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. 2022 Mar 14:13:863039.
doi: 10.3389/fimmu.2022.863039. eCollection 2022.

Longitudinal Tracking of Immune Responses in COVID-19 Convalescents Reveals Absence of Neutralization Activity Against Omicron and Staggered Impairment to Other SARS-CoV-2 Variants of Concern

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Longitudinal Tracking of Immune Responses in COVID-19 Convalescents Reveals Absence of Neutralization Activity Against Omicron and Staggered Impairment to Other SARS-CoV-2 Variants of Concern

Ivan Odak et al. Front Immunol. .

Abstract

Evaluating long-term protection against SARS-CoV-2 variants of concern in convalescing individuals is of high clinical relevance. In this prospective study of a cohort of 46 SARS-CoV-2 patients infected with the Wuhan strain of SARS-CoV-2 we longitudinally analyzed changes in humoral and cellular immunity upon early and late convalescence. Antibody neutralization capacity was measured by surrogate virus neutralization test and cellular responses were investigated with 31-colour spectral flow cytometry. Spike-specific, isotype-switched B cells developed already during the disease phase, showed a memory phenotype and did not decrease in numbers even during late convalescence. Otherwise, no long-lasting perturbations of the immune compartment following COVID-19 clearance were observed. During convalescence anti-Spike (S1) IgG antibodies strongly decreased in all patients. We detected neutralizing antibodies against the Wuhan strain as well as the Alpha and Delta but not against the Beta, Gamma or Omicron variants for up to 7 months post COVID-19. Furthermore, correlation analysis revealed a strong association between sera anti-S1 IgG titers and their neutralization capacity against the Wuhan strain as well as Alpha and Delta. Overall, our data suggest that even 7 month after the clearance of COVID-19 many patients possess a protective layer of immunity, indicated by the persistence of Spike-specific memory B cells and by the presence of neutralizing antibodies against the Alpha and Delta variants. However, lack of neutralizing antibodies against the Beta, Gamma and Omicron variants even during the peak response is of major concern as this indicates viral evasion of the humoral immune response.

Keywords: B cells; antibodies; delta; omicron; protection; spike; variants of concern.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Leukocyte responses in convalescing patients. Absolute cells numbers per ml of blood in patients with disease, early and late convalescence. (A) Cell numbers of various leukocyte populations. (B) Cell numbers of blood of major T cell subsets (C) Cell numbers of blood of NK cell subsets (D) Cell numbers of blood of monocyte subsets. (E) Absolute cell numbers of memory subsets of conventional CD4+ T cells. (F) Absolute cell numbers of memory subsets of conventional CD8+ T cells. (G) Absolute cell numbers of blood of CD8+CD38+HLA-DR+ effector memory subpopulation. (H) Absolute cell numbers of B cell subsets. Each dot represents one biologically individual sample taken from one patient. Lines represent median. N (disease)=24; n (early conv.)=32; n (late conv.)=25. Statistics: Kruskal-Wallis multiple comparison test with Dunn’s post hoc correction.*p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
Figure 2
Figure 2
Deep profiling of circulating Spike- specific B cells by flow cytometry in patients. (A) Gating strategy for identification of Spike- specific B cells. Spike+ B cell gate was set based on the background level binding of CD3+ T cells. (B) Frequencies (left) and absolute numbers (right) of Spike- specific B cells in patients with disease or in early and late convalescence. Each dot represents one biologically individual sample taken from one patient. n(disease)=24; n(Early conv.)=32; n(Late conv.)=25. (C) Longitudinal analysis of frequencies (left) and absolute numbers (right) of Spike- specific B cells in patients 3-7 months after the disease. Each connected dot represent one individual patient (n=11). (D) Phenotype comparison of endogenous naïve and memory B cells and Spike- specific B cells. Shown is one representative sample from a patient in late convalescence. Statistics: Kruskal-Wallis multiple comparison test with Dunn’s post hoc correction. *p<0.05.
Figure 3
Figure 3
Anti-SARS-CoV-2 antibodies are declining in sera of convalescing patients. (A) Anti-Spike IgG levels in patients over time. Each individually colored dot and connecting line represent one patient (n=39 patients). Crimson shaded area represents the time during the disease. (B) Ratio of anti-nucleocapsid protein (NCP) IgG antibodies (left) and anti-Spike IgA (right) antibodies in patients over time. (C) Anti-Spike IgG levels in patients with disease, in early (early conv.) and late convalescence (late conv.). Each dot represents one biologically individual sample taken from one patient. N (disease)=23; n (early conv.)=32; n (late conv.)=25. (D) Ratio of anti-NCP IgG (left) and anti-Spike IgA (right) levels in patients. (E) Paired analysis of anti-Spike IgG levels in patients 3-7 months after the disease. Each connected dot represent one individual patient (n=11). (F) Paired analysis of ratios of anti-NCP IgG (left) and anti-Spike IgA (right) levels in patients 3-7 months after the disease. Statistics: (C, D) Kruskal-Wallis multiple comparison test with Dunn’s post hoc correction. (E, F) Two-tailed Wilcoxon matched-pairs signed rank test. BAU, Binding Antibody Units; **p<0.01; ***p<0.001; ****p<0.0001.
Figure 4
Figure 4
Waning of humoral protection against Wuhan strain and variants of concern. (A) Reciprocal titers of neutralizing antibodies against Wuhan strain, Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529) SARS-CoV-2-S variants over time, measured using the sVNT. Each individually colored dot and connecting line represent one patient (n=39 patients). Crimson shaded area represents time during the disease. (B) Reciprocal dilution titers of antibodies against Wuhan strain, Alpha, Beta, Gamma, Delta and Omicron variants. Each dot represents one biologically individual sample taken from one patient. N (disease)=23; n (early conv.)=32; n (late conv.)=25. (C) Longitudinal analysis of neutralizing antibodies titers in patients 3-7 months after the disease. Each connected dot represent one individual patient (n=11). (B, C) for better visualization of identical titer values, data were randomly and proportionally adjusted closely around the precise titer results. Statistics: (B) Kruskal-Wallis multiple comparison test with Dunn’s post hoc correction. (C) Two-tailed Wilcoxon matched-pairs signed rank test. *p<0.05; **p<0.01; ***p<0.001.
Figure 5
Figure 5
Correlate of total anti-Spike S1-IgG and neutralization antibody titers. Lines represent linear regression and dotted lines 95% confidence interval. Each dot represents one biologically individual sample taken from one patient. N (disease)=23; n (early conv.)=32; n (late conv.)=25. Absolute values of Spike-IgG (in RU/ml) were transformed into 7 categorical variables as described in Supplementary Table 3 . For better visualization of identical titer values, data were randomly and proportionally adjusted closely around the precise titer results. Statistics: nonparametric Spearman correlation. rs= Spearman’s correlation coefficient.

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