Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity
Authors: Dietz Lisa Loksø , Juhl Anna Karina , Søgaard Ole Schmeltz , Reekie Joanne , Nielsen Henrik , Johansen Isik Somuncu , Benfield Thomas , Wiese Lothar , Stærke Nina Breinholt , Jensen Tomas Østergaard , Jakobsen Stine Finne , Olesen Rikke , Iversen Kasper , Fogh Kamille , Bodilsen Jacob , Petersen Kristine Toft , Larsen Lykke , Madsen Lone Wulff , Lindvig Susan Olaf , Holden Inge Kristine , Raben Dorthe , Andersen Sidsel Dahl , Hvidt Astrid Korning , Andreasen Signe Rode , Baerends Eva Anna Marianne , Lundgren Jens , Østergaard Lars , Tolstrup Martin ,   the ENFORCE Study Group,   Sponsor, Lundgren J. ,   Principal Investigator, Østergaard L. J. ,   Study personnel, Benfield T. , Krohn-Dehli L. , Petersen D. K. , Fogh K. , Højmark E. , Iversen K. , Klastrup V. , Larsen F. , Stærke N. B. , Schieber S. , Søndergaard A. , Tousgaard M. , Yehdego Y. , Bodilsen J. , Nielsen H. , Petersen K. T. , Ruwald M. , Thisted R. K. , Caspersen S. F. , Iversen M. , Knudsen L. S. , Meyerhoff J. L. , Sander L. G. , Wiese L. , Abildgaard C. , Holden I. K. , Johansen I. S. , Larsen L. , Lindvig S. O. , Madsen L. W. , Øvrehus A. ,   Scientific Steering Committee, Kruse N. A. , Lomholdt H. , Krause T. G. , Valentiner-Branth P. , Søborg B. , Fischer T. K. , Erikstrup C. , Ostrowski S. R. , Tolstrup M. , Søgaard O. S. , Raben D. ,   Operational Group, Benfield T. , Jylling E. , Hougaard D. ,   Coordinating Centre, Andersen S. D. , Lykkegaard K. ,   ENFORCE Lab, Andreasen S. R. , Baerends E. , Dietz L. L. , Hvidt A. K. , Juhl A. K. , Olesen R. ,   Data and Statistical Centre, Andersen K. K. , Bannister W. , Bjernved C. , Esmann F. V. , Gravholdt E. , Jensen C. M. , Jakobsen S. F. , Jakobsen M. L. , Jensen T. Ø , Kristensen D. , Matthews C. , Normand N. , Olsson C. , Reekie J. , Traytel A. 
Published: April 2023

Abstract
Background
Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood.

Methods
In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51–72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections.

Results
We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified.

Conclusions
SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.