Severe Acute Respiratory Syndrome Coronavirus 2 Third Vaccine Immune Response in Multiple Sclerosis Patients Treated with Ocrelizumab

Abstract

The introduction of a third-dose vaccination along with new variants of concern raises questions regarding serology and T-cell responses in patients with multiple sclerosis (pwMS) treated with B-cell depletion who develop attenuated humoral response to vaccines. The aim of this study was to longitudinally evaluate humoral and cellular response to SARS-CoV-2 mRNA vaccine in ocrelizumab-treated pwMS before and following a third vaccine dose. Following the third vaccine dose, patients who are low or nonresponders following initial vaccination did not increase antibody titers. In healthy controls and ocrelizumab-treated pwMS, cellular response decreased 6 months after initial vaccination and increased significantly after the third dose. ANN NEUROL 2022;91:796-800.

FIGURE 1

Serology response to the third dose of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine in patients with multiple sclerosis (MS) treated with ocrelizumab (OCR) and healthy controls (HCs). (A–D) Longitudinal SARS‐CoV‐2 receptor‐binding domain (RBD) immunoglobulin G (IgG) titers in HCs and MS patients treated with OCR at 3 time points. (A) HCs 2 to 4 weeks after the second vaccine dose: n = 34, 14,352 ± 9,453 arbitrary units (AU)/ml; 6 months after the second vaccine: n = 34, 1,241 ± 885 AU/ml; and 2 to 8 weeks after the third vaccine dose: n = 30, 25,851 ± 11,302 AU/ml. (B) MS patients treated with OCR: 2 to 4 weeks after the second vaccine dose: n = 32, 307.6 ± 604.2 AU/ml; 6 months after the second vaccine dose: n = 24, 121.2 ± 329.2 AU/ml; and 2 to 8 weeks after the third vaccine dose: n = 27, 1,413 ± 3,742 AU/ml. (C) RBD‐IgG titers in 32 HCs. Each line represents one participant. (D) RBD‐IgG titers in 32 patients with MS treated with OCR. Each line represents one participant. (E, F) Correlation between time from OCR infusion to vaccination.  Triangular represent seropositivity after the second vaccine dose. The dotted lines indicate the cutoff for a positive response (≥50 AU/ml). *p < 0.05, **p < 0.01, ***p < 0.001. Data are presented as mean ± standard deviation. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike‐specific T‐cell response following vaccination with 3 vaccine doses.(A‐D) Longitudinal postvaccination T‐cell responses to SARS‐CoV‐2 peptides. Participants' peripheral blood mononuclear cells were stimulated with SARS‐CoV‐2 spike and nucleocapsid proteins peptides, nil control, and phytohemagglutinin control. Response was measured by an interferon‐γ enzyme‐linked immunosorbent spot (T‐SPOT; Oxford Immunotec). (A) SARS‐CoV‐2–specific T‐cell response of healthy controls (HCs) at 3 time points: 2 to 4 weeks after the second vaccine dose: n = 11, 25.4 ± 10.8; 6 months after the second vaccine dose: n = 29, 11 ± 5.4; and 2 to 8 weeks after the third vaccine dose: n = 23, 26.6 ± 15. (B) SARS‐CoV‐2–specific T‐cell response of patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) at 3 time points: 2 to 4 weeks after the second vaccine dose: n = 22, 27.4 ± 22.1; 6 months after the second vaccine dose: n = 19, 16.3 ± 9.2; and 2 to 8 weeks after the third vaccine dose: n = 23, 30.3 ± 21. (C–E) Cytokine secretion following stimulation with SARS‐CoV‐2 spike and nucleocapsid peptides. Cytokine analysis was performed after reduction of response to nucleocapsid peptides for each participant. In OCR‐treated pwMS, interleukin (IL)‐2, IL‐6, and tumor necrosis factor α (TNFα) levels followed the same pattern as the interferon‐γ (IFNγ)‐secreting cells, decreased at 6 months after the second vaccine dose and increased with the third vaccine dose (IL‐2: 37.9 ± 63.3pg/ml, 28 ± 51.7pg/ml, 35.6 ± 31.7pg/ml, p = 0.2; IL‐6: 6,426 ± 7,878pg/ml, 4,913 ± 4,643pg/ml, 6,523 ± 6,172pg/ml, p = 0.34; TNFα: 44.5 ± 83pg/ml, 29.9 ± 59.8pg/ml, 99.2 ± 183.8pg/ml, p = 0.6). In HCs, IL‐2 and IL‐6 levels followed the same pattern of decreased levels 6 months after the second vaccine dose and increased levels following the third vaccine (IL‐2: 26 ± 36.2pg/ml, 15.5 ± 14.6pg/ml, 42.9 ± 48pg/ml, p = 0.3; IL‐6: 5,247 ± 5,028pg/ml, 4,338 ± 3,482pg/ml, 6,482 ± 6,124pg/ml, p = 0.2; TNFα: 2 ± 18.5pg/ml, 19.3 ± 46.7pg/ml, 63.4 ± 192pg/ml, p = 0.2). (F–H) Correlation between cytokine level and the level of IFNγ‐secreting cells. *p < 0.05, ***p < 0.001. Data are presented as mean ± standard deviation. SFC, spot‐forming cell. [Color figure can be viewed at www.annalsofneurology.org]