#MSCOVID19: to delay anti-CD20 dosing or not

Barts-MS rose-tinted-odometer: ★ (It’s a Black-and-White Friday #000000 & #FFFFFF)

At the beginning of the COVID-19 pandemic, we made the case that B-cells and antibodies against SARS-CoV-2 were not necessary to clear the coronavirus and protecting you from severe disease. However, almost all emerging data challenges this position, therefore I have changed my position.  

It is now clear that cross-reactive immunity from common coronavirus infections provides some protection from COVID-19. IVIG (intravenous immunoglobulin) formulations collected prior to COVID-19 contain neutralizing anti-SARS-CoV-2 antibodies and may have contributed to the survival of agammaglobulinaemic patients who had COVID-19. 

Neutralizing monoclonal anti-SARS-CoV2 antibodies have been shown to be effective against COVID-19 and severe COVID-19 and are now part of our therapeutic armamentarium for treating COVID-19. 

People on anti-CD20 therapy are more likely to get COVID-19, severe COVID-19, are more likely to need ITU and hence more likely to die from COVID-19. 

The study below shows that antibody neutralization levels against SARS-CoV-2 and the observed protection from SARS-CoV-2 infection are clearly related. In other words, anti-SARS-CoV-2 antibodies are important.  

They estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean antibody level in convalescent serum from people who have recovered from COVID-19. The estimated neutralization level required for 50% protection from severe infection was significantly lower at 3% of the mean convalescent level. This means you need fewer antibodies to protect you against severe disease. Another interpretation, which I think is more likely,  is that antibodies are a marker of protective T-cell immunity. 

Worryingly the modelled decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained as you need less antibody. Again the latter may be due to T-cell immunity that must be present in the background. Despite this, it is quite clear that antibody neutralization level is highly predictive of immune protection be it via the antibodies themselves or the associated T-cell immunity. 

This study implies that if you don’t have antibodies you won’t be protected. The question that needs to be urgently answered is ‘ is T-cell immunity in the absence of antibody immunity sufficient to protect you against SARS-CoV-2 infection and severe disease?’. Unfortunately, we don’t have real-life data on this at the moment. 

My interpretation of this – based on the observation that people who are on anti-CD20 therapy have a higher risk of severe COVID-19 and hence have on average less cross-reactive anti-SARS-CoV-2 neutralizing antibodies – is that if possible it would be better to have anti-SARS-CoV-2 antibodies than not to have them. The is really important for pwMS on anti-CD20 therapies or S1P modulators who have blunted antibody responses to the COVID-19 vaccines. This is why I have moved my position from getting vaccinated ASAP to let’s time your vaccine to give you the best chance of seroconverting. This means waiting for B-cell reconstitution post-anti-CD20 before vaccinating

An adaptive vaccination/vaccine-booster strategy is logistically challenging for the simple reason that B-cell reconstitution post anti-CD20 therapy is quite variable. This means that after a certain period of time, say 9 months after your last dose of ocrelizumab, 6 months after your last dose of rituximab and 4 months after your last dose of ofatumumab you will have to have monthly B-cell counts to make sure your peripheral B-cell count is above 10 B-cells/mm3 before you can get vaccinated. I also suspect we will then have to check if you seroconvert and if not re-vaccinate you before redosing with the relevant anti-CD20. 

What this strategy won’t answer is even if these patients make an antibody response will the antibody and associated T-cell responses are good enough to protect you from infection or reinfection with the emerging variants? 

So until we have more evidence I am sitting on the fence. It is only fair to tell pwMS about the problem and the uncertainty around this issue and give them the choice to delay or miss their next dose of anti-CD20 therapy. So far some patients are delaying their next course of treatment and others are not on the grounds that they are not prepared to take a chance of undertreating their MS. A lot of the former group of patients are older with more comorbidities and hence are at higher risk of dying from COVID-19. In contrast, the latter group tend to be younger and hence are more willing to take their chances if they get COVID-19. As with all decisions around managing MS during the COVID-19 pandemic, there are no easy black-and-white answers. 

