CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

Abstract The SARS-CoV-2 pandemic has tremendous implications for the management of patients with autoimmune conditions such as multiple sclerosis (MS) under immune therapies targeting CD20+ B cells (aCD20). We here investigated humoral and cellular immune responses, including neutralization against SARS-CoV-2 WT and delta variant and T cell responses of aCD20-treated MS patients following SARS-CoV-2 vaccination compared to healthy controls. aCD20-treated MS patients had lower anti-SARS-CoV-2-Spike titers, which correlated with B-cell repopulation. Sera of aCD20 treated patients had reduced capacity to neutralize WT and delta pseudoviruses in vitro. On the contrary, aCD20 treated patients elicited higher frequencies of CD3+ T cells, Th1 cells, Th2 cells, Tc1 cells and CD8+IFN-γ+IL-2+ cells. In summary, aCD20 treated patients have a reduced humoral immune response, depending on B cell repopulation, in accordance with a shift of cellular immune response to a stronger Th1, Th2 and Tc1 phenotype, suggesting strong cellular protection against SARS-CoV-2.

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Determining the best window for BNT162b2 mRNA vaccination for SARS-CoV-2 in patients with multiple sclerosis receiving anti-CD20 therapy

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/20552173211062142 ◽

2021 ◽

Vol 7 (4) ◽

pp. 205521732110621

Author(s):

Audrey Rico ◽

Laetitia Ninove ◽

Adil Maarouf ◽

Clémence Boutiere ◽

Pierre Durozard ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Serologic Response ◽

Cell Counts ◽

Anti Cd20 ◽

Cell Proportion ◽

Cell Repopulation

We studied the serologic response to the BNT162b2 mRNA vaccine at four weeks after the second dose in patients with RRMS treated with rituximab with extended-interval dosing ( n = 26). At four weeks, 73% of patients were seropositive. No patient without B cells at the first dose ( n = 4) was seropositive. Four of seven (57%) patients with B-cell proportion >0% and ≤5% were seropositive. All patients with B-cell proportion >5% ( n = 15) were seropositive. In all patients, quantitative ELISA measures after vaccination were correlated with B-cell counts measured before vaccination. In patients receiving rituximab, seropositivity after BNT162b2 mRNA vaccination emerged only after B-cell repopulation.

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Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000004950 ◽

2018 ◽

Vol 90 (7) ◽

pp. e601-e605 ◽

Cited By ~ 18

Author(s):

Thomas Wehrum ◽

Lena-Alexandra Beume ◽

Oliver Stich ◽

Irina Mader ◽

Mathias Mäurer ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

B Cell ◽

B Lymphocytes ◽

Case Series ◽

Retrospective Case ◽

Cell Lineages ◽

The Subject ◽

Cell Repopulation ◽

Lesion Morphology

ObjectiveTo report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab.MethodsRetrospective case series.ResultsPatient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab. Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab.ConclusionThis is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease. Whether this is due to different rates of B- and T cell repopulation has to be the subject of further research. Moreover, further effects on the interactions between the adaptive and innate immunity as well as between B and T cell lineages might explain the observed disease activation.

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CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

10.1101/2021.09.26.21264023 ◽

2021 ◽

Author(s):

David Baker ◽

Amy MacDougall ◽

Angray S Kang ◽

Klaus Schmierer ◽

Gavin Giovannoni ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Trial Data ◽

Phase Iii ◽

European Medicines Agency ◽

Link Type ◽

Monthly Dosing ◽

Low Levels ◽

Cell Repopulation

BACKGROUND: CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown. METHODS: Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal. RESULTS: Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab. CONCLUSIONS. Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

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