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. 2024 Apr 5;9(1):73.
doi: 10.1038/s41541-024-00866-4.

COVID-19 vaccination induces distinct T-cell responses in pediatric solid organ transplant recipients and immunocompetent children

Katerina Roznik  1   2 , Jiashu Xue  2 , Georgia Stavrakis  1   2 , T Scott Johnston  2 , Divya Kalluri  3 , Rivka Ohsie  3 , Caroline X Qin  3   4 , John McAteer  4 , Dorry L Segev  3   5 , Douglas Mogul  4 , William A Werbel  2 , Andrew H Karaba  2 , Elizabeth A Thompson  2 , Andrea L Cox  6   7
Affiliations

COVID-19 vaccination induces distinct T-cell responses in pediatric solid organ transplant recipients and immunocompetent children

Katerina Roznik et al. NPJ Vaccines. .

Abstract

Immune responses to COVID-19 vaccination are attenuated in adult solid organ transplant recipients (SOTRs) and additional vaccine doses are recommended for this population. However, whether COVID-19 mRNA vaccine responses are limited in pediatric SOTRs (pSOTRs) compared to immunocompetent children is unknown. Due to SARS-CoV-2 evolution and mutations that evade neutralizing antibodies, T cells may provide important defense in SOTRs who mount poor humoral responses. Therefore, we assessed anti-SARS-CoV-2 IgG titers, surrogate neutralization, and spike (S)-specific T-cell responses to COVID-19 mRNA vaccines in pSOTRs and their healthy siblings (pHCs) before and after the bivalent vaccine dose. Despite immunosuppression, pSOTRs demonstrated humoral responses to both ancestral strain and Omicron subvariants following the primary ancestral strain monovalent mRNA COVID-19 series and multiple booster doses. These responses were not significantly different from those observed in pHCs and significantly higher six months after vaccination than responses in adult SOTRs two weeks post-vaccination. However, pSOTRs mounted limited S-specific CD8+ T-cell responses and qualitatively distinct CD4+ T-cell responses, primarily producing IL-2 and TNF with less IFN-γ production compared to pHCs. Bivalent vaccination enhanced humoral responses in some pSOTRs but did not shift the CD4+ T-cell responses toward increased IFN-γ production. Our findings indicate that S-specific CD4+ T cells in pSOTRs have distinct qualities with unknown protective capacity, yet vaccination produces cross-reactive antibodies not significantly different from responses in pHCs. Given altered T-cell responses, additional vaccine doses in pSOTRs to maintain high titer cross-reactive antibodies may be important in ensuring protection against SARS-CoV-2.

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Conflict of interest statement