What is clear from this study below is that there is a clear hierarchy when it comes to vaccine potency with the mRNA vaccine, Moderna in particular, being superior to the other vaccines in inducing protective immunity. So if you have a choice I would go with one of the mRNA vaccines when it comes to maximising your antibody levels.

Image from Nature Medicine.

Khoury et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211. 

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

73 tomorrow – some achievement

Barts-MS rose-tinted-odometer: ★★★★★ (Today’s colours are NHS blue & yellow #005EB8 & #FAE100)

Tomorrow the NHS turns 73. If you love the NHS and want to give it and its staff a present please have your COVID-19 vaccine. Barts Health NHS Trust and many other NHS services are running walk-in vaccine centres.


We are now in the long tail of this pandemic and the sooner we all get vaccinated the sooner the curve will flatten and the tail will get shorter.

Thank you.  

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

#MSCOVID19: T-cells and anti-CD20 therapy

Barts-MS rose-tinted-odometer: ★★★

I have hypothesised that the reason pwMS on anti-CD20 therapy are at greater risk of getting COVID-19 and severe COVID-19 is not about the now, but the past. There is really no reason why a pwMS on anti-CD20 therapy is at increased risk of getting exposed to SARS-CoV-2 compared to pwMS on other DMTs, be it injectables, oral tablets or other infusion therapies. However, people on anti-CD20 therapies are likely to have blunted cross-reactive immune responses to community-acquired coronaviruses. This cross-reactive immunity is protective and reduces your chances of getting symptomatic or severe COVID-19, in other words in the figure below, cross-reactive immunity shifts the population to the left and being on an anti-CD20 therapy prevents this immunity from developing and shifts the curve to the right. I hope this makes sense. 

In the study below on healthcare workers, SARS-CoV-2 cross-reactive antibodies elicited by past common community-acquired coronavirus infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher antibody titers, i.e. less severe infection. 

As antibody titers decline over time after common coronavirus infections, individuals with higher anti-coronavirus antibody titers are more likely to be recently infected with community-acquired common coronaviruses compared to individuals with lower antibody titers. Therefore recent community-acquired coronavirus infections are likely to prevent or reduce the severity of COVID-19 in line with my hypothesis above. What is different is that this protection is unlikely to be purely antibody-mediated, but rather T-cell responses are likely to be responsible for this protection. 

What is the relevance of these findings? I suspect that anti-CD20 therapies also blunt protective T-cell responses; possibly by reducing the efficiency of SARS-CoV-2 antigen presentation to T-cells. Based on this study and what happens to people on anti-CD20 who get COVID-19 I would not be surprised if T-cell COVID-19 vaccine responses on anti-CD20 therapies are blunted, similar to antibody responses. The good news is that we won’t have to wait too long for this data to emerge. 

Please note, although interesting, this data does not change my current advice, i.e. #StayCalm and #GetVaccinatedASAP

Gouma et al. Sero-monitoring of health care workers reveals complex relationships between common coronavirus antibodies and SARS-CoV-2 severity. MedRxIV 2021 https://doi.org/10.1101/2021.04.12.21255324

Recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection, however the immunological mechanisms involved are unknown. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 severity. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (βCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher βCoV antibody titers were more likely recently infected with common βCoVs compared to individuals with lower antibody titers. Therefore, our data suggest that recent βCoV infections potentially limit the severity of SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common βCoV infections transiently reduce disease severity following SARS-CoV-2 infections.

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.

COVID-19 vaccine thrombosis update

Barts-MS rose-tinted-odometer: ★★

Last week I heard from an Italian colleague that in Italy when many people arrive for the COVID-19 vaccine slot and find out that the vaccine on offer is the Oxford-AstraZenca (AZ) vaccine they say no thank you and leave. The main reason they give for turning down the AZ vaccine is the thrombosis risk. I wonder if these people are aware of the new data that emerged last week (see below). 

