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The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

  • David Baker
    Affiliations
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT; United Kingdom
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  • Sandra Amor
    Correspondence
    Corresponding author at: PhD, Neuropathology, Dept Pathology, Amsterdam UMC Locatie VUmc, ZH 2E 49, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
    Affiliations
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT; United Kingdom

    Pathology Department, VUmc, Amsterdam UMC, Amsterdam, The Netherlands
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  • Angray S. Kang
    Affiliations
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT; United Kingdom

    Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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  • Klaus Schmierer
    Affiliations
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT; United Kingdom

    Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
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  • Gavin Giovannoni
    Affiliations
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT; United Kingdom

    Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
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      Highlights

      • COVID-19 is a pandemic, sometimes fatal disease caused by the SARS-Cov-2 coronavirus.
      • Disease modifying treatments are a perceived risk factor for COVID-19.
      • Immunity eliminates the virus, but in some individuals it causes severe morbidity.
      • The essential immune elements to control MS and the virus may not be the same.
      • Understanding COVID-19 pathobiology and the mechanism of drug action in multiple sclerosis, will help inform choices for treatment

      Abstract

      Background

      SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS.

      Objective

      To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis.

      Observations

      Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS.

      Implications

      In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.

      Abbreviations:

      ACE2 (angiotensin converting enzyme two), ARDS (acute respiratory distress syndrome), ASC (antibody secreting cells), CNS (central nervous system), DMT (disease modifying therapies), (HSCT) (haematopoietic stem cell therapy), IRT (immune reconstitution therapies), MS (multiple sclerosis), RBD (receptor binding domain), RNA (ribonucleic acid), SARS (Severe acute respiratory syndrome)

      1. SARS-Cov-2 and COVID-19 a new pandemic

      COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) infection (
      • Zhu N
      • Zhang D
      • Wang W
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      China Novel Coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in China, 2019.
      a;
      • Zhou P
      • Yang XL
      • Wang XG
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ). About 80% of people infected with SARS-CoV-2 develop a self-limiting illness, 20% require hospitalisation, largely due to cardiovascular issues and about 5% require critical care and potential ventilatory support (
      • Kimball A
      • Hatfield KM
      • Arons M
      • et al.
      Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility - King County, Washington, March 2020.
      ;
      • Day M
      Covid-19: four fifths of cases are asymptomatic, China figures indicate.
      ). The mortality in those requiring ventilatory support is about 40–50% (
      • Weiss P
      • Murdoch DR.
      Clinical course andmortality risk of severe COVID-19.
      ;
      • Zhu J
      • Ji P
      • Pang J
      • Zhong Z
      • et al.
      Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis.
      b). Death from COVID-19 is associated with older age and comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (
      • Zhu N
      • Zhang D
      • Wang W
      • et al.
      China Novel Coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in China, 2019.
      a;
      • Lippi G
      • Mattiuzzi C
      • Sanchis-Gomar F
      • et al.
      Clinical and demographic characteristics of patients dying from COVID-19 in Italy versus China.
      ;
      • Richardson S
      • Hirsch JS
      • Narasimhan M
      • et al.
      Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
      ). Mortality in young people and those without comorbidities may be related to excessive viral load (
      • Liu Y
      • Liao W
      • Wan L
      • et al.
      Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19.
      a;
      • Chen W
      • Lan Y
      • Yuan X
      • et al.
      Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity.
      a). Whilst the typical clinical features requiring self-isolation, and potentially hospitalization are fever, dry cough and shortness of breath related to respiratory tract infection, other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (
      • Zhu J
      • Ji P
      • Pang J
      • Zhong Z
      • et al.
      Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis.
      b;
      • Richardson S
      • Hirsch JS
      • Narasimhan M
      • et al.
      Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
      ;
      • Huang L
      • Zhang X
      • Zhang X
      • et al.
      Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.
      ). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develop and resolve, often for more than 7 days after symptom onset (
      • Lauer SA
      • Grantz KH
      • Bi Q
      • et al.
      The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application.
      ;
      • Xu Y
      • Li X
      • Zhu B
      • Liang H
      • et al.
      Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding.
      a;
      • He X
      • Lau EHY
      • Wu P
      • et al.
      Temporal dynamics in viral shedding and transmissibility of COVID-19. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16–23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.
      a).
      SARS-CoV-2 is a betacoronavirus closely-related to virus that caused the SARS outbreak in 2002-2004 (
      • Zhou P
      • Yang XL
      • Wang XG
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ). The viral ribonucleic acid (RNA) is bound by the nucleocapsid protein and is encapsulated in a host cell membrane-derived lipid envelope containing the viral spike, envelope and membrane proteins (
      • Chen Y
      • Liu Q
      • Guo D
      Emerging coronaviruses: Genome structure, replication, and pathogenesis.
      b,
      • Lu R
      • Zhao X
      • Li J
      • et al.
      Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
      ). The spike protein contains the receptor binding domain (RBD), which is important for binding to the angiotensin converting enzyme two (ACE2) cell receptor, and thus key to the cellular target, host range and viral infection (
      • Zhou P
      • Yang XL
      • Wang XG
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ;
      • Ou X
      • Liu Y
      • Lei X
      • et al.
      Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.
      ;
      • Shi J
      • Wen Z
      • Zhong G
      • et al.
      Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2.
      . Fig. 1). Viral ACE2 binding is facilitated by host cell, serine proteases such as TMPRSS2 necessary to prime the spike protein (
      • Hoffmann M
      • Kleine-Weber H
      • et al.
      SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
      ;
      • Tai W
      • He L
      • Zhang X
      • et al.
      Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine.
      ). The ACE2 receptor is expressed on the vasculature and is present in many tissues, such as the kidney, gut, cardiomyocytes and lung epithelia (
      • Hamming I
      • Timens W
      • Bulthuis ML
      • et al.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ;
      • Lukassen S
      • Chua RL
      • Trefzer T
      • et al.
      SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.
      ). There is very low expression of ACE2 on immune cells, but other co-receptors, including: CD147, proteases and probably lectins, based on similarities with the SARS-CoV virus, may be important in SARS-CoV-2 entry (
      • Letko M
      • Marzi A
      • Munster V
      Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.
      ;
      • Yang ZY
      • Huang Y
      • Ganesh L
      • et al.
      pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN.
      ;
      • Wang K
      • Chen W
      • Zhou YS
      • et al.
      SARS-CoV-2 invades host cells via a novel route: CD147-spike protein.
      a;
      • Gramberg T
      • Hofmann H
      • Möller P
      • et al.
      LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus.
      ).
      Fig 1
      Fig. 1The protective and destructive immune response against the SARS-CoV-2 virus.
      Immune cells target the SARS-CoV-2 virus that initially involves the innate immune response, which is then supplemented with anti-viral cytotoxic T cell responses and neutralizing and binding antibodies.

      2. Multiple sclerosis in the COVID-19 era

      The immune system provides vital defence against viral infections. This has led to concern for people taking immunosuppressive agents, as immune compromised people are particularly vulnerable to infection (

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      ;
      • Willis MD
      • Robertson NP.
      Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2.
      ;
      • Luna G
      • Alping P
      • Burman
      • et al.
      Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.
      ). Infections are more common in people taking DMT and are more frequent with the higher efficacy drugs (
      • Willis MD
      • Robertson NP.
      Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2.
      ;
      • Luna G
      • Alping P
      • Burman
      • et al.
      Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.
      ). This is consistent with their more potent immunosuppressive activities. Immunosuppressed people have been advised to self-shield and socially distance themselves to avoid infection and will remain a problem, until herd immunity, anti-viral agents or effective vaccines have been developed (
      • Kwok KO
      • Lai F
      • Wei WI
      • et al.
      Herd immunity - estimating the level required to halt the COVID-19 epidemics in affected countries.
      ;
      • Stein RA
      COVID-19 and rationally layered social distancing.
      ). Multiple sclerosis (MS) is a major neurological disease that causes disability and can require hospitalisation for uncontrolled disease activity (
      • Compston A
      • Coles A
      Multiple sclerosis.
      ). MS is currently managed with immunomodulatory drugs (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ). This has led neurologists to recommend maintaining the status quo or curtailing the use of certain disease modifying treatments (DMT) in a pragmatic or non-pragmatic way (

