#MSCOVID19: CATCH-22

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Barts-MS rose-tinted-odometer: ★

I know it sounds like a cliche but Catch-22 would definitely be on my list of most impressionable books I read as a teenager.  I liked it because of its dark satirical humour, it was written in the third-person and it taught me how absurd war actually is. Catch-22 (and the Great Gatsby) also taught me if you love a book you should never watch the movie; the screenwriters, actors and directors can never do your imaginary characters justice. 

The book has become so influential that ‘Catch-22’ has become a noun and refers to a dilemma or difficult circumstance from which there is no escape because of mutually conflicting or dependent conditions. 

Although I am meant to be at home recovering from injuries I am doing some emails. Over the last few days, I have received numerous emails from patients and neurologists asking for advice about COVID-19/SARS-CoV-2  vaccines and DMTs and what am I telling my patients. One patient tells me that her neurologist referred her the excellent MS Society webpage for advice, but the site then referred her back to her neurologist for definitive advice. A Catch-22?

Some US neurologists have picked-up that my advice and position on vaccines and vaccine readiness has changed since I first started talking about this issue on the blog. They are correct, my position has changed. I always took the position that we should continue to manage MS the way we managed it before COVID-19 with certain caveats* around the risk of being exposed to SARS-CoV-2 and whether or not individuals could self-isolate or not, and that we should cross the vaccine bridge when it arrives. Now that the vaccines are arriving and the ambitious national roll-out suggests the whole country will be vaccinated within the next 6 months, advice has to be given and given quite quickly. 

In my opinion, all the COVID-19 vaccines that the UK Government has purchased can be used in people with MS regardless of whether or not they are on a DMT. This advice is based on the fact that the MHRA and other regulatory bodies have licensed or will license these vaccines because of their safety and efficacy profile in the general population. 

Importantly none of these vaccines is likely to be a ‘live viral vaccine’. There is some confusion around the Oxford-AstraZeneca vaccine that does use a chimpanzee adenovirus vector to deliver the immunogen to our cells so that the immunogen can be expressed. The virus in this vaccine is able to infect cells and express its relevant proteins, but because some of its genes for replication have been mutated it cannot replicate itself and cause ongoing infection. I am not sure how this vaccine will be classified by the MHRA or other regulatory authorities, but in my opinion, it is likely to be safe to use in pwMS. 

I say these vaccines are likely to be safe in pwMS. However, none of the COVID-19 vaccines has specifically been tested in pwMS so we have to extrapolate data from the general population data. There may be something we don’t know about having MS that predisposes pwMS to some rare complications. However, based on other vaccines that have been used in MS this is very unlikely. 

It is clear that being on some immunosuppressive DMTs may reduce your chances of responding adequately to the vaccine and hence being fully immune to infection from wild-type SARS-CoV-2. Until we do detailed immunological studies in pwMS on each DMT we won’t be able to answer specific questions about each DMT with certainty. 

Interferon-beta , glatiramer acetate and immune reconstitution therapies

In general being on interferon-beta and glatiramer acetate, immunomodulatory DMTs, are unlikely to interfere with vaccine responses. Similarly, if you have had one of the immune reconstruction therapies, such as alemtuzumab, cladribine, mitoxantrone or HSCT in the past and have reconstituted your peripheral immune system you should respond to the vaccines. If on the other hand, you have not had completely reconstitution of your immune system you may still consider having the vaccine, but the immune response may be blunted. Waiting for immune reconstitution or having the vaccine now will be a trade-off between wanting to protect yourself now or waiting months when the pandemic may be almost over. Please note vaccination is not only about you, but slowing and preventing transmission of the virus in the general population, which is a factor you may want to consider. This may relevant, for example, if you want to see unvaccinated vulnerable relatives or if you want to travel to parts of the world with a delayed vaccination programme.  

Fumarates, teriflumide and natalizumab

If you are fumarates (DMF,  diroximel fumarate), teriflunomide or natalizumab, based on other vaccine studies, COVID-19 vaccine responses are likely to be reasonably preserved. Therefore there is no need to stop these DMTs or delay getting a vaccine if you are on these treatments. 

S1P modulators

For the so-called S1P modulators (fingolimod, siponimod, ozanimod and ponesimod) vaccine responses are likely to be blunted, but whether or not the blunted responses will be sufficient to prevent SARS-CoV-2 infection is a moot point.  However, I would not recommend stopping these treatments to have a vaccine as these therapies are associated with MS rebound activity. My advice would be that if you are on these therapies to go ahead with the vaccine when it is offered to you. 

Anti-CD20 therapies

When I initially wrote about vaccine hesitancy I suggested that pwMS on an anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab) may have to delay their next infusion or miss one or two infusions to allow B-cell reconstitution before they have a coronavirus vaccine. Since making this statement more immunological data has emerged and there really is no definitive evidence to support this position. 

