Distinct features of humoral and cellular immunity against Omicron breakthrough infection among chronic liver disease patients: An experience from a follow-up cohort

Immunity response following vaccination and infection toward the SARS-CoV-2 Omicron variant remains limited in chronic liver disease (CLD) population. This study aims to investigate humoral and cell-mediate immunity to Omicron BA.4/5 among CLD patients with/without breakthrough infections (BI). This longitudinal study characterized immune responses to Omicron infection across three CLD patient groups: vaccinated without BI (group 1, n = 10), vaccinated with BI (group 2, n = 43), and unvaccinated infected (group 3, n = 7). SARS-CoV-2-specific antibodies/T-cell responses and lymphocyte phenotypes were quantified by ELISA and flow cytometry. Logistic regression identified immunological correlates of BI event, viral clearance and liver disease progression. Dynamic immunity changes after infection analyzed using Spearman's correlation. Patients in group 2 exhibited the highest levels of neutralizing antibodies (NAbs) against wildtype (WT) and Omicron BA.4.5, anti-RBD IgG, and total anti-SARS-CoV-2 antibodies compared to groups 1 and 3. Comparable T cell responses were observed between two vaccinated groups, stronger than unvaccinated individuals. Hybrid immune (vaccination plus infection) elicited stronger NAbs-WT, total anti-SARS-CoV-2 antibodies, anti-RBD IgG, MBCs, and Omicron-specific IFN-γ⁺/IL-4⁺CD4⁺T cells compared to primary Omicron infection. Besides, severe liver disease was not only a risk factor for BI, but also impaired Omicron-specific IFN-γ⁺CD8⁺T, CD38⁺CD4⁺T, and CD45RA⁺CD8⁺T cells responses after infection. Importantly, IgG⁺/IgM⁺MBCs and NAbs showed positive associations with central memory (CD45RA^-CD62L⁺CD4/8) or naive (CD45RA⁺CD62L⁺CD4) T cells. Low levels of CD45RA⁺CD62L⁺CD8⁺T cells and resting MBCs were identified as the independent risk factors for viral clearance and disease progression, respectively. BI predominantly stimulates humoral immunity without enhancing cellular responses. Weaker immune response induced by primary Omicron infection underscores the need for additional vaccinations in vaccine-naïve CLD patients. The positive correlations between humoral/cellular immunity and memory/activated T cells reveal their coordinated role in adaptive immune defense against SARS-CoV-2. These findings emphasize the importance of regular immune monitoring and timely interventions to optimize protection for CLD patients against emerging Omicron subvariants.