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      ,
      • Giovannoni G
      • Hawkes C
      • Lechner-Scott J
      • et al.
      The COVID-19 pandemic and the use of MS disease-modifying therapies.
      ;
      • Brownlee W
      • Bourdette D
      • Broadley S
      • et al.
      Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.
      . Table 1). It is understandable that a conservative “primum non nocere” (first do not harm) approach was adopted when considering treatments, given the paucity of knowledge surrounding SARS-CoV2 biology when COVID-19 first emerged. However, it is important to recognize the risks of poorly controlled MS may outweigh the perceived risks from COVID-19 (
      • Giovannoni G
      • Hawkes C
      • Lechner-Scott J
      • et al.
      The COVID-19 pandemic and the use of MS disease-modifying therapies.
      ;
      • Brownlee W
      • Bourdette D
      • Broadley S
      • et al.
      Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.
      ) and an essential goal of MS care must be to limit SARS-CoV-2 infection. Therefore, care must be to prevent disease activation and limit the need for hospitalization that could potentially increase the risk of exposure to SARS-CoV-2. This must be balanced by the requirement of hospitalization for infusion treatments and the level of monitoring that each agent requires, that is particularly arduous with alemtuzumab, but minimal with ocrelizumab and glatiramer acetate (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ).
      Table 1Initial recommendations use of MS-related DMT by some European neurological associations.
      Summary of SIN/ABN Guidelines
      At risk categoryClassTrade NameSafe to start treatmentOn treatmentCOVID-19 infectionMode of action
      LowInterferon-betaBetaferon, Avonex, Rebif, PlegridyYESCONTINUESTOPImmunomodulatory (not immunosuppressive), pleiotropic immune effects
      LowGlatiramer acetateCopaxoneYESCONTINUESTOPImmunomodulatoy (not immunosuppressive), pleiotropic immune effects
      LowTeriflunomideAubagioYESCONTINUESTOPDihydro-orotate dehydrogenase inhibitor (reduced de novo pyrimidine synthesis), anti-proliferative
      LowDimethyl fumarateTecfideraYESCONTINUESTOPPleiotropic, NRF2 activation, downregulation of NFΚβ
      LowNatalizumabTysabriYESCONTINUESTOPAnti-VLA4, selective adhesion molecule inhibitor
      LowS1P modulatorsFingolimod (Gilenya)YESCONTINUESTOPSelective S1P modulator, prevents egress of lymphocytes from lymph nodes
      IntermediateAnti-CD20Ocrelizumab (Ocrevus)NO (YES)SUSPENDDELAYAnti-CD20, B-cell depleter
      High
      risk refers to acquiring infection during the immunodepletion phase. Post immune reconstitution the risk is low. Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (Coles et al. 2020).
      CladribineMavencladNOSUSPENDDELAYDeoxyadenosine (purine) analogue, adenosine deaminase inhibitor, selective T and B cell depletion
      High
      risk refers to acquiring infection during the immunodepletion phase. Post immune reconstitution the risk is low. Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (Coles et al. 2020).
      AlemtuzumabLemtradaNOSUSPENDDELAYAnti-CD52, non-selective immune depleter
      High
      risk refers to acquiring infection during the immunodepletion phase. Post immune reconstitution the risk is low. Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (Coles et al. 2020).
      HSCT-NO-DELAYNon-selective immune depleter
      low asterisk risk refers to acquiring infection during the immunodepletion phase. Post immune reconstitution the risk is low.Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      ).
      It is important that such recommendations about treatment are made on a rational basis using knowledge of the mode of actions of the various agents and their ability to impact on the functioning of the components of the immune system. This is important as there is no evidence that immunosuppressed people are at increased risk to coronavirus infections (
      • D'Antiga L
      Coronaviruses and immunosuppressed patients. The facts during the third epidemic.
      ). Therefore, to understand the risks posed to people with MS using DMT, it is crucial to understand the mechanisms of action, the impact of the treatments on infection-risk, vaccination responses and the mechanisms of pathology and immunity to SARS-CoV-2. Although there are gaps in our knowledge, understanding can be gained from the study of SARS-CoV infection, as well as other coronaviruses and lower respiratory tract infections (
      • Channappanavar R
      • Fett C
      • Zhao J
      • et al.
      Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.
      ;
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ;
      • Rokni M
      • Ghasemi V
      • Tavakoli Z
      Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS.
      ,
      • Sarzi-Puttini P
      • Giorgi V
      • Sirotti S
      • et al.
      COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?.
      ).

      3. Immune response against SARS-CoV-2 virus

      Protection against coronaviruses involves both the innate and adaptive immunity, typical for most viral infections (
      • Yen YT
      • Liao F
      • Hsiao CH
      • et al.
      Modelling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      ;
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ). However, consistent with SARS, some influenza infections and COVID-19, it appears to be the immune response and destruction of virally-infected cells and lung epithelial tissue that cause the acute respiratory distress syndromes (ARDS) and the, sometimes fatal, pneumonia (
      • Chen Y
      • Liu Q
      • Guo D
      Emerging coronaviruses: Genome structure, replication, and pathogenesis.
      b;
      • Zhang Y
      • Gao Y
      • Qiao L
      • et al.
      Inflammatory response cells during acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19).
      a). It appears that the immune response to SARS-CoV-2 occurs in two phases involving an immune and a tissue, often lung, damaging phase.

      3.1 Immune phase

      Following infection there is an asymptomatic period of 4–5 days, although some reports indicate this can be up to 3 weeks (
      • Pung R
      • Chiew CJ
      • Young BE
      • et al.
      Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures.
      ,
      • Lauer SA
      • Grantz KH
      • Bi Q
      • et al.
      The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application.
      ;
      • Lai CC
      • Liu YH
      • Wang CY
      • et al.
      Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths.
      ), during which time the virus attempts to escape immune surveillance through the inhibition of interferon production and blockade of interferon receptor signalling activity, similar to SARS-CoV (
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ;
      • Chu H
      • Chan JF
      • Wang Y
      • et al.
      Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19.
      ;
      • O'Brien TR
      • Thomas DL
      • Jackson SS
      • et al.
      Weak induction of interferon expression by sars-cov-2 supports clinical trials of interferon lambda to treat early COVID-19.
      ). There is an early immune response where the innate and then the adaptive immune response eliminates the virus as seen in non-human primates and by inference in humans (
      • Bao L
      • Deng W
      • Gao H
      • et al.
      Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.
      ;
      • Thevarajan I
      • Nguyen THO
      • Koutsakos M
      • et al.
      Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.
      ). Given that the majority of infections are asymptomatic (
      • Kimball A
      • Hatfield KM
      • Arons M
      • et al.
      Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility - King County, Washington, March 2020.
      ;
      • Day M
      Covid-19: four fifths of cases are asymptomatic, China figures indicate.
      ) indicates that this is a dominant mechanism in most people with COVID-19. In vitro data suggest an early innate response, notably from the alveolar macrophages and/or monocytes that may be recruited from the circulation (
      • Yen YT
      • Liao F
      • Hsiao CH
      • et al.
      Modelling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      ;
      • Thevarajan I
      • Nguyen THO
      • Koutsakos M
      • et al.
      Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.
      ). Histological studies of cancerous lungs of people subsequently positive for COVID19, exhibited significant macrophage activity (
      • Cai Y
      • Hao Z
      • Gao Y
      • et al.
      COVID-19 in the perioperative period of lung resection: a brief report from a single thoracic surgery department in Wuhan.
      ;
      • Tian S
      • Hu W
      • Niu L
      • et al.
      Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer.
      a). Thus, macrophages rather than neutrophils appear to be important as an early defence mechanism in SARS and COVID-19 lesions (
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ;
      • Tian S
      • Hu W
      • Niu L
      • et al.
      Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer.
      a;
      • Cai Y
      • Hao Z
      • Gao Y
      • et al.
      COVID-19 in the perioperative period of lung resection: a brief report from a single thoracic surgery department in Wuhan.
      ). This is probably followed by a CD8 cytotoxic T cell response that is generated within days of infection (
      • Channappanavar R
      • Fett C
      • Zhao J
      • et al.
      Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.
      ;
      • Prompetchara E
      • Ketloy C
      • Palaga T
      Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic.
      ;
      • Thevarajan I
      • Nguyen THO
      • Koutsakos M
      • et al.
      Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.
      ).
      SARS-CoV-2 may be eliminated before significant blood antibody titres are generated as seen in non-human primate infections and case reports (Fig.2.
      • Thevarajan I
      • Nguyen THO
      • Koutsakos M
      • et al.
      Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19.
      ;
      • Bao L
      • Deng W
      • Gao H
      • et al.
      Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.
      ;
      • Soresina A
      • Moratto D
      • Chiarini M
      • et al.
      Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
      ). These antibody responses are generated around 12 days (IgM) and 14 days (IgG), although this is earlier in some individuals (Zhoa et al. 2020;

      Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease 2019 patients. Emerg Infect Dis.2020;26(7). doi: 10.3201/eid2607.200841. [Epub].

      ;
      • Xiang F
      • Wang X
      • He X
      • et al.
      Antibody Detection and Dynamic Characteristics in Patients with COVID-19.
      ). Antibodies are predominantly generated against the nucleocapsid and spike proteins (

      Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease 2019 patients. Emerg Infect Dis.2020;26(7). doi: 10.3201/eid2607.200841. [Epub].

      ;

      de Assis RR, Jain A, Nakajima R, Jasinskas A, et al. Analysis of SARS-CoV-2 Antibodies in COVID-19 convalescent plasma using a coronavirus antigen microarray. BioRχiv doi: 10.1101/2020.04.15.043364.

      ). Antibodies against the RBD of the spike protein are clearly neutralizing, are able to prevent infection (

      Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease 2019 patients. Emerg Infect Dis.2020;26(7). doi: 10.3201/eid2607.200841. [Epub].

