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Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19

Nature Aging volume 4, pages 1121–1136 (2024)Cite this article

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Abstract

Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.

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Fig. 1: Cohort overview.
Fig. 2: Cellular and humoral immune responses after vaccination against SARS-CoV-2.
Fig. 3: Coordination of cellular and humoral immune responses as a function of intrinsic factors after vaccination against SARS-CoV-2.
Fig. 4: S protein-specific CD4+ and CD8+ T cell responses as a function of age after vaccination against SARS-CoV-2.
Fig. 5: Cytotoxic and humoral immune responses as a function of age after vaccination against SARS-CoV-2.
Fig. 6: S protein-specific cellular and humoral immune responses in older individuals as a function of primary vaccination schedule after boosting with BNT162b2 or mRNA-1273.

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Source data are provided with this paper. Any other data underlying this study will be provided by the corresponding author upon reasonable request.

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Acknowledgements

We thank the study participants for their willingness to contribute, staff at the Laboratorio Unico Provinciale of St. Anna Hospital and the Azienda Unità Sanitaria Locale della Romagna, namely R. Biguzzi, M. Di Benedetto, T. Dogana, A. Porcellini, A. Ricci and A. R. Torri, for assistance with serology, M. P. Carbone and N. Sirri for technical support, and all healthcare professionals working at Residenza Caterina, the Geriatric Department and the Laboratorio Unico Provinciale of St. Anna Hospital, and the Ferrara Blood Bank (AVIS) in Italy and the Harborne Medical Practice, the Lapal Medical Practice, New Road Surgery, Northumberland House Surgery, Ridgacre House Surgery and the Wychbury Medical Group in the UK. This study was funded by a grant from the University of Ferrara (FIR). B.D. and D.P. were partially supported by the Consorzio Interuniversitario Biotecnologie. H.M.P. and P.A.H.M. were supported via a National Core Studies Immunity Award from UK Research and Innovation (MC_PC_20060) and by the UK Coronavirus Immunology Consortium (MR/V028448/1). D.A.P. was supported by the National Institute for Health Research (COV-LT2-0041) and by the PolyBio Research Foundation (Balvi B43).

Author information

Author notes

  1. These authors contributed equally: Beatrice Dallan, Davide Proietto.

Authors and Affiliations

  1. Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

    Beatrice Dallan, Davide Proietto, Martina De Laurentis, Eleonora Gallerani, Mara Martino, Salvatore Pacifico, Martina De Laurentis, Antonella Caputo, Riccardo Gavioli & Francesco Nicoli

  2. Laboratory of Clinical Pathology, University Hospital St. Anna, Ferrara, Italy

    Sara Ghisellini & Michela Boni

  3. Department of Medical Sciences, University of Ferrara, Geriatrics Unit, University Hospital of Ferrara, Ferrara, Italy

    Amedeo Zurlo, Stefano Volpato, Benedetta Govoni, Elena Barbieri & Linda Dall’Olio

  4. Department of Economics and Management, University of Ferrara, Ferrara, Italy

    Michela Borghesi & Stefano Bonnini

  5. Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy

    Valentina Albanese & Tatiana Bernardi

  6. Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, Bordeaux, France

    Victor Appay

  7. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK

    Sian Llewellyn-Lacey, Kristin Ladell & David A. Price

  8. Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

    Laura Grumiro, Martina Brandolini & Vittorio Sambri

  9. Unit of Microbiology, Greater Romagna Area Hub Laboratory, Cesena, Italy

    Simona Semprini & Vittorio Sambri

  10. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    Helen M. Parry & Paul A. H. Moss

  11. Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK

    David A. Price

  12. Residenza Caterina, Ferrara, Italy

    Caterina Fiorini & Michele Fiorini

  13. Blood Transfusion Service, University Hospital St. Anna, Ferrara, Italy

    Maurizio Govoni

  14. Department of Medical Sciences, Section of Public Health Medicine, University of Ferrara, Ferrara, Italy

    Margherita Neri

  15. AVIS, Ferrara, Italy

    Fabio Palma

  16. Azienda Unità Sanitaria Locale FE, Ferrara, Italy

    Franco Romagnoni

Authors
  1. Beatrice Dallan
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  2. Davide Proietto
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  3. Martina De Laurentis
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  4. Eleonora Gallerani
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  5. Mara Martino
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  6. Sara Ghisellini
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  7. Amedeo Zurlo
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  8. Stefano Volpato
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  9. Benedetta Govoni
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  10. Michela Borghesi
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  11. Valentina Albanese
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  12. Victor Appay
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  13. Stefano Bonnini
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  14. Sian Llewellyn-Lacey
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  15. Salvatore Pacifico
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  16. Laura Grumiro
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  17. Martina Brandolini
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  18. Simona Semprini
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  19. Vittorio Sambri
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  20. Kristin Ladell
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  21. Helen M. Parry
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  22. Paul A. H. Moss
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  23. David A. Price
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  24. Antonella Caputo
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  26. Francesco Nicoli
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Consortia

