COVID-19 vaccines and multiple sclerosis disease-modifying therapies

  • Gavin Giovannoni,
  • Christopher H. Hawkes,
  • Jeannette Lechner-Scott,
  • Michael Levy,
  • E. Ann Yeh,
  • David Baker

MSARDS DOI:https://doi.org/10.1016/j.msard.2021.103155

Much more evidence has emerged since our first editorial in April 2020 on the use of multiple sclerosis (MS) disease-modifying therapies (DMTs) during the pandemic (Giovannoni et al., 2020) and a further publication in MSARDs by Baker and colleagues on the biology underpinning the interaction between DMTs and SARs-CoV-2 (Baker et al., 2020).

It is now clear that apart from anti-CD20 therapies (rituximab and ocrelizumab) MS DMTs do not appear to increase the risk of COVID-19 or severe COVID-19 (Sormani et al., 2021Simpson-Yap et al., 2021Salter et al., 2021).

The risks of COVID-19 associated with anti-CD20 therapy are relatively small with an approximate doubling of liability compared to people on other DMTs (Sormani et al., 2021Simpson-Yap et al., 2021.). The most important drivers of severe COVID-19 and death are age, disability and the presence of comorbidities (Sormani et al., 2021Louapre et al., 2020). Male sex and other social determinants of health such as deprivation and ethnicity also play an important role in outcomes from COVID-19 (Bhaskaran et al., 2021). When counselling individual patients about the doubling of the risk of getting severe COVID-19 when on an anti-CD20 therapy it should be stressed that a doubling of a low risk, particularly a low absolute risk, remains still a low absolute risk.

People with MS could use one of the online risk calculators, for example the online QCovid® risk calculator developed by the University of Oxford (https://qcovid.org/) to assess their personal risk.

As we hopefully approach the final wave of the COVID-19 pandemic, some countries anticipate herd immunity towards the end of the summer in the northern hemisphere. The question of vaccine readiness in relation to DMTs (Baker et al., 2020Reyes et al., 2021) and vaccine hesitancy concerning the long-term safety of the COVID-19 vaccines remain very topical (Reyes et al., 2021Xiang et al., 2021Moniz Dionísio et al., 2021).A recent publication from Israel shows blunted antibody response to the Pfizer-BionTech mRNA-COVID-19 vaccine in ocrelizumab and fingolimod treated patients, compared to those treated with cladribine or no DMT (Achiron et al., 2021). The suboptimal ocrelizumab and fingolimod vaccine response results have been substantiated by a small French study (Bigaut et al., 2021) and in part refuted by an Italian real-life study that examined 32 patients with MS. In 10 out of 16 (62.5%) patients managed with fingolimod and 6 out of 16 (37.5%) treated with ocrelizumab there was a positive serological response after vaccination (S et al., 2021).

These results are not surprising as there is good evidence that both anti-CD20 therapies (Cioc et al., 2008) and fingolimod (Han et al., 2004), a S1P modulator, disrupt germinal centre (GC) functioning in lymphoid tissue where naive B-cells are educated with the help of follicular T-helper cells. In the GCs, antibody gene rearrangement results in class switching, for example from IgM to one of the IgG subtypes, followed by affinity maturation and selection of high-affinity B-cell receptors or membrane-bound antibodies, prior to formation of memory B-cells and plasmablast clones that exit the GCs to produce high-affinity soluble IgG that can be detected in the peripheral blood (Lu and Craft, 2021).

It is important to stress that vaccine immunity is not all about antibody responses (B-cell mediated) and that T-cell responses are also important (Teijaro and Farber, 2021). A Swiss study, that has yet to be peer-reviewed, evaluated 96 anti-CD20 treated patients and 29 immunocompetent controls. Anti-spike SARS-CoV-2 IgG antibodies were detected in 49% of patients after the second mRNA-COVID-19 vaccine dose, compared to 100% of controls. SARS-CoV2 specific interferon-γ release, a T-cell assay, was detected in 17% of patients and 86% of healthy controls (Moor et al., 2021). Only 5% of patients, but 86% of healthy controls showed positive results in both the antibody (B cell) and T cell assays.

