A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals
- 1Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie
Abstract
Substantial inter-individual variation in susceptibility to viral infection persists despite widespread vaccination, and its immunological basis remains poorly understood. We investigated how innate and adaptive immune responses contribute to susceptibility to SARS-CoV-2 infection during the early COVID-19 pandemic. We compared two groups of vaccinated individuals who either remained uninfected or became infected during the first Omicron wave. Blood samples were collected at baseline and 24 weeks later. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated and stimulated with the TLR7/8 agonist R848 to assess innate responses. PBMCs were stimulated with SARS-CoV-2 peptide pools and highly purified inactivated viruses (ancestral and Omicron BA.1) to evaluate adaptive immunity. Prior to infection, individuals in the infected group exhibited reduced CD4 and CD8 T cells proliferative responses, alongside with increased TNF production across all stimulation conditions, despite largely comparable immune phenotypes, indicating a pre-existing functional immune deficit. Following infection, T-cell proliferation and IFN-{gamma} production were partially restored in response to viral antigens, although responses to Omicron BA.1 remained suboptimal. This functional deficit was accompanied by heightened inflammatory activity, including increased TNF and IFN-{gamma} production, elevated anti-nucleocapsid IgG3 levels, higher frequencies of B cells and myeloid cells, reduced circulating interferon-inducible T-cell Alpha Chemoattractant (I-TAC) concentrations, and a modest impairment in PMN IL-8 responses. Notably, these alterations were detectable prior to infection and persisted thereafter, indicating that they represent determinants rather than consequences of viral infection. Importantly, beyond differences in the magnitude of immune responses, protection was associated with the degree of functional coordination within the humoral compartment, as reflected by the relationship between Spike-binding antibodies and neutralizing activity. Together, these results demonstrate that susceptibility to Omicron infection is linked to a pre-existing and persistent functional immune imbalance affecting both innate and adaptive arms of immunity.
HighlightsO_LIPre-existing impairment in CD4 and CD8 T cell proliferative capacity identifies individuals at higher risk of Omicron infection. C_LIO_LISusceptibility to Omicron infection is associated with a combined immune signature including altered cytokines (I-TAC, TNF), anti-N IgG3 antibodies, and cellular phenotypes. C_LIO_LIOmicron infected individuals displayed higher frequency of B cells and myeloid cells. C_LIO_LIOmicron infection partially restores T-cell function but fails to normalize responses to homologous viral stimulation. C_LIO_LIExtended 7-day proliferation assays using highly purified viral antigens enhance detection of functional immune deficits undetected by usual analysis alone such as ELISpot IFN-{gamma} AIM assay or phenotype analysis. C_LI
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BibTeX
@misc{jarras2026multidimensional,
title = {{A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals}},
author = {H. Jarras and W. W. Bazie and I. Blais and B. Goyer and J. Boucher and A. Pakenham and K. Dancause-Caron and H. Rabezanahary and M. Theriault and K. Santerre and M.-A. Langlois and P. A. Tessier and J.-F. Masson and J. N. Pelletier and N. Brousseau and D. Boudreau and S. Trottier and M. Baz and C. Gilbert},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361844},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361844v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals
AU - H. Jarras
AU - W. W. Bazie
AU - I. Blais
AU - B. Goyer
AU - J. Boucher
AU - A. Pakenham
AU - K. Dancause-Caron
AU - H. Rabezanahary
AU - M. Theriault
AU - K. Santerre
AU - M.-A. Langlois
AU - P. A. Tessier
AU - J.-F. Masson
AU - J. N. Pelletier
AU - N. Brousseau
AU - D. Boudreau
AU - S. Trottier
AU - M. Baz
AU - C. Gilbert
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361844
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361844v1
AB - Substantial inter-individual variation in susceptibility to viral infection persists despite widespread vaccination, and its immunological basis remains poorly understood. We investigated how innate and adaptive immune responses contribute to susceptibility to SARS-CoV-2 infection during the early COVID-19 pandemic. We compared two groups of vaccinated individuals who either remained uninfected or became infected during the first Omicron wave. Blood samples were collected at baseline and 24 weeks later. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated and stimulated with the TLR7/8 agonist R848 to assess innate responses. PBMCs were stimulated with SARS-CoV-2 peptide pools and highly purified inactivated viruses (ancestral and Omicron BA.1) to evaluate adaptive immunity. Prior to infection, individuals in the infected group exhibited reduced CD4 and CD8 T cells proliferative responses, alongside with increased TNF production across all stimulation conditions, despite largely comparable immune phenotypes, indicating a pre-existing functional immune deficit. Following infection, T-cell proliferation and IFN-{gamma} production were partially restored in response to viral antigens, although responses to Omicron BA.1 remained suboptimal. This functional deficit was accompanied by heightened inflammatory activity, including increased TNF and IFN-{gamma} production, elevated anti-nucleocapsid IgG3 levels, higher frequencies of B cells and myeloid cells, reduced circulating interferon-inducible T-cell Alpha Chemoattractant (I-TAC) concentrations, and a modest impairment in PMN IL-8 responses. Notably, these alterations were detectable prior to infection and persisted thereafter, indicating that they represent determinants rather than consequences of viral infection. Importantly, beyond differences in the magnitude of immune responses, protection was associated with the degree of functional coordination within the humoral compartment, as reflected by the relationship between Spike-binding antibodies and neutralizing activity. Together, these results demonstrate that susceptibility to Omicron infection is linked to a pre-existing and persistent functional immune imbalance affecting both innate and adaptive arms of immunity. HighlightsO_LIPre-existing impairment in CD4 and CD8 T cell proliferative capacity identifies individuals at higher risk of Omicron infection. C_LIO_LISusceptibility to Omicron infection is associated with a combined immune signature including altered cytokines (I-TAC, TNF), anti-N IgG3 antibodies, and cellular phenotypes. C_LIO_LIOmicron infected individuals displayed higher frequency of B cells and myeloid cells. C_LIO_LIOmicron infection partially restores T-cell function but fails to normalize responses to homologous viral stimulation. C_LIO_LIExtended 7-day proliferation assays using highly purified viral antigens enhance detection of functional immune deficits undetected by usual analysis alone such as ELISpot IFN-{gamma} AIM assay or phenotype analysis. C_LI
ER -