RIV Study Group

  • Elena Barbieri
  • , Tatiana Bernardi
  • , Michela Boni
  • , Antonella Caputo
  • , Beatrice Dallan
  • , Linda Dall’Olio
  • , Martina De Laurentis
  • , Caterina Fiorini
  • , Michele Fiorini
  • , Eleonora Gallerani
  • , Riccardo Gavioli
  • , Sara Ghisellini
  • , Benedetta Govoni
  • , Maurizio Govoni
  • , Mara Martino
  • , Margherita Neri
  • , Francesco Nicoli
  • , Fabio Palma
  • , Davide Proietto
  • , Franco Romagnoni
  • , Stefano Volpato
  •  & Amedeo Zurlo

Contributions

A.C., R.G. and F.N. conceptualized the study. B.D., D.P., E.G., V. Albanese, S.L.-L., S.P. and D.A.P. devised the methodology. B.D., D.P. and H.M.P. carried out the investigation. S.G., A.Z., S.V. and B.G. recruited the main cohort. B.D., D.P., M.D.L., E.G., M.M., L.G., M. Brandolini and S.S. carried out the laboratory analysis. M. Borghesi, S.B., K.L. and F.N. carried out the statistical analysis. P.A.H.M., D.A.P. and A.C. acquired the funding. V. Appay, V.S., D.A.P., A.C., R.G. and F.N. supervised the study. B.D., D.P., E.G., A.C., R.G. and F.N. wrote the manuscript. V. Appay, D.A.P., A.C., R.G. and F.N. reviewed and edited the manuscript.

Corresponding author

Correspondence to Francesco Nicoli.

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Competing interests

The authors declare no competing interests.

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Peer review information

Nature Aging thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Jie Pan, in collaboration with the Nature Aging team.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Immune profiling of donors stratified by age.

Absolute numbers of naive (N, CD27+CD45RA+), central memory (CM, CD27+CD45RA−), effector memory (EM, CD27−CD45RA−), and terminally differentiated effector memory T cells (EMRA, CD27−CD45RA+), naive (CD27−CD38+) and memory B cells (CD27+CD38–), and plasmablasts (CD27+CD38+) quantified in whole blood directly ex vivo. Data are shown as radar plots representing mean values stratified by age (Y, n = 90; M, n = 125; O, n = 48). *P < 0.05, **P < 0.01, ***P < 0.001 (Y versus M versus O, one-way ANOVA with Tukey’s test).

Source data

Extended Data Fig. 2 Factor analysis of coordinated cellular and humoral immune responses after vaccination against SARS-CoV-2.

(a) Criteria for donor stratification as B/T responders or B/T nonresponders. (b) B/T responder versus B/T nonresponder frequencies stratified by primary vaccination schedule, physical activity, serostatus for CMV, and sex (B/T responders after primary vaccination, n = 6; B/T nonresponders after primary vaccination, n = 41; B/T responders after the booster dose, n = 9; B/T nonresponders after the booster dose, n = 17). *p < 0.05, ***p < 0.001 (B/T responders versus B/T nonresponders, Fisher’s exact test). (c) Age distribution, body mass index (BMI), and comorbidities for B/T responders (primary vaccination, n = 6; booster dose, n = 9) versus B/T nonresponders (primary vaccination, n = 41; booster dose, n = 17). (d) Absolute numbers of naive (CD27−CD38+) and memory B cells (CD27+CD38–) and plasmablasts (CD27+CD38+) for B/T responders (primary vaccination, n = 6; booster dose, n = 9) versus B/T nonresponders (primary vaccination, n = 41; booster dose, n = 15). (e) Absolute numbers of naive CD4+ and CD8+ T cells for B/T responders (primary vaccination, n = 6; booster dose, n = 9) versus B/T nonresponders (primary vaccination, n = 41; booster dose, n = 15). Horizontal lines represent median values (c, d, e). *P < 0.05 (B/T responders versus B/T nonresponders, two-sided Mann–Whitney U test with Bonferroni correction).

Source data

Extended Data Fig. 3 Cellular and humoral immune responses stratified by serostatus for CMV.

(a) Serostatus for CMV by age (groups Y, M, and O). (b) Absolute numbers of naive (N, CD27+CD45RA+), central memory (CM, CD27+CD45RA−), effector memory (EM, CD27−CD45RA−), and terminally differentiated effector memory T cells (EMRA, CD27−CD45RA+), naive (CD27−CD38+) and memory B cells (CD27+CD38–), and plasmablasts (CD27+CD38+) in donors aged 18–49 years stratified as seronegative (n = 61) or seropositive for CMV (n = 72). Data are shown as radar plots representing mean values. (c) Anti-RBD IgG titers after primary vaccination in donors aged 18–49 years stratified as seronegative (ChAdOx1-S, n = 14; BNT162b2, n = 45) or seropositive for CMV (ChAdOx1-S, n = 30; BNT162b2, n = 36). (d) Spike-specific CD8+ T cell frequencies measured via the recall induction of IFNγ or TNF after transient expansion from donors aged <50 years stratified as seronegative (ChAdOx1-S, n = 9; BNT162b2, n = 23) or seropositive for CMV (ChAdOx1-S, n = 21; BNT162b2, n = 16). Horizontal lines represent median values (c, d). ***P < 0.001 (CMV− versus CMV+, two-sided Mann–Whitney U test with Bonferroni correction).