Importantly, the time elapsed since the last dose of an anti-CD20 therapy (>7.6 months), peripheral blood B-cell reconstitution (CD19+ cells >27/µl) and CD4+ lymphocyte count above 653/µl predicted an antibody vaccine response (Moor et al., 2021). In contrast, a US group of investigators confirmed that anti-CD20 therapy significantly reduced an anti-SARS-CoV-2 spike and receptor-binding domain (RBD) specific antibody and memory B cell responses in most patients. They also demonstrated that the effect was reduced with longer duration from the last infusion of anti-CD20 treatment and extent of B cell reconstitution (Apostolidis et al., 2021). In contrast, all patients treated with anti-CD20 therapies generated antigen-specific CD4+ and CD8+ T-cell responses following vaccination with mRNA vaccines (Apostolidis et al., 2021). In their group of patients, anti-CD20 therapy tended to skew the immune response away from so-called T-follicular helper cells and augmented the induction of antigen-specific CD8+ T cells (Apostolidis et al., 2021).

These conflicting results are probably due to methodological issues. It is generally agreed that a reasonable IgG antibody response to a vaccine indicates a good CD4+ T cell response, particularly a T-follicular helper cell reaction, which is required to help educate and produce antigen-specific memory B-cells and plasmablasts in GCs (Lu and Craft, 2021). In the Swiss study above, 49% of anti-CD20 treated patients made an antibody response compared to 17% with the interferon-γ or T-cell assay. This suggests a problem with the sensitivity of their T-cell assay (Moor et al., 2021).It is important to note that the majority of patients with MS on anti-CD20 therapy or a S1P-modulator make an unremarkable recovery from COVID-19. This implies that innate and T-cell responses which are critical in clearing SARS-CoV-2, are functional. In comparison, B-cell and antibody responses are not vital for eliminating the primary infection (Sormani et al., 2021) (Hughes et al., 2021), but are likely to play an important role in secondary immune responses, particularly sterilizing immunity, i.e. preventing repeat infection in people infected in the past or infection after vaccination (Sette and Crotty. 2021).

Putting all of this in context, it seems highly likely that patients with MS placed on anti-CD20 therapy or a S1P-modulator will have blunted, but not necessarily absent, antibody responses to the COVID-19 vaccines. These patients are likely to benefit from protective or at least partially protective T-cell responses to the vaccine, in keeping with what happens when they experience naturally occuring SARS-CoV-2 infection. This immunity is unlikely to be sterilizing, particularly because the new emerging SARS-CoV-2 varieties, e.g. the delta variant, are partially immune escape strains.

Despite this, this immunity may be sufficient to prevent symptomatic infection, severe disease or death from COVID-19. The message should therefore remain the same; patients on anti-CD20 therapy or a S1P modulator (fingolimod, siponimod, ozanimod, ponesimod) should receive one of the licensed COVID-19 vaccines as soon as possible on the principle that during the pandemic some immunity, particularly T-cell immunity, is better than no immunity. At this point in the pandemic we would not recommend withdrawal of anti-CD20 or S1P modulator therapy, to optimise vaccine responses.

The risk of rebound disease activity from stopping and washing out a S1P modulator is particularly hazardous (Barry et al., 2019). Conversely, the longer duration of action of anti-CD20 therapies makes rebound disease activity after withdrawal less of an issue (Baker et al., 2020). Despite this, we do not know whether this is necessary and if needed, what level of B-cell reconstitution is required to optimise vaccine responses. We anticipate through studies,we will find out if pwMS on these therapies, who are vaccinated against COVID-19, albeit suboptimally from a immunological perspective, have enough immunity to prevent COVID-19 in any shape or form.

