A cohort of 222 anti-CD20 treated patients with multiple sclerosis followed through the COVID-19 pandemic: Attenuated humoral but robust cellular immune responses after vaccination and infection

Abstract

Importance: Data on immune responses following SARS-CoV-2 vaccinations/infections and on detection rate of SARS-CoV-2 infections in anti-CD20 treated patients with multiple sclerosis (pwMS) are important for guiding management of pwMS during the current SARS-CoV-2 pandemic. Objective: To analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations/infections and to determine the detection rate of SARS-CoV-2 infections in anti-CD20 treated pwMS. Design: Prospective single-center cohort study from March 2020 to August 2021. Setting: MS referral center, Charite - Universitaetsmedizin Berlin, Germany. Participants: 222 consecutive pwMS (128 [57.7%] female, median [range] age 39 [17-81] years). 181 patients were on anti-CD20 therapy at study inclusion, 41 began anti-CD20 therapy during the study. Hospital employees (HE, n=19) served as controls. Exposures: pwMS were exposed to anti-CD20 therapy for 169.5 patient years. 51 patients under anti-CD20 treatment, 14 patients before anti-CD20 treatment, and 19 HE were vaccinated twice against SARS-CoV-2. Main outcomes: SARS-CoV-2 spike protein immunoglobulin (Ig)G (ELISA and immunofluorescence), IgA (ELISA), IgG to four recombinant SARS-CoV-2 antigens (solid phase immunoassay), neutralizing capacity of SARS-CoV-2 antibodies (plaque reduction neutralization test), SARS-CoV-2 IgG avidity (modified ELISA), and SARS-CoV-2 specific T cells (interferon-{gamma} release assay). Results: Following two SARS-CoV-2 vaccinations, median (IQR) levels of SARS-CoV-2 spike protein IgG (OD ratio: 1.2 [0.1-5.1] vs. 9.0 [6.8-9.9] vs. 8.8 [8.0-9.4], p<0.0001), neutralizing capacity (PRNT50 Titer: 40 [0-80] vs. 640 [80-640] vs. 640 [320-640], p[≤]0.006), and antibody avidity (43.6% [14.8-54.6%] vs. 84.1% [53.1-86.8%] vs. 89.7 [76.8-93.4%], p[≤]0.003) were lower in anti-CD20 treated pwMS than in pwMS before initiation of anti-CD20 therapy and in HE. All anti-CD20 treated pwMS vaccinated twice developed SARS-CoV-2 specific T cells, whose levels did not differ from those of pwMS before initiation of anti-CD20 therapy and HE. SARS-CoV-2 IgG levels (r=0.42, p=0.002) and antibody avidity (r=0.70, p<0.001) increased with time between anti-CD20 infusion and second vaccination. The detection rate of SARS-CoV-2 infections in anti-CD20 treated pwMS (2.36/100 patient years) was similar to that of RT-PCR confirmed SARS-CoV-2 cases in the general Berlin population (3.75/100 person years) during the study period. Interpretation: These findings are relevant for treatment decisions as well as management of SARS-CoV-2 vaccinations in pwMS.