Diverging humoral and cellular immune responses due to Omicron—a national study from the Faroe Islands

ABSTRACT Immunity following infection and vaccination with the SARS-CoV-2 Omicron variant is poorly understood. The aim was to investigate immunity assessed with antibody response, neutralizing antibodies (NAbs), and IFN-γ release under different scenarios: in vaccinated and unvaccinated individuals with and without SARS-CoV-2 infection with the Omicron variant. This nationwide single-center study was conducted between January and March 2022, where all convalescent individuals were infected with the Omicron variant and included six study groups: unvaccinated-naïve, unvaccinated convalescent, vaccinated-naïve (second dose), vaccinated-naïve (third dose), vaccinated convalescent (second dose), and vaccinated convalescent (third dose). Antibody responses were assessed by determining receptor binding domain-specific antibodies and NAbs levels in serum, and IgG in saliva. T-cell responses in whole blood were measured as IFN-γ levels released after stimulation with spike peptides. We found that the humoral response against the spike protein was higher among vaccinated-naïve than unvaccinated convalescent. Unvaccinated with and without infection had comparable low humoral responses, while those vaccinated with a second or third dose, independent of infection status, had increasingly higher levels. Only 22% of the unvaccinated convalescent individuals mounted consistent detectable humoral responses following Omicron infection. However, 98% had spike peptide T-cell responses assessed by IFN-γ release. In conclusion, primary Omicron infection mounts a low humoral immune response, significantly enhanced by prior vaccination. Omicron infection induced a robust T-cell response in both unvaccinated and vaccinated, demonstrating that the evasive immune potential of primary Omicron infection affects humoral immunity more significantly than T-cell immunity. IMPORTANCE The immunity following infection and vaccination with the SARS-CoV-2 Omicron variant is poorly understood. We investigated immunity assessed with antibody and T-cell responses under different scenarios in vaccinated and unvaccinated individuals with and without Omicron infection. We found that the humoral response was higher among vaccinated-naïve than unvaccinated convalescent. Unvaccinated with and without infection had comparable low humoral responses, whereas vaccinated with a second or third dose, independent of infection status, had increasingly higher levels. Only a minor fraction of unvaccinated individuals had detectable humoral responses following Omicron infection, while almost all had positive T-cell responses. In conclusion, primary Omicron infection mounts a low humoral immune response, enhanced by prior vaccination. Omicron infection induced a robust T-cell response in both unvaccinated and vaccinated, demonstrating that immune evasion of primary Omicron infection affects humoral immunity more than T-cell immunity.