key: cord-0307313-lc1y3zhv
authors: Kister, I.; Patskovsky, Y.; Curtin, R.; Pei, J.; Perdomo, K.; Rimler, Z.; Voloshnya, I.; Samanovic, M. I.; Cornelius, A. R.; Velmurugu, Y.; Nyovanie, S.; Kim, J.; Tardio, E.; Bacon, T. E.; Zhovtis Ryerson, L.; Raut, P.; Pedotti, R.; Hawker, K.; Raposo, C.; Priest, J.; Cabatingan, M.; Winger, R. C.; Mulligan, M. J.; Krogsgaard, M.; Silverman, G. J.
title: Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational study
date: 2022-01-10
journal: nan
DOI: 10.1101/2022.01.10.22268752
sha: 0fffbfc51afc2acb46da1b0677c6e3a3dfaea0f7
doc_id: 307313
cord_uid: lc1y3zhv

Objective: To determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection. Methods: MS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike RBD antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture ELISA; and IL-2 and IFN{gamma} ; ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. Results: Between 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) - 40%; natalizumab - 17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 - asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p[≤]0.0001). T-cell responses (IFN{gamma}) were decreased in S1P (p=0.03), increased in natalizumab (p<0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r=0.45, p=0.0002) and non-OCR (r=0.64, p<0.0001). Immune responses did not differ by race/ethnicity. COVID-19 clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. Interpretation: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and non-disabled group of MS patients.

Multiple Sclerosis (MS) is treated with disease-modifying therapies (DMTs), some of which may impair immune responses to the pandemic SARS-CoV-2 infection. The commonly used anti-CD20 therapies (aCD20) are associated with reduced antibody titers following SARS-CoV-2 infection and vaccination 1-10 , likely due to depletion of peripheral B cells that would otherwise be available for recruitment into germinal centers for antigen-mediated activation and clonal expansion. T-cell compartment is relatively unaffected by aCD20 as only a small subset of CD20-bearing CD3+ lymphocytes are removed by aCD20. 11, 12 Overall, T-cells counts and functional responses remain intact, 13, 14 and, accordingly, Spike protein-specific T-cell responses to COVID-19 vaccination in aCD20-treated patients are robust. 11, [15] [16] [17] [18] [19] T-cell responses following natural infection in aCD20-treated patients have received less attention, but are an active area of investigation. 20, 21 There is very limited data on immune responses to SARS-CoV-2 infection under other commonly used DMTs, such as sphingosine-1-phosphate receptor modulators (S1P), which interfere with T-cell egress from lymphoid tissue, and fumarates, which induce mild-moderate lymphopenia. 20, 22, 23 Understanding the impact of DMTs on the immune response to SARS-CoV-2 infection is critical for counseling MS patients about COVID-19 risks and determining whether a patient who experienced COVID-19 on a particular DMT is likely to derive a similar degree of protective immunity as untreated individuals. [24] [25] [26] [27] To address the knowledge gaps, we designed a prospective study with the goals of: 1. determining the impact of ocrelizumab (OCR) and other DMTs on the development of cellular and humoral immune memory to SARS-CoV-2 natural infection; 2. characterizing the relationship between humoral and cellular post-infection immune responses in patients with and without peripheral B-cell depletion; 3. investigating the relationship between the clinical severity of COVID-19 and immune responses to SARS-CoV-2 in MS patients with different DMTs. We recruited a large, ethnically-diverse group of MS patients from the NYU MS Care Center in New York City, New York, one of the epicenters of the COVID-19 pandemic in 2020-21, 28, 29 and comprehensively characterized humoral and cellular responses to SARS-CoV-2 using several complementary antibody and T-cell SARS-CoV-2 -specific assays. A notable strength of our study is the inclusion of a large number of non-White patients -over 60% of all patients, which allowed us to investigate immune responses to SARS-CoV-2 in MS patients from underrepresented racial/ethnic groups.

