Thomas R. Müller[1], Takuya Sekine[1], Julia Niessl[1], Curtis Cai[1], Yu Gao[1], Anna Olofsson[2], Piotr Nowak[3,4,5], Ola Blennow[3,6,7], Lotta Hansson[8,9], Stephan Mielke[10,11], Annika C. Karlsson[2], Peter Bergman[3,12], Hans-Gustaf Ljunggren[1], Soo Aleman[3,4] and Marcus Buggert[1]

Affiliates

1Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden. 2Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 3Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden. 4Department of Medicine Huddinge, Infectious Diseases, Karolinska Institute, Stockholm, Sweden 5Laboratory for Molecular Infection Medicine Sweden MIMS, Umeå University, Umeå , Sweden 6Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden 7Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden 8Department of Hematology, Karolinska University Hospital, Stockholm, Sweden 9Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 10Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Stockholm, Sweden 11Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden 12Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden

Abstract

Background: After two and a half years of SARS-CoV-2 evolution, Omicron (B.1.1.529) and its subvariants have taken other. A plethora of mutations in the surface glycoprotein abrogates vaccination-induced antibody responses, resulting in high infection rates around the globe. However, we and others have shown that T cell responses are affected only to a minor degree by these mutations, thereby keeping up anti-viral immunity and protecting from severe disease. Here, we set out to investigate the magnitude, functional capacity, and potential longevity of Omicron-reactive and Omicron-specific T cell responses particularly in immunocompromised individuals before and after booster vaccination as well as natural infection during the Omicron wave.

Methods:
Pre/post booster vaccination blood and serum samples were collected from 279 individuals covering five different immunodeficiencies and healthy controls. Omicron-reactive T cell responses were evaluated via stimulation with SARS-CoV-2 full-length WT as well as Omicron spike peptide pools. Omicron-specific T cell responses were determined using subpools containing spike peptides exclusively present in Omicron as well as corresponding WT peptides. Extensive immunophenotyping was performed using multiparameter flow cytometry, including detection of activation-induced surface markers and further functional assays to determine the cytotoxic and proliferative capacity of Omicron-reactive T cells.

Results: Robust yet variable Omicron-reactive responses were observed in all patient groups. Booster vaccination significantly increased T cell responses in all groups and we observed that particularly patients with low responses after two vaccine doses benefitted most from a third one. In all patient groups, a larger increase of Omicron-reactive CD8+ T cells was detectable compared to CD4+ T cells, accompanied by a shift towards a more cytotoxic profile. Moreover, Omicron-reactive T cell responses showed signs of longevity represented by a novel Temra subpopulation with stem-cell like characteristics and increased proliferative capacity. Investigating WT- and Omicron-reactive as well as WT- and Omicron-specific T cell responses, we observed an increased formation of Omicron-specific T cell responses in Omicron-wave infected compared to infection-naïve individuals, despite a strong immunological imprint of three WT-based vaccine doses.

Conclusion: Robust Omicron-reactive T cell responses are induced in healthy and immunocompromised individuals by common WT-based vaccines and can be further ameliorated with additional booster doses. Furthermore, Omicron-specific T cell responses expand or are generated de novo after Omicron-infection, thereby likely improving immunological defenses against subsequent infections.