      ;
      • Tai W
      • He L
      • Zhang X
      • et al.
      Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine.
      ;
      • Tian X
      • Li C
      • Huang A
      • et al.
      Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody.
      b). These appear to be protective, as evidenced by the use of convalescent sera to protect against severe COVID-19 (
      • Duan K
      • Liu B
      • Li C
      • et al.
      Effectiveness of convalescent plasma therapy in severe COVID-19 patients.
      ;
      • Pei S
      • Yuan X
      • Zhang Z
      • et al.
      Convalescent plasma to treat covid-19: Chinese strategy and experiences.
      ;
      • Shen C
      • Wang Z
      • Zhao F
      • et al.
      Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma.
      ). People with X-linked agammaglobulinemia have been infected and survived COVID-19 (
      • Soresina A
      • Moratto D
      • Chiarini M
      • et al.
      Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
      ). This further suggests that B cells and immunoglobulin may not be an obligate immune element required for protection against SARS-CoV-2 infection. Although CD8 T cells are important in viral immunity, antibodies will however, be an essential for the vaccination response to prevent primary infection and reinfection. Most infected subjects will develop an immunoglobulin anti-viral response within 1 month (
      • Zhao J
      • Yuan Q
      • Wang H
      • et al.
      Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.
      ,

      Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease 2019 patients. Emerg Infect Dis.2020;26(7). doi: 10.3201/eid2607.200841. [Epub].

      ;

      de Assis RR, Jain A, Nakajima R, Jasinskas A, et al. Analysis of SARS-CoV-2 Antibodies in COVID-19 convalescent plasma using a coronavirus antigen microarray. BioRχiv doi: 10.1101/2020.04.15.043364.

      ). This appears to prevent re-infection as shown in non-human primates (
      • Bao L
      • Deng W
      • Gao H
      • et al.
      Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.
      . Fig. 2). However, immunity may not be completely protective since people with COVID-19 can rarely present with SARS-CoV-2 re-activation (
      • Ye G
      • Pan Z
      • Pan Y
      • et al.
      Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation.
      a;
      • Chen D
      • Xu W
      • Lei Z
      • Huang Z
      • et al.
      Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report.
      c). However, as the virus may persist in many sites and may not be eliminated at the same rates (
      • Chen Y
      • Chen L
      • Deng Q
      • et al.
      The Presence of SARS-CoV-2 RNA in Feces of COVID-19 Patients.
      d). This may in part explain why viral RNA is detected in faeces when nasopharyngeal swabs become negative (
      • Chen Y
      • Chen L
      • Deng Q
      • et al.
      The Presence of SARS-CoV-2 RNA in Feces of COVID-19 Patients.
      d). There are clearly viral variants (
      • Forster P
      • Forster L
      • Renfrew C
      • Forster M
      Phylogenetic network analysis of SARS-CoV-2 genomes.
      ;
      • Yao H
      • Lu X
      • Chen Q
      • et al.
      Patient-derived mutations impact pathogenicity of SARS-CoV2.
      a) and may be important as vaccines will need to target disease-causing pathogenic variants. This data suggests that immunosuppression of macrophage function and probably CD8 activity may limit anti-viral protection, while blunting or inhibition of antibody formation may limit immunity to reinfection.
      Fig 2
      Fig. 2Removal of the SARS-CoV-2 virus occurs before a significant anti-viral antibody response is generated. Rhesus macaques were infected with coronavirus and the viral titre was assessed using nasal swabs. Animals were re-infected one month later. The results show the responses of two individual (blue and orange) monkeys, as seen in two additional monkeys, relating to viral titre and anti-viral antibody response. A.U. arbitrary units. Adapted from
      • Bao L
      • Deng W
      • Gao H
      • et al.
      Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.
      . DoI.org/10.1101/2020.03.13.990226

      3.2 Destructive phase

      Although most people appear to tolerate COVID-19 a significant number of people experience respiratory distress (
      • Chen G
      • Wu D
      • Guo W
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      e;
      • Zhu J
      • Ji P
      • Pang J
      • Zhong Z
      • et al.
      Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis.
      b). It has also been suggested that abnormal coagulation, pulmonary embolism, and endothelial dysfunction are other pathologies of severe COVID-19, which could in part be related to virus and inflammation-induced oxidative stress (
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • et al.
      Pulmonary and cardiac pathology in COVID-19: the first autopsy series from New Orleans.
      ;
      • Poor HD
      • Ventetuolo CE
      • Tolbert T
      • et al.
      critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis.
      ). However, severe disease is associated with peripheral blood neutrophilia and notably lymphopenia (
      • Chen G
      • Wu D
      • Guo W
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      e,
      • Liu Z
      • Long W
      • Tu M
      • et al.
      Lymphocyte subset (CD4+, CD8+) counts reflect the severity of infection and predict the clinical outcomes in patients with COVID-19.
      b,
      • Wang D
      • Hu B
      • Hu C
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      b), where viral load relates to the severity of lymphopenia (
      • Liu Y
      • Liao W
      • Wan L
      • et al.
      Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19.
      c). The lymphopenia could relate to sequestration of cells into the infected tissues as part of the anti-viral response. Post-mortem histology demonstrates significant mononuclear infiltration into the lung and often, but not always, a paucity of natural killer cells and neutrophils, unless associated with secondary infection (
      • Xu Z
      • Shi L
      • Wang Y
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      b;
      • Fox SE
      • Akmatbekov A
      • Harbert JL
      • et al.
      Pulmonary and cardiac pathology in COVID-19: the first autopsy series from New Orleans.
      ;
      • Yao XH
      • Li TY
      • He ZC
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      b;
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ; Aurelio Sonzogni et al. 2020). There is a paucity of B cells and perhaps of relevance is that the lymphocytes are predominantly CD4 T cells (
      • Xu Z
      • Shi L
      • Wang Y
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Yao XH
      • Li TY
      • He ZC
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      b). Low peripheral blood CD8 T cell numbers are a poor prognostic feature (
      • Du RH
      • Liang LR
      • Yang CQ
      • et al.
      Predictors of mortality for patients with COVID-19 Pneumonia caused by SARS-CoV-2: a prospective cohort study.
      ) consistent with a common feature of the COVID-19 lung pathology, where there is a paucity of CD8 T cells (
      • Xu Z
      • Shi L
      • Wang Y
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Yao XH
      • Li TY
      • He ZC
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      b;
      • Zhang T
      • Sun LX
      • Feng RE
      Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019].
      b). This may reflect senescence and exhaustion of the anti-viral CD8 response (
      • Zheng M
      • Gao Y
      • Wang G
      • et al.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ;
      • Cossarizza A
      • De Biasi S
      • Guaraldi G
      • et al.
      Modena COVID-19 working group (moco19)#. Sars-cov-2, the virus that causes COVID-19: cytometry and the new challenge for global health.
      ). Whether this contributes to severe disease and fatality remains to be established. However, this would be consistent with age being a major poor prognostic feature (
      • Huang L
      • Zhang X
      • Zhang X
      • et al.
      Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.
      ). It appears that T cells can be infected via CD147 (
      • Wang X
      • Xu W
      • Hu G
      • et al.
      SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion.
      c). In addition, infection and expression of envelope protein and Open Reading Frame protein sequestration that has been shown to have an apoptotic effect at least after SARS-CoV infection (
      • Yang Y
      • Xiong Z
      • Zhang S
      • et al.
      Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors.
      ). This may play a role in the lymphopenia and immune suppression of the anti-viral response. There is marked atrophy of lymphoid tissues that may contribute to the lymphopenic state (
      • Chen Y
      • Feng X
      • Diao B
      • et al.
      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes.
      f;
      • Zhang T
      • Sun LX
      • Feng RE
      Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019].
      b,
      • Yao XH
      • Li TY
      • He ZC
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      b). Macrophages may also become infected and can take-up the virus due to expression of CD147, lectins and Toll-like receptors known to recognize SARS-CoV pathogen associated molecular pattern recognition elements such as single stranded viral RNA or uptake of viral antibody complexes (
      • Wang K
      • Chen W
      • Zhou YS
      • et al.
      SARS-CoV-2 invades host cells via a novel route: CD147-spike protein.
      a;
      • Yang ZY
      • Huang Y
      • Ganesh L
      • et al.
      pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN.
      ;
      • Li Y
      • Chen M
      • Cao H
      • et al.
      Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response.
      ;
      • Iwasaki A
      • Yang Y.
      The potential danger of suboptimal antibody responses in COVID-19.
      ). Macrophage activity may contribute to the lymphopenia (
      • Chen Y
      • Feng X
      • Diao B
      • et al.
      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes.
      f). Macrophage derived cytokines are produced, which lead to cytokines storms associated with worse prognosis (
      • Chen D
      • Xu W
      • Lei Z
      • Huang Z
      • et al.
      Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report.
      c;
      • Herold T
      • Jurinovic V
      • Arnreich C
      • et al.
      Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients.
      ;

      Wen W, Su W, Tang H, et al. immune cell profiling of covid-19 patients in the recovery stage by single-cell sequencing. medRxiv. doi: 10.1101/2020.03.23.20039362.

      ;
      • Wilk AJ
      • Rustagi A
      • Zhoa NQ
      • et al.
      A single cell atlas of the peripheral immune response to severe COVID-10.
      ). Therefore, agents such as IL-6 receptor and IL-1 blockers used in rheumatoid arthritis, and the case of IL-6R off-label in neuromyelitis optica, are being used to limit severe COVID-19 (
      • Luo P
      • Liu Y
      • Qiu L
      • et al.
      Tocilizumab treatment in COVID-19: A single center experience.
      ). Plasma cell-supporting cytokines such as TNFSF13 may be associated with recovery (

      Wen W, Su W, Tang H, et al. immune cell profiling of covid-19 patients in the recovery stage by single-cell sequencing. medRxiv. doi: 10.1101/2020.03.23.20039362.

