Risk factors of impaired humoral response to COVID-19 vaccination in rituximab-treated patients

Abstract

Objective: To identify which factors influence humoral response to coronavirus disease 2019 (COVID-19) vaccination in rituximab (RTX)-treated patients.

Methods: This was an observational, prospective, usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a two-dose regimen COVID-19 vaccination. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured at the time of the new RTX infusion.

Results: From the recruited patients, 16/45 (36%) produced antibodies reaching the assay cut-off value of 15 AU/ml and 29/45 (64%) had a negative serology. Within RTX-treated patients, 25 (56%) had undetectable B cells. Negative serology was associated with undetectable B cells (24/25 vs 5/20, P < 0.001). Moreover, SARS-CoV-2 spike antibodies correlated with CD19 counts (r = 0.86, P < 0.001). The effect of RTX and MTX was additive in terms of seroconversion rates (23% vs 50% in patients receiving RTX in monotherapy, P = 0.12) and SARS-CoV-2 spike antibody levels [3.80 (95% CI 3.80, 7.50) vs 75 (95% CI 3.8, 353) AU/ml in patients receiving RTX in monotherapy; P = 0.025]. Multivariate analyses including demographics, disease characteristics, gammaglobulin levels, RTX and other therapies used, CD19 counts, and the time between the last RTX infusion and vaccination identified detectable B cells as the only variable independently associated with seropositivity [odds ratio 35.2 (95% CI 3.59, 344.20)].

Conclusions: B cell depletion is the main independent contributing factor of antibody response to SARS-CoV-2 vaccination in RTX-treated patients. Monitoring CD19 may be of interest to identify the most appropriate period to perform vaccination.

Keywords: COVID-19; chronic inflammatory rheumatic disorder; rituximab; vaccination.

Fig. 1

Antibody response to SARS-CoV-2 vaccination according to B cell depletion (A) Schematic diagram representing the median time between the last RTX infusion, the first and second doses of vaccine, and the sampling for seropositivity testing the day of the new RTX infusion. (B) Distribution of SARS-CoV-2 spike antibody levels in the whole cohort. (C) S1/S2 antibody levels according to RTX-induced B cell depletion. Results are expressed as medians and 95% CI. ****P < 0.0001 by Mann–Whitney test. Dotted red line corresponds to the seropositivity threshold. (D) Cumulative seropositive rate (with 95% CI in red) according to CD19 counts. COVID-19: coronavirus disease 2019; RTX: rituximab; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.