Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations

König, Marton; Lorentzen, Åslaug R.; Torgauten, Hilde Marie; Tran, The Trung; Schikora-Rustad, Stine; Vaage, Eline Benno; Mygland, Åse; Wergeland, Stig; Aarseth, Jan Harald; Aaberge, Ingeborg; Torkildsen, Øivind; Holmøy, Trygve; Berge, Tone; Myhr, Kjell–Morten; Harbo, Hanne F.; Andersen, Jan Terje; Munthe, Ludvig A.; Søraas, Arne; Celius, Elisabeth Gulowsen; Vaage, John Torgils; Lund‐Johansen, Fridtjof; Nygaard, Gro Owren

doi:10.1136/jnnp-2021-327612

Cited by 50 publications

(58 citation statements)

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“… 21 We defined antibody concentrations higher than the second percentile of those from healthy individuals vaccinated with two doses, corresponding to concentrations of 70 AU/mL or more, as response. 22 Concentrations of less than 5 AU/mL were defined as no response and concentrations of 5–69 AU/mL were defined as weak response. Calibration to the WHO international standard showed that 70 AU/mL corresponds to approximately 40 binding antibody units per mL.…”

Section: Methodsmentioning

confidence: 99%

Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

Jyssum¹,

Kared²,

Tran³

et al. 2022

The Lancet Rheumatology

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Background In rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap. Methods This prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2–4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7–10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov , NCT04798625 , and is ongoing. Findings Between Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222–324] in responders vs 107 days [80–152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4 + T-cell responses and 14 (74%) had CD8 + T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4 + and CD8 + T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths. Interpretation This study provides important insight into the divergent humoral an...

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Section: Methodsmentioning

confidence: 99%

Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

Jyssum¹,

Kared²,

Tran³

et al. 2022

The Lancet Rheumatology

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140

124

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“…Pooled very-low-certainty evidence (Supplementary Figure 9) suggests lower odds of anti-S1 seroconversion among pwMS on ALEM compared to UX people (OR [95%CI]: 0.32 [0.10, 0.96], P=0.04). One study assessed anti-S seroconversion, but its data could not be extracted 30 . PwMS on ALEM in three studies 16,25,28 showed 100% seroconversion rates similar to the UX people in two of them 16,25 , and none of the studies suggested lower concentrations of post-vaccination antibodies among them – not even the study that indicated lower odds of seroconversion 26 .…”

Section: Resultsmentioning

confidence: 99%

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Etemadifar

Nouri

Pitzalis

et al. 2022

Preprint

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Importance: An evidence-based appraisal of the COVID-19 vaccination policies among people with multiple sclerosis (pwMS) with respect to disease-modifying therapies (DMT) is important for our understandings and their further management. Objective: To synthesize the available evidence concerning the effect of DMTs on COVID-19 vaccination immunogenicity and effectiveness. Data Sources: We searched MEDLINE, Scopus, Web of Science, MedRxiv, and Google Scholar from January 2021 until January 2022. Study Selection: The exclusion criteria included: not a primary investigation; retracted/withdrawn; no eligible participants - people with no history/evidence of previous COVID-19 and corticosteroid administration within two months of vaccination; no eligible exposures - all nine DMT classes; and no eligible comparators - DMT-unexposed at the time of vaccination. Data Extraction and Synthesis: Entries were assessed independently by two reviewers for eligibility and quality. Dichotomized data was extracted by two reviewers in accordance with Cochrane guidelines, and were pooled using either Peto fixed-effects or Inverse-variance random-effects methods. Main Outcomes and Measures: Main outcomes were i) B-cell response, measured by seroconversion odds ratio (OR); ii) T-cell response, measured by interferon-gamma release response OR, and CD4+/CD8+ activation-induced marker+ OR. Further outcomes including immunity waning speed and breakthrough COVID-19 incidence/severity were synthesized narratively. Results: Data from 28 studies (5,025 pwMS and 1,635 healthy participants) after COVID-19 vaccination suggests mildly-lower B-cell responses in teriflunomide- and alemtuzumab-treated, extensively-lower B-cell responses in sphingosine-1-phosphate receptor modulator (S1PRM)- and anti-CD20 (aCD20)-treated, and lower T-cell responses in interferon-, S1PRM-, alemtuzumab- and cladribine-treated pwMS. Every ten-week increase in aCD20-to-vaccine period is associated with a 1.94-time (95%CI: 1.57, 2.41, P<0.00001) increase in odds of seroconversion. B-cell-depleting therapies seem to accelerate post-vaccination humoral waning, and booster immunogenicity is predictable with the same factors affecting the priming vaccination. Furthermore, comparatively-increased breakthrough COVID-19 incidence and severity is being observed only among S1PRM- and anti-CD20-treated pwMS - i.e., among the pwMS with extensively-blunted B-cell response, despite adequate T-cell responses in the aCD20-treated. To date, pwMS on only-T-cell-blunting DMTs have not shown increased susceptibility to breakthrough COVID-19. Conclusion and Relevance: The implemented vaccination strategy to date has been effective for pwMS on all DMTs other than S1PRM and aCD20. As B-cell immunity seems to be a more important predictor of vaccine effectiveness than T-cell immunity, optimization of humoral immunogenicity and ensuring its durability among pwMS on DMTs are the necessities of an effective COVID-19 vaccination policy.

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“…20,22,23 Understanding the impact of DMTs on the immune response to SARS-CoV-2 infection is critical for counseling patients with MS 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; and (3) investigating the relationship between the clinical severity of COVID-19 and immune responses to SARS-CoV-2 in patients with MS with different DMTs. We recruited a large, ethnically diverse group of patients with MS from the New York University Multiple Sclerosis Care Center in New York City, New York, one of the epicenters of the COVID-19 pandemic in 2020 to 2021, 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.…”

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confidence: 99%

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

Kister

Patskovsky

Curtin

et al. 2022

Annals of Neurology

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Objective 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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Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations

Cited by 50 publications

References 16 publications

Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

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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