      ), however, the antibody response may contribute to macrophage hyper-activation. As such, severe disease is associated with the highest titres of antibodies (
      • Liu L
      • Wei Q
      • Lin Q
      • et al.
      Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection.
      ;
      • Zhao J
      • Yuan Q
      • Wang H
      • et al.
      Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.
      ) and antibody-dependent enhancement of disease may occur (
      • Iwasaki A
      • Yang Y.
      The potential danger of suboptimal antibody responses in COVID-19.
      ). There is complement activation, vascular damage and microthrombi that develop, indicative of damage consistent with oxidative stress, IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils (
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ;
      • Zhang T
      • Sun LX
      • Feng RE
      Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019].
      b). Interestingly, it has been shown that spike-specific antibody may promote IL-8 and CCL2 production that skews macrophage accumulation towards a destructive phenotype (
      • Liu L
      • Wei Q
      • Lin Q
      • et al.
      Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection.
      ). As such in other lower respiratory tract infections antibodies can sometimes have destructive potential (
      • Kim HW
      • Canchola JG
      • Brandt CD
      • et al.
      Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine.
      ), therefore immunomodulation during periods of lung damage may offer some benefit.

      4. Mechanisms driving multiple sclerosis may be distinct from COVID-19 protection and pathogenesis

      Although it is widely considered that CD4, TH17 T cells are the central mediators of MS (
      • Kunkl M
      • Frascolla S
      • Amormino C
      • et al.
      T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis.
      ), all active DMT inhibit memory B cell activity in a hierarchical fashion that reflects their therapeutic activity (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      , Baker et al. 2017,
      • Baker D
      • Pryce G
      • Amor S
      • et al.
      Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
      ). This could be secondary to inhibition of T cell function (
      • Sabatino Jr, JJ
      • Zamvil SS
      • Hauser SL
      B-Cell Therapies in Multiple Sclerosis.
      a,
      • Sabatino Jr, JJ
      • Wilson MR
      • Calabresi PA
      • et al.
      Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.
      b). Targeting memory B cell subsets, and possibly CD4, Th17 T cells, is not likely to prevent SARS-CoV-2 elimination by CD8 T cells and the innate immune responses. This may only be relevant with continuous treatments that maintain peripheral B cells in a nadir state and prevent antibody secreting cell (ASC) formation (
      • Sabatino Jr, JJ
      • Zamvil SS
      • Hauser SL
      B-Cell Therapies in Multiple Sclerosis.
      a;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). However, ASC can be generated by germinal centre cells independent of the CD27+, memory B cell pathway (
      • Baker D
      • Pryce G
      • Amor S
      • et al.
      Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
      ;
      • Hammarlund E
      • Thomas A
      • Amanna IJ
      • et al.
      Plasma cell survival in the absence of B cell memory.
      ;
      • Khodadadi L
      • Cheng Q
      • Radbruch A
      • Hiepe F
      The Maintenance of Memory Plasma Cells.
      ). Novel vaccine responses will be generated from the immature/naïve B cell compartments that regenerate most rapidly following B cell depleting therapies (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.
      b,
      • Baker D
      • Pryce G
      • Herrod SS
      • Schmierer K
      Potential mechanisms of action related to the efficacy and safety of cladribine.
      ,
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). Once formed, anti-viral responses will reside within the long-lived plasma cell pool with lymphoid tissue and bone marrow (
      • Khodadadi L
      • Cheng Q
      • Radbruch A
      • Hiepe F
      The Maintenance of Memory Plasma Cells.
      ;
      • Baker D
      • Pryce G
      • Amor S
      • et al.
      Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
      ). Plasma cells are relatively quiescent (
      • Khodadadi L
      • Cheng Q
      • Radbruch A
      • Hiepe F
      The Maintenance of Memory Plasma Cells.
      ) and thus avoid the action of agents targeting proliferating cells and they also express low levels of CD52, deoxycytidine kinase and CD20 targeted by high-efficacy, depleting DMT (
      • Baker D
      • Ali L
      • Saxena G
      • Pryce G
      • et al.
      The irony of humanization: alemtuzumab, the first, but one of the most immunogenic, humanized monoclonal antibodies.
      b;
      • Sabatino Jr, JJ
      • Zamvil SS
      • Hauser SL
      B-Cell Therapies in Multiple Sclerosis.
      a,
      • Baker D
      • Pryce G
      • Herrod SS
      • Schmierer K
      Potential mechanisms of action related to the efficacy and safety of cladribine.
      ). Furthermore, they reside predominantly in the bone marrow, a site that may not be effectively targeted by depleting antibodies as cell elimination requires entry of antibodies, complement components and effector accessory cells required for depletion (
      • Baker D
      • Pryce G
      • Amor S
      • et al.
      Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
      ). Thus once formed, plasma cells may not be particularly well targeted by the current DMT, except haematopoietic stem cell therapy (HSCT) that purges the lymphoid tissues. It will be important to consider how best to deliver a SARS-CoV-2 vaccine in the future (
      • Amanat F
      • Krammer F
      SARS-CoV-2 Vaccines: status report.
      ;
      • Chen WH
      • Strych U
      • Hotez PJ
      • Bottazzi ME
      The SARS-CoV-2 Vaccine Pipeline: an Overview.
      ). Strategies could be developed for the highly-active agents that accommodate the long-depletion of memory B cells and the more rapid population of naïve cells to allow a vaccination response against SARS-CoV-2 whilst maintaining protection against MS.

      5. Low efficacy MS immunomodulators are unlikely to limit anti-viral immunity

      The components of the immune response that drive autoimmunity and control infection use overlapping cellular mechanisms. Therefore, removal of significant immune subsets may have the capacity to reduce anti-viral responses in a manner that reflects their immunosuppressive potential. Low treatment-efficacy agents such as glatiramer acetate, beta interferons and teriflunomide (Table 1) are not associated with significant immunosuppression, notable increased risk of viral infections, nor lack of responsiveness to vaccines (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Comi G
      • Miller AE
      • Benamor M
      • et al.
      Characterizing lymphocyte counts and infection rates with long-term teriflunomide treatment: Pooled analysis of clinical trials.
      a;
      • Wijnands JMA
      • Zhu F
      • Kingwell E
      • et al.
      Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study.
      ;
      • Olberg HK
      • Eide GE
      • Cox RJ
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory.
      ;
      • Hauser SL
      • Bar-Or A
      • Cohen J
      • et al.
      Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. 336.
      ). Indeed, interferon beta and teriflunomide may have anti-viral activity that could be beneficial (
      • Hensley LE
      • Fritz LE
      • Jahrling PB
      • et al.
      Interferon-beta 1a and SARS coronavirus replication.
      ;
      • Bilger A
      • Plowshay J
      • Ma S
      • et al.
      Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.
      ). As such beta interferon has been shown to inhibit SARS-CoV replication and is currently being trialled in COVID-19 (
      • Dahl H
      • Linde A
      • Strannegård O
      In vitro inhibition of SARS virus replication by human interferons.
      ;
      • Hensley LE
      • Fritz LE
      • Jahrling PB
      • et al.
      Interferon-beta 1a and SARS coronavirus replication.
      ; NCT04350671; NCT04343768). However, these agents have a downside in that they are not that effective in controlling MS disease activity.

