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Effect of a SARS-CoV-2 booster vaccine dose on the immune response of adults with Down syndrome

  • Ayla Yarci-Carrión
    Affiliations
    Microbiology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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  • Laura Esparcia-Pinedo
    Affiliations
    Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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  • Gloria Mateo-Jiménez
    Affiliations
    Fundación de Investigación Biomédica del Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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  • Arantzazu Alfranca
    Affiliations
    Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain

    Department of Medicine, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
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  • Diego Real de Asúa
    Correspondence
    Corresponding author at: Internal Medicine Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Diego de León 62, Madrid 28006, Spain
    Affiliations
    Department of Medicine, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

    Internal Medicine Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Diego de León 62, Madrid 28006, Spain
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  • Ainhoa Gutiérrez-Cobos
    Affiliations
    Microbiology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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Published:November 19, 2022DOI:https://doi.org/10.1016/j.jinf.2022.11.014

      Highlights

      • Immune protection granted by COVID-19 vaccines wanes over time.
      • Individuals with Down syndrome (DS) are considered an at-risk population for COVID-19 hospitalization and death.
      • Our findings show that a booster COVID-19 vaccine dose promotes a renewed, effective cellular and humoral immune response in adults with DS, akin to the general population.

      Keywords

      To the editor,
      Adults with Down syndrome are a high-risk population for hospitalization and death due to COVID-19, and have been frequently compared to other immunocompromised populations, as recently reviewed by Marra et al. in this journal.
      • Marra A.R.
      • Kobayashi T.
      • Suzuki H.
      • et al.
      Short-term effectiveness of COVID-19 vaccines in immunocompromised patients: a systematic literature review and meta-analysis.
      ,
      • Hüls A.
      • Costa A.C.S.
      • Dierssen M.
      • et al.
      Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey.
      Their worse prognosis has been attributed to a higher prevalence of comorbidities and to a congenital immune dysregulation, which impairs the generation of a protective immunity after vaccination.
      • Hüls A.
      • Costa A.C.S.
      • Dierssen M.
      • et al.
      Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey.
      Though adults with DS develop an effective immune response after receiving a two-dose regime of SARS-CoV-2 vaccination,
      • Esparcia-Pinedo L.
      • Yarci-Carrion A.
      • Mateo-Jimenez G.
      • et al.
      Development of an effective immune response in adults with Down syndrome after SARS-CoV-2 vaccination.
      SARS-COV-2-specific IgG titers wane over time, especially in adults over 40 years of age, and the duration of vaccine-elicited protection is unknown. A third vaccine dose (booster dose) has been recommended for adults with DS, but its impact on the immune response of this population has not been studied. Following an initial study on a cohort of adults with DS one to three (V1) and six (V2) months after a two-dose SARS-CoV-2 vaccination regime,
      • Esparcia-Pinedo L.
      • Yarci-Carrion A.
      • Mateo-Jimenez G.
      • et al.
      Development of an effective immune response in adults with Down syndrome after SARS-CoV-2 vaccination.
      we here describe the dynamic changes in the cellular and humoral responses of 41 DS patients after receiving a booster vaccine dose.
      The description of the study population, determination of specific IgG, analysis of T cell response, ethical considerations and statistical analysis are detailed in Supplementary material. A total of 41 adults with DS and 20 age-matched, non-DS donors received a third booster SARS-CoV-2 vaccine dose 6.1 months (5–8) after completing the initial two-dose schedule. Evaluations occurred 66 days (55–98.5) and 77.5 days (72–105) after the administration of this third dose (DS and non-DS subjects respectively, Suppl. Table 1). T cell response showed a similar degree and specificity profile in both cohorts. This response was mainly CD4+in both groups (95% in DS vs. 100% in non-DS donors, Fig. 1A), with a predominant Th1 specificity. However, the latter subpopulation was significantly higher in non-DS donors, particularly in those under 40 years (p<0.05, Fig. 1B). Comparable levels of SARS-CoV-2-specific circulating T follicular helper cells were also observed in both cohorts (Fig. 1C). All DS subjects developed specific anti-S IgG antibodies after the third dose of vaccine and reached similar titers than non-DS controls (Fig. 1D), though mean IgG titers were lower in individuals with DS over 40 years (Fig. 1D).
      Fig 1
      Fig. 1Immune response in Down syndrome patients after a third dose of SARS-CoV-2 vaccine. A., Pie charts indicate the percentages of SARS-CoV-2-specific CD4+ and CD8+ lymphocytes in non-DS and DS donors after third dose administration. B., Upper panels, graphics show the percentage (mean+SD) of Th1 (left) and Th2 (right) CD4+ subsets in non-DS and DS donors. Lower panels, the percentage (mean+SD) of Th1 (left) and Th2 (right) CD4+ subsets in non-DS and DS donors under and over 40 years is shown. C., Percentage of circulating CD4+CXCR5+ Tfh cells in non-DS and DS individuals. D., Left, specific anti-SARS-CoV-2 S IgG titers (BAU/ml) in non-DS and DS donors; right, specific anti-SARS-CoV-2 S IgG titers (BAU/ml) in non-DS and DS 〈 40 and 〉 40 years. *p<0.01; ns, non-significant.
      These results must be put in context against what was already known about the dynamics of the immune response after two doses of SARS-CoV-2 vaccination in DS
      • Esparcia-Pinedo L.
      • Yarci-Carrion A.
      • Mateo-Jimenez G.
      • et al.
      Development of an effective immune response in adults with Down syndrome after SARS-CoV-2 vaccination.
      • Valentini D.
      • Cotugno N.
      • Scoppola V.
      • et al.
      Safety and long-term immunogenicity of BNT162b2 vaccine in individuals with Down syndrome.
      • Sali M.
      • Carfi A.
      • Di Paola A.
      • et al.
      SARS-CoV-2 vaccine humoral response in adults with Down syndrome.
      . Prior reports have observed that, after developing an adequate humoral response 1 to 3 months after vaccination, antibody titers decreased over time in adults with DS, especially among adults over 40 years, a subgroup of particular higher risk of COVID-19 infection and death
      • Esparcia-Pinedo L.
      • Yarci-Carrion A.
      • Mateo-Jimenez G.
      • et al.
      Development of an effective immune response in adults with Down syndrome after SARS-CoV-2 vaccination.
      • Valentini D.
      • Cotugno N.
      • Scoppola V.
      • et al.
      Safety and long-term immunogenicity of BNT162b2 vaccine in individuals with Down syndrome.
      • Sali M.
      • Carfi A.
      • Di Paola A.
      • et al.
      SARS-CoV-2 vaccine humoral response in adults with Down syndrome.
      . This decline has been interpreted as reflecting “the risk of no longer being protected by the effects of vaccination at an earlier time than the general population”.
      • Sali M.
      • Carfi A.
      • Di Paola A.
      • et al.
      SARS-CoV-2 vaccine humoral response in adults with Down syndrome.
      Unfortunately, prior studies by Valentini et al. and Sali et al.
      • Valentini D.
      • Cotugno N.
      • Scoppola V.
      • et al.
      Safety and long-term immunogenicity of BNT162b2 vaccine in individuals with Down syndrome.
      ,
      • Sali M.
      • Carfi A.
      • Di Paola A.
      • et al.
      SARS-CoV-2 vaccine humoral response in adults with Down syndrome.
      did not address cellular immunity nor provided information after a booster dose. In our experience, adults with DS developed a milder, delayed cellular immune response to the initial two doses of vaccine compared to non-DS donors (73.21% adults with DS with specific CD4+ and 16.36% with specific CD8+ at 6 months compared to 100% CD4+ and 33.33% CD8+ specific response in controls at the same time point,
      • Esparcia-Pinedo L.
      • Yarci-Carrion A.
      • Mateo-Jimenez G.
      • et al.
      Development of an effective immune response in adults with Down syndrome after SARS-CoV-2 vaccination.
      ). After a booster dose, the percentage of CD4/CD8 positive DS individuals, their Th1 response and T-cell follicular helper populations significantly improved compared to those evaluated 6 months after receiving the first two doses, a response which was comparable to that of non-DS donors.
      Our study presents several limitations. Although we have been able to follow-up the same cohort of adults with DS since their vaccination, we have used different populations as controls over time. Because vaccine recommendations changed over time, a prolonged follow-up of healthy donors was not initially planned. However, this limitation only affects the comparison of non-DS results over time and does not weaken the conclusions about vaccine effectiveness in adults with DS.
      In all, our present results show that, despite showing a relatively delayed T-cell response after vaccination, adults with DS showed a comparable response to that of non-DS donors after a booster dose, which was not the case 6 months after the initial 2-dose regime. It is our hope that these results may help overcome vaccination hesitancy in this population and further improve healthcare policy recommendations. Considering our findings, a standard, three dose SARS-CoV-2 vaccine schedule should be established for adults with DS.