Patients seen for routine visits at the NYU Multiple Sclerosis Comprehensive Care Center in New York City (New York) were invited to participate if they had clinician-diagnosed MS (revised 2017 McDonald . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. ; https://doi.org/10.1101/2022.01. 10 .22268752 doi: medRxiv preprint criteria); 30 were treated with an FDA-approved DMT for MS, or were on no treatment; were aged 18 to 60; had Expanded Disability Status Scale (EDSS) score of 0 (normal) to 7 (wheelchair-bound). Exclusion criteria were: concurrent immunosuppressive therapy; active systemic cancer; primary or acquired immunodeficiency (unrelated to DMT); active drug or alcohol abuse; aCD20 therapy other than OCR; uncontrolled diabetes mellitus; end-organ failure ( Patients' final SARS CoV-2 infection status (previously infected vs. non-infected) was determined based on laboratory evidence of infection prior to enrollment or serologic tests conducted during the study as described in the next section.

Patients' serologic status was assessed using three different methods:

1. Electro-chemiluminescence immunoassay using the Elecsys® platform (Roche Diagnostics), measuring antibodies to Nucleocapsid (N) (qualitative) and Receptor Binding Domain (RBD) of Spike (S) protein (quantitative). All samples were processed and measured by a specialized laboratory according to the manufacturers' instructions. Values ≥ 1.0 U/mL were interpreted as 'positive' for anti-N SARS-CoV-2 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 10, 2022. Inc.) coupled to commercial paramagnetic beads (MagPix, Luminex), as adapted from the manufacturer's instructions as previously described. 33, 34 Positivity of individual MBI was set as the 3SD above the mean of pre-pandemic healthy adult controls. Assay reactivity was also confirmed with non-autoimmune serum from individuals with PCR-documented prior COVID-19 infection (samples provided by the NYU COVID-19 Bio Repository). MBI data for S, RBD, and NTD for healthy control and COVID-19 patient specimens and respective positivity cut-offs are shown in the Supplemental Figure 1 . Serologic confirmation of prior SARS-CoV-2 infection ('MBI seropositive') was defined conservatively as two or more independent S, RBD, and NTD positive assay results.

3. SARS-CoV-2 viral neutralization activity of plasma was measured in an immunofluorescence-based assay that detects the neutralization of infectious virus (SARS-CoV-2 isolate USA-WA1/2020 (NR-52281, GenBank accession no. MT233526) in cultured Vero E6 cells (African Green Monkey Kidney; ATCC #CRL-1586) as described in detail in 35 . All SARS-CoV-2 infection assays were performed in the BSL3 facility of NYU Grossman School of Medicine (New York, NY).

T-cell responses to SARS-CoV-2 Spike protein were assessed in whole blood samples with TruCulture® stimulation system (Myriad RBM) according to the manufacturer's instructions. Whole blood samples were incubated for 48 hours at 37 o C. Collected supernatants were analyzed with IFNγ and IL-2 ELISA assay for measuring cytokine production following manufacturer's protocol (Fisher Scientific, Cat # ENEHIFNG and 50-112-5363, respectively). The response for the TruCulture system was conservatively defined as positive if both IFNγ and IL-2 assays were at the level of ≥ 1 pg/ml. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 10, 2022. Multivariate analyses were performed to account for possible confounding characteristics, including the patients' COVID-19 clinical severity and MS treatments. Missing data were not imputed.

The study was approved by the NYU Grossman School of Medicine IRB.

Demographic and clinical characteristics of the patients Table 1 .

The patients were relatively young (mean age: 40.3±10.8 years, range 18-60), non-disabled (68% fully . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 10, 2022. ; 1 0 ambulatory), and otherwise healthy (68% without any COVID19-relevant comorbidities). Sex ratio (74% female) and race/ethnic composition (62% non-White) of the patients are representative of our clinic population. 36 'COVID history at enrollment' was classified as 'laboratory-supported COVID at enrollment' in 101 patients (26% of all patients), 'suspected COVID at enrollment' (symptoms only) in 76 patients (20%), and 'COVID non-suspected' in 212 patients (54%). These three subgroups had similar demographic and clinical MS characteristics (data not shown).

All patients underwent serologic testing by Elecsys assay for antibodies to N and the S RBD, and by MBI for whole S protein and the S RBD and NTD components of Spike. There was a strong correlation between the individual assays for the whole Spike and Spike components by MBI (r= 0.77-0.82, p<0.0001), and between anti-RBD antibody levels by MBI and by Elecsys (r=0.69, p<0.0001). SARS-CoV-2 antibody responses did not differ by race/ethnicity (White v. Black v. Hispanics v. Other) with either Elecsys or MBI assay systems (Supplemental Table 1 ).

The sensitivity and specificity of two antibody assays are summarized in Table 2 . The patients with 'laboratory-supported COVID at enrollment' are shown in the first column. Despite the more stringent definition of seropositivity for MBI (≥2 of 3 independent antibody assays with >3SD above pre-pandemic means) than Elecsys (either one of the two antibodies positive), MBI had greater sensitivity for antibody detection in patients with laboratory-confirmed COVID-19 on enrollment: 92% for MBI v. 81% for Elecsys. Eight patients were considered false-negative by MBI, as they had a lab-confirmed infection before enrollment by commercial tests but were negative by MBI; all eight patients were on OCR at the time of infection.

The second column of Table 2 presents the prevalence of SARS-CoV-2-specific antibodies in patients with 'suspected COVID on enrollment' (symptoms only) and the third column -in non-suspected cases. In the 'suspected COVID at enrollment' group, MBI identified 29 out of 76 as 'MBI-seropositive' (≥2 of 3 independent antibody assays with >3SD above pre-pandemic mean levels) and in the non-suspected group, MBI identified 47 out of 212 as MBI-seropositive. Thus, there was a total of 76 patients from 'suspected' and 'non-suspected' subsets who had strong serologic evidence of SARS-CoV-2 infection. Of these patients, half (n=38) were also positive by Elecsys. In contrast, Elecsys identified only a single case that was negative by MBI. Overall, MBI's greater sensitivity for antibody detection proved useful in the study of immune responses to chronologically remote SARS-CoV-2 infections, especially in immunosuppressed individuals.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 

In addition to the 101 patients with lab-supported COVID-19 on enrollment, we identified 76 patients who did not have laboratory testing for SARS CoV-2 prior to enrollment, but tested positive on at least 2 out of 3 independent antibody levels on MBI and were thus considered to have had SARS-CoV-2 infection. Thus, the total number of patients with test-supported SARS-CoV-2 infection in our group was 177, or 46% of all patients. Table 3 . The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. 

Among patients with prior SARS-CoV-2 infection, the seropositivity rate by MBI was 100% for all DMTs except for OCR, for which the seropositivity rate was 89%. Seropositivity rates by Elecsys for non-OCR DMTs and the no-treatment group ranged from 83% to 100%, while for OCR it was only 36%.

Levels of anti-Spike antibodies by Elecsys ( Figure 2A ) and MBI ( Figure 2B ) were approximately 10-fold lower in OCR patients with prior SARS-CoV-2 compared to untreated patients with prior infection. S1P patients had significantly lower antibody levels than the untreated patients as measured by Elecsys, but the difference was not statistically significant with the MBI assay. For OCR-treated patients with a history of COVID-19, there was a non-significant trend for increased anti-SARS-CoV-2 Ab titers on MBI assay with longer time from the last OCR infusion prior to infection and infection onset (r=0.285, p=0.064).