      6. Moderate efficacy MS immunomodulators carry higher, but modest infection risks

      Dimethyl fumarate is modestly immunosuppressive and targets lymphocytes rather than monocytes (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ). Immature/transitional B cells are less affected compared to memory B cell targeting (
      • Mehta D
      • Miller C
      • Arnold DL
      • et al.
      Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.
      ). Although plasmablasts and plasma cells can be affected by dimethyl fumarate therapy (
      • Mehta D
      • Miller C
      • Arnold DL
      • et al.
      Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.
      ), immunoglobulin levels are not unduly reduced (
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ). Importantly, vaccine responses in people on dimethyl fumarate were no different to those treated with beta interferons (
      • von Hehn C
      • Howard J
      • Liu S
      • et al.
      Immune response to vaccines is maintained in patients treated with dimethyl fumarate.
      ). However, in some individuals persistent lymphopenia has been reported (
      • Mehta D
      • Miller C
      • Arnold DL
      • et al.
      Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.
      ;
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ), notably about 20% of people will exhibit CD8 T cell levels below the lower limit of normal (
      • Mehta D
      • Miller C
      • Arnold DL
      • et al.
      Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice.
      ). Although this is not generally associated with increased infection rates (
      • Boffa G
      • Bruschi N
      • Cellerino M
      • et al.
      Fingolimod and dimethyl-fumarate-derived lymphopenia is not associated with short-term treatment response and risk of infections in a real-life ms population.
      ), viral infections, including upper respiratory and lung infections occur with the monomethyl fumarate producing compounds (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ;
      • Perini P
      • Rinaldi F
      • Puthenparampil M
      • et al.
      Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient.
      ;
      • Fernández Ó
      • Giovannoni G
      • Fox RJ
      • et al.
      Efficacy and safety of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: an integrated analysis of define and confirm.
      ;
      • Naismith RT
      • Wolinsky JS
      • Wundes A
      • et al.
      Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.
      ).
      Functional lymphopenia occurs with sphingosine-1-phosphate receptor modulators such as fingolimod (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ). This appears to modestly elevate efficacy and infection risks (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Kalincik T
      • Kubala Havrdova E
      • et al.
      Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.
      ). These agents are reported to sequester lymphocytes within lymphoid tissues and exhibit limited activity on the innate immune response (
      • Kowarik MC
      • Pellkofer HL
      • Cepok S
      • et al.
      Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.
      ;
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Thomas K
      • Sehr T
      • Proschmann U
      • et al.
      Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation.
      ;
      • Angerer IC
      • Hecker M
      • Koczan D
      • et al.
      Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.
      ). Fingolimod targets CD4 more than CD8 T cells and notably the naïve and central memory T cell subsets to retain them in lymphoid tissues where anti-viral responses would be generated (
      • Kowarik MC
      • Pellkofer HL
      • Cepok S
      • et al.
      Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.
      ;
      • Angerer IC
      • Hecker M
      • Koczan D
      • et al.
      Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.
      ;
      • Hjorth M
      • Dandu N
      • Mellergård J
      Treatment effects of fingolimod in multiple sclerosis: Selective changes in peripheral blood lymphocyte subsets.
      ). It also exhibits a more modest decrease in effector memory CD4 and CD8 T cells that will enter inflamed tissues (
      • Angerer IC
      • Hecker M
      • Koczan D
      • et al.
      Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.
      ). Infections rates are modest (
      • Diebold M
      • Sievers C
      • Bantug G
      • et al.
      Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.
      ), but some bacterial and viral, infections such as herpes and varicella, are marginally more common after fingolimod treatment (
      • Calabresi PA
      • Radue EW
      • Goodin D
      • et al.
      Lancet Neurol. 2014 Jun;13(6):545-56. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.
      ;
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Diebold M
      • Fischer-Barnicol B
      • Tsagkas C
      • et al.
      Hepatitis E virus infections in patients with MS on oral disease-modifying treatment.
      ). There may be subtle differences between fingolimod and the other sphingosine-1-phosphate receptor modulators in terms of infections and adverse effects, however it has a relatively long-half-life compared to other agents, which may be relevant if one wants to stop treatment (
      • Subei AM
      • Cohen JA.
      Sphingosine 1-phosphate receptor modulators in multiple sclerosis.
      ;
      • Swallow E
      • Patterson-Lomba O
      • Yin L
      • et al.
      Comparative safety and efficacy of ozanimod versus fingolimod for relapsing multiple sclerosis.
      ). A small scale trial of fingolimod has been reported for severe COVID-19 (NCT04280588). Sphingosine-1-phosphate is involved with maintaining the germinal centre and B cell niche (
      • Cinamon G
      • Zachariah MA
      • Lam OM
      • et al.
      Follicular shuttling of marginal zone B cells facilitates antigen transport.
      ) and there may be reduced serum immunoglobulin level following fingolimod treatment (
      • Zoehner G
      • Miclea A
      • Salmen A
      • et al.
      Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course.
      ) as such vaccine responses are slightly reduced compared to the interferons (
      • Olberg HK
      • Eide GE
      • Cox RJ
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory.
      ;
      • Signoriello E
      • Bonavita S
      • Sinisi L
      • et al.
      Is antibody titer useful to verify the immunization after VZV Vaccine in MS patients treated with Fingolimod? A case series.
      ) as occurs with natalizumab (
      • Olberg HK
      • Eide GE
      • Cox RJ
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory.
      ).

      7. Natalizumab as the preferred high-efficacy agent

      Currently natalizumab is perceived to be the high-efficacy treatment of choice (

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      . Table 1). Natalizumab, unlike depleting highly-active DMT, is potentially more rapidly reversible using plasma exchange and is not likely to inhibit migration of immune cells into lymphoid tissues and prevent novel immune responses, and as such has no or limited influence on vaccine antibody responses (
      • Vågberg M
      • Kumlin U
      • Svenningsson A
      Humoral immune response to influenza vaccine in natalizumab-treated MS patients.
      ;
      • Kaufman M
      • Pardo G
      • Rossman H
      • et al.
      Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis.
      ;
      • Olberg HK
      • Eide GE
      • Cox RJ
      • et al.
      Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory.
      ). The value of the use of natalizumab may also be enhanced because it is perceived to inhibit T cell migration into the central nervous system (CNS) (
      • Yednock TA
      • Cannon C
      • Fritz LC
      • et al.
      Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin.
      ;
      • Schwab N
      • Schneider-Hohendorf T
      • Wiendl H
      Therapeutic uses of anti-α4-integrin (anti-VLA-4) antibodies in multiple sclerosis.
      ). However, both B cells and importantly monocytes express alpha 4 integrin (CD49d) and thus the antibody directed to CD49d inhibits monocyte binding to vascular cell adhesion molecule one (VCAM-1) (
      • Yednock TA
      • Cannon C
      • Fritz LC
      • et al.
      Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin.
      ;
      • Hyduk SJ
      • Cybulsky MI.
      Role of alpha4beta1 integrins in chemokine-induced monocyte arrest under conditions of shear stress.
      ). Importantly, although natalizumab is used to block migration into the inflamed CNS and gut (
      • Schwab N
      • Schneider-Hohendorf T
      • Wiendl H
      Therapeutic uses of anti-α4-integrin (anti-VLA-4) antibodies in multiple sclerosis.
      ), VCAM-1 is expressed in virally-inflamed lungs (
      • Brodie SJ
      • de la Rosa C
      • Howe JG
      • et al.
      Pediatric AIDS-associated lymphocytic interstitial pneumonia and pulmonary arterio-occlusive disease: role of VCAM-1/VLA-4 adhesion pathway and human herpesviruses.
      ). Therefore, CD49d is likely involved in mononuclear cell diapedesis into the inflamed lung during SARS-CoV-2 infection (
      • Brodie SJ
      • de la Rosa C
      • Howe JG
      • et al.
      Pediatric AIDS-associated lymphocytic interstitial pneumonia and pulmonary arterio-occlusive disease: role of VCAM-1/VLA-4 adhesion pathway and human herpesviruses.
      ;
      • Yen YT
      • Liao F
      • Hsiao CH
      • et al.
      Modelling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      ). This potential activity is perhaps consistent with increased lung infections in MS following treatment with natalizumab (
      • Polman CH
      • O'Connor PW
      • Havrdova E
      • et al.
      A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
      ). Furthermore, that SARS-CoV-2 is neutrotrophic, (
      • Baig AM
      • Khaleeq A
      • Ali U
      • Syeda H
      Evidence of the COVID-19 virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms.
      ;
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2.
      ,
      • Helms J
      • Kremer S
      • Merdji H
      • et al.
      Neurologic Features in Severe SARS-CoV-2 Infection.
      ) suggests that a potential risk of natalizumab treatment is that it blocks viral immunosurveillance of the CNS (
      • Hoepner R
      • Faissner S
      • Salmen A
      • et al.
      Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis.
      ), however this issue is perhaps limited by the extended interval dosing suggested to limit MS activation and reduce the risk of progressive multifocal leukoencephalopathy (
      • Ryerson LZ
      • Foley J
      • Chang I
      • et al.
      Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.
      ;
      • Clerico M
      • De Mercanti SF
      • Signori A
      • et al.
      Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?.
      ). Thus, whilst natalizumab use could potentially be a risk factor for severe COVID-19, it is likely to limit monocyte and T cell damage to the lung and avoiding severe complications.

      8. High-efficacy depleting agents are not the same and have distinct COVID-19 risks

      Based on initial suggestions, immune reconstitution therapies (IRT) were not recommended to be started and ongoing treatment, i.e. additional courses, should be delayed (Table 1.

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      ). Autologous HSCT is seen as a high-risk strategy to initiate during the mass-infection stage of COVID-19 pandemic (Table 1) and will probably remain so until herd immunity (
      • Kwok KO
      • Lai F
      • Wei WI
      • et al.
      Herd immunity - estimating the level required to halt the COVID-19 epidemics in affected countries.
      ) develops. Myeloablative HSCT removes both the adaptive and notably the innate immune systems and it is already well recognised that loss of the neutrophils, monocytes and other elements of the innate immune system increases the risk of mortality from infection, and until the innate and adaptive immune response reconstitutes people will be at risk for some time (
      • Storek J
      • Geddes M
      • Khan F
      • et al.
      Reconstitution of the immune system after hematopoietic stem cell transplantation in humans.
      ;
      • Ge F
      • Lin H
      • Li Z
      • Chang T
      Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis.
      ;
      • Rush CA
      • Atkins HL
      • Freedman MS
      Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis.
      ). However, once reconstituted the capacity to generate new immune responses occurs as seen following vaccination against childhood infections, to replace the lost immunity due to the HSCT procedure (
      • Brinkman DM
      • Jol-van der Zijde CM
      • ten Dam MM
      • et al.
      Resetting the adaptive immune system after autologous stem cell transplantation: lessons from responses to vaccines.
      ,
      • Rush CA
      • Atkins HL
      • Freedman MS
      Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis.
      ). Therefore, there are clear risks from viral infections until the immune system reconstitutes. It is suggested that current licenced IRT, which both deplete T and B cells (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.
      b;
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c) carry similar risk (

      Coles A, Lim M, Giovannoni G, et al. ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic. 20202 Apr (https://cdn.ymaws.com/www.theabn.org/resource/collection/65C334C7-30FA-45DB-93AA-74B3A3A20293/02.04.20_ABN_Guidance_on_DMTs_for_MS_and_COVID19_VERSION_4_April_2nd.pdf.

      ). However, this does not accommodate the biologies and as such, oral cladribine is dissimilar to alemtuzumab, in terms of its risk for SARS-CoV-2 infection and appears more similar to ocrelizumab in its immunodepletion profile (Table 2).
      Table 2High efficacy agents are not the same and oral cladribine is more similar to ocrelizumab than alemtuzumab.
      ALEMTUZUMAB1CLADRIBINE7OCRELIZUMAB12
      PracticalityINFUSION1ORAL TABLETS8INFUSION
      STEROIDS TO STOP CRS1NO STEROIDSSTEROIDS TO STOP CRS
      HOSPITAL VISITS REQUIRED MONITORING FREQUENT1HOSPITAL VISITS NOT REQUIRED MONITORING MINIMAL8HOSPITAL VISIT REQUIRED MONITORING MINIMAL12
      DRUG PRESISTANCE ~1 MONTH1DRUG PERSISTANCE 1 DAY8DRUG PERSISTANCE 5-6 MONTHS12
      Differential Infection RiskEARLY DELETION MONOCYTE2-4MONOCYTES IN NORMAL RANGE9MONOCYTES IN NORMAL RANGE 13
      NEUTROPHILS IN NORMAL RANGE3,5NEURTROPHILS IN NORMAL RANGE (~10%)9NEUTROPHILS IN NORMAL RANGE12
      CD4 DEPLETED (70-90%)5CD4 IN NORMAL RANGE (40-50%)9CD4 IN NORMAL RANGE (~2%)13
      CD8 DEPLETED (70-90%)5CD8 IN NORMAL RANGE (30-40%)9CD8 IN NORMAL RANGE (6-8%)13
      NK CELLS IN NORMAL RANGE (40%)NK CELLS IN NORMAL RANGE (50%)9NK CELLS IN NORAML RANGE (<10%)13
      EfficacyIMMATURE B CELL DEPLETED (3-6 MONTHS)5IMMATURE B CELL DEPLETED (6-9 MONTHS)10IMMATURE B CELLS DEPLETED PERMANENTLY13,14
      MEMORY B CELLS DEPLETED (> 1 YEAR)5MEMORY B CELLS DEPLETED (>1YEAR)10MEMORY B CELLS DEPLETE PERMANENTLY13,14
      PLASMA CELLS. LOW CD525PLASMA CELLS LOW DEOXYCYTODINE KINASE11PLASMA CELLS, NO CD2012
      EARLY INFECTION RISK1LIMITED INCREASED RISK8LIMITED INCREASED RISK12
      Infection risk(EARLY ANTI-VIRAL REQUIRED)(MAINLY BACTERIAL, INCREASE HERPES)(MAINLY BACTERIAL, INCREASE HERPES)
      VACCINATION COMPETENT AFTER 6 MONTHS7?VACCINATION COMPENTENT and BUT BLUNTED15
      Different characteristics of alemtuzumab, cladribine and ocrelizumab, relevant to efficacy and side-effect potential and their capacity to control MS and exhibit an effective anti-viral immune response. CRS cytokine release syndrome. NK natural killer cell. 1.

      Lemtrada® EU Summary of product characteristics. Nov 2019.

      . 2.
      • Thomas K
      • Eisele J
      • Rodriguez-Leal FA
      • et al.
      Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS.
      , 3.
      • Baker D
      • Giovannoni G
      • Schmierer K
      Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment.
      d, 4.
      • Gross CC
      • Ahmetspahic D
      • Ruck T
      • et al.
      Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis.
      , 5.
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.
      b, 6.
      • Baker D
      • Ali L
      • Saxena G
      • Pryce G
      • et al.
      The irony of humanization: alemtuzumab, the first, but one of the most immunogenic, humanized monoclonal antibodies.
      b, 7.
      • McCarthy CL
      • Tuohy O
      • Compston DA
      • et al.
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      , 8.

      Mavenclad® EU Summary of product characteristics. Jul 2018.

      , 9.
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c, 10.
      • Ceronie B
      • Jacobs BM
      • Baker D
      • et al.
      Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.
      , 11.
      • Baker D
      • Pryce G
      • Herrod SS
      • Schmierer K
      Potential mechanisms of action related to the efficacy and safety of cladribine.
      , 12.

      Ocrevus® EU Summary Product Characterisitics, Sep 2018.

      ; 13.
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a, 14.
      • Fernandez Velasco JI
      • Villarrubia Migallon N
      • Monreal E
      • et al.
      Effects of ocrelizumab treatment in peripheral blood leukocyte subsets of primary progressive multiple sclerosis patients.
      , 15.
      • Stokmaier D
      • Winthrop K
      • Chognot C
      • et al.
      Effect of ocrelizumab on vaccine responses in pateinets with multiple sclerosis (S36.002).
      .

      8.1 Alemtuzumab

      This is a CD52-depleting antibody that induces long-lasting and marked (80-90%) depletion of CD4, CD8 T cells and memory B cells (Table 2. Baker et al. 2017;
      • Akgün K
      • Blankenburg J
      • Marggraf M
      • et al.
      Event-Driven immunoprofiling predicts return of disease activity in alemtuzumab-treated multiple sclerosis.
      ). Alemtuzumab induces long-term disease remission if treated sufficiently early after symptom onset (
      • Cohen JA
      • Coles AJ
      • Arnold DL
      • et al.
      Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
      .
      • Havrdova E
      • Arnold DL
      • Cohen JA
      • et al.
      Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.
      ,
      • He A
      • Merkel B
      • Brown JWL
      • et al.
      Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.
      b). Two short cycles of treatment give long-term disease remission. Alemtuzumab treatment cycles are generally given at least 12 months apart, but this interval may be extended up to 18 months, which supports the important activity of memory B cells as they, and CD4 T cells, can be depleted for at least this time (
      • Tuohy O
      • Costelloe L
      • Hill-Cawthorne G
      • et al.
      Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.
      ,
      • Havrdova E
      • Arnold DL
      • Cohen JA
      • et al.
      Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.
      ,
      • Akgün K
      • Blankenburg J
      • Marggraf M
      • et al.
      Event-Driven immunoprofiling predicts return of disease activity in alemtuzumab-treated multiple sclerosis.
      ). However, alemtuzumab induces transient monocyte depletion and can induce very long-term CD4 and CD8 T cell depletion (
      • Kousin-Ezewu O
      • Azzopardi L
      • Parker RA
      • et al.
      Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.
      ;
      • Thomas K
      • Eisele J
      • Rodriguez-Leal FA
      • et al.
      Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS.
      ,
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.
      b;
      • Akgün K
      • Blankenburg J
      • Marggraf M
      • et al.
      Event-Driven immunoprofiling predicts return of disease activity in alemtuzumab-treated multiple sclerosis.
      ). This influences responses to viral and other infections (
      • Cohen JA
      • Coles AJ
      • Arnold DL
      • et al.
      Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
      ;
      • Wray S
      • Havrdova E
      • Snydman DR
      • et al.
      Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study.
      ) and could thus impact on SARS-CoV-2 outcome. Severe lymphopenia increases the risk of infections and pneumonia (
      • Warny M
      • Helby J
      • Nordestgaard BG
      • et al.
      Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study.
      ). Neutropenia after alemtuzumab can be marked and significant, but is unusual (
      • Baker D
      • Giovannoni G
      • Schmierer K
      Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment.
      d). Infection risk is notable following infusion and decreases with time as cellular repopulation occurs (
      • Buonomo AR
      • Zappulo E
      • Viceconte G
      • et al.
      Risk of opportunistic infections in patients treated with alemtuzumab for multiple sclerosis.
      ;
      • Wray S
      • Havrdova E
      • Snydman DR
      • et al.
      Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study.
      ). Alemtuzumab has a relatively short half-life and is cleared from the circulation within about a month (
      • Li Z
      • Richards S
      • Surks HK
      • et al.
      Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis.
      ). Therefore, surviving cells can repopulate in response to infection and given the relatively low dose and delivery over a single week, allows cells escaping elimination to recover. Transitional/immature B cells rapidly repopulate in the relative absence of T cell regulation, possibly related to limited purging of the bone marrow, and can generate anti-drug responses within a month of treatment in 60-83% of people in the virtual absence of peripheral B and T cell (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.
      b;
      • Baker D
      • Ali L
      • Saxena G
      • Pryce G
      • et al.
      The irony of humanization: alemtuzumab, the first, but one of the most immunogenic, humanized monoclonal antibodies.
      b). Therefore, perhaps it may be possible to generate anti-viral responses. As such childhood vaccine responses persist and novel vaccine responses are not notably inhibited with alemtuzumab within 6 months of treatment (
      • McCarthy CL
      • Tuohy O
      • Compston DA
      • et al.
      Immune competence after alemtuzumab treatment of multiple sclerosis.
      ). Thus with time people with MS are likely to be able to generate a SARS-CoV-2 response and respond to vaccination. Although the treatment protocol means that few infusion visits are required (
      • Cohen JA
      • Coles AJ
      • Arnold DL
      • et al.
      Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
      ;
      • Havrdova E
      • Arnold DL
      • Cohen JA
      • et al.
      Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.
      ), the adverse events, notably the secondary autoimmunities that develop in many people with MS (
      • Tuohy O
      • Costelloe L
      • Hill-Cawthorne G
      • et al.
      Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy.
      ;
      • Havrdova E
      • Arnold DL
      • Cohen JA
      • et al.
      Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.
      ) means that intensive monitoring is required, compared to ocrelizumab that required essentially no inter-infusion monitoring (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ).

