key: cord-0780452-ft72zamr
authors: Wallach, Asya I.; Schiebel, Matthew; Picone, Mary Ann
title: Antibody response to SARS-CoV-2 vaccination following typical and three-dose dosing schedules in multiple sclerosis patients treated with disease modifying therapies
date: 2022-05-06
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2022.103856
sha: cd1ca6ea51e85c454c5fd4faead2d10dcdc77c4c
doc_id: 780452
cord_uid: ft72zamr

Background: Immunizations against SARS-CoV-2 virus are now available and recommended, but the effect of additional dosing of the vaccine in immunocompromised MS patients is unknown. Methods: Part I - A retrospective chart review of MS patients who were vaccinated against SARS-CoV-2 and tested commercially for Sars Covid Spike Protein Antibody between March 1 – June 30, 2021. Part II - Patients on treatment with anti-CD20 infusion medications who received a SARS-CoV-2 third mRNA vaccination dose August 13, 2021 – October 31, 2021 and were subsequently commercially tested for Sars Covid Spike Protein Antibody. Results: Part I - A total of N=208 MS patients, age range 23-76 were tested, with 49% (102/208) demonstrating a humoral response. Stratified by DMT type, patients treated with interferon, teriflunomide, or a remote history of alemtuzumab (>2 years since last DMT) yielded 100% measurable antibodies; >90% amongst patients treated with natalizumab, fumarates and glatiramer acetate; <50% measurable antibodies following vaccination in S1P modulators and anti-CD20 treated patients. Subsequently, in Part II – N=40 patients on anti-CD20 treatments (33 ocrelizumab, 7 rituximab) who received 3 mRNA vaccinations yielded 20% humoral response. Conclusions: MS patients are able to mount a humoral vaccine response to SARS-CoV-2, irrespective of the vaccine type administered; patients treated with S1P modulators and anti-CD20 agents are least likely to mount such a response with a typical dosing schedule. Patients treated with ocrelizumab/rituximab show a similar modest humoral immune system benefit following three doses as with standard dosing.

1. MS patients treated with most DMTs make a humoral response following a standard vaccination schedule.

anti-CD20 treatment made a humoral response; following an additional mRNA vaccination dose, 20% of patients on infusion anti-CD20 treatment made a humoral response. Results: Part I -A total of N=208 MS patients, age range 23-76 were tested, with 49% (102/208) demonstrating a humoral response. Stratified by DMT type, patients treated with interferon, teriflunomide, or a remote history of alemtuzumab (>2 years since last DMT) yielded 100% measurable antibodies; >90% amongst patients treated with natalizumab, fumarates and glatiramer acetate; <50% measurable antibodies following vaccination in S1P modulators and anti-CD20 treated patients. Subsequently, in Part II -N=40 patients on anti-CD20 treatments (33 ocrelizumab, 7 rituximab) who received 3 mRNA vaccinations yielded 20% humoral response.

Conclusions: MS patients are able to mount a humoral vaccine response to SARS-CoV-2, irrespective of the vaccine type administered; patients treated with S1P modulators and anti-CD20 agents are least likely to mount such a response with a typical dosing schedule. Patients treated with ocrelizumab/rituximab show a similar modest humoral immune system benefit following three doses as with standard dosing.

In the United States, we currently have three vaccines approved by the FDA against the Sars-CoV-2 virus, with an additional vaccine dose recommended for all adults at least 6-months after the initial series. Previously published work has demonstrated that multiple sclerosis (MS) patients on treatment with anti-CD20 medications are at a disadvantage with respect to mounting a humoral immune response following Sars-CoV-2 vaccination 1-3 , as are sphingosine-1phosphate receptor modulator (S1P) treated patients 1 , while other disease modifying treatments Antibodies. We obtained IRB approval to retrospectively review the clinical and demographic data for patients whose serum was collected between March 1, 2021 and June 30, 2021.

Part II: Patients of the Holy Name MS Center who were on treatment with an anti-CD20 infusion medication (and initially vaccinated with an mRNA vaccine) were encouraged to receive a third dose as per CDC guidelines; afterwards, commercial serum testing for Covid Spike Protein IgG Ab was offered 1 at least 3 weeks following the final vaccine dose. We obtained IRB approval to retrospectively review the clinical and demographic data for those on anti-CD20 infusions who 

A total of 208 patients were tested in Part I, 67% (140/208) female, age range 23-76y, average ± SD 49.1y ±12.6. Ninety five percent of the tests (198/208) were performed by Quest (SARS COV2 Ab (IgG) Spike, Semiquantitative) with values greater than 1 Index interpreted as positive; 2% of tests (4/208) were performed by Abbot Architect which reported 50 AU/mL as positive; 2% (4/208) Roche Elecsys anti-SARS Cov2 S Reagent Assay (greater than 0.8 U/mL considered positive), 1% (2/208) DiaSorin Liaison SARS CoV2 S1/S2 IgG Assay with qualitative result only.

In total, 49% (n=102) of patients formed a detectable humoral antibody response.

Antibodies were tested on average, 52.3 ± SD 12.0 days (range 13-165 days) following vaccination. Table 1 outlines the humoral response following vaccination in each DMT group.

Patients least likely to make a humoral response were on S1P modulators 46% (6/13), and monoclonal anti-CD20 medications (rituximab, ocrelizumab, ofatumumab) 19% (21/116).