In this big data study from the US, the incidence of cerebral venous thrombosis (CVT) after COVID-19 diagnosis was 39.0 cases per million people who get COVID-19. This was higher than the CVT incidence after influenza (0.0 per million people or adjusted relative risk = 6.7) or after receiving the Pfizer-BionTech or Moderna RNA vaccines (4.1 per million people, adjusted relative risk = 6.4 higher).

The bottom line is COVID-19 is way riskier than the COVID-vaccines in causing thrombus and contrary to a common belief the risk is not only restricted to the AZ or J&J vaccines, which use adenoviral vectors but with the COVID-19 mRNA vaccines well. This suggests it may be the immune response to the SARS-CoV-2 spike protein that induces cross-reactivity and sets up a very rare thrombotic state.  

It is never easy to explain risks and relative risks, but the following infographic doing the rounds on social media may help. What do you think? 

Please #StayCalm and #GetVaccinatedASAP

Taquet et al. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. OSF 15-April-2021.

Using an electronic health records network we estimated the absolute incidence of cerebral venous thrombosis (CVT) in the two weeks following COVID-19 diagnosis (N=513,284), or influenza (N=172,742), or receipt of the BNT162b2 or mRNA-1273 COVID-19 vaccines (N=489,871). The incidence of portal vein thrombosis (PVT) was also assessed in these groups, as well as the baseline CVT incidence over a two-week period. The incidence of CVT after COVID-19 diagnosis was 39.0 per million people (95% CI, 25.2–60.2). This was higher than the CVT incidence after influenza (0.0 per million people, 95% CI 0.0–22.2, adjusted RR=6.73, P=.003) or after receiving BNT162b2 or mRNA1273 vaccine (4.1 per million people, 95% CI 1.1–14.9, adjusted RR=6.36, P<.001). The relative risks were similar if a broader definition of CVT was used. For PVT, the incidence was 436.4 per million people (382.9-497.4) after COVID-19, 98.4 (61.4-157.6) after influenza, and 44.9 (29.7-68.0) after BNT162b2 or mRNA-1273. The incidence of CVT following COVID-19 was higher than the incidence observed across the entire health records network (0.41 per million people over any 2-week period). Laboratory test results, available in a subset of the COVID-19 patients, provide preliminary evidence suggestive of raised D-dimer, lowered fibrinogen, and an increased rate of thrombocytopenia in the CVT and PVT groups. Mortality was 20% and 18.8% respectively. These data show that the incidence of CVT is significantly increased after COVID-19, and greater than that observed with BNT162b2 and mRNA-1273 COVID-19 vaccines. The risk of CVT following COVID-19 is also higher than the latest estimate from the European Medicines Agency for the incidence associated with ChAdOx1 nCoV-19 vaccine (5.0 per million people, 95% CI 4.3–5.8). Although requiring replication and corroboration, the present data highlight the risk of serious thrombotic events in COVID-19, and can help contextualize the risks and benefits of vaccination in this regard

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.

Stay calm and get vaccinated

Barts-MS rose-tinted-odometer: ★★★

We can speculate until the cows come home, but speculation remains guesswork. Until a similar study to the one below on T-cell responses to the COVID-19 vaccine is done in people with MS on different DMTs we can’t be confident that people who don’t seroconvert after the vaccine have adequate or protective anti-SARS-CoV2 spike protein T-cell responses.

However, my message remains the same around vaccinations. The COVID-19 vaccines are safe and we don’t have any reason to suspect the vaccines have any effect on your MS in the long term. Apart from transient worsening of symptoms, which are reversible, in response to the flu-like symptoms from the vaccine pwMS seem to be tolerating the vaccine without any problems. The latter is more common in patients with advanced disability and can be managed with prophylactic paracetamol and/or ibuprofen. 

Good things come to communities who are patient. My advice would be to stay calm and #GetVaccinatedASAP

Image from bioRxiv

Painter et al. Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. bioRxiv 2021 doi: https://doi.org/10.1101/2021.04.21.440862

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naive subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.

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.

#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.

#MSCOVID19: antibody testing post-vaccine

Barts-MS rose-tinted-odometer: ★★★

Should I get an antibody test to prove that I have responded to the COVID-19 vaccine? No, you shouldn’t. Most diagnostic COVID-19/SARS-CoV-2 antibody tests are based on detecting antibodies to the so-called nucleocapsid protein and not the spike protein, which is the protein or immunogen used in the current vaccines. There are, however, a few private laboratories that are providing anti-spike protein antibody tests. However, antibody levels both from wild-type SARS-CoV-2 infection and the vaccine are not long-lasting and will wane with time. They also don’t tell us about T-cell responses. So even if you don’t seroconvert and are found to have no anti-spike protein antibodies post-vaccine you may still have immunity to the virus, which is likely to protect you from getting severe COVID-19. 

At the moment we don’t know what to do with the seroconversion information, i.e. in patients who don’t seroconvert do we revaccinate them? At the moment vaccinologists are saying no. I am a firm proponent of only doing tests as part of routine clinical practice if you are going to act upon them. As I won’t act on the information that somebody has or has not seroconverted post-vaccination I don’t want to know the result.

Yes, this information also applies to pwMS on anti-CD20 therapies (rituximab, ocrelizumab, ofatumumab) or S1P modulators (fingolimod, siponimod, ozanimod, ponesimod). I suspect when we see the data in pwMS on these two classes of therapy, those who don’t seroconvert will still have effector T-cell responses to the spike protein. Clearly, if the data shows I am wrong we will have to adapt our vaccination practice(s). This will then be evidence-based. However, until then #GetVaccinatedASAP

One can ask what have we learnt from the COVID-19 saga? As they say, hindsight is 20/20 or perfect vision. However, at the time the pandemic hit us I think we the MS community overreacted to the potential risks associated with SARS-CoV-2 and COVID-19 in relation to MS and DMTs and now we are overreacting to the vaccine readiness issue. 

It is quite clear from the study below that COVID-19 seronegative care home residents make a reasonably good anti-spike antibody response from the vaccine. This is telling me that they have immunological memory and that the immune system responds robustly to the vaccine. I see no reason why this won’t happen to pwMS on DMTs. Not having an antibody response or losing an antibody response to the SARS-CoV-2 be it from wild-type infection and/or a vaccine doesn’t mean you have lost your immunity to the virus; in all likelihood, it will be there to protect you from getting severe COVID-19. 

from JAMA

Blain et al. Spike Antibody Levels of Nursing Home Residents With or Without Prior COVID-19 3 Weeks After a Single BNT162b2 Vaccine Dose. JAMA. Published online April 15, 2021. doi:10.1001/jama.2021.6042

Conflicts of Interest

Preventive Neurology




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

#MSCOVID19: triMSx-online

You may remember that about 6 years ago the idea was germinated on this blog to launch an online version of ECTRIMS to reach people in low- and middle-income countries and to allow more women with family commitments to attend meetings. The other aim was to usher in the next generation of young MSologists; more women, younger people, more ethnic diversity and from all regions of over the world, i.e. not stale, pale and male 😉 Unfortunately, ECTRIMS didn’t want us to use the name OCTRIMS so we launched with the name triMS-online.

The concepts behind triMS-online have now been adopted, in part, because of COVID-19 by many other conference organisers. However, we think we have something special and we are not just trying to duplicate the face-2-face 3-5 day conferences the other platforms are doing. Since launching triMS-online we have extended the concept into standalone themed meetings with single sponsors. These meetings are to address specific unmet needs and hot topics.

The next triMSx-online meeting, which is being held this evening and tomorrow evening, is covering COVID-19 vaccines and their relevance to MS. If you have not registered please do so now. Don’t worry if you can’t watch it live the talks will be recorded and available via the triMSx-online portal for asynchronous viewing. In addition, we will be also doing a podcast on the meeting for you to listen to in your own time.

COVID-19 and MS: where are we now and where next?

8 and 9 April 2021
19:00–19:45 BST I 14:00–14:45 EDT I 20:00–20:45 CEST

CoI: multiple

Why does fingolimod affect antibody responses?

