Postvaccination anti-S IgG levels predict anti-SARS-CoV-2 neutralising activity over 24 weeks in patients with RA

Abstract

Objectives: To correlate immune responses following a two-dose regimen of mRNA anti-SARS-CoV-2 vaccines in patients with rheumatoid arthritis (RA) to the development of a potent neutralising antiviral activity.

Methods: The RECOVER study was a prospective, monocentric study including patients with RA and healthy controls (HCs). Assessments were performed before, and 3, 6, 12 and 24 weeks, after the first vaccine dose, respectively, and included IgG, IgA and IgM responses (against receptor binding domain, S1, S2, N), IFN-γ ELISpots as well as neutralisation assays.

Results: In patients with RA, IgG responses developed slower with lower peak titres compared with HC. Potent neutralising activity assessed by a SARS-CoV-2 pseudovirus neutralisation assay after 12 weeks was observed in all 21 HCs, and in 60.3% of 73 patients with RA. A significant correlation between peak anti-S IgG levels 2 weeks after the second vaccine dose and potent neutralising activity against SARS-CoV-2 was observed at weeks 12 and 24. The analysis of IgG, IgA and IgM isotype responses to different viral proteins demonstrated a delay in IgG but not in IgA and IgM responses. T cell responses were comparable in HC and patients with RA but declined earlier in patients with RA.

Conclusion: In patients with RA, vaccine-induced IgG antibody levels were diminished, while IgA and IgM responses persisted, indicating a delayed isotype switch. Anti-S IgG levels 2 weeks after the second vaccine dose correlate with the development of a potent neutralising activity after 12 and 24 weeks and may allow to identify patients who might benefit from additional vaccine doses or prophylactic regimen.

Keywords: COVID-19; Rheumatoid Arthritis; Vaccination.

Figure 1

Antibody kinetics and neutralizing activity is influenced by DMARD regimen. (A) Boxplots showing anti-S antibodies as determined by Elecsys Anti-SARS-CoV-2 (S) assay at 6, 12 and 24 weeks following the first vaccine dose in HC and RA patients stratified by different DMARD regimen. (B) Boxplots showing NT50 values as assessed by a pseudovirus neutralization assay of HC compared to RA patients stratified by DMARD regimen at 12 weeks after first vaccination. The dashed line corresponds to an NT50 of 250. (C) Boxplots showing sum S1 reactivity (SOC) in HC compared to RA patients stratified by different DMARD regimen at 6, 12 and 24 weeks after first vaccination. Dashed lines correspond to a sum S1 of 17.3 that represents the threshold for prediction of neutralizing activity against Wuhan-Hu-1 387 *p<0.05, **p<0.01, ***p<0.001. T1=3 weeks after 1st vaccination, T2=2 weeks after 2nd vaccination, T3=12 weeks after 1st vaccination, T4= 24 weeks after 1st vaccination

Figure 2

Postvaccination anti-S IgG responses predict antiviral neutralization (NT50) at week 12. (A) The violins illustrate the kernel probability density. Red lines indicate the medians, black lines indicate 1st and 3rd IQR. Dots represent individual patients. ***p<0.001, ****p<0.0001. (B) ROC curve peak anti-S IgG at week 2 and NT50 at week 12. Performance of peak anti-S titers in discriminating RA patients with low neutralizing activity (NT50 > 250) at week 12. Anti-S 937 U/ml represents the decisive anti-S threshold value. ROC curve = receiver operating characteristic curves. Sensitivity 66%, specificity 97% (C) Spearman correlation (r = 0.78, p = p < 0.0001; Regression r2 = 0.6814, y = 7.391*x + 108.5, F = 151.8, p < 0.0001) between anti-S IgG at week 2 and sum S1 at week 12. (D) Spearman correlation (r = 0.67, p < 0.0001; Regression r2 = 0.4926, y = 7.477*x + 384.4, F = 68.94, p < 0.0001) between anti-S IgG at week 2 and sum S1 at week 24. T1=3 weeks after 1st vaccination, T2=2 weeks after 2nd vaccination, T3=12 weeks after 1st vaccination, T4= 24 weeks after 1st vaccination.

Figure 3

Longitudinal vaccine-induced antibody responses by isotypes of vaccinated RA patients compared to healthy controls. (A) Comparison of IgA and IgG responses in RA patients capable of mounting an immune response after vaccination (n=64) and HC at visits T1 and T2. Levels of significance are calculated by unpaired t-test. *p<0.05, **p<0.01, ***p<0.001. (B) Heatmaps summarizing the measured MFI signals normalized to empty bead control (MFI FOE) that visualize IgG, IgA and IgM responses to RBD, S1, S2 and N on different DMARD regimen after the first (T1) and second vaccine dose (T2) and after 12 (T3) and 24 weeks (T4) for HC and RA patients. T1=3 weeks after 1st vaccination, T2=2 weeks after 2nd vaccination, T3=12 weeks after 1st vaccination, T4= 24 weeks after 1st vaccination *p<0.05, **p<0.01, ***p<0.001.