Evaluating anti-CD20 patients (92 ocrelizumab, 23 rituximab, 1 ofatumumab), 19%

(21/116) made a measurable humoral response following vaccination. With respect to the infusion anti-CD20 treatments, patients who developed a positive vaccine antibody result were more likely to have waited longer (as demonstrated in Figure 1 ) after their last infusion prior to vaccinating (average ± SD; range) 197.8d ± 144.0; 73-598 days vs 133.5d ± 55.0; 39-403 days as would be expected, t(11)=3.4, p<.001 (one-tailed t-test of 2 independent means). Patients who developed a positive humoral response were more likely to have had fewer treatment cycles of ocrelizumab/rituximab (average ± SD; range) 3.6 ± 1.7; 1-7 vs. 5.5 ± 2.5; 1-16, t(11)=-3.4, p<.001 (one-tailed t-test). A chi-square test of independence showed that there was no significant association between humoral response to vaccination and vaccine type (mRNA vaccine vs adenovector vaccine) amongst anti-CD20 treated patients. Of note, one patient receiving infusion treatment also required concomitant high dose steroids for five days, and another transitioned from infusion to injectable ofatumumab three months prior to vaccination (neither formed a humoral response).

A total of 40 patients (39 with MS, 1 with NMO) were tested following three mRNA SARS-CoV-2 vaccination doses, 26/40 (65%) female, age range 28-73yo, average ± SD 53.2y ±12.2. These patients were on treatment with ocrelizumab (n=33), or rituximab (n=7). Twenty percent (n=8/40) tested positive for Covid Spike Protein Ab following the 3 rd mRNA dose, of which three were not tested for antibodies prior to the third dose, and one was on treatment with natalizumab at the time of her initial mRNA seriesher response was >20 (maximum reportable value for Quest testing) following dose 2 and 8.47 (on the same test) following dose 3. None of these patients are known to our center as having had Sars-CoV-2. Of the total group, three anti-CD20 treated patients had Sars-CoV-2, 1 with mild symptomatic disease prior to vaccination (had a low positive Spike Protein Ab result following mRNA dose #2 and negative following mRNA dose #3), and two asymptomatic, but lab positive. Patients who made a positive vs negative Spike Protein Ab result following mRNA dose #3 had similar delays between the antecedent infusion cycle and subsequent vaccination, t(38) = 0.26, p= .40, although there was a significant effect of the number of cycles of anti-CD20 infusion medication administered, t(38) = -1.7, p < .05.

We have confirmed that MS patients are able to mount a humoral immune response following vaccination against SARS-CoV-2, with 49% of tested patients mounting a detectable response following the initial CDC recommended vaccination series. Patients least likely to mount a humoral response included, as expected 1,5,8-10 , anti-CD20 treated patients (19%) and S1P treated patients (46%). Although of note, the experience with fingolimod treated patients has been quite variable in the literature, 3.6%-96.9% humoral responses depending on the study 1,5,9 . We focused on ocrelizumab and rituximab treated patients with respect to antibody response following a third dose of SARS-CoV-2 mRNA vaccination, and found 20% (n=8/40) made a humoral response (but cannot exclude that one patient was a 'carry-over' as her initial vaccination series preceded her initiation of ocrelizumab). There were too few subjects with measured antibody levels following both the second and the third vaccination to permit a withinpatient longitudinal assessment. None of these 'responders' are known to our center to have had prior Sars-CoV-2 infection, although we did not routinely check for Covid IgG and it is possible that some may have had asymptomatic infection. In replication of Sabatino et al. 10 but in contrast to Brill et al. 2 we did find an association between the number of anti-CD20 infusions and likelihood of forming a serological response post-vaccination in both our 'typical vaccination' dosage group, and 'three time vaccination group'. We were able to show a benefit of a longer wait time between infusion and vaccination in our 'typical vaccination' group, in replication of previous work 23, 9 , but not seen by Sabatino et al. 10 and not seen by us in our '3 dose' vaccination group.

There are several limitations to this observational study, including our modest number of subjects. We did not systematically perform serological assessments for asymptomatic infection, although we did routinely query patients regarding any infections at clinical encounters. Finally, this study is limited to commercially available tests which were performed with different laboratories thus we cannot make comparisons about antibody levels beyond positive and negative.

In summary, treated MS patients are able to mount a humoral vaccine response to SARS-CoV-2. The likelihood of attaining a humoral response is dependent on the DMT; we did not find evidence that it is dependent on the specific vaccine administered, although others have found differences in antibody levels following mRNA vaccinations 11 . Patients on treatment with S1P modulators and anti-CD 20 monoclonal antibodies are least likely to make a humoral response to vaccination following a typical vaccine schedule, and in the case of anti-CD20 infusions, following a 3-dose mRNA vaccine regiment as well. This study provides support for MS clinicians to consider complementary strategies to protect their patients against SARS-CoV-2 in case a blunted humoral response is expected to vaccination, for example, by recommending the recently FDA emergency use authorized, tixagevimab/cilgavimab intramuscular injection for pre-covid-19 exposure prophylaxis. Questions for future research include: what is the optimal dosing schedule for anti-CD20 infusion patients in terms of interval between vaccine doses, timing following infusion, and number of vaccine administrations, especially in light of reassuring data related to cellular immunity in these patients. 

Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies

Time between last infusion and vaccination

Humoral and T-Cell Response to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Treated With Ocrelizumab

Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy

Humoral response to SARS-CoV-2 mRNA vaccine in patients with multiple sclerosis treated with natalizumab

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies. EBioMedicine

Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients

Booster-dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series

Humoral immune response following SARS-CoV-2 mRNA vaccination concomitant to anti-CD20 therapy in multiple sclerosis

Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis

Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function. JCI Insight

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies