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Correlates of protection against symptomatic SARS-CoV-2 in vaccinated children

Nature Medicine (2024)Cite this article

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Abstract

The paucity of information on longevity of vaccine-induced immune responses and uncertainty of the correlates of protection hinder the development of evidence-based COVID-19 vaccination policies for new birth cohorts. Here, to address these knowledge gaps, we conducted a cohort study of healthy 5–12-year-olds vaccinated with BNT162b2. We serially measured binding and neutralizing antibody titers (nAbs), spike-specific memory B cell (MBC) and spike-reactive T cell responses over 1 year. We found that children mounted antibody, MBC and T cell responses after two doses of BNT162b2, with higher antibody and T cell responses than adults 6 months after vaccination. A booster (third) dose only improved antibody titers without impacting MBC and T cell responses. Among children with hybrid immunity, nAbs and T cell responses were highest in those infected after two vaccine doses. Binding IgG titers, MBC and T cell responses were predictive, with T cells being the most important predictor of protection against symptomatic infection before hybrid immunity; nAbs only correlated with protection after hybrid immunity. The stable MBC and T cell responses over time suggest sustained protection against symptomatic SARS-CoV-2 infection, even when nAbs wane. Booster vaccinations do not confer additional immunological protection to healthy children.

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Fig. 1: Adaptive immune responses following BNT162b2 vaccination in children aged 5–12 years were comparable or superior to adults despite reduced vaccine dose.
Fig. 2: A booster dose increased antibody titers but had no effect on memory B cell and T cell responses for SARS-CoV-2-naive children.
Fig. 3: Superiority of the adaptive immune parameters in children who acquired hybrid immunity within 6 months post-vaccination compared to vaccination or infection alone.
Fig. 4: A booster dose had minimal effects on adaptive immune responses in children with hybrid immunity.
Fig. 5: Anti-S IgG S+ MBCs and T cell responses are correlates of protection against symptomatic SARS-CoV-2 infection before hybrid immunity.
Fig. 6: nAb titers correlate with protection against symptomatic SARS-CoV-2 infection when prevalence of hybrid immunity was high.

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Data availability

All aggregate data supporting the findings of this study are available within the paper and its supplementary materials. Individual-level participant data are not publicly available. Only the data of individuals who consented to further research can be accessible with the consent of the ethics committees from the requestor’s and corresponding authors’ institutions. A formal data transfer agreement between the institutions will be required upon ethics approval. The corresponding authors can be contacted for access to data and will respond within 1 month; data transfer can take place once the data transfer agreement is completed.

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Acknowledgements

We gratefully acknowledge the support from A. Bertoletti and A. Tanoto Tan for suggestions on data interpretation; E. Shuyi Gan, T. Siriphanitchakorn, Y. S. Leong, K. W. Teng, C. Qui and M. Qui from Duke-NUS and C.-H. Huang, G. C. Yap, H. Wen, B. Shunmuganathan and R. Gupta from NUS for technical assistance; clinical research coordinators S. Wong, J. Lim, J. Yap, R. Chua and N. Siti Binte Roslan from NUH for assistance with participant recruitment and follow-up; and S. Nishanti Ramasamy for assistance with manuscript editing, formatting and submission. E.H.T. is supported by the National Medical Research Council (NMRC) Transition Award (MOH-000269), C.W.T. is supported by the NMRC Open Fund – Large Collaborative Grant (OFLCG19May-0034) and the National University of Singapore Startup grant (NUHSRO/2023/018/Startup/10) and E.E.O. is supported by the NMRC Singapore Translational Research (STaR) Award (MOH-001271-00). This study was supported by the NUS award of E.H.T. (NUHSRO/2021/081/NUS Med/07/MARVELS) from the Yong Loo Lin School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Most of all, we gratefully acknowledge the heroic efforts of all the children and families who gave their precious time and biosamples to the MARVELS study.

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Author notes

  1. These authors contributed equally: Elizabeth Huiwen Tham, Eng Eong Ooi.

Authors and Affiliations

  1. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore

    Youjia Zhong, Alicia Y. H. Kang, Carina J. X. Tay, Hui’ En Li, Nurul Elyana, Lynette P. Shek & Elizabeth Huiwen Tham

  2. Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore

    Youjia Zhong, Wee Chee Yap, Joey M. E. Lim, Nina Le Bert, Kuan Rong Chan, Eugenia Z. Ong, Jenny G. Low & Eng Eong Ooi

  3. Khoo Teck Puat-National University Children’s Medical Institute, National University Health System (NUHS), Singapore, Singapore

    Youjia Zhong, Lynette P. Shek & Elizabeth Huiwen Tham

  4. Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Chee Wah Tan & Wee Chee Yap

