key: cord-0932531-lie4t2zx
authors: Conte, William L.
title: Attenuation of antibody response to SARS-CoV-2 infection in patients with multiple sclerosis on ocrelizumab: a case-control study
date: 2021-05-07
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2021.103014
sha: 6230a24c0624f60ada76c9b8657bc579d350c79e
doc_id: 932531
cord_uid: lie4t2zx

OBJECTIVE: Ocrelizumab (OCR) is a monoclonal antibody directed at B-cells that is FDA approved for treatment of RRMS and PPMS. Prior studies have raised concerns about patients’ ability to form antibodies in response to various antigens, especially SARS-CoV-2. The objective of this study is to determine whether OCR attenuates the antibody response to SARS-CoV-2 in patients with MS as compared with other disease modifying therapies. METHODS: This is a case-control study looking at the odds of developing antibodies to SARS-CoV-2 in patients treated with OCR versus other disease modifying therapies. From May 13, 2020 through March 1, 2021, patients with a RT-PCR-confirmed infection to SARS-CoV-2 were tested for presence of antibodies and the data was recorded. Outpatients with MS at the Methodist Hospitals Comprehensive MS Center were selected who had a prior infection with COVID-19 as demonstrated by RT-PCR in the electronic health records. Odds ratios were calculated to compare rates of antibody formation with OCR exposure vs other DMT. RESULTS: 24 patients had evidence of COVID-19 and had antibody testing available at the time of analysis. Patients who received OCR had decreased odds of forming antibodies (OR 0.045, p=0.011, 95% CI (0.004,0.488)). CONCLUSIONS: Patients who received OCR within the prior 6 months of COVID-19 infection had decreased odds of developing antibodies as compared with other DMTs. This suggests that OCR may attenuate the antibody response to SARS-CoV-2. Additional studies should analyze the odds of spike protein antibody formation in response to SARS-CoV-2 vaccines for patients on OCR.

Attenuation of antibody response to SARS-CoV-2 infection in patients with multiple sclerosis on 3 ocrelizumab: a case-control study 4 5 6 7

William L. Conte 1. Introduction 2 3 Ocrelizumab (OCR) is a monoclonal antibody directed against CD20+ B-cells. It is approved for 4 both relapse-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis 5 (PPMS) in the United States. 1,2 I previously reported a case of a patient on OCR with 6 hypogammaglobulinemia who did not have detectable antibodies to SARS-CoV-2 after a course 7 of COVID-19. 3 Since then, other case reports have emerged regarding various antibody 8 responses after OCR exposure. Lucchini and colleagues reported two patients without SARS-9

CoV-2 antibodies following OCR exposure, with one patient having hypogammaglobulinemia. 4 10 Thornton and Harel reported an additional two cases of negative antibody testing, but with 11 normal immunoglobulin levels. 5 However, not all case reports have shown negative antibodies. 12

Flores-Gonzalez and associates reported a case of a patient on ofatumumab, which is another 13 B-cell-depleting agent similar to OCR, with normal immunoglobulin levels and evidence of B-cell 14 depletion who did in fact develop antibodies to SARS-CoV-2. 6 A recent study showed that only 15 17.6% of patients on OCR developed antibodies and another study found that in their cohort, 16 90% of those that tested negative for antibodies were on CD20 modulators. of analysis and had SARS-CoV-2 IgG testing available. Fifteen patients were on OCR and 9 1 patients were on other DMTs. "Other" DMTs included fingolimod (2), ozanimod (2), 2 teriflunomide (2), alemtuzumab (1), natalizumab (1) and oral cladribine (1). Baseline 3 characteristics are reported in Table 1 , which were similar between the two groups. Ages 4 ranged between 21 and 65. There were 22 females and 2 males. There exists a concern about the immunogenicity of SARS-CoV-2 in patients on FDA-approved 1 B-cell depleting agents such as OCR, rituximab, and ofatumumab. I had previously postulated in 2 a single case report that hypogammaglobulinemia could drive the attenuation of the antibody 3 response. However, in the current study, immunoglobulin levels did not influence antibody 4 status. Indeed, this study shows that mere exposure to OCR significantly attenuates the 5 antibody response to SARS-CoV-2. 6 7 With the exception of one patient, all the non-OCR DMTs showed antibody formation. The one 8 patient was on ozanimod. This could have been a scenario where she did not produce 9 antibodies naturally, as a previous study showed a 93.1% seroconversion rate for SARS-CoV-2 10 antibodies for normal patients. 9 There was another patient in the cohort who was on ozanimod 11 and did in fact develop antibodies. 12 13 It should be noted that absence of antibody production in response to a COVID-19 infection 14

should not be equated to predicting whether or not there would be a humoral response to a 15 vaccine. In the recently published VELOCE trial, patients were able to mount a humoral 16 response to various antigens although the response was attenuated. 10 17 18 This study is limited by a relatively small sample size and that not all FDA-approved DMTs were 19

included. There is also no information about other B-cell depleting agents such as rituximab 20 and ofatumumab. Data will continue to be collected as more patients are infected with SARS-21 

Ocrelizumab versus Interferon Beta-1a in Relapsing 1

Multiple Sclerosis

Ocrelizumab versus Placebo in Primary 3 Progressive Multiple Sclerosis

Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab 6 with hypogammaglobulinemia

Is serological 9 response to SARS-CoV-2 preserved in MS patients on ocrelizumab treatment? A case 10 report

Negative SARS-CoV-2 antibody testing following COVID-19 infection 12 in Two MS patients treated with ocrelizumab

Development of 15 SARS-CoV-2 IgM and IgG antibodies in a relapsing multiple sclerosis patient on 16 ofatumumab

COVID-19 in multiple sclerosis patients: 19 susceptibility, severity risk factors and serological response

The presence of SARS-CoV2 antibodies in MS patients

Antibody Responses to SARS-CoV-2 in Patients With Novel 24

Effect of ocrelizumab on vaccine responses in 27 patients with multiple sclerosis: The VELOCE study