      8.2 Ocrelizumab

      This is a CD20-depleting antibody used to treat relapsing and active primary progressive MS (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ;
      • Montalban X
      • Hauser SL
      • Kappos L
      • et al.
      Ocrelizumab versus placebo in primary progressive multiple sclerosis.
      ). This depletes peripheral B cells including memory B cells (
      • Fernandez Velasco JI
      • Villarrubia Migallon N
      • Monreal E
      • et al.
      Effects of ocrelizumab treatment in peripheral blood leukocyte subsets of primary progressive multiple sclerosis patients.
      ). Based on a common mechanism of action (
      • Baker D
      • Marta M
      • Pryce G
      • et al.
      Memory B Cells are major targets for effective immunotherapy in relapsing multiple sclerosis.
      a), there is an unanswered question of whether ocrelizumab will behave like alemtuzumab and cladribine and provide long-term disease inhibition from a short-term treatment cycle (Table 2). Even if it acts as an IRT, based on memory B cell depletion and slow repopulation characteristics (
      • Palanichamy A
      • Jahn S
      • Nickles D
      • et al.
      Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.
      ;
      • Baker D
      • Pryce G
      • Amor S
      • et al.
      Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.
      ), it may provide some comfort to suggest that delays of 6-12 months may be feasible without MS disease activity reoccurring. The latter is based on information from off-label and phase I/II studies with rituximab in MS (
      • Bar-Or A
      • Calabresi PA
      • Arnold D
      • et al.
      Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial.
      ;
      • Juto A
      • Fink K
      • Al Nimer F
      • Piehl F
      Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity.
      ) and phase II extension trial data of ocrelizumab (
      • Kappos L
      • Li D
      • Calabresi P
      • O'Connor P
      • et al.
      Long-term safety and efficacy of ocrelizumab in patients with relapsing–remitting multiple sclerosis: week 144 results of a Phase II, randomised, multicentre trial.
      ;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). As such retreatment to maintain remission based on repopulation of CD27+ memory B cell population, after 3-4 cycles it seems that doses, at least with rituximab, can be extended to less than once a year (
      • Novi G
      • Fabbri S
      • Bovis F
      • et al.
      Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study. P971.
      ). Given that ocrelizumab exhibits depletion for a longer duration than rituximab suggests similar or better results can be obtained with rituximab (
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). Although ocrelizumab can deplete CD8 T cells, this is only a relatively mild steady state depletion of only 6-8% depletion of CD8 cells and 1-2% of CD4 T cells and has a minor impact on monocytes (
      • Gingele S
      • Jacobus TL
      • Konen FF
      • et al.
      Ocrelizumab Depletes CD20⁺ T Cells in Multiple Sclerosis Patients.
      ;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). Although infections are generally mild following ocrelizumab treatment (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ), some viral infections do occur and can be serious and very rarely life threatening (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ;
      • Nicolini LA
      • Canepa P
      • Caligiuri P
      • et al.
      Fulminant hepatitis associated with echovirus 25 during treatment with ocrelizumab for multiple sclerosis.
      ). Importantly, this may become a problem with persistent B cell depletion as that which occurs with ocrelizumab (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ). In time this can lead to IgM, IgA and IgG hypogammaglobulinemia that will increase infection risk (
      • Tallantrye EC
      • Whittam DH
      • Jolles S
      • et al.
      Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation.
      ;
      • Vollmer B
      • Vollmer T
      • Corboy J
      • Alvarez E
      Evaluation of risk factors in developing lymphopenia and hypogammaglobulinemia in anti-CD20 treated multiple sclerosis patients.
      ). However, a delay in repeated cycles may allow immature cells that provide immunity to new infections to partially regenerate, although this process is slow with ocrelizumab (
      • Kappos L
      • Li D
      • Calabresi P
      • O'Connor P
      • et al.
      Long-term safety and efficacy of ocrelizumab in patients with relapsing–remitting multiple sclerosis: week 144 results of a Phase II, randomised, multicentre trial.
      ;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a), and improve the vaccination response. Consistent with marked B cell depletion, it is apparent that vaccination responses are blunted when initiated 3 months after infusion however, they are not absent (
      • Stokmaier D
      • Winthrop K
      • Chognot C
      • et al.
      Effect of ocrelizumab on vaccine responses in pateinets with multiple sclerosis (S36.002).
      ). As plasma cells do not express CD20, once formed they will not be directly targeted by ocrelizumab (
      • Sabatino Jr, JJ
      • Zamvil SS
      • Hauser SL
      B-Cell Therapies in Multiple Sclerosis.
      a). Ofatumumab is a novel subcutaneous CD20-depleting antibody awaiting licencing following a successful phase III programme (
      • Hauser SL
      • Bar-Or A
      • Cohen J
      • et al.
      Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. 336.
      ). Ofatumumab dosing shows relatively rapid repopulation of immature B cells compared with slower repopulation with ocrelizumab (
      • Savelieva M
      • Kahn J
      • Bagger M
      • et al.
      Comparison of the B-cell recovery time following discontinuation of anti-CD20 therapies. EP1624.
      ;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a) and thus it remains to be established if the advantage of home injection and reversibility changes the use of anti-CD20 therapies compared to infusions with rituximab and ocrelizumab (
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ,
      • Hauser SL
      • Bar-Or A
      • Cohen J
      • et al.
      Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. 336.
      ). Likewise, the real-life extended dosing experiment with rituximab and ocrelizumab is ongoing (Table 1). If data captured by registries shows maintained efficacy it is likely that the dosing schedule of ocrelizumab will eventually change on grounds of conveniences, safety and cost-effectiveness, although this will need formal testing (
      • Novi G
      • Fabbri S
      • Bovis F
      • et al.
      Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study. P971.
      ;
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a).

      8.3 Cladribine

      This is an oral small molecule that behaves as an IRT that gives long term-term benefit from short treatment cycles (
      • Giovannoni G
      • Comi G
      • Cook S
      • et al.
      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
      ;
      • Giovannoni G
      • Soelberg Sorensen P
      • Cook S
      • et al.
      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study.
      ). This is a B and T cell depletion agent that is eliminated within one day of treatment (Table 2) (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c;
      • Baker D
      • Pryce G
      • Herrod SS
      • Schmierer K
      Potential mechanisms of action related to the efficacy and safety of cladribine.
      ;
      • Hermann R
      • Karlsson MO
      • Novakovic AM
      • et al.
      The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis.
      ). Treatment induces depletion via apoptosis rather than cell lysis and thus avoids the need for steroids to manage infusion reactions associated with alemtuzumab and ocrelizumab (
      • Cohen JA
      • Coles AJ
      • Arnold DL
      • et al.
      Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
      ;
      • Hauser SL
      • Bar-Or A
      • Comi G
      • et al.
      Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.
      ). Cladribine can induce comparable long-term memory B cell depletion similar to that observed with alemtuzumab, but without the innate cell and the severe lymphopenia associated with alemtuzumab (
      • Ceronie B
      • Jacobs BM
      • Baker D
      • et al.
      Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.
      ;
      • Ruggieri M
      • Gargano C
      • Iaffaldano A
      • et al.
      Changes in lymphocyte subpopulations in highly active multiple sclerosis patients during cladribine treatment.
      ). Indeed, the T cell depletion is more modest and CD4 cells are depleted by about 40-50% and CD8 T cells are depleted by 30-40% compared to baseline. In comparison, alemtuzumab results in B and T cell depletion of 80-90% (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c). As such the T cells generally remain within the lower limit of the normal range as do natural killer cells that show modest depletion (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c;
      • Comi G
      • Cook S
      • Giovannoni G
      • et al.
      Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis.
      b). The CD19+ B cells recover perhaps slower than post-alemtuzumab, as cladribine probably penetrates and acts more in lymphoid tissues, and the dosing schedule of doses being given a month apart targets any rapidly emerging cells (
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c,
      • Baker D
      • Pryce G
      • Herrod SS
      • Schmierer K
      Potential mechanisms of action related to the efficacy and safety of cladribine.
      ). However, B cells probably emerge faster after cladribine compared to ocrelizumab as depleting titres of ocrelizumab remain high for months after infusion (
      • Genovese MC
      • Kaine JL
      • Lowenstein MB
      • et al.
      Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study.
      ;
      • Baker D
      • Herrod SS
      • Alvarez-Gonzalez C
      • et al.
      Both cladribine and alemtuzumab may effect MS via B-cell depletion.
      c,
      • Baker D
      • Pryce G
      • James LK
      • et al.
      The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
      a). Unfortunately, there is no information available concerning the influence of vaccination responses of oral cladribine. Although there is an increased risk of viral infections (
      • Giovannoni G
      • Comi G
      • Cook S
      • et al.
      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
      ), these are notably less severe than with alemtuzumab (
      • Pardo G
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ) associated with the milder immunosuppression induced by cladribine. Thus, oral cladribine, behaves like a chemical CD19/CD20 depleter with some additional T cell activity and is perhaps functionally closer to CD20-depleting antibodies than CD52 depleting antibody. It has the advantage that treatment is not continuous. During the time of self-isolation and shielding to prevent COVID-19 agents such as cladribine may have some merit as it is a high efficacy IRT that can be administered at home, with minimal post-dosing monitoring requirements (Table 2).