Samples were available to measure functional neutralizing antibody (Nabs) titers in 77 patients with prior SARS CoV-2 infection. Nab levels showed a strong correlation with anti-RBD antibody levels detected by MBI assay (r=0.71, p<0.001), yet 21% of patients with high levels of binding antibodies did not have detectable functional Nabs. Compared to untreated patients, Nab titers were marginally lower in OCRtreated (p=0.055), and higher in Natalizumab-treated patients (p=0.01) ( Figure 2C ).

For each patient with symptomatic COVID-19 after OCR infusion, we plotted in Figure 3 Multivariate analyses of all SARS-CoV-2 infected patients showed that treatment with OCR and the absence of hypertension predicted lower Elecsys antibody (the biological significance of the latter correlation is unknown). In symptomatic COVID-19 patients, treatment with OCR and longer infection-tocollection time correlated with lower MBI levels. In the subset of previously SARS-CoV-2 infected patients who were tested for Nabs, only OCR treatment at the time of infection was a predictor of lower Nabs titers, though the number of available samples for non-OCR DMTs was limited, e.g., only 5 samples for S1P.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table) .

We also performed in vitro T-cell stimulation studies on 130 MBI-seronegative patients who did not meet showed depressed responses (p=0.0285) and Natalizumab had elevated responses (p=0.0002) ( Figure 4A ). IL-2 responses by TruCulture were also elevated with Natalizumab (p<0.0001), but were similar for all other DMTs, including OCR ( Figure 4B) . T-cell responses assessed by ELISpot are presented in Figure 4C for IFNγ and Figure 4D for IL-2. Only Natalizumab-treated patients had marginally elevated IL-2 responses (p=0.048), while S1P had marginally depressed IL-2 responses by ELISpot.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. TruCulture assay, longer COVID-19 symptom duration was associated with lower T-cell responses, but this relationship was driven by few outliers with 'long COVID' and was not present if patients with symptoms that persisted for >1 month were excluded. In the nine hospitalized patients, the mean anti-SARS-CoV-2 antibody values and T-cell responses were similar to the non-hospitalized group, except for TruCulture IFNγ responses that were higher in the hospitalized patients (data not shown).

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The copyright holder for this preprint this version posted January 10, 2022. ; https://doi.org/10.1101/2022.01.10.22268752 doi: medRxiv preprint

In an ethnically-diverse group of 389 MS patients from the NYU MS Care Center in New York City, 46% had laboratory evidence of prior SARS-CoV-2 infection. This prevalence is higher than what would be expected for our area based on the NYC Department of Health seroprevalence study from July 2021 (the end of our study period), 29 possibly due to over-representation in our Center of patients from Brooklyn, Queens, and Bronx neighborhoods with a very high incidence of prior SARS-CoV-2 infections (40-50%); use of highly sensitive multiplex bead-based immunoassays to measure seroprevalence; and the presumed greater motivation to participate in the study on the part of patients with suspected or known prior COVID-19. We confirmed COVID-19 diagnosis in 38% of patients with a history of COVID-19-like illness, but no commercial laboratory confirmation prior to enrollment, which is almost identical to the rate of SARS CoV-2 seropositivity among undocumented cases in a population-based study from New York City. 38 The rate of asymptomatic infection in our patients -27% -is lower than 33% rate in two large European studies, but higher than the 16% among World Trade Center responders in New York City area. 39 Our results suggest that asymptomatic SARS CoV-2 infections are not uncommon among MS patients and occur at a rate comparable to the general population. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. Taken together, our data suggests that previously infected or vaccinated patients on aCD20 are less likely to be protected against 'breakthrough' infection than others, a prediction born out by a recent population-based study from UK, 43 but are probably still protected against COVID progression due to intact T cell immunity. 15, 18, 44, 45 Memory T cells that contribute to protection against severe disease by eliminating infected cells and limiting viral replication may explain, at least in part, why vaccines prevent hospitalizations and death even against variants that exhibit limited neutralization by vaccine-induced humoral immunity. 46, 47 Indeed, T cells responses to Beta and Omicron variants have been documented following the third dose of mRNA vaccines even in aCD20-treated patients. 48 Patients who experienced SARS-CoV-2 infection while on S1P receptor modulators tended to have depressed humoral and, to a larger extent, cellular immune responses than untreated patients. This may be a consequence of peripheral lymphopenia, disruption of immune cell traffic to and from the germinal center, or the impact of the drug on the downstream signaling pathways involved in cytokine production. T-cell responses in S1P-treated patients are also reduced following COVID-19 vaccination. 1, 44, 45 In another example of clinical-immunologic dissociation, COVID-19 outcomes were not worse in patients on S1P in our group or other large series. 9, 49 A possible explanation is that S1P modulators may help protect against immune system hyperactivation -'cytokine storm' -and stabilize pulmonary epithelium, 50 thereby preventing more severe disease.

