Impaired non-spike-specific Th1 CD4+ T cell responses to inactivated SARS-CoV-2 vaccines and Omicron breakthrough infection in older individuals who had recovered from COVID-19

Older adults face a disproportionately high risk of severe COVID-19 due to age-related impairments in antiviral and vaccine-induced immunity. However, the specific defects in T cell responses, particularly in antigen-specific CD4+ T cells, remain insufficiently defined in this population. We performed comprehensive longitudinal immunophenotyping of CD4+ T cell responses in younger (18–59 years) and older (≥60 years) adults who had recovered from COVID-19, received inactivated SARS-CoV-2 vaccines, and subsequently experienced Omicron BA.5.2/BF.7 breakthrough infection. Using activation-induced marker assays (AIM), we assessed the magnitude of spike- and non-spike-specific CD4+ T cell responses, the dynamics of memory/helper subsets, and cytokine secretion profiles from peripheral blood mononuclear cells (PBMCs). Younger adults exhibited robust CD4+ T cell activation following vaccination, whereas older adults showed attenuated responses, including reduced Th1 frequencies in non-spike-specific CD4+ T cells and a higher proportion of central memory cells. PBMCs from older adults produced lower IFN-γ but higher levels of inflammatory cytokines (IL-10, IL-1β, and IL-8) upon non-spike peptide stimulation. These age-associated impairments persisted after Omicron breakthrough infection, marked by compromised CD4+ T cell recall responses and blunted expansion of non-spike-specific Th1 cells. Our findings demonstrate that aging selectively compromises the magnitude of non-spike-specific Th1 CD4+ T cell responses induced by inactivated SARS-CoV-2 vaccines and Omicron breakthrough infection. These findings underscore the need for age-tailored vaccine strategies to enhance protective cellular immunity in older adults.