#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0


Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side. 

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination. 

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP. 

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug.  So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines. 

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Not a lot of rose-tint there if you take fingolimod 🙁 I’m curious why you remain optimistic about T-cell response when the authors of the paper basically concluded that a vaccine given to someone on fingolimod is a waste of vaccine.

    • They also had the same view with ocrelizumab, when I saw the work presented a month ago. There are a number of papers clearly showing a T cell response in vaccinated anti-CD20 (not MS) treated individuals.

      P.S. ProfG is a glass half full person

    • Re: “fingolimod is a waste of vaccine”

      I don’t agree with this. PwMS on fingolimod get better from COVID-19. How do you think this happens? Antibodies? No innate immunity and T-cells. Why then wouldn’t they generate a T-cell response to a vaccine?

  • “So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod”-> What about siponimod?

    • You are quite possibily right but S1P3 is involved in B cell shuttling in lymph glands and ozanimod, ponesimod, siponimod do not bind to S1P3 unlike fingolimod however I am guessing S1P1 is at the heart of it but this needs to be shown. I guess it is now a headache for all the new manufacturers

    • Re: Siponmod

      I say the following in the post: “As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines”.

  • Not having access to a vaccine before starting cladribine, I am pleased to read the results of this study. I found the Tables they presented in the paper to be very helpful.

    MD/Prof. G – Could you provide some insight around this statement from the study. Specifically, what does this figured indicate……p=0.0211?

    “ANOVA model analysis of SARS-CoV-2 antibody titer by DMT adjusted for age, time from the last dose to COVID-19 vaccination, and lymphocyte count, demonstrated a significant effect of time from last treatment dose to vaccination for MS patients treated with cladribine (p = 0.0211)”

    P.S. Glad to see the Spring sun had encouraged Prof. G to dust off his rose tinted glass. Peace and Love, Peace and Love.

    • In the study there were no one vaccinated less than 4 months and the level of antibody would have been higher the longer the time gap between dose and vaccination I think

  • Prof G, doesn’t the fingo data in this paper, and the outcomes of patients on fingo in CoviMS published recently highlight the fact that the T cell response to SARS-COV2 is significantly more crucial than the antibody response?

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