Natalizumab-treated patients antibody and cellular responses were on par, or better, than in untreated patients, possibly as a consequence of elevated T-and B-cell lymphocyte counts in the peripheral circulation with this therapy. 51 In patients treated with fumarates, both humoral or cellular responses were intact despite the lower peripheral lymphocyte counts with these drugs. 52 In contrast to a prior study, 20 we did not observe impairment in immune responses in IFNβ-treated patients, in line with the observation from large cohorts that COVID-19 outcomes are actually better in IFNβ -treated patients than with other DMTs. 9 In patients on glatiramer and teriflunomide, immune responses were intact though firm conclusions cannot be made given the relatively small number of infections in each of these DMT classes (<11 patients per DMT groups).

Several strengths of our study deserve mention. First, the large number of studied patients and high SARS-CoV-2 seropositive rate allowed for statistically meaningful comparisons of immunologic outcomes for the different DMTs. 20 Secondly, our population largely reflects the diversity of New York City, with 29% of patients self-identifying as African-Americans and 27% -as Hispanics. (Asians were relatively . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. ; https://doi.org/10.1101/2022.01.10.22268752 doi: medRxiv preprint underrepresented in our Center, likely due to the lower prevalence of MS in this ethnic group.) In univariate and multivariate analyses, race/ethnicity was not a predictor of clinical outcomes, nor of antibody or cellular anti-SARS-CoV-2 responses in either OCR or non-OCR patients (Supplemental Table 1 ). Third, due to the epidemiology of COVID-19 spread in our area -with a highly destructive first wave in Spring of 2020 followed by a large second wave in Fall-Winter 2020 -we were able to collect samples with a wide range of time-to-infection and investigate the durability of immune responses over the median interval of 43 week from infection (interquartile range: 14-50 week). Fourth, we used a custom Multiepitope Bead-based Immunoassay (MBI) specially designed to interrogate immune responses to SARS-CoV-2 antigens with enhanced sensitivity. MBI was instrumental in identifying serologic evidence of infection in OCR-treated patients with depressed antibody responses and asymptomatic infections, which were often missed with the commercially available Elecsys test designed for high throughput in the clinical setting. Differences in seropositivity rates in OCR patients with past infection (36% by Elecsys and 89% by MBI) emphasize the importance of considering assay sensitivity and the clinical context when interpreting published seroprevalence studies. The higher sensitivity of multiplex bead array over electro-chemiluminescence immunoassay has been noted by others as well. 20 Fifth, we assessed functional neutralizing responses with live virus microneutralization assays in a subset of patients with binding antibodies to SARS-CoV-2.

Despite a high degree of correlation between binding (MBI IgG Spike) and neutralizing antibody levels (r=0.71), one in five patients with binding antibodies had low or undetectable neutralizing antibodies. This finding calls into question over-reliance on commercially available antibody binding assays as surrogates of serologic immunoprotection. Sixth, we used a technically simple, rapid test of cellular responses to SARS-CoV-2 -TruCulture assay -and showed its utility even in patients with suppressed humoral immunity.