Barts-MS rose-tinted-odometer:  ★

The Twittersphere is abuzz with the preliminary seroconversion rates in Israelis patients with MS on various DMTs in response to the Pfizer-BionTech COVID-19 vaccine (see below). As expected the antibody seroconversion rates in response to anti-CD20 therapies and S1P modulators are blunted and in most cases inhibited. The backstory or biology around anti-CD20 therapy is well-rehearsed; anti-CD20 therapy depletes B-cells and annihilates germinal centres in lymph nodes and the spleen.

The question I have just been asked is why does fingolimod block antibody responses? To answer this we need to go back to the basics of immunology. 

Fingolimod and other S1P modulators work by internalising the S1P receptor making lymphocytes unresponsive to the S1P signalling or chemotaxis gradient in secondary lymph organs such as lymph nodes. In lay language, this causes lymphocytes to park-up in a long-term car park with a wheel lock-on. Even if you wanted to drive your car out of the car park by starting it up you wouldn’t be able to move it without removing the wheel-lock (fingolimod). By blocking lymphocyte mobility helper T-cells can’t migrate to the so-called germinal centres in the lymph nodes and spleen to help B-cells switch from IgM to IgG antibody production and to then help the B-cells to affinity mature their antibodies, i.e. to make good quality antibodies. Normally these affinity matured B-cells would leave the germinal centre to become memory B-cells or plasmablasts. The plasmablasts then mature to become plasma cells and produce high-quality antibodies, which in the case of anti-spike protein protect you from getting COVID-19 in particular severe COVID-19. Fingolimod and other S1P modulators prevent this normal immunology from happening hence the low or absent anti-COVID-19 antibody response after COVID-19 vaccination.

I like to think of the germinal centres as being the immune system’s university; this is where the immune system sends its primed T-cells to help educate B-cells. After a brutal natural selection process in the germinal centres, a few B-cells survive and graduate with a PhD, i.e. a highly specialised degree or class-switched high-affinity IgG antibodies. This then allows the B-cells to become memory B cells and go into semi-retirement or to set-up their own production company as plasma cells and to produce high-quality antibodies. Anti-CD20 therapies work by blowing up the B-cell university and S1P modulators stop the teachers (T-cells) from educating their students (B-cells). Having no university or no teacher-student interactions have the same effect and result in no educated B-cells and hence no IgG antibody responses.

Please note the above information does not change my personal advice regarding vaccination, whether you are on an anti-CD20 therapy, fingolimod or another S1P modulator (siponimod, ozanimod, ponesimod) #GetVaccinated ASAP; some immunity is better than no immunity. Please note having no anti-SARS-CoV-2 antibodies doesn’t necessarily mean you have no immunity. These antibody studies don’t tell us anything about T-cell responses, which are likely to be as important as antibodies in providing protecttive immunity against SARS-CoV-2.

Han et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood. 2004 Dec 15;104(13):4129-33. doi: 10.1182/blood-2004-06-2075. Epub 2004 Aug 19.

FTY720 is a novel immunosuppressant that is highly effective in inhibiting rejection of allografts and autoimmunity in various animal models. It has been shown that the sphingosine 1 phosphate (S1P) receptors are the direct molecular targets of FTY720. However, the mechanisms responsible for inhibiting specific immune responses by FTY720 are not well resolved. In particular, there is no available information on whether or how this compound affects humoral immunity. We have investigated the effect of FTY720 treatment on B-cell response during the immune response to a well-defined T-dependent antigen. Our data demonstrated that germinal center reaction was significantly reduced in peripheral lymphoid tissues of mice treated with FTY720. In addition, FTY720 treatment inhibited the production of high-affinity, class-switched antibodies, but not the production of low-affinity, immunoglobulin M (IgM) antibody. Consistently, FTY720 did not have a significant effect on antibody response to a T-independent antigen. Our results may have important implications in application of FTY720 in immune regulation.

