Long-term follow-up of antibody and T-cell responses after COVID-19 mRNA vaccination in infection-naïve and infected individuals with focus on breakthrough infections.

BACKGROUND

Long-term prospective data on antibody and T-cell responses beyond the third COVID-19 mRNA vaccine dose, particularly in relation to prior SARS-CoV-2 infections and breakthrough infections, remain limited.

METHODS

Health care workers (HCWs) vaccinated with BNT162b2 were enrolled in January 2021. Blood samples were collected before and one month after each of four vaccine doses through December 2022. IgG antibodies against the spike receptor-binding domain (RBD) and the nucleocapsid (N) proteins were analysed, and T-cell responses (IFN-γ, IL-2, TNF-α) were measured after spike peptide stimulation. Neutralising antibodies (NAbs) against Omicron BA.1 were assessed in a subset (n = 61). RBD-IgG and cytokine levels were compared between infected and infection-naïve individuals, adjusted for age and sex.

RESULTS

Among 108 HCWs, 32% were infected before vaccination. Breakthrough infections were rare before dose 3 but increased with the emergence of Omicron, affecting 77% of the participants until study end. RBD-IgG levels were consistently significantly higher in individuals with hybrid immunity than in infection-naïve participants, except one month after dose 3. When breakthrough infections were excluded, this difference only persisted through dose 3. IFN-γ responses largely mirrored RBD-IgG, while IL-2 responses were less affected by repeat doses and TNF-α responses were highly variable.

CONCLUSIONS

Individuals with hybrid immunity had significantly higher RBD-IgG levels than infection-naïve subjects up to 23 months post-vaccination when including breakthrough infections, while elevated antibody responses were limited to the first year in those infected pre-vaccination. Differences were more pronounced for antibody than T-cell responses when comparing individuals with and without breakthrough infections.