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. 2024 Jul;11(7):1750-1764.
doi: 10.1002/acn3.52081. Epub 2024 May 7.

Longitudinal study of immunity to SARS-CoV2 in ocrelizumab-treated MS patients up to 2 years after COVID-19 vaccination

Ilya Kister  1 , Ryan Curtin  2 , Amanda L Piquet  3 , Tyler Borko  3 , Jinglan Pei  4 , Barbara L Banbury  5 , Tamar E Bacon  1 , Angie Kim  1 , Michael Tuen  6 , Yogambigai Velmurugu  2 , Samantha Nyovanie  2 , Sean Selva  3 , Marie I Samanovic  6 , Mark J Mulligan  6 , Yury Patskovsky  2 , Jessica Priest  4 , Mark Cabatingan  4 , Ryan C Winger  4 , Michelle Krogsgaard #  2 , Gregg J Silverman #  7
Affiliations

Longitudinal study of immunity to SARS-CoV2 in ocrelizumab-treated MS patients up to 2 years after COVID-19 vaccination

Ilya Kister et al. Ann Clin Transl Neurol. 2024 Jul.

Abstract

Objectives: (1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity.

Methods: Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses.

Results: The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity.

Interpretation: Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.

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Conflict of interest statement

This work was supported by an unrestricted investigator‐initiated grant from Genentech. IK served on the scientific advisory board for Biogen Idec, Genentech, Alexion, EMDSerono; received consulting fees from Roche; and received research support from Guthy‐Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen Idec, Serono, Genzyme, and Genentech/Roche; he receives royalties from Wolters Kluwer for “Top 100 Diagnosis in Neurology” (co‐written with Jose Biller). GJS received honoraria from BMS, Eli Lilly, and Human Biosciences, and research support from BMS, Genentech, Biogen, Lupus Research Alliance, NIH‐NIAMS, NIH‐NIAID, and the Colton Center at NYU. MK is on the scientific advisory board for Merck, NexImmune, and Genentech and received research support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Genentech, the Mark Foundation, NIH‐NIGMS, and NIH‐NCI. BLB receives salary and owns stock from Adaptive Biotechnologies. MJM reported potential competing interests: laboratory research and clinical trials contracts for vaccines or MAB vs SARS‐CoV‐2 with Lilly, Pfizer, and Sanofi; research grant funding from USG/HHS/NIH for vaccine and MAB clinical trials; personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc., and Pfizer. ALP reports research grants from the University of Colorado, Rocky Mountain MS Center, and the Foundation for Sarcoidosis; consulting fees from Genentech/Roche, UCB, EMD Serono, and Alexion; and honorarium from MedLink and publication royalties from Springer as coeditor of a medical textbook. All others declare no conflicts of interest.

Figures

Figure 1
Figure 1
Study design. Bw, between; OCR, ocrelizumab; PB, post booster; pts; patients; PV, post vaccine; SOC, standard of care; wk, week. n = number of blood samples available for analyses at each time point. aAt least 2 weeks between last OCR and first vaccine. bVaccine anticipated within 4–6 weeks of baseline.
Figure 2
Figure 2
Timing of COVID‐19 infections or vaccinations and ocrelizumab infusions in patients with MS. CU‐AMC, University of Colorado Anschutz Medical Center; NYU, New York University; OCR, ocrelizumab. Study participants numbers shown in purple (left‐most column) indicate that the respective participant was COVID‐19‐infected prior to vaccination, while those in orange were not infected prior to vaccination. Times from the last OCR infusion to vaccination is shown as dotted lines. “Time zero” refers to the day of the first vaccine dose. Gray lines indicate the duration of participation. The darker gray shade refers to CU‐AMC patients and the lighter gray shade refers to NYU patients.
Figure 3
Figure 3
Post‐vaccination (N = 60) and post‐booster (n = 33) antibody responses as assessed by (A) MBI anti‐Spike, (B) Elecsys anti‐SARS‐CoV‐2, (C) Wuhan strain‐neutralizing, and (D) Omicron strain neutralizing antibodies. PB, post booster; PV, post vaccine. Tables under each figure provide antibody levels for each time point for all patients, as well as for subsets of patients who were infected prior to the given time point (purple) and those who were not infected (orange). p Values compare log‐10 transformed values of neighboring time points, determined by paired t‐tests. Bolded p values are significant.
Figure 4
Figure 4
Post‐vaccination (N = 60) and post‐booster (n = 33) T‐cell responses as assessed by (A) IFNγ and (B) IL‐2. IFN, interferon; IL, interleukin; PB, post booster; PV, post vaccine. Tables under each figure provide cytokine levels for each time point for all patients, as well as for subsets of patients who were infected prior to the given time point (purple) and those who were not infected (orange). p Values compare log‐10 transformed values of neighboring time points, determined by paired t‐tests. Bolded p values are significant.
Figure 5
Figure 5
T‐cell characteristics of vaccinated VIOLA patients who had Omicron infection versus vaccinated reference healthy controls who had Omicron infection. p Values were determined by Wilcoxon test. Bolded p values are significant.
Figure 6
Figure 6
COVID v3 score correlations with participant characteristics and immune responses. IFN, interferon; Ig, immunoglobulin; IL, interleukin; MBI, multi‐epitope bead‐based immunoassay. “Pre” corresponds to samples collected prior to booster or Omicron. “Post” corresponds to samples collected after booster or Omicron. “Pre” and “post” samples are analyzed separately. R and p values were determined via Spearman correlation. Bolded p values and Blue boxes indicate correlations that reached significance in either pre‐ or post‐booster/Omicron subsets of samples.
Figure 7
Figure 7
COVID v3 scores before and aftera booster or Omicron strain infection. p Values were determined via Wilcoxon test. a12 weeks after booster and at the next collection after COVID‐19 infection.
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