Also see the post by MD from a few days ago. Fingolimod also stops B cells moving within the follciles and and stops them contacting areas where they the B cells are likely to be stimulated.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush

Barts-MS rose-tinted-odometer: ★★★★★

I think the North American MS community have made some mistakes with their COVID-19 vaccine recommendations, in particular, the NMSS COVID-19 vaccine guidelines for cladribine. In view of the immunology of cladribine’s mode of action and new data that is emerging, I would suggest the NMSS considers updating its guidelines. 

Lemtrada and Mavenclad

If you are about to start Lemtrada or Mavenclad, consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is done 4 weeks or more prior to starting Lemtrada or Mavenclad. If you are already taking Lemtrada or Mavenclad, consider administering the vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose2. When possible, resume Lemtrada or Mavenclad 4 weeks or more following the second vaccine injection. This suggested scheduling is not always possible and getting the vaccine when it becomes available to you may be more important than timing the vaccine with your DMT. Work with your MS healthcare provider to determine the best schedule for you.

Lumping cladribine and alemtuzumab together as being immune-depleters of the same ilk is simply wrong. Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes. This is why there is a major infection signal (e.g. listeriosis) with alemtuzumab in the 4-6 weeks after each course of treatment. The latter does not occur with the doses of cladribine we use to treat people with MS.

In comparison, the mode of action of cladribine is very subtle and more in keeping with a selective B-cell depleting agent. Cladribine depletes B-cells by about 85-90% and hits mainly memory B-cells, in other words, large numbers of naive B-cell persist in the peripheral blood. We think as memory B-cells are being killed fresh naive B-cells are being released from the bone marrow. This is important because it is the naive B-cell population that is required to make new antibody responses to vaccines. 

Cladribine only depletes T-cells by about 50% a level that in general is not sufficient to put patients at risk of opportunistic infections or even viral infections. When we recently reanalysed all of the cladribine safety data there was no novel or new exogenous (from outside the body) viral infection signal. The only viral infection signal we saw was zoster or shingles, i.e. a reactivation of a latent virus, which is common and occurs with all immunosuppressive therapies. 

Another very big difference between cladribine and alemtuzumab is the fact that cladribine leaves the innate immune system intact, which is important for fighting infections and for processing vaccine antigens and presenting them to the immune system. 

Another factor that is different is the temporal profile of immunodepletion that occurs with alemtuzumab and cladribine. Alemtuzumab causes rapid cell lysis with its effect noticeable in hours to days; in other words, peripheral blood lymphocyte and monocyte counts are depleted to very low levels (nadir) very quickly. In comparison, cladribine works by triggering apoptosis of cells and lymphocytes die slowly over weeks to months reaching a nadir at about 3 to 4 months after each course. Therefore for the NMSS guidance to say “consider administering the vaccine injections starting 12 weeks or more after the last Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose” is actually recommending giving the vaccine from the start of the nadir. 

Unlike alemtuzumab, I think the timing of vaccination in patients treated with cladribine is unlikely to make much of a difference because both the afferent (antigen processing and presentation) and efferent (B-cells/antibodies and T-cells) limbs of the immune system is intact, i.e. there is enough hardware or cells at all times post cladribine to make an immune response. Saying this the summary of product characteristics of cladribine clearly states that live vaccines should be avoided until the immune system has reconstituted and the cells counts have returned to normal. Please note this refers to live vaccines and doesn’t apply to the currently licensed COVID-19 vaccines, which are not live attenuated vaccines or LAVs.

The good news is that the above predictions are being borne out by some real-life flu and VZV vaccine data in cladribine-treated patients that have been presented at ACTRIMS this week. My interpretation of this data is that regardless of when a vaccine is administered in patients on cladribine the appear to mount a good antibody response. I agree the number of subjects studied is small and no subject has had grade 4 lymphopaenia (<200/mm3), but these data at least confirm what you would expect to happen based on immunological principles. 

My advice, therefore, remains the same for pwMS on DMTs; during the height of the pandemic having some immunity to SARS-CoV-2 is better than having no immunity. This is why you should get vaccinated ASAP. If you live in an environment where the background risk of COVID-19 is low then you may want to optimise the timing of your vaccine, when you are next dosed with an immunodepleting therapy or when you start or switch therapies.

