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. 2024 Sep 23;230(3):e605-e615.
doi: 10.1093/infdis/jiae215.

Longitudinal Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 T-Cell Immunity Over 2 Years Following Vaccination and Infection

Anna Karina Juhl  1   2 , Lisa Loksø Dietz  1   2 , Ole Schmeltz Søgaard  1   2 , Joanne Reekie  3 , Henrik Nielsen  4   5 , Isik Somuncu Johansen  6   7 , Thomas Benfield  8   9 , Lothar Wiese  10 , Nina Breinholt Stærke  1   2 , Tomas Østergaard Jensen  3 , Rikke Olesen  2 , Kasper Iversen  11 , Kamille Fogh  11 , Jacob Bodilsen  4   5 , Lone Wulff Madsen  6   12 , Susan Olaf Lindvig  7 , Dorthe Raben  3 , Sidsel Dahl Andersen  1 , Astrid Korning Hvidt  1 , Signe Rode Andreasen  1 , Eva Anna Marianne Baerends  1 , Jens Lundgren  3   9   13 , Lars Østergaard  1   2 , Martin Tolstrup  1   2 ; ENFORCE Study Group
Collaborators, Affiliations

Longitudinal Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 T-Cell Immunity Over 2 Years Following Vaccination and Infection

Anna Karina Juhl et al. J Infect Dis. .

Abstract

Background: Within a year of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, vaccines inducing a robust humoral and cellular immune response were implemented worldwide. However, emergence of novel variants and waning vaccine-induced immunity led to implementation of additional vaccine boosters.

Methods: This prospective study evaluated the temporal profile of cellular and serological responses in a cohort of 639 SARS-CoV-2-vaccinated participants, of whom a large proportion experienced a SARS-CoV-2 infection. All participants were infection naïve at the time of their first vaccine dose. Proportions of SARS-CoV-2 spike-specific T cells were determined after each vaccine dose using the activation-induced marker assay, while levels of circulating SARS-CoV-2 antibodies were determined by the Meso Scale serology assay.

Results: We found a significant increase in SARS-CoV-2 spike-specific CD4+ and CD8+ T-cell responses following the third dose of a SARS-CoV-2 messenger RNA vaccine as well as enhanced CD8+ T-cell responses after the fourth dose. Furthermore, increased age was associated with a poorer response. Finally, we observed that SARS-CoV-2 infection boosts both the cellular and humoral immune response, relative to vaccine-induced immunity alone.

Conclusions: Our findings highlight the boosting effect on T-cell immunity of repeated vaccine administration. The combination of multiple vaccine doses and SARS-CoV-2 infections maintains population T-cell immunity, although with reduced levels in the elderly.

Keywords: COVID-19; Spike-specific T cells; cellular response; hybrid immunity; longitudinal study; vaccination.

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Conflict of interest statement

Potential conflicts of interest . T. B. reports the following grants from the past 36 months: unrestricted grant to his institution from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen’s Charitable Fund; unrestricted grant to his institution, principal investigator [PI]/clinical trial, advisory board from Pfizer, MSD, GSK, and Gilead Sciences; and grant for PI/clinical trial from Boehringer Ingelheim, Roche, Novartis, Kancera AB, Janssen, and AstraZeneca. T. B. is board member in Pentabase; serves on advisory boards for Janssen and AstraZeneca; and reports receiving payment or honoraria for lectures at GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, and AstraZeneca. L. W. M. reports receiving travel support from AbbVie in September 2023. N. B. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees on study regarding respiratory syncytial virus from Pfizer and serving as PI in clinical studies sponsored by Pfizer, Bavarian Nordic, Moderna, and AstraZeneca. O. S. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees from UNION therapeutics and participation on a data and safety monitoring board or advisory board with Immunocore, ViiV Healthcare, and Gilead. M.T. reports funding from Danish Ministry of Health for the manuscript. All other authors report no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/longitudinal-evaluation-of-sars-cov-2-t-cell-immunity-over-2-years-following-vaccination-and-infection?utm_campaign=tidbitlinkshare&utm_source=ITP
Figure 1.
Figure 1.
Trajectory of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific CD4+ and CD8+ T cells from baseline to 2 years after first vaccine dose. S-specific CD4+ (A) and CD8+ (B) T cells from baseline to day 730 after first vaccine dose. Where no baseline visit was available, the percentage of S-specific T cells was set to zero. SARS-CoV-2 vaccination is shown by syringes from BioRender.com. The solid line represents the median value and bands the 95% confidence interval. The y-axis scale differs between panels.
Figure 2.
Figure 2.
Proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific CD4+ and CD8+ T cells before and after third and fourth vaccine dose. S-specific CD4+ (n = 391; A) and CD8+ (n = 385; B) T cells before and after a third vaccine dose (days 190 and 255, respectively). S-specific CD4+ (n = 184; C) and CD8+ (n = 181; D) T cells before and after a fourth vaccine dose (days 540 and 570, respectively). Violin plots show the kernel density estimation of the underlying distribution. Boxplots show median, and whiskers extend to show 1.5 × interquartile range. Data are compared using the Wilcoxon signed-rank test. Not significant (ns), 5.00 × 10-2 < P; ****P ≤ 1.00 × 10-4. The y-axis scale differs between panels.
Figure 3.
Figure 3.
Proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific CD4+ and CD8+ T cells before and after third and fourth vaccine dose, stratified by age group. S-specific CD4+ (age <65 y: n = 196, 65–74 y: n = 105, ≥75 y: n = 90) (A) and CD8+ (<65 y: n = 195, 65–74 y: n = 104, ≥75 y: n = 86) (B) T cells before and after a third dose (days 190 and 255, respectively). S-specific CD4+ (<65 y: n = 76, 65–74 y: n = 61, ≥75 y: n = 47) (C) and CD8+ (<65 y: n = 76, 65–74 y: n = 60, ≥75 y: n = 45) (D) T cells before and after a fourth dose (days 540 and 570, respectively). Boxplots show median, and whiskers extend to show 1.5 × interquartile range. Data are compared using the Wilcoxon signed-rank test. Not significant (ns): 5.00 × 10-2 < P; **1.00 × 10-3 < P ≤ 1.00 × 10-2; ***1.00 × 10-4 < P ≤ 1.00 × 10-3; ****P ≤ 1.00 × 10-4. The y-axis scale differs between panels.
Figure 4.
Figure 4.
Trajectory of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific T cells and anti-S serum antibodies from baseline to day 365, stratified by infection. A, CD4+ T cells. B, CD8+ T cells. C, S serum antibodies. SARS-CoV-2 vaccination is shown by syringes. Where no baseline visit was available, the percentage of S-specific T cells was set to zero. SARS-CoV-2 vaccination is shown by syringes from BioRender.com. Data are unpaired; the solid line represents the median value and bands the 95% CI. The y-axis scale differs between panels.
Figure 5.
Figure 5.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific T cells and anti-S serum antibodies at days 255 and 365, stratified by infection. A, S-specific CD4+ T cells. B, S-specific CD8+ T cells. C, Anti-S serum antibodies. Data were compared using the Mann-Whitney U test. Not significant (ns): 5.00 × 10-2 < P; ****P ≤ 1.00 × 10-4. The y-axis scale differs between panels.
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