AUTHOR=Paniskaki Krystallenia , Anft Moritz , Meister Toni L. , Marheinecke Corinna , Pfaender Stephanie , Skrzypczyk Sarah , Seibert Felix S. , Thieme Constantin J. , Konik Margarethe J. , Dolff Sebastian , Anastasiou Olympia , Holzer Bodo , Dittmer Ulf , Queren Christine , Fricke Lutz , Rohn Hana , Westhoff Timm H. , Witzke Oliver , Stervbo Ulrik , Roch Toralf , Babel Nina TITLE=Immune Response in Moderate to Critical Breakthrough COVID-19 Infection After mRNA Vaccination JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.816220 DOI=10.3389/fimmu.2022.816220 ISSN=1664-3224 ABSTRACT=

SARS-CoV-2 variants of concern (VOCs) can trigger severe endemic waves and vaccine breakthrough infections (VBI). We analyzed the cellular and humoral immune response in 8 patients infected with the alpha variant, resulting in moderate to fatal COVID-19 disease manifestation, after double mRNA-based anti-SARS-CoV-2 vaccination. In contrast to the uninfected vaccinated control cohort, the diseased individuals had no detectable high-avidity spike (S)-reactive CD4+ and CD8+ T cells against the alpha variant and wild type (WT) at disease onset, whereas a robust CD4+ T-cell response against the N- and M-proteins was generated. Furthermore, a delayed alpha S-reactive high-avidity CD4+ T-cell response was mounted during disease progression. Compared to the vaccinated control donors, these patients also had lower neutralizing antibody titers against the alpha variant at disease onset. The delayed development of alpha S-specific cellular and humoral immunity upon VBI indicates reduced immunogenicity against the S-protein of the alpha VOC, while there was a higher and earlier N- and M-reactive T-cell response. Our findings do not undermine the current vaccination strategies but underline a potential need for the inclusion of VBI patients in alternative vaccination strategies and additional antigenic targets in next-generation SARS-CoV-2 vaccines.