Roy & Boschert. Analysis of Influenza and Varicella-Zoster Virus Vaccine Antibody Titers in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets. P059 – ACTRIMS 2021

Background: There is a lack of data available to determine the effect of cladribine tablets (CladT) on the antibody response to vaccination in patients with relapsing multiple sclerosis (MS).

Objectives: To investigate the immunoprotective response to seasonal influenza and varicella-zoster virus (VZV) vaccination in patients treated with CladT (3.5mg/kg over 2 years) for relapsing MS.

Methods: Blood samples collected during the MAGNIFY-MS study (NCT03364036) from 9 patients with relapsing MS treated with CladT who received seasonal influenza (n=8) or VZV vaccinations (n=1; Shingrix) as a standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CladT and closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers in response to the seasonal influenza and VZV vaccine were measured by hemagglutination inhibition (HAI) assay and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The seroprotection titer level for the seasonal influenza vaccine is considered ≥40, and was ≥100 IU/L for the VZV vaccine.

Results: Influenza: All patients vaccinated against influenza A and B during year 1 or 2 of CladT treatment retained seroprotection titers of ≥40 in post-vaccination samples across all strains present in the vaccine administered. The number of seropositive patients (HAI ≥40) with a ≥4-fold and ≥2-fold increase against at least 1 strain in post-vaccination titers were 3/8 and 7/8, respectively. VZV: Post-vaccination antibody titers were 40-fold increased over the protective titer at all time points (titers >4748 IU/L).

Conclusions: In this small retrospective investigation, post-vaccination antibody titers in patients treated with CladT for relapsing MS remained at levels that offer protective immunity against seasonal influenza and VZV.

Wu et al.  Evaluating the Impact of Cladribine Tablets on the Development of Antibody Titers: Interim Results from The CLOCK-MS Influenza Vaccine Substudy. P071 ACTRIMS 2021

Background: Cladribine tablets have been approved in more than 80 countries for the treatment of relapsing forms of multiple sclerosis (RMS), and are hypothesized to function as an immune reconstitution therapy with potential to cross the blood-brain barrier. The CLOCK-MS study (cladribine tablets: collaborative study to evaluate impact on central nervous system biomarkers in multiple sclerosis), is a 24-month, open-label, randomized, multicenter, collaborative Phase IV biomarker research study. The COVID-19 pandemic, and pending vaccine availability, have raised important questions around the impact of MS disease modifying therapies on vaccine efficacy.

Objectives: To evaluate the potential impact of prior treatment with cladribine tablets on the development of antibody titres post-influenza vaccination via a sub-study of CLOCK-MS.

Methods: The CLOCK-MS main study will enroll approximately 50 subjects age 18-65, diagnosed with relapsing-remitting MS or active secondary progressive MS, who had inadequate response to, or were unable to tolerate, an alternate drug indicated for the treatment of RMS. Study participants who have taken at least one dose of cladribine tablets and are planning to obtain one standard-of-care influenza vaccine are eligible to take part in the sub-study if they consent to blood draws. Blood sampling will occur 1) 3 Weeks Pre-Vaccine (within 21 days prior to obtaining a standard of care vaccine), 2) 4 Weeks Post-Vaccine (+/- 7 days), and 3) 6 Months Post-Vaccine (+/- 7 days). Measurements of antibody responses will be performed.

Results: So far 5 patients have been enrolled in this sub-study and had initial titers drawn. All patients fulfilled the per-label requirements for vaccination after cladribine tablets treatment. Initial results at Week 4 post-vaccination will be presented.

Conclusions: The impact of cladribine tablets, a lymphocyte-lowering agent, on the immune system’s ability to develop antibodies in response to a vaccine has not yet been studied. These results are expected to provide preliminary observations around the impact of cladribine tablets on influenza vaccine efficacy in patients with RMS.

CoI: multiple

Twitter: @gavinGiovannoni                                      Medium: @gavin_24211