      Author contributions

      Project coordination, original idea: AA, AGC, DRA. Subject recruitment and follow-up: GM, DRA. Database compilation: GM, AYC, LEP. Sample processing, collection preservation/storage: GM, AYC, LEP. Serological assays: AGC, AYC. Cellular immunity assays: LEP, AA. Statistical analysis: AGC, AA, DRA. Results evaluation, manuscript drafting and publication: All.

      Funding sources

      This work was supported by grants to AA from the “Fondo de Investigación Sanitaria del Instituto de Salud Carlos III”, co-funded by the “ Fondo Europeo de Desarrollo Regional FEDER ” [FIS PI19/00549 ]; and “Sociedad Cooperativa de Viviendas Buen Suceso, S.Coop.Mad”. To LEP, through [Inmunovacter REACT-UE]. DRA was supported by the “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” [PI19/00634], co-funded by “The European Regional Development Fund (ERDF), A way to make Europe"; and the “Fondation Jérôme Lejeune” [grant no. 2021a-2069]. The Adult Down syndrome Outpatient unit at Hospital Universitario de La Princesa is grateful to Licenciado don Jesús Coronado Hinojosa for his financial support.

      Declaration of Competing Interest

      The authors have no conflicts of interest to disclose.

      Appendix. Supplementary materials

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