Source data

Extended Data Fig. 4 CD8+ T cell response diversity as a function of age after vaccination against SARS-CoV-2.

HLA-A2-restricted spike epitope-specific and pooled memory epitope-specific CD8+ T cell frequencies were measured using IFNγ ELISpot assays directly ex vivo. (a) Left: response diversity stratified by vaccination schedule. Right: donor age distribution (ChAdOx1-S, n = 14; BNT162b2, n = 16; ChAdOx1-S + boost, n = 15; BNT162b2 + boost, n = 19). (b) Cumulative response frequencies stratified by vaccination schedule (spike: ChAdOx1-S, n = 14; BNT162b2, n = 16; ChAdOx1-S + boost, n = 15; BNT162b2 + boost, n = 19; memory: ChAdOx1-S, n = 18; BNT162b2, n = 20; ChAdOx1-S + boost, n = 21; BNT162b2 + boost, n = 30). (c) Epitope-specific response frequencies stratified by vaccination schedule. Numbers as in (a). Dotted lines indicate the threshold of detection. Data are shown as median + SEM. (d) Epitope recognition frequencies as a binary function stratified by age (Y, n = 16–20; M, n = 43–54; O, n = 9–13). (e) Epitope-specific CD8+ T cell frequencies as a function of age. Data are shown as heatmaps depicting the magnitude of each epitope-specific response in spot-forming units (SFUs) per 106 input cells (key). Numbers as in (d). X denotes missing values. All data are shown after background subtraction. Horizontal lines represent median values (a, b). *P < 0.05 (ChAdOx1-S versus BNT162b2, two-sided Mann–Whitney U test with Bonferroni correction). #P < 0.05, ##P < 0.01 (prime versus boost, two-sided Mann–Whitney U test with Bonferroni correction). aP < 0.05 (Wilcoxon matched-pairs signed-rank test showing values significantly >10 SFUs/106 input cells). Age-associated differences in epitope recognition were assessed using a two-sided Chi-squared test (d). Spike peptides are listed in Supplementary Table 4, and other viral peptides (memory) are listed in Supplementary Table 5.

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Extended Data Fig. 5 Cellular and humoral immune responses as a function of age in donors aged <70 years after vaccination against SARS-CoV-2.

(a–b) Correlations between age and spike-specific CD4+ and CD8+ T cell frequencies (CD4+ T cells: ChAdOx1-S, n = 43; BNT162b2, n = 39; ChAdOx1-S + boost, n = 38; BNT162b2 + boost, n = 41; CD8+ T cells: ChAdOx1-S, n = 61; BNT162b2, n = 47; ChAdOx1-S + boost, n = 39; BNT162b2 + boost, n = 41) measured via the recall induction of CD107a (top), IFNγ (middle), or TNF (bottom) after transient expansion. (c) Correlations between age and YLQ-specific CD8+ T cell frequencies measured via tetramer staining after transient expansion (ChAdOx1-S, n = 37; BNT162b2, n = 30; ChAdOx1-S + boost, n = 22; BNT162b2 + boost, n = 21). (d) Correlations between age and RBD-specific IgG titers (ChAdOx1-S, n = 86; BNT162b2, n = 112; ChAdOx1-S + boost, n = 51; BNT162b2 + boost, n = 50). Correlations were determined using a two-sided Spearman’s rank test.

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Extended Data Fig. 6 Cellular and humoral immune responses in older individuals after boosting with BNT162b2 or mRNA-1273.

(a) RBD-specific IgG titers (ChAdOx1-S + boost, n = 7; BNT162b2 + boost, n = 28), (b) YLQ-specific CD8+ T cell frequencies measured via tetramer staining after transient expansion (ChAdOx1-S + boost, n = 3; BNT162b2 + boost, n = 13), and (c) spike-specific CD4+ (ChAdOx1-S + boost, n = 5; BNT162b2 + boost, n = 16) and CD8+ T cell frequencies (ChAdOx1-S + boost, n = 6; BNT162b2 + boost, n = 14) measured via the recall induction of CD107a (left), IFNγ (center), or TNF (right) after transient expansion among donors in group O after boosting with BNT162b or mRNA-1273. Correlations were determined using a two-sided Spearman’s rank test.

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Dallan, B., Proietto, D., De Laurentis, M. et al. Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19. Nat Aging 4, 1121–1136 (2024). https://doi.org/10.1038/s43587-024-00644-w

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