Because TruCulture is a relatively new assay that has only been used in a few published studies, 53 we corroborated TruCulture results with a conventional but more technically demanding ELISpot in a subset of patients. The two tests were largely concordant, though slightly better for for IFNγ responses -less than 25% of patients had discordant results by the two assays. Specificity of TruCulture merits further investigation. We identified a group of 14 out of 130 (11%) patients who were positive on TruCulture, but serologically negative by MBI. These TruCulture-positive, seronegative patients may represent false positives (possibly due to cross-reaction with other coronaviruses), or true-positives, with absent antibody titers during convalescence, 42 or 'aborted infection' in which antibody responses fail to develop in the first place. 54 Limitations of our study include the lack of SARS-CoV-2 PCR confirmation for all of our patients, especially those infected during the first wave, in which 80% of patients were not PCR-confirmed. 55 Our inclusion criteria, though intentionally broad, precluded older, systemically immunocompromised, severely disabled patients from participation. Patients who were lost due to fatal COVID-19 infection could not be . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. ; https://doi.org/10.1101/2022.01.10.22268752 doi: medRxiv preprint accounted for in our study. Our patients largely reflect the mild range within the spectrum of SARS-CoV-2, as evidenced by the fact that only 7% of our symptomatic cases were hospitalized as compared to the average hospitalization rate of 16% across MS studies 56 . Our findings may not be generalizable to older and more disabled patients, who account for the bulk of excess morbidity and mortality in MS. 57 The main conclusion of our study is that relatively young and otherwise healthy MS patients generally had favorable clinical course across DMTs despite markedly impaired adaptive immune responses associated with some of the DMTs (aCD20, S1P). To better understand the uncoupling of T-cell from antibody responses in aCD20 treated patients and to identify predictors of immune response in patients on the different DMTs, we are conducting in-depth immunophenotyping and activation-induced marker studies.

Race/ethnicity did not predict either clinical or immunologic outcomes.

Acknowledgments: The authors wish to gratefully acknowledge our medical assistants, Ms. Apphia Daniel, Ms. Teodora Drakulovic, Ms. Rosetta Ellis, for their gentle bedside manner and great phlebotomy skills.

We are grateful to all of our colleagues who assisted us with patient recruitment and provided feedback on our study and to all the patients who participated in this study.

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The copyright holder for this preprint this version posted January 10, 2022. Neutralizing antibody titers are shown as log10 of half-maximal inhibitory dilution (ID50).

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The copyright holder for this preprint this version posted January 10, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. ; modulators; SD -standard deviation Q1 (quartile 1) and Q3 (quartile 3) represent median of the lower and upper half of the data.

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The copyright holder for this preprint this version posted January 10, 2022. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 10, 2022. .

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The copyright holder for this preprint this version posted January 10, 2022. 

Median (Q1, Q3) 1. Comorbidities included: hypertension, chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus, obesity, sickle cell disease, chronic kidney disease, chronic liver disease, and cancer (non-skin cancers only).

b COVID-relevant comorbidities: hypertension, chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus, obesity, sickle cell disease, chronic kidney disease, chronic liver disease and (non-skin) cancer.

Abbreviations: DMT, disease-modifying therapy; GA, glatiramer acetate; NAT, natalizumab; OCR, ocrelizumab; S1P, sphingosine 1phosphate receptor modulators.

.

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National Study Group for C-V. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants

Omicron-specific cytotoxic T-cell responses are boosted following a third dose of mRNA COVID-19 vaccine in anti-CD20-treated multiple sclerosis patients

Outcomes and risk factors associated with SARS-CoV-2 infection in a North American registry of patients with multiple sclerosis

Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions

Real-World Lab Data in Natalizumab treated multiple sclerosis patients up to 6 years long-term follow up

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States

Increased risk of death from COVID-19 in multiple sclerosis: a pooled analysis of observational studies

COVID-19 severity in multiple sclerosis: putting data into context