We would like to conclude by addressing the recommendation for people with MS to have seasonal influenza vaccines, 5-year pneumococcal vaccines or travel vaccines as required and perhaps a seasonal/booster COVID-19 vaccine. At some point people with MS on anti-CD20 and S1P modulators, and potentially other emerging MS DMTs, such as the Bruton Tyrosine Kinase (BTK) inhibitors, must accept that they are immunocompromised and that this immunosuppression extends to blunted, but not necessarily absent, vaccine responses as well.

Through accumulation of global data we will learn if and how optimization of vaccine responses may be achieved without compromising effective management of MS. It is vital that MS-treating clinicians balance the small absolute risks of suffering severe COVID-19 and potentially death and the blunted vaccine responses on anti-CD20 therapies and the blunted vaccine responses on S1P modulators against the risks of under-treating or not treating MS.

COI Multiple

Disclaimer: Please note that the opinions expressed here are those of the authors and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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  • Thank you Mouse for this interpretation. I’m on Fingo so it’s felt a bit like stumbling about in the dark since the Israeli report. I like a bit of straight talking.

  • The Oxford calculator does NOT have an algorithm for patients w no cancer (or h/o cancer).
    It is not everyone, is it ?

    Jay Avasarala

  • How often would the panel recommend the Shringex vaccine for zoster reactivation for patients on the DMTs (anti CD 20 and S1P modulators as well as anti integrins)?

    • Re: Shringex vaccine…..in the US this vaccine is only approved for individuals over 50 years old, so pwms under 50yrs old can sometimes experience difficultly getting the shingles vax before certain DMTs.

      As an alternative, my doctors have decided to use antivirals as a prophylaxis.


      • I should note……..my doctors recommended I start out taking 200mg once a day, NOT the 400mg twice a day that is recommended (for the HIV patients) in the above referenced article.

        I provided the article as evidence that using antivirals as a shingles prophylaxis, for individuals with a compromised immune system, is a valid approach and possible alternative to the shingles vaccine in pwms.

        Plus there might be an added benefit of being on strong antivirals during the reconstitution phase of an IRT….any thoughts Mouse Doctor🧐

  • one question MD:
    given the israeli data (frontrunnere rmna) that shows antibodies wane within a few months and so infections rise in fully vaxxed people (guess protection is down to 50% and in another study even down to 16% when it comes to Delta for people vaxxed in January) but same time still highly (>90%) effective against hospitalisation that is pointing towards good t-cell protection-and it seems that cd20 treated people even do a better cd8+ t-cell response than healthy control group-are then the cd20 patients maybe even better protected against delta than „normal“ ones?

    • Nice synopsis and quite possible. Until we hear of vacccinated anti-CD20ers getting infected we should be positive

  • Suppose someone gets a rituximab / ocrelizumab infusion a month or a few months after the second vaccine dose (Astra-Zeneca)

    Is that likely to reduce protection against Covid?
    Govt policy does not allow a 3rd dose. What should the patient do?

    • If you get vaccinated before you start ocrelizumab you get a vaccine response antibodies and all.
      Theorectical it could reduce the memory B cell pool but studies have shown that even if you do that once the long lived antibody-prodcing plasma cells have formed you have the repsonse for at least a decade.

      Government policy will change once data emerges in UK current plan is to offer to over 50s and vulnerable starting in septemeber so you can watch our success or failure

      • Thank you
        Is there any way to check whether the long-lived antibody producing plasma cells have formed?
        The vaccines were taken a year after the last infusion of rituximab

        • It would be theorectically be possible but practically no-one will do this…theres will be living in your lymph glands and importantly your bone marrow, One could take a drill to your femur and then hunt for plasma cells but do not volunteer for this. Get a booster and then check your antibody levels far simpler:-)

          • pS with dr ruths cohort there is some who gave sample before vaccine and the were positive when they give blood again we will see what happens over time

  • As we hopefully approach the final wave of the COVID-19 pandemic…

    Well who knows about that, with so many people on the planet remaining unvaccinated? The virus won’t disappear. It seems to me that the best we can hope for are localised outbreaks that don’t spread efficiently due to vaccination and monitoring.

    • The virus will eventually evolve into a far less pathogenic entity but until then………………

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