Immunological memory to COVID-19 vaccines in immunocompromised and immunocompetent children

Abstract

Background: Most children in Argentina received only the initial COVID-19 vaccine series, with presumed hybrid immunity after multiple Omicron waves. However, the durability of immune memory, particularly in immunocompromised (IC) children, remains poorly studied.

Methods: A cohort of IC (n=45) and healthy children (HC, n=79) was assessed between 13 to 17 months after receiving two or three doses of BBIBP-CorV and/or BNT162b2. Plasma anti-spike IgG, neutralizing activity and antigen-specific CD4+ and CD8+ T cells against Wuhan and Omicron BA.5 variants were assessed.

Results: Most children remained seropositive after two vaccine doses, but compared with HC, IC exhibited lower neutralizing titers against both Wuhan and Omicron BA.5, particularly those vaccinated with BBIBP-CorV. Even after three vaccine doses, IC showed weaker neutralizing antibody response, CD8+ T cell responses and lower IFN-γ production compared with HC. Integrated analysis of neutralizing antibodies, memory CD4⁺, and CD8⁺ T cells revealed a weak immune memory among IC with an important compromise in memory CD8⁺ T cell responses.

Conclusions: Immunity can last up to 17 months, but reduced effectiveness against new variants highlights the need for updated COVID-19 vaccines, especially for IC children. Additional efforts are essential to enhance vaccination coverage and protect this vulnerable population.

Keywords: SARS-CoV-2; T cells; antibodies; children; vaccines; variants.

Figure 1

Antibody response against Wuhan and Omicron BA.5 variants in vaccinated IC and HC. (A) Titers of IgG anti-spike antibodies defined by end point dilution in plasma from IC (n=19) and HC (n=43) receiving two-doses of COVID-19 vaccines. (B) Neutralizing activity against Wuhan and Omicron BA.5 variants in plasma from IC and HC receiving two-doses of COVID-19 vaccines. Left: Bars show the percentage of positive samples for neutralizing activity. Right: Neutralization antibody titers determined by the reciprocal IC50. (C) Neutralizing activity against Wuhan and Omicron BA.5 variants in plasma from children receiving two-doses of BBIBP-CorV (IC, n=10 and HC, n=34) or BNT162b2 (IC, n=9 and HC, n=9) vaccines. (D) Titers of IgG anti-spike antibodies defined by end point dilution in plasma from IC (n=18) and HC (n=36) receiving three-doses of COVID-19 vaccines. (E) Neutralizing activity against Wuhan and Omicron BA.5 variants in plasma from IC and HC receiving three-doses of COVID-19 vaccines. Left: Bars show the percentage of positive samples for neutralizing activity. Right: Neutralization antibody titers determined by the reciprocal IC50. (F) Neutralizing activity against Wuhan and Omicron BA.5 variants in plasma from children receiving three-doses of COVID-19 vaccines: 2 doses BBIBP-CorV plus 1 dose BNT162b2 (IC, n=8 and HC, n=19) or 3 doses of BNT162b2 (IC, n=10 and HC, n=17). Dotted line indicates the limit of detection value. Median and min to max of n donors are shown in (A, B) right, (C–E) right and (F) P values were determined by Pearson’s Chi square test (B left and E left) and Mann-Whitney U test (A, B) right, (C–E) right and (F). *p<0.05, **p<0.01. HC (blue circle), IC (red circle), two-doses (open circle), three-doses (filled circle), negative (white square), positive two-doses (dotted square), positive three-doses (filled square).

Figure 2

SARS-CoV-2 specific T cell response in vaccinated IC and HC. Antigen-specific T cells were measured as a percentage of CD4+OX40+CD137+ and CD8+CD69+CD137+ T cells after stimulation of PBMCs from children receiving two or three doses of COVID-19 vaccines with CD4_S and CD8_S peptide megapools of Wuhan and Omicron BA.5 compared to negative control (DMSO) analyzed by flow cytometry. (A) Gating strategies to define SARS-CoV-2-specific CD4+ and CD8+ T cells by flow cytometry. (B) Left: Bars show the percentage of IC and HC vaccinated with 2 doses that presented circulating specific CD4+ and CD8+ T cell response against Wuhan (IC, n=16 and HC, n=17) and Omicron BA.5 (IC, n=20 and HC, n=26). Right: Stimulation index quantitation of AIM+ T cells (fold change over the DMSO condition). (C) Left: Bars show the percentage of IC and HC vaccinated with 3 doses that presented circulating specific CD4+ and CD8+ T cell response against Wuhan (IC, n=8 and HC, n=16) and Omicron BA.5 (IC, n=22 and HC, n=21). Right: Stimulation index quantitation of AIM+ T cells (fold change over the DMSO condition). (D) Levels of IFN-γ in the supernatant culture of PBMCs from IC and HC stimulated with peptide megapools of Wuhan and Omicron BA.5 determined by ELISA. Dotted line indicates the fold change ≥ 2. Median and min to max of n donors are shown in (B) right, (C) right and (D) P values were determined by Pearson’s Chi square test (B) left and (C) left] and Mann-Whitney U test (B) right, (C) right and (D)]. *p<0.05, **p<0.01, ***p<0.01. HC (blue circle), IC (red circle), two-doses (open circle), three-doses (filled circle), negative (white square), positive two-doses (dotted square), positive three-doses (filled square).

Figure 3

Immune memory components relationship. Percentage dot plots showing frequencies (normalized to 100%) of IC (n=18) and HC (n=25) participants who received 3 doses with indicated immune memory components evaluated. Comparison of positive responses in more than one of the parameters analyzed (antibodies, CD4+ T cell response and CD8+ T cell response) is shown. **p<0.01. Pearson’s Chi square test. HC has no cases in the category N-4+8- and IC has no cases in the category N+4-8+. N, neutralizing antibodies, 4, SARS-CoV-2–specific CD4+ T cells; 8, SARS-CoV-2–specific CD8+ T cells. P values were determined by Pearson’s Chi square test, **p<0.01.