W.A.W. received advisory board fees from Novavax and consulting fees from AstraZeneca and GlobalData. W.A.W. is a consultant for the CDC/IDSA COVID-19 Real-Time Learning Network. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Pediatric solid organ transplant recipients with an extra dose of ancestral monovalent vaccine do not exhibit significantly different humoral responses from their healthy siblings.
a Anti-S and anti-S1 RBD IgG titers in pHCs (n = 10) and pSOTR monovalently vaccinated (M) (n = 20) at approximately 6 months (180 days) since last vaccination and pSOTRs who received the bivalent dose (B) (n = 8) 300 days post-vaccination. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. Kruskal–Wallis test, ns = not significant. b Anti-nucleocapsid IgG titers. The WHO cutoff of 12.3 units (positivity for natural infection) is depicted by dotted line. Filled circles represent individuals with self-reported or documented SARS-CoV-2 infection. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. Kruskal–Wallis tests, *p < 0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). d Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5. e Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 for each individual within the groups. Wilcoxon matched-pairs rank test, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. f Anti-S and anti-S1 RBD IgG titers in pSOTR (n = 8) six months since last vaccination and adult SOTRs (n = 38) at peak vaccine responses (day 14). Mann–Whitney test, *p < 0.05. g Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in pSOTRs (n = 8) and adult SOTRs (n = 38). Mann–Whitney tests, *p < 0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). h Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 in pSOTRs (n = 8) and adult SOTRs (n = 38). Wilcoxon matched-pairs rank test, *p < 0.05, ****p < 0.0001. In (a–c, f, g), boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values).
Fig. 2
Fig. 2. Bivalent boosting improves vaccine-induced antibody responses to both the ancestral strain and Omicron BA.5 and wane over time.
a Anti-S and anti-S1 RBD IgG titers in the pSOTR bivalent group at days 0 (D0; pre-bivalent) (n = 4), 14 (D14; peak responses) (n = 9) and 300 (D300; waning responses) (n = 8). Kruskal–Wallis test, *p < 0.05, **p < 0.01. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). b Anti-S and anti-S1 RBD IgG titers at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in bivalent vaccine pSOTR recipients. Kruskal–Wallis tests, *p < 0.05, **p < 0.01, ***p < 0.001. The dotted line represents 25% ACE2 inhibition (limit of detection). Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Percent ACE2 binding inhibition of the ancestral strain and Omicron BA.5 at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. e Percent ACE2 binding inhibition of the ancestral strain and Omicron variants of concern (VOC) in bivalent dose recipients at peak (left) and day 300 (right). A single individual was infected between days 14 and 300 (red circles). Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). f Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5 at peak responses (see Fig. 1d for correlations at day 300). g Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 at days 0 and 14 (see Fig. 1e for day 300). Wilcoxon matched-pairs rank test, **p < 0.01.
Fig. 3
Fig. 3. S-specific CD4 T+ cells in immunocompetent children produce more interferon-γ compared to pediatric solid organ transplant recipients.
a Representative flow cytometry gating of cytokine-producing S-specific CD4+ T cells. b Representative cytokine production by S-specific CD4+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5 S protein peptides. c Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5 S peptides in pSOTRs and pHCs vaccinated with monovalent mRNA COVID-19 vaccines. One-way ANOVA with Tukey correction, ns = not significant. d Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptide stimulation. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. Two-way ANOVA with Tukey correction for multiple comparisons, **p < 0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). e Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs (n = 8) six months since the last vaccine dose and adult SOTRs (n = 19) for which we had PBMC samples at peak vaccine responses (day 14). Two-way ANOVA with Tukey correction, *p < 0.05, **p < 0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values).
Fig. 4
Fig. 4. CD4+ T-cell responses are improved after bivalent boosting and maintain cross-reactivity against Omicron BA.5.
a Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides at 0, 14, and 300 days post-bivalent vaccination. Two-way ANOVA with Tukey correction, *p < 0.05, **p < 0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at 0, 14, and 300 days post-bivalent vaccination. d Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5 S peptides at days 0, 14, and 300 post-bivalent vaccination. One-way ANOVA with Tukey correction, ns = not significant.
Fig. 5
Fig. 5. CD8+ T-cell responses are low six+ months post-vaccination.
a Representative cytokine production by S-specific CD8+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5 S protein peptides. b Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5 S peptides in monovalently vaccinated pSOTRs and pHCs. One-way ANOVA with Tukey correction, ns = not significant. c Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values).
Fig. 6
Fig. 6. Bivalent boosting does not improve CD8+ T-cell responses vaccine responses in pSOTRs.
a Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs at days 0, 14, and 300 post-bivalent dose. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD8+ T cells in response to BA.5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at days 0, 14, and 300 post-bivalent dose. d Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5 S peptides in pSOTRs bivalent recipients at days 0, 14, and 300 post-bivalent dose. One-way ANOVA with Tukey correction, ns = not significant.
Fig. 7
Fig. 7. pSOTRs produce qualitatively different polyfunctional CD4+ T cells compared to pHCs in response to vaccination.
a Ancestral and BA.4/5 peptide stimulation induced no significant differences in frequencies of polyfunctional CD4+ T cells in each group. Pie charts are broken down by the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category (1–15). c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptides. Two-way ANOVA with Tukey correction, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars represent standard error of the mean.
Fig. 8
Fig. 8. Bivalent boosting temporarily improved CD4+ T-cell polyfunctionality in pSOTRs.
a Cytokine production by CD4+ T cells in response to ancestral and Omicron BA.4/5 peptides at days 0, 14, and 300 post-bivalent vaccination. Pie charts depict the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category. c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptide stimulation. Two-way ANOVA with Tukey correction, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars represent standard error of the mean.
Fig. 9
Fig. 9. pSOTRs generate metabolically active but qualitatively distinct CD4+ T cells following mRNA vaccination compared to pHCs.
a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 8 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Error bars represent standard error of the mean. e MFI plots for significant clusters determined in (d), ungated clusters (gray) and bulk T cells (black).
Fig. 10
Fig. 10. Bivalent boosting further promotes altered CD4+ T-cell phenotype in pSOTRs.
a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 7 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, all not significant. Error bars represent standard error of the mean.
Fig. 11
Fig. 11. S-specific T-cell proliferation in response to ancestral spike peptides in pHCs and pSOTRs.
a Representative gating of cell trace violet-labeled, S-specific, proliferating daughter T cells in response to ancestral SARS-CoV-2 S peptides. b Proliferating S-specific CD4+ and CD8+ T cells (% memory) in pHC, pSOTR M, and pSOTR B groups at the time of waning immunity. No significant relationships. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). c Proliferating CD4+ and CD8+ T cells (% memory) in pSOTR B at days 0, 14, and 300. Kruskal-Wallis test, *p < 0.05, ns = not significant. Boxplots were used to summarize data (median, 1st–3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Heatmap depicting correlations between proliferation of S-specific CD4+ T cells and cytokine production in pHCs and pSOTRs. The “cytokine” category combines TNF, IL-21, IL-2, and IFN-γ production. Pearson correlation coefficients are depicted in each square. Higher coefficient represents greater correlation.
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References

    1. Boyarsky BJ, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325:1784–1786. doi: 10.1001/jama.2021.4385. - DOI - PMC - PubMed
    1. Boyarsky BJ, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204–2206. doi: 10.1001/jama.2021.7489. - DOI - PMC - PubMed
    1. Kwon JH, et al. mRNA vaccine effectiveness against coronavirus disease 2019 hospitalization among solid organ transplant recipients. J. Infect. Dis. 2022;226:797–807. doi: 10.1093/infdis/jiac118. - DOI - PMC - PubMed
    1. Lopez A, et al. Vaccination recommendations for the adult immunosuppressed patient: a systematic review and comprehensive field synopsis. J. Autoimmun. 2017;80:10–27. doi: 10.1016/j.jaut.2017.03.011. - DOI - PubMed
    1. Kumar D, et al. Neutralization against Omicron variant in transplant recipients after three doses of mRNA vaccine. Am. J. Transplant. 2022;22:2089–2093. doi: 10.1111/ajt.17020. - DOI - PMC - PubMed