Study on SARS-CoV-2 breaktrough infections at University Hospital Essen
Background: Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) are increasingly observed in vaccinated individuals. We investigated the humoral and cellular immune responses towards SARS-CoV-2 wildtype virus and VOCs of hospitalized COVID-19 patients during Delta and Omicron infection waves.   Methods: Whole genome sequences were analyzed to identify the corresponding VOC. Humoral immune responses were analyzed by ELISA and cell-culture based neutralization assay against SARS-CoV-2 D614G isolate (wildtype), Alpha, Delta (AY.43) and Omicron (BA.1 and BA.5). Cellular immunity was evaluated with an IFN-gamma ELISpot assay. Results: Double-vaccinated patients with Delta breakthrough infection displayed a significantly increased neutralizing antibody response against Delta compared to double-vaccinated uninfected controls (median complete neutralization titer (NT100) 640 versus 80, p smaller than 0.05). Omicron-BA.1 infection increased neutralization titers against BA.1 in double-vaccinated patients (median NT100 of 160 in patients versus 20 in controls, p=0.0684) and patients that received booster vaccination (median NT100 of 50 in patients versus 20 in controls, p=0.6832). For boosted patients with BA.5 breakthrough infection, we found no enhancing effect on humoral immunity against VOCs. Furthermore, ELISA-binding antibody levels against wildtype SARS-CoV-2 correlated with neutralization of SARS-CoV-2 VOCs. Patients showed a small IFN-gamma response after stimulating PBMCs with mutated regions of VOCs.  Conclusion: Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced in SARS-CoV-2 breakthrough infections. Delta and Omicron-BA.1 infections boosted the humoral immunity in double-vaccinated patients and patients with booster vaccination. Omicron-BA.5 did not enhance humoral immunity, which could increase the likelihood for reinfections with BA.5.