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[https://doi.org/10.1080/22221751.2025.2602317](https://doi.org/10.1080/22221751.2025.2602317)  \nPredictive markers of SARS-CoV-2 spike-specific cytotoxic T cell activity following Omicron breakthrough infection  \nKayla A. Holdera, b,c, Danielle P. Ingsc, Keeley M. Hatfieldc, Kathleen E. Fifieldc, David A. Barnesc, Keeley A. Barnablec, Debbie O. A. Harnumd and Michael D. Grantc  \naDepartment of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA; bDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; cImmunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada; dNewfoundland and Labrador Health Services, St. John’s, NL, Canada  \nABSTRACT  \nAt a population level, evaluation of vaccine efficacy and of immunity in general focuses on measuring humoral immunity, especially antibody-mediated neutralization. However, antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular immunity are key processes for pathogen clearance and often provide broader protection against emerging variants. More information on vaccine and infection-related determinants or markers of cell-mediated cytotoxicity is needed to inform design of standardized, high throughput tests assessing these processes. We previously showed that persons infected with SARS-CoV-2 prior to vaccination (hybrid immunity) had polyfunctional CD8+ T cells and robust ADCC against SARS-CoV-2 spike (S), while persons infected with Omicron after vaccination (breakthrough infection) had weak ADCC. In the current study, we investigated the impact of Omicron breakthrough infection on Sspecific cellular immunity, including polyfunctional CD8+ T cell and cytotoxic T lymphocyte (CTL) levels of 28 previously uninfected individuals vaccinated either two or three times against SARS-CoV-2 . In the group with three vaccinations, Omicron breakthrough infection significantly increased the frequency of circulating SARS-CoV-2 Sspecific T cells, polyfunctional interferon-gamma and interleukin-2-producing SARS-CoV-2 S-specific CD8+ T cells and CTL after in vitro stimulation. Matrix testing with overlapping S peptides indicated recognition of one to two CTLepitopes per individual and revealed two previously unreported epitopes. Circulating S-specific cellular immune response magnitude neither correlated with, nor predicted CTL activity against SARS-CoV-2 S, but polyfunctional S  \nspecific CD8+ T cell frequency seven days after stimulation and antibody reactivity against determinants indicating robust ADCC were both associated with day 10 CTL activity.  \nARTICLE HISTORY Received 19 August 2025; Revised 9 November 2025; Accepted 7 December 2025  \nKEYWORDS SARS-CoV-2; COVID-19; Omicron breakthrough infection; Cytotoxic T cells; Polyfunctional CD8+ T cells  \nIntroduction  \nMeasuring serum or plasma antibody reactivity is a simple, accessible way to assess an anti-microbial immune response, with higher antibody levels generally indicating better responses. Adaptive immunity that prevents microbial infection is largely mediated by neutralizing antibodies that physically block receptor-mediated entry into susceptible host cells [ 1] . However, when antigenic variation or other immune evasion mechanisms enable microbes to establish chronic infection or to reinfect, neutralizing antibody levels against transient variants have little relevance to ongoing immune protection [2] . Once infection occurs, specific cell-mediated killing of infected cells limits cell-to-cell spread and attempts microbial clearance. Cell-mediated killing of infected host cells can limit the severity of illness and is often maintained against microbial variants that evade antibody  \nneutralization [3–6] . Natural killer (NK) cell triggering by IgG subclass antibodies against microbial antige","cbCaidOCHVJTtLJs","https://ap.wps.com/l/cbCaidOCHVJTtLJs","pdf",3570070,13,"English","# Abstract\n## Introduction\n## Article information and acknowledgements","[{\"question\":\"What immune processes does the study emphasize beyond neutralizing antibodies?\",\"answer\":\"The study highlights antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular immunity, including cytotoxic T lymphocyte responses, as key processes for pathogen clearance and protection against variants.\"},{\"question\":\"How does Omicron breakthrough infection affect spike-specific cellular immunity in the study?\",\"answer\":\"In participants receiving three vaccine doses, Omicron breakthrough infection significantly increased the frequency of circulating SARS-CoV-2 spike-specific T cells, including polyfunctional interferon-gamma and interleukin-2-producing CD8+ T cells, and CTL activity after in vitro stimulation.\"},{\"question\":\"What markers are associated with later CTL activity according to the results summary?\",\"answer\":\"Spike-specific polyfunctional CD8+ T cell frequency measured seven days after stimulation and antibody reactivity consistent with robust ADCC were associated with day 10 CTL activity, while overall cellular response magnitude did not predict CTL activity.\"}]","Predictive markers of SARS-CoV-2 spike-specific cytotoxic T cell activity following Omicron breakthrough infection | PDF",1790730253,33]