      9. Preliminary experience and personal view of treatment

      As analysis of the mechanisms of action of the different DMT coupled with emerging knowledge of the anti-viral and pathogenic mechanisms in COVID-19, suggest that initial fears relating to immunosuppression in MS, have yet to be realised, supporting that found in the SARS epidemics (
      • D'Antiga L
      Coronaviruses and immunosuppressed patients. The facts during the third epidemic.
      ;
      • Giovannoni G
      Anti-CD20 immunosuppressive disease-modifying therapies and COVID-19.
      ). The pragmatic approach of examining an individual patient's circumstances, their prognostic profile and level of MS disease activity may help guide treatment approaches (
      • Giovannoni G
      • Hawkes C
      • Lechner-Scott J
      • et al.
      The COVID-19 pandemic and the use of MS disease-modifying therapies.
      ;
      • Giovannoni G
      Anti-CD20 immunosuppressive disease-modifying therapies and COVID-19.
      ). Although these are early days in the initial infection wave of COVID-19, already a number of people with MS have been infected with SAR-CoV-2 with the majority surviving based on early social media and registry data. Although a few people with MS have died they have tended to be older, with more advanced disease and multiple comorbidities. There are now over 360 people with MS and COVID-19 within Italian COVID MS registry with only 5 reported deaths, with only 2 people being treated with DMT and all having comorbidities associated with poor COVID-19 prognosis in the general population. Thus, there does not yet appear evidence that people with MS are at particular risk of severe COVID-19. As such we suggest that risks should be reviewed (Table 3) and advice regarding the risks associated with individual MS-DMT adjusted. Delays in treatment cycles may provide information on the biology of relapsing MS and, if successful may change prescribing habits in the future as there are risk/cost/benefit advantages of reduced dosing frequency. Thus, it will be interesting to determine whether one returns to the current status quo after the COVID-19 pandemic wanes or whether extended interval-dosing remains. Likewise, it will be intriguing to determine if real-life data shows that ocrelizumab exhibits IRT-like characteristics whereby long-term benefit can be seen with only short-term treatment cycle as seen with alemtuzumab and oral cladribine. The positive aspect of this unfortunate human experiment created by the SARS-CoV-2 epidemic, is that it will teach us more about the biology of MS and help inform how best to treat this disease and as safely as possible
      Table 3Our opinion of altered risks of different MS DMT for COVID-19.
      Main attributes of licensed MS DMTs in relation to the COVID-19 pandemic (Version 4.0, 18-April-2020)
      At risk categoryRankClassTrade NameMode of actionEfficacyClassSafe to start treatmentAdvice regarding treatmentIn the event of COVID-19 infection?Immuosuppression?Response to future SARS-CoV-2 vaccineAttributes and caveats
      Very low1Interferon-betaBetaferon, Avonex, Rebif, PlegridyImmunomodulatory (not immunosuppressive), pleiotropic immune effectsModerateMaintenance immunomodulatoryYesContinueContinueNoLikely to be intactHas antiviral properties that may be beneficial in the case of COVID-19
      Very low2Glatiramer acetateCopaxoneImmunomodulatory (not immunosuppressive), pleiotropic immune effectsModerateMaintenance immunomodulatoryYesContinueContinueNoLikely to be intact-
      Very low3Cladribine / Alemtuzumab / Mitoxantrone / HSCTsee belowPost-immune reconstitution with normal innate and adaptive immunity (lymphocyte count > 1000/mm^3)High / Very highIRTN/AN/AN/ANoLikely to be intactSome patients who may have mitoxantrone or chemotherapy-induced (HSCT) cardiomyopathy may be at increased risk of severe COVID-19
      Very low4TeriflunomideAubagioDihydro-orotate dehydrogenase inhibitor (reduced de novo pyrimidine synthesis), anti-proliferativeModerate (1st-line) / Moderate to high (2nd-3rd-line)Maintenance immunomodulatoryYesContinueContinuePossible (no well-defined immunosupressive signature)Likely to be intactHas antiviral properties that may be beneficial in the case of COVID-19
      Low5Dimethyl fumarateTecfideraPleotropic, NRF2 activation, downregulation of NFΚβModerate (2nd-3rd-line) / High (1st-line)Maintenance immunosuppressiveProbablyContinue / Switch if lymphopenicContinueYes, continousLikely to be intactThe risk can only be considered low in paients who do not develop a persistent lymphopenia. Patients with a total lymphocyte count of less than 800/mm^3 should be considered be at a higher risk of develping complications from COVID19 infection.
      Low6Natalizumab (EID / extended interval dosing)TysabriAnti-VLA4, selective adhesion molecule inhibitorVery highMaintenance immunosuppressiveYesContinueContinue or miss infusion depending on timingYes, continousLikely to be intactAs COVID-19/SARS-CoV-2 is neurotropic natalizumab will potentially prevent viral clearance from the CNS; this risk is likely to be very low on EID or extended interval dosing. We still have concerns about creating an environment in mucosal surfaces and the gut that may promote prolonged viral shedding; again this risk will be lower with EID.
      Low7Anti-CD20Ocrelizumab (Ocrevus), Ofatumumab. Rituximab, UblituximabAnti-CD20, B-cell depleterVery highMaintenance immunosuppressiveProbablyRisk assessment - continue or suspend dosingTemporary suspension of dosing depending on timingYes, continousBlunted, particularly to glycoprotein components of a vaccineDoes drop the both CD4+ and CD8+ T-cell populations by up to 20% and this may interact with other factors to affect antiviral responses. Theoretical risk that ocrelizumab and other anti-CD20 therapies may result in prolonged viral shedding.
      Intermediate8CladribineMavencladDeoxyadenosine (purine) analogue, adenosine deaminase inhibitor, selective T and B cell depletionHigh / Very high (highly-active RMS)IRT (semi-selective)ProbablyRisk assessment - continue or suspend dosingTemporary suspension of dosing depending on timingYes, intermittentPossibly blunted.Only reduces the T-cell compartment by ~50% and has less of an impact on the CD8+ population. Provided total lymphocyte counts are above 500/mm^3 allowing appropriate antiviral responses should be maintained. Theoretical risk that in the immune depletion phase cladribine may result in prolonged viral shedding.
      Intermediate9S1P modulatorsFingolimod (Gilenya), Siponimod (Mazent), Ozanimod, PonesimodSelective S1P modulator, prevents egress of lymphocytes from lymph nodesHighMaintenance immunosuppressiveProbablyContinueContinue or temporary suspension of dosingYes, continousBluntedTheoretical risk that S1P modulators may result in prolonged viral shedding. Paradoxically S1P modulators may reduce the severity of COVID-19; fingolimod is currently being trialed.
      Intermediate10Natalizumab (SID / standard interval dosing)TysabriAnti-VLA4, selective adhesion molecule inhibitorVery highMaintenance immunosuppressiveYesContinue, but consider EIDContinue or miss infusion depending on timingYes, continousLikely to be intactAs COVID-19/SARS-CoV-2 is neurotropic natalizumab will prevent viral clearance from the CNS.Intermediate risk; higher theoretical risk on SID. I have that natalizumab will create an environment in mucosal surfaces and the gut that may promote prolonged viral shedding.
      High
      risk refers to acquiring an infection during the immunodepletion phase ( E.g. rank 11,12,13). Post immune reconstitution the risk is low (rank 3). This opinion was formed 18 April 2020.
      11MitoxantroneNovatroneImmune depleter (topoisomerase inhibitor)Very highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentBluntedTheoretical risk that in the immune depletion phase mitoxantrone may result in prolonged viral shedding.
      High
      risk refers to acquiring an infection during the immunodepletion phase ( E.g. rank 11,12,13). Post immune reconstitution the risk is low (rank 3). This opinion was formed 18 April 2020.
      12AlemtuzumabLemtradaAnti-CD52, non-selective immune depleterVery highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentBluntedTheoretical risk that in the immune depletion phase alemtuzumab may result in prolonged viral shedding.
      High
      risk refers to acquiring an infection during the immunodepletion phase ( E.g. rank 11,12,13). Post immune reconstitution the risk is low (rank 3). This opinion was formed 18 April 2020.
      13HSCT-Immune depletion and haemopoietic stem cell reconstitutionVery highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentBluntedTheoretical risk that in the immune depletion phase HSCT may result in prolonged viral shedding.
      low asterisk risk refers to acquiring an infection during the immunodepletion phase ( E.g. rank 11,12,13). Post immune reconstitution the risk is low (rank 3).This opinion was formed 18 April 2020.

      Disclosures

      No company was involved in the decision to write or was involved in the content of this paper. Therefore, disclosures are not considered relevant, however within the past 5 years: DB received consultancy/speaker fees from: Canbex therapeutics, Inmunebio, Lundbeck, Merck, Novartis, Sanofi Genzyme. SA has received consultancy from Novartis. SA is section editor of multiple sclerosis and related disorders and associative editor at Clinical and Experimental Immunology. ASK has nothing relevant to declare. KS has received consultancy, speaker fees from: Biogen, Lipomed, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. GG has received received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. GG has received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. Editor of multiple sclerosis and related disorders.

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