Hybrid immunity by two COVID‐19 mRNA vaccinations and one breakthrough infection provides a robust and balanced cellular immune response as basic immunity against severe acute respiratory syndrome coronavirus 2

Abstract This longitudinal prospective controlled multicenter study aimed to monitor immunity generated by three exposures caused by breakthrough infections (BTI) after COVID‐19‐vaccination considering pre‐existing cell‐mediated immunity to common‐corona‐viruses (CoV) which may impact cellular reactivity against SARS‐CoV‐2. Anti‐SARS‐CoV‐2‐spike‐IgG antibodies (anti‐S‐IgG) and cellular reactivity against Spike‐(S)‐ and nucleocapsid‐(N)‐proteins were determined in fully‐vaccinated (F) individuals who either experienced BTI (F+BTI) or had booster vaccination (F+Booster) compared to partially vaccinated (P+BTI) and unvaccinated (U) from 1 to 24 weeks post PCR‐confirmed infection. High avidity anti‐S‐IgG were found in F+BTI compared to U, the latter exhibiting increased long‐lasting pro‐inflammatory cytokines to S‐stimulation. CoV was associated with higher cellular reactivity in U, whereas no association was seen in F. The study illustrates the induction of significant S‐specific cellular responses in F+BTI building‐up basic immunity by three exposures. Only U seem to benefit from pre‐existing CoV immunity but demonstrated inflammatory immune responses compared to F+BTI who immunologically benefit from enhanced humoral and cellular immunity after BTI. This study demonstrates that individuals with hybrid immunity from COVID‐19‐vaccination and BTI acquire a stable humoral and cellular immune response that is maintained for at least 6 months. Our findings corroborate recommendations by health authorities to build on basic immunity by three S‐protein exposures.