Yes, I agree that in general people on anti-CD20 therapies have blunted antibody responses to wild-type SARS-CoV-2 infection and to other vaccines including vaccines with containing new antigens that the immune system has not seen before. However, this doesn’t mean these people haven’t developed immunity to the infection or vaccine that is long-lasting. For one the vast majority of pwMS on an anti-CD20 therapy who get COVID-19 make an uneventful recovery. Why? Almost certainly this recovery is due to cellular and not humoral (antibody) immunity and this immunity won’t vanish and is likely to persist longterm. 

Even normal people who have had COVID-19 and who lose their antibody responses still have detectable cellular immunity. My interpretation of this data is that pwMS who are on an anti-CD20 therapy should simply go ahead and have the coronavirus vaccine when it is offered to them and not to worry about whether or not they mount an antibody response. 

I am aware that some pwMS are planning to delay their next infusion regardless of what I or their HCP says. The question I ask is for how long? One, two, three or more months? Some pwMS plan to wait for peripheral B-cell reconstitution that can take months to years to occur and even then there is no consensus of what normal B-cell reconstitution looks like. You need to weigh the lack of evidence that delaying your next anti-CD20 therapy or waiting for B-cell reconstitution will make any difference to your vaccine response against the time-sensitive nature of the vaccine to protect you during the high-risk period of the pandemic. If you wait too long and the pandemic is over the benefits of the vaccine will be reduced. 

The only evidence base we have at the moment is the recently published VELOCE study that delayed vaccination until 12 weeks after an initial course of ocrelizumab. This study showed blunted, but not absent, antibody responses to recall and new vaccines. Based on this study if you have just had a recent course of ocrelizumab you may want to delay getting the COVID-19 vaccine for 12 weeks after the last infusion. However, as 12 weeks is a long time to wait in the current climate I have been recommending at least 4 weeks; a pragmatic compromise.

In my opinion, it is more important for pwMS on anti-CD20 therapies to be vaccinated than to not be vaccinated. This is because vaccination policy is really about population, or subpopulation, health and stopping the spread of the virus and protecting the individual is a secondary aim. 

MS relapses

Will the COVID-19 vaccines trigger MS relapses? This hypothesis is based on extrapolating data on two non-peer-reviewed cases of CNS demyelination in the Oxford-AstraZenca (Ox-AZ) trial and several cases of transverse myelitis in patients who have had COVID-19. One case on in the Ox-AZ trial, who received the vaccine, had an initial attack or relapse and was subsequently diagnosed as having MS; i.e. I assume because they had pre-existing lesions and were now shown to have a second attack or new lesions consistent with dissemination in time. The other case had an episode of vaccine-related transverse myelitis (TM), which is relatively common with vaccines in general. Please note that vaccine-related TM is not MS. The only vaccine that has been reported to potentially trigger MS relapse is the live yellow-fever vaccine and this is based on one report that has subsequently not been replicated. Therefore, there is no current evidence that coronavirus infection or coronavirus vaccines trigger MS relapses. In my opinion, there is no reason to avoid the COVID-19 vaccine based on this hypothesis. Clearly, my opinion may change if new data emerges to the contrary.

Summary

If you have not had COVID-19 having a vaccine will offer you the opportunity of preventing getting COVID-19 or at least if you do get it, of having milder disease. All the licensed vaccines, which have been shown to be safe in the general population are likely to be safe in pwMS. Although some people on immunosuppressive therapies, in particular, S1P modulators and anti-CD20 therapies, may have blunted antibody vaccine responses these may still be sufficient to protect you against infection or at least severe COVID-19. There is no evidence that stopping or delaying treatment, in the hope of boosting vaccine responses will work and may result in you missing out on being protected when your risk of infection is highest. Please be aware that stopping some DMTs, in particular, natalizumab and S1P modulators, is associated with a rebound of disease activity and is not recommended. Hopefully, the pharmaceutical industry and the wider MS community will collect data and do specific studies to answer the many questions we have around vaccination and vaccine responses in pwMS on specific DMTs. 

* The caveats refer to alemtuzumab and HSCT, which affect both innate (monocytes and/or neutrophils) and adaptive (particularly cytotoxic CD8+ T lymphocytes), which are required for fighting SARS-CoV-2. My advice for the other DMTs has not to self-isolate, but to simply stick to the current government guidelines in relation to social distancing and personal hygiene. 

Bar-Or et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology October 06, 2020; 95 (14) 

Objective: The phase IIIb VELOCE study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.

Methods: Patients were randomized 2:1 into Group OCR (n=68; OCR 600mg); or Control (n=34;interferon-β or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax® (23-PPV) and keyhole limpet hemocyanin (KLH). Group OCR was subdivided into OCR1 (n=33) and OCR2 (n=35) at randomization. OCR1 received Prevnar® (13-PCV) 4 weeks after 23-PPV; OCR2 and Control received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (Group OCR) or on Day 1 (Control).

Results: Positive response rate to TT vaccine at 8 weeks was 23.9% in OCR vs 54.5% in Control. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in OCR and 100% in Control. Prevnar® did not enhance response to pneumococcal serotypes in common with Pneumovax®. Humoral response to KLH was decreased in OCR vs Control. Seroprotection rates at 4 weeks against five influenza strains ranged from 55.6–80.0% in OCR2 and 75.0–97.0% in Control.

