The Effects of Past COVID-19 and Vaccination on Antibody Levels, Cellular Immunity, and Cytokine Production by Peripheral Blood Mononuclear Cells

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Abstract
Background/Objective: This study Investigates long-term immune responses (up to 4–4.5 years) to SARS-CoV-2 in individuals with: Past COVID-19 infection, Vaccination, Combined exposure, with focus on immune reactivity to recombinant spike (S) and nucleocapsid (N) proteins. Materials and methods: Serum antibody responses were assessed up to 4–4.5 years after infection or immunization, including virus-specific IgG, IgA, IgM, and neutralizing antibodies. Cellular immunity was evaluated by phenotypic and functional analysis of peripheral blood mononuclear cells (PBMCs), including memory T-helper and cytotoxic T-cell subsets, as well as cytokine production following in vitro stimulation with recombinant SARS-CoV-2 proteins. Multiplex cytokine profiling was used to characterize effector and regulatory immune responses. Results: Virus-specific IgG antibodies persisted for several years after SARS-CoV-2 exposure, with anti-RBD IgG showing the strongest correlation with virus-neutralizing activity, whereas antibodies to the N- protein primarily reflected prior infection. Vaccinated individuals exhibited a distinct immunoglobulin profile characterized by a higher prevalence of IgA. No IgM detected suggesting the detected immune responses reflect immunological memory rather than active infection. PBMCs from individuals with combined COVID-19 and vaccination history demonstrated enhanced responsiveness and more memory T cells. Hybrid immunity (infection and vaccination) provides stronger and broader immune responses.. Stimulation with S - protein induces stronger cytokine production (IFN-γ, TNF-α, IL-12p70) than N- protein. Regulatory cytokines (IL-10, TGF-β) also elevated which suggests immune regulation rather than chronic inflammation.Conclusion: SARS-CoV-2 infection and vaccination induce persistent humoral and cellular immunity. Neutralizing activity correlates only with anti-RBD and anti-S IgG. Future research should focus on long-term effects, hybrid immunity, and optimizing other vaccine types, in addition to Adenovector vaccines, such as recombinant antigen-based vaccines .

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