COVID-19 vaccines and DMTs

What is happening to people with MS on DMTs getting vaccinated with the COVID-19 vaccines. Are they immune or not?

Yes, we are seeing vaccine breakthroughs in vaccinated patients with MS on ocrelizumab. A colleague of mine has just had two patients admitted to the hospital over the weekend with COVID-19 despite being double-jabbed.

Photo by Fusion Medical Animation on Unsplash

The message is clear if you are on an anti-CD20 or fingolimod or another S1P-modulator (siponimod, ozanimod, ponesimod) please remain vigilant; avoid close contact with people, particularly in indoor spaces, keep using a mask and keep up the hand hygiene. And yes, take up the offer for the booster jab in the autumn when it is likely to be bundled with the flu vaccine. 

Much more evidence has emerged on the use of multiple sclerosis (MS) disease-modifying therapies (DMTs) during the pandemic. It is now clear that apart from anti-CD20 therapies (rituximab and ocrelizumab) MS DMTs do not appear to increase your risk of getting COVID-19 or severe COVID-19. PwMS treated with interferon-beta are less likely to get severe COVID-19, presumably due to its antiviral effects.

The risks of COVID-19 associated with anti-CD20 therapy are relatively small with an approximate doubling of risk compared to people on other DMTs and the general population. The most important drivers of severe COVID-19 and death from it are age, disability and the presence of comorbidities (obesity, hypertension, diabetes, lung disease, cardiac disease, kidney disease, etc). Male sex and other social determinants of health such as deprivation and ethnicity also play an important role in outcomes from COVID-19. 

Please note even doubling the risk of getting severe COVID-19 if you are on an anti-CD20 therapy when your absolute risk is low, the risk still remains low. I suggest you use the online QCovid® risk calculator developed by the University of Oxford to assess your personal risk. Simply double your odds of a poor outcome if you are on an anti-CD20 therapy. 

B-cells

Recent data 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. These results have been substantiated by a small French study, but refuted in part by an Italian real-life study which showed that over 60% of patients on fingolimod and 38% of patients treated with ocrelizumab developed an antibody response to the vaccine. I suspect the discrepancy in these results may relate to sensitivity of the assay used to detect the anti-SARS-CoV-2 spike protein antibodies. 

However, these results are not surprising as there is good evidence that both anti-CD20 therapies and fingolimod disrupt lymph node function and hence antibody production. It is clear this is not an all or nothing response as some patients can make antibodies. 

T-cells

It is important to stress that vaccine immunity is not all about antibody responses and that T-cell responses are also important. 

A Swiss study has just shown that in anti-CD20 treated patients 50% had antibodies against the spike protein after their second dose of an mRNA-COVID-19 vaccine; this compared to 100% of controls. More importantly, 17% of patients and 86% of healthy controls had a T-cell response, with only 5% of patients, but 86% of healthy controls showing positive results in both the antibody and the T cell assays. The time elapsed since the last dose of an anti-CD20 therapy (>7.6 months), peripheral blood B-cell numbers from reconstitution (CD19+ cells >27/µl) and CD4+ T-lymphocyte counts above 653/µl predicted an antibody vaccine response. 

In contrast, a US study of anti-CD20-treated pwMS showed a reduced antibody response to the vaccine in most patients. But 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. Importantly all patients treated with anti-CD20 therapies in this study generated T-cell responses following vaccination.

I think these conflicting results are probably due to differences in the methods used. 

Context

I will now try and put this into context. 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 their innate immunity 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 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.  Does this make sense?

Therefore 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. 

My message, therefore, remains the same; patients on anti-CD20 therapy or an 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, I 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 an S1P modulator is particularly dangerous. Conversely, the longer duration of action of anti-CD20 therapies makes rebound disease activity after withdrawal less of an issue. Despite this, I do not know whether delaying dosing of anti-CD20 is necessary, for how long and/or what level of B-cell reconstitution is required to optimise vaccine responses. I anticipate data to help us make a decision around this issue will emerge in the next few months and we will also find out if pwMS on these therapies, who are vaccinated against COVID-19, albeit suboptimally from an immunological perspective, have enough immunity to prevent COVID-19 in any shape or form. 

I would like to conclude by saying that pwMS need to have seasonal influenza vaccines, 5-year pneumococcal vaccines and travel vaccines as required and perhaps a seasonal/booster COVID-19 vaccine. At some point pwMS 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. 

It is vital that you balance the small absolute risks of suffering severe COVID-19 and a 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. The latter is my biggest concern; I suspect in hindsight the MS community will be seen to have overreacted to the potential risks posed by COVID-19 and the vaccine readiness issue.

Please #GetVaccinatedASAP

MS-Selfie

Conflicts of Interest

Twitter

LinkedIn

Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as generic advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.