  5. Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore

    Eugenia Z. Ong, Jenny G. Low & Eng Eong Ooi

  6. Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore

    Jenny G. Low

  7. Department of Clinical Translational Research, Singapore General Hospital, Singapore, Singapore

    Eng Eong Ooi

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Contributions

Y.Z., L.P.S., E.H.T. and E.E.O. designed and conceptualized the pediatric MARVELS study. J.G.L. designed and conceptualized the adult healthcare worker study used for comparison. L.P.S. and E.H.T. acquired funding and supervised the project. A.Y.H.K., C.J.X.T., H.E.L., N.E., W.C.Y., C.W.T., J.M.E.L. and N.L.B. provided administrative, technical and material support. Y.Z. and C.J.X.T. performed the statistical analyses. Y.Z., K.R.C., E.Z.O. and E.E.O. interpreted the data. Y.Z. and E.E.O. wrote the paper. All authors contributed to the revision of the paper and approved the final version for publication.

Corresponding authors

Correspondence to Youjia Zhong or Eng Eong Ooi.

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N.L.B. reports a patent for a method to monitor SARS-CoV-2-specific T cells in biological samples, which is pending. The other authors declare no competing interests.

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

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Extended data

Extended Data Fig. 1 Isotypes and binding activity of Spike-specific memory B cells (S + MBC) in children with immunity against SARS-CoV-2.

A. Representative flow cytometric staining plots for vaccine-only (VV), hybrid (VVI), and infection-only immunity (n = 1 each). B. S + MBC isotypes in children with vaccine-only immunity (n = 34), at pre-vaccination baseline, and 3- and 6 months post vaccination. C. Binding activity against Spike proteins from three SARS-CoV-2 variants in B cell ELISPOT. Spike-specific memory B cells (S+ MBCs) were extracted from a pediatric subject 3 months after 2 doses of mRNA BNT162b2, and then cultured and differentiated ex vivo into antibody secreting cells.

Extended Data Fig. 2 Children vaccinated with 2 doses of mRNA SARS-CoV-2 vaccine have low levels of Th2 cytokines (n = 34).

A, B, C. Spike-reactive Th2 responses, measured by interleukin-4, interleukin-5 and interleukin-13 for children with vaccine-only immunity, and adults. For box-whisker graphs, upper and lower boundaries of boxes indicate upper and lower quartile respectively, line indicates median, and whiskers represent the range.

Extended Data Fig. 3 Vaccine-associated local and systemic adverse events and symptoms of SARS-CoV-2 infection reported by MARVELS children.

A. Percentages and severity of parent and / or subject – reported local and systemic symptoms for 10 days after vaccination. Blue = adverse events after doses 1 and 2, with color gradient representing spectrum of severity; Red = adverse events after booster (dose 3), with color gradient representing spectrum of severity. B. Clinical features of symptomatic SARS-CoV-2 infections for all episodes of symptomatic SARS-CoV-2 infection among vaccinated children. Two-tailed Fisher’s exact test was used for comparison between groups; ns: not significant, *: p ≤ 0.05, **: p ≤ 0.01, ***: p ≤ 0.001, ****: p ≤ 0.0001. For pain at injection site, p-value = 0.0189. For fever, p-value = 0.0091.

Extended Data Fig. 4 Nucleocapsid (N)-specific antibodies and T cells in children with asymptomatic SARS-CoV-2 infections.

A. Venn diagram showing all episodes of asymptomatic COVID-19 identified in this study (n = 30), separated into whether they were identified via seropositivity, T cell reactivity, or both against SARS-CoV-2 N protein. B, C. N-reactive T cell responses measured by post-stimulation interferon-γ and interleukin-2 levels, at pre-vaccination baseline, 3- and 6 months post vaccination, from vaccinated (two doses) children who remained uninfected (VV, n = 34), with symptomatic infection (VVI(S), n = 49) and asymptomatic infection (VVI(A), n = 11). D. N-reactive T cell responses measured by post-stimulation interferon-γ and E. interleukin-2 levels, at 6- and 12 months post vaccination, for VV children at 6 months. F. N-reactive T cell responses measured by post-stimulation interferon-γ and G. interleukin-2 levels, at 6- and 12 months post vaccination, for children with hybrid immunity at 6 months. In D-G, children were grouped into the following categories: 1) Those who did not develop SARS-CoV-2 infection between 6 and 12 months, 2) those who developed symptomatic SARS-CoV-2 re-infection (S), or 3) those who had asymptomatic re-infection. In all graphs, subjects with serological evidence of asymptomatic SARS-CoV-2 are colored in blue.

Extended Data Fig. 5 The proximity of last immunity-boosting event is similar for children who had symptomatic SARS-CoV-2 infection between doses 1 and 2 (VIV), and children who had symptomatic SARS-CoV-2 infection after 2 doses (VVI(S)).

