The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic variation and breakthrough infection is not well defined among persons with Delta variant SARS-CoV-2 infection.
Methods
In a retrospective cohort, we assessed whether individual nonlineage defining mutations and overall genomic variation (including low-frequency alleles) were associated with breakthrough infection, defined as SARS-CoV-2 infection after coronavirus disease 2019 primary vaccine series. We identified all nonsynonymous single-nucleotide polymorphisms, insertions, and deletions in SARS-CoV-2 genomes with ≥5% allelic frequency and population frequency of ≥5% and ≤95%. Using Poisson regression, we assessed the association with breakthrough infection for each individual mutation and a viral genomic risk score.
Results
Thirty-six mutations met our inclusion criteria. Among 12 744 persons infected with Delta variant SARS-CoV-2, 5949 (47%) were vaccinated and 6795 (53%) were unvaccinated. Viruses with a viral genomic risk score in the highest quintile were 9% more likely to be associated with breakthrough infection than viruses in the lowest quintile, but including the risk score improved overall predictive model performance (measured by C statistic) by only +0.0006.
Conclusions
Genomic variation within SARS-CoV-2 Delta variant was weakly associated with breakthrough infection, but several potential nonlineage defining mutations were identified that might contribute to immune evasion by SARS-CoV-2.
Genomic variation within the Delta variant of SARS-CoV-2 was weakly associated with breakthrough infection, but several potential nonlineage defining mutations were identified that might contribute to immune evasion by SARS-CoV-2.