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

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Abstract

The objective of this study was to determine the impact of multiple sclerosis (MS) disease‐modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection.

Methods

Patients with MS aged 18 to 60 years were evaluated for anti‐nucleocapsid and anti‐Spike receptor‐binding domain (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 enzyme‐linked immunosorbent assay (ELISA); and IL‐2 and IFNγ 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 January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non‐White). Most common DMTs were ocrelizumab (OCR)—40%; natalizumab —17%, Sphingosine 1‐phosphate receptor (S1P) modulators −12%; and 15% untreated. One hundred seventy‐seven patients (46%) had laboratory evidence of SARS‐CoV‐2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups ( p  ≤0.0001). T‐cell responses (IFNγ) 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. Coronavirus disease 2019 (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 nondisabled group of patients with MS. ANN NEUROL 2022;91:782–795

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  1. SciScore for 10.1101/2022.01.10.22268752: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Values ≥1.0 U/mL were interpreted as ‘positive’ for anti-N SARS-CoV-2 antibodies.
    anti-N SARS-CoV-2
    suggested: None
    The levels of antibodies were expressed in U/mL, which are considered equivalent to Binding Antibody Units (BAU)/mL (Elecsys S Units = 0.972 x BAU), as defined by the first World Health Organization (WHO) International Standard for anti-SARS-CoV-2 immunoglobulin (NIBSC code 20/136).32 2.
    anti-SARS-CoV-2 immunoglobulin
    suggested: None
    NYU proprietary custom Multiepitope Bead-based Immunoassay (MBI), which measures antibody responses to three recombinant proteins (Wuhan variant total Spike, RBD and the S amino-terminal domain (NTD); Sino Biological cat no. 40590-V08B, 40592-V08B, 40591-V49H-B, respectively), using control analytes of Human serum albumin (HSA), tetanus toxoid and anti-human IgG (Jackson Immunoresearch Inc.) coupled to commercial paramagnetic beads (MagPix, Luminex), as adapted from the manufacturer’s instructions as previously described.
    anti-human IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    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.
    Vero E6
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).


    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    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 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.

    Results from TrialIdentifier: No clinical trial numbers were referenced.


    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.


    Results from JetFighter: We did not find any issues relating to colormaps.


    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.


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