The accelerated waning of immunity and reduced effect of booster in patients treated with bDMARD and tsDMARD after SARS-CoV-2 mRNA vaccination

Abstract

Objectives: This study aimed to assess the duration of humoral responses after two doses of SARS-CoV-2 mRNA vaccines in patients with inflammatory joint diseases and IBD and booster vaccination compared with healthy controls. It also aimed to analyze factors influencing the quantity and quality of the immune response.

Methods: We enrolled 41 patients with rheumatoid arthritis (RA), 35 with seronegative spondyloarthritis (SpA), and 41 suffering from inflammatory bowel disease (IBD), excluding those receiving B-cell-depleting therapies. We assessed total anti-SARS-CoV-2 spike antibodies (Abs) and neutralizing Ab titers 6 months after two and then after three doses of mRNA vaccines compared with healthy controls. We analyzed the influence of therapies on the humoral response.

Results: Patients receiving biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) showed reduced anti-SARS-CoV-2 S Abs and neutralizing Ab titers compared with HC or patients receiving conventional synthetic (cs)DMARDs 6 months after the first two vaccination doses. Anti-SARS-CoV-2 S titers of patients with b/tsDMARDs declined more rapidly, leading to a significant reduction in the duration of vaccination-induced immunity after two doses of SARS-CoV-2 mRNA vaccines. While 23% of HC and 19% of patients receiving csDMARDs were without detectable neutralizing Abs 6 months after the first two vaccination doses, this number was 62% in patients receiving b/tsDMARDs and 52% in patients receiving a combination of csDMARDs and b/tsDMARDs. Booster vaccination led to increased anti-SARS-CoV-2 S Abs in all HC and patients. However, anti-SARS-CoV-2 S Abs after booster vaccination was diminished in patients receiving b/tsDMARDs, either alone or in combination with csDMARDs compared to HC.

Conclusion: Patients receiving b/tsDMARDs have significantly reduced Abs and neutralizing Ab titers 6 months after mRNA vaccination against SARS-CoV-2. This was due to a faster decline in Ab levels, indicating a significantly reduced duration of vaccination-induced immunity compared with HC or patients receiving csDMARDs. In addition, they display a reduced response to a booster vaccination, warranting earlier booster vaccination strategies in patients under b/tsDMARD therapy, according to their specific Ab levels.

Keywords: IBD; SARS-CoV-2; arthritis; bDMARD; humoral immune response; immunomodulatory therapy.

FIGURE 1

(A) Analysis of anti-SARS-CoV-2 S titers 6 months after the first two vaccination doses in HC (n = 85) and patients with inflammatory arthritis (n = 75) and inflammatory bowel disease (n = 41). (B) Analysis of anti-SARS-CoV-2 S titers 6 months after the first two vaccination doses comparing different treatment classes HC (n = 85), csDMARD (n = 30), b/tsDMARD (n = 54), and a combination of csDMARD and b/tsDMARD (n = 28). (C) Anti-SARS-CoV-2 S titers 6 months after the first two vaccination doses in patients with IBD and inflammatory arthritis according to the specific immunomodulatory treatments. HC (n = 85), methotrexate monotherapy (MTX mono; n = 19), tumor necrosis alpha-inhibitors (TNFi; n = 48), interleukin-17 inhibitors (IL-17i; n = 7), Janus kinase inhibitor (JAKi; n = 4), interleukin-6 receptor inhibitors (IL-6Ri; n = 3), interleukine-12/23 inhibitor (IL-12/23i n = 7). (D) Determination of neutralizing antibody activity in sera of HC (n = 56) and patients with inflammatory arthritis (n = 75) receiving the indicated therapies. Statistics used: Kruskal–Wallis test and subsequent Dunn’s test, adjusting for multiple testing using the Benjamini–Hochberg method. ns: non significant p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; and ****p ≤ 0.001.

FIGURE 2

(A) Rate of decline in anti-SARS-CoV-2 S titers at a given peak antibody titer according to the indicated treatment: b/tsDMARDs (n = 54; light blue) and a combination of csDMARDs and b/tsDMARDs (n = 28; green) in patients vs. HC (n = 85; gray). Colored lines indicate linear regression. Thick colored lines indicate the mean slopes of the indicated patient group or HC. Indicated p-values are derived from a linear regression model with the estimated decrease (BAU/ml/day) as predicted variable and initial anti-SARS-CoV-2 S titers, therapy, and age as independent variables. Statistics used: Kruskal–Wallis test and subsequent Dunn’s test. (B) Decline of anti-SARS-CoV-2 S titers from peak levels after the second immunization and the 6-month time point in HC (n = 85; green) and patients receiving csDMARDs (n = 23; blue), b/tsDMARDs (n = 47; gray), and a combination of csDMARDs and b/tsDMARDs (n = 14; yellow). Thick colored lines indicate the mean slopes of the indicated patient group or HC. ns: non significant p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; and ****p ≤ 0.001.

FIGURE 3

Estimation of median days above 300 BAU/ml in HC or inflammatory arthritis patients or inflammatory bowel disease (IBD) patients receiving the indicated treatments: csDMARD (n = 30), b/tsDMARD (n = 54), and a combination of csDMARD and b/tsDMARD (n = 28) compared with healthy controls. Statistics used: Kruskal–Wallis test and subsequent Dunn’s test. ns: non significant p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; and ****p ≤ 0.001.

FIGURE 4

(A) Comparison of anti-SARS-CoV-2 S antibody levels before and after a third immunization with an mRNA vaccination in HC (n = 40) vs. patients (n = 58) (Mann–Whitney U-test). (B) Anti-SARS-CoV-2 S antibody levels after the third immunization of patients with Inflammatory arthritis (n = 38) and inflammatory bowel disease (IBD; n = 20) receiving csDMARDs (n = 16), b/tsDMARDs (n = 26), or a combination of both (n = 13). Statistics used: Kruskal–Wallis test and subsequent Dunn’s test. ns: non significant p > 0.05; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; and ****p ≤ 0.001.