{
  "abstract": "Introduction People with multiple sclerosis (pwMS) receiving B-cell depleting disease-modifying therapy (BCD-DMT) are vulnerable to severe COVID-19. Data on vaccine immunogenicity in this patient group are incomplete. In the context of the rapid evolution of SARS-CoV-2 2020–22, we compared vaccine responses in pwMS and healthy vaccinated adults (HVA) after three doses of messenger RNA vaccine encoding Ancestral SARS-CoV-2 Spike.Methods In this prospective observational cohort study, we collected serum from 226 pwMS prevaccine and postvaccine and quantified neutralising antibody titres (nAbT) in a high-throughput live virus assay against SARS-CoV-2 Ancestral, Alpha, Delta, Omicron BA.1, BA.2 and BA.5. We compared nAbT in pwMS and HVA, matched by age, sex, vaccine type, number of doses and time since exposure, using Wilcoxon signed-rank and χ 2 tests. We further investigated nAbT vaccine response in pwMS on BCD-DMTs or non-depleting DMTs.Results Prior to third vaccination, nAbTs against nearly all variants tested were significantly lower (p<0.05) in pwMS taking BCD therapy than those in HVA or B-cell replete pwMS, and were not significantly boosted following vaccination. In contrast, B-cell replete pwMS versus HVAs exhibited equivalent prevaccination nAbTs against all variants, which were comparably boosted against most variants following vaccination. Consequently, differences in nAbTs against all variants tested were further magnified between B-cell replete and B-cell depleted pwMS post-third vaccination. Across the entire cohort, there were no COVID-19 hospitalisations or deaths. Notably, sera collected prior to the pandemic from pwMS demonstrated pre-existing, pan-coronavirus neutralising activity against seasonal HCoV-OC43 and SARS-CoV-2 variants.Conclusions PwMS taking BCD therapy have limited antibody boosting following repeated COVID-19 vaccination. However, the absence of severe outcomes in pwMS, despite reduced immunogenicity, suggests a lower threshold for effective protection than previously reported. These findings support more nuanced risk stratification in clinical policy.",
  "authors": [
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, UCLH, London, UK"
      ],
      "name": "Marianne J Shawe-Taylor"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK"
      ],
      "name": "David Greenwood"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK",
        "Department of Neuroscience, Monash University, Melbourne, Victoria, Australia"
      ],
      "name": "Anna He"
    },
    {
      "affiliations": [
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK"
      ],
      "name": "Agnieszka Hobbs"
    },
    {
      "affiliations": [
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK"
      ],
      "name": "Giulia Dowgier"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK"
      ],
      "name": "Rebecca Penn"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK"
      ],
      "name": "Theo Sanderson"
    },
    {
      "affiliations": [
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK"
      ],
      "name": "Phoebe Stevenson-Leggett"
    },
    {
      "affiliations": [
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK"
      ],
      "name": "James Bazire"
    },
    {
      "affiliations": [
        "Worldwide Influenza Centre, The Francis Crick Institute, London, UK"
      ],
      "name": "Ruth Harvey"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Dimitrios Champsas"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK"
      ],
      "name": "Suraiya Sharmin"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Anuriti Aojula"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Alessia Bianchi"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Sarmad Al-Araji"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Yael Hacohen"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Charmaine Yam"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Suraya Mohamud"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Ronja Christensen"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK"
      ],
      "name": "Marcello Moccia"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, UCLH, London, UK",
        "National Hospital for Neurology and Neurosurgery, London, UK",
        "Department of Neuroscience, Monash University, Melbourne, Victoria, Australia",
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK",
        "Worldwide Influenza Centre, The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK",
        "Department of Infectious Disease, St Mary’s Hospital, London, UK",
        "UCL, London, UK",
        "University College London Cancer Institute, London, UK",
        "Genotype-to-Phenotype 2 Consortium, The Francis Crick Institute, London, UK",
        "Neurology and Neuroscience Biomedical Research Centre, UCL, London, UK"
      ],
      "name": "Crick COVID Serology Pipeline"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, UCLH, London, UK",
        "National Hospital for Neurology and Neurosurgery, London, UK",
        "Department of Neuroscience, Monash University, Melbourne, Victoria, Australia",
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK",
        "Worldwide Influenza Centre, The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK",
        "Department of Infectious Disease, St Mary’s Hospital, London, UK",
        "UCL, London, UK",
        "University College London Cancer Institute, London, UK",
        "Genotype-to-Phenotype 2 Consortium, The Francis Crick Institute, London, UK",
        "Neurology and Neuroscience Biomedical Research Centre, UCL, London, UK"
      ],
      "name": "Legacy Investigators"
    },
    {
      "affiliations": [
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK"
      ],
      "name": "Vincenzo Libri"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "Department of Infectious Disease, St Mary’s Hospital, London, UK"
      ],
      "name": "George Kassiotis"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK"
      ],
      "name": "Steve Gamblin"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "Worldwide Influenza Centre, The Francis Crick Institute, London, UK"
      ],
      "name": "Nicola Lewis"
    },
    {
      "affiliations": [
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, UCLH, London, UK",
        "UCL, London, UK"
      ],
      "name": "Bryan Williams"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "University College London Cancer Institute, London, UK"
      ],
      "name": "Charles Swanton"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "UCL, London, UK"
      ],
      "name": "Sonia Gandhi"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "Genotype-to-Phenotype 2 Consortium, The Francis Crick Institute, London, UK"
      ],
      "name": "David Bauer"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "COVID Surveillance Unit, The Francis Crick Institute, London, UK"
      ],
      "name": "Mary Wu"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "UCL, London, UK"
      ],
      "name": "Edward Carr"
    },
    {
      "affiliations": [
        "The Francis Crick Institute, London, UK",
        "National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and NIHR UCLH Clinical Research Facility, UCLH, London, UK"
      ],
      "name": "Emma Wall"
    },
    {
      "affiliations": [
        "National Hospital for Neurology and Neurosurgery, London, UK",
        "Neurology and Neuroscience Biomedical Research Centre, UCL, London, UK"
      ],
      "name": "Olga Ciccarelli"
    }
  ],
  "title": "Immunogenicity of three-dose COVID-19 vaccines in people living with multiple sclerosis",
  "uid": "43e5ae42-941f-539b-9755-07fe0a368110"
}