A. Schematic representation of the different last immunity-boosting event, for VIV and VVI(S) children. Created with BioRender.com. B. Comparison of proximity of immunity-boosting event for VIV and VVI(S) children. For box-whisker graphs, upper and lower boundaries of boxes indicate upper and lower quartile respectively, line indicates median, and whiskers represent the range. Two-tailed Mann–Whitney U test was used for comparison between groups; ns: not significant, *: p ≤ 0.05, **: p ≤ 0.01, ***: p ≤ 0.001, ****: p ≤ 0.0001.

Extended Data Fig. 6 Eight-cytokines measured in the cytokine release assay for Spike-reactive T cell responses among children with hybrid immunity.

A. Schematic of cytokine release assay and analytical methods (after DMSO control subtraction) using unsupervised clustering algorithm (UMAP). The cytokines quantified were interferon-γ (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), Granzyme-B, interleukin-10 (IL-10), interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). B. UMAP plots generated with all analyzed samples (n = 391, consisting of adults, infected children and vaccinated children at all time points) with levels of secreted cytokines shown in heatmaps. C. Concatenated cytokine secretion profiles of S peptide pool-stimulated whole blood from children with VIV, VVI(S) and VVI(A). Cytokine secretion profiles were overlaid on the global UMAP plot of all analyzed samples (black dots; each dot corresponds to one culture supernatant).

Extended Data Fig. 7 Immune correlates of protection against symptomatic SARS-CoV-2 infection between 3- and 6 months from start of vaccination.

N = 23 children had symptomatic SARS-CoV-2 infection between months 3 and 6, while n = 66 did not; of these, n = 3 had asymptomatic SARS-CoV-2 infection. A. 3-month Spike (S)-reactive T cell responses, quantified using interferon- γ (IFN-γ) and interleukin-2 (IL-2), for children with no infection, symptomatic and asymptomatic SARS-CoV-2 infection between 3 and 6 months. For comparison between no infection and symptomatic infection, p-value for IFN-γ = 0.000688 and for IL-2 = 0.025786. For comparison between symptomatic infection and asymptomatic infection, p-value for IFN-γ = 0.015810 and for IL-2 = 0.031621. B. 3-month Omicron BA.2 pVNT50 titers in children who did and did not develop symptomatic SARS-CoV-2 infection between 3 and 6 months. Color of dots indicate the type of pre-existing immunity they had at month 3 (p-value = 0.000589). C. Receiver operator characteristics (ROC) curve for BA.2 measured at 3 months from start of vaccination. D. pVNT50 titers Anti-S IgG titers, E. Percentage of S+ MBCs out of total B cells (p-value 0.004599), and F. S-reactive T cell responses measured by post-stimulation interferon-γ levels at month 3 post-vaccination (p-value 0.047200), for VVI(S) and non-VVI(S) children with and without symptomatic SARS-CoV-2 infection. For box-whisker graphs, upper and lower boundaries of boxes indicate upper and lower quartile respectively, line indicates median, and whiskers represent the range. Two-tailed Mann–Whitney U test was used to compare between groups. The ROC curve analysis was performed using the Wilson/Brown test. ns: not significant, *: p ≤ 0.05, **: p ≤ 0.01, ***: p ≤ 0.001, ****: p ≤ 0.0001.

Extended Data Fig. 8 Protection from symptomatic SARS-CoV-2 infection was associated with hybrid immunity but not age.

A. Superior protective capacity of hybrid immunity, demonstrated by the different in percentages of children who developed symptomatic SARS-CoV-2 infection between 6 and 12 months, among children with vaccine-only (VV) immunity at 6 months, compared to children with hybrid immunity at 6 months. Two-tailed Fisher’s exact test was used for comparison between groups. P-value = 0.0018. B, C. Symptomatic SARS-CoV-2 infection was not associated with age, as demonstrated by B. age distribution of all children getting their first infection after 2 doses of mRNA vaccination (n = 57 symptomatic, n = 16 asymptomatic), and C. age distribution of all children with hybrid immunity getting a re-infection (n = 3 symptomatic and n = 11 asymptomatic). For box-whisker graphs, upper and lower boundaries of boxes indicate upper and lower quartile respectively, line indicates median, and whiskers represent the range. Two-tailed Mann–Whitney U test was used to compare between different groups. ns: not significant, *: p ≤ 0.05, **: p ≤ 0.01, ***: p ≤ 0.001, ****: p ≤ 0.0001.

Extended Data Table 1 Baseline demographic and clinical features of all pediatric subjects
Full size table
Extended Data Table 2 Multivariate regression model of the humoral and cellular immune parameters and their correlation with symptomatic SARS-CoV-2 infection between 3 and 6 months post-vaccination (dependent variable)
Full size table

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Zhong, Y., Kang, A.Y.H., Tay, C.J.X. et al. Correlates of protection against symptomatic SARS-CoV-2 in vaccinated children. Nat Med (2024). https://doi.org/10.1038/s41591-024-02962-3

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