Conclusion: Peripherally B-cell depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen, KLH, suggesting use of standard non-live vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR, as a potentially protective humoral response, even if attenuated, can be expected. Classification of evidence This study provides Class II evidence confirming that the humoral response to non-live vaccines in patients with RMS following ocrelizumab treatment is attenuated compared with untreated or interferon-β–treated patients, though can still be expected to be protective.

Twitter: @gavinGiovannoni                                   Medium: @gavin_24211

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.

37 comments

  • Thanks for this. Question: for those of us on an immunosuppressive DMT – such as cladribine (Mavenclad), Ocrelizumab (Ocrevus), alemtuzumab or fingolimod (Gilenya) or HSCT should we consider ourselves in the government’s “clincally extremely vulnerable” Number 4 group or in the “clinically vulnerable” Number 6 group?
    Best,
    Rachel H

    • The only people with MS who are extremely vulnerable are those who have recently had HSCT or alemtuzumab, i.e. in last few weeks are months, and still have suppressed innate immunity ( low monocytes and neutrophils) in combination with suppressed lymphocytes (grade 3 & 4) lymphopaenia. Please note the level of lymphopaenia is relative and its affected by other factors like age and other diseases.

      The other group of people who are extremely vulnerable will include those over 70, or over 60 with comorbidities, and those with and advanced disability and a history of recurrent chest infections and/or swallowing problems.

    • I’m classing myself as clinically extremely vulnerable as placed on the Shielded Patient List by my neurologist due to ocrelizumab. I’d rather be cautious if I’m honest so more than happy with being classed as CEV as this allows me to be supported to work from home which, given that I’m NHS staff, helps to protect me from COVID 19 exposure.

  • “the immune reconstruction therapies, such as alemtuzumab, cladribine, mitoxantrone or HSCT in the past and have reconstituted your peripheral immune system”

    Is mitoxantrone an IRT..?

    Thought it was just chemo…Interesting if it is as Dr. Terry Wahls claimed in her book her diet halted her spms but it came out that she had Mitoxantrone treatment.

  • Thank you so much for this. I’m having my vaccine at 8:30 tomorrow, super excited but Ive not been able to get through to my MS team on the phone so was slightly nervous about how all this was going to pan out. Looks like Im doing the right thing even if its a bit of an unknown. Thank you so much – very grateful for this information!

  • Thank you for this! I’m due my next course of ocrelizumab in the next month, and this makes me feel better about deciding to continue with it. Happy holidays!

  • Excellent, thank you for this timely advice. It will benefit and guide many MSers and their neurologists. Glad the vaccine may give me some protection despite my DMD. But The Willingness of my community to get the vaccine concerns me. It should concern everyone who wants COVID eradicated. Sometimes you need to witness to believe. https://tiktok.com/zmjgdop96/

  • Hi as someone with progressive MS I am reliant on my partner who is my carer for all aspects of my care air
    The flu vaccine is always given to my carer as well as myself so what will the guidelines be regarding a vaccine and my carer/partner,?

    • Originally the plan was to vaccineate in families but on the later iteration of the green book this was removed so I am guessing they will vacine per individual rather than per hosehold so I guesss you may get vaccine at different times

      • I have been reading that Age UK and various other people for example Ed Davey from the Lib Dems are pushing for carers to be vaccinated which makes complete sense
        If they get ill they cannot isolate from those who they care for in most cases.
        As usual unpaid carers get overlooked

  • I am very worried about vaccination. My major flare up and the one for which I was diagnosed occurred 2 years ago. The only major change I had before was being vaccinated with pneumococcus, smallpox and hepatitis vaccines. The latter two were boosts.

    I am very worried that my two years on Mavenclad are going to be affected if I get this SARS Co V2 vaccine. If possible, which of all the SARS Co V2 vaccines is the most suitable for me?

    • The only ones available in UK is Pfizer and in US Pfizer and Moderna, both are RNA vacines and should be suitable for you

  • I would advise patients who are on anti CD20 drugs to have the vaccine at the end of their treatment cycle ie at 6 months after the treatment was received and at least 3 weeks before the next treatment is due to maximise the response to the vaccine.

    • But you where is the evidence for this? That is the problem everyone makes assumptions the longer you wait the better. But as most people still have zero or very low B cell numbers in their peripheral blood at 6 months it may not necessarily result in a better antibody response. Also waiting 6 months means you miss out on potential immunity now at the height of he pandemic. In 6 months time, the pandemic is likely to be over.

  • Hi Prof G,
    A quick clarification– the study states that vaccines were given 12 weeks after OCR infusion rather than 4 weeks (as written above). Too bad they couldn’t power the study for several different post-OCR infusion timepoints to assess if antibody responses depended on this. Anyway, it’s still unclear to me from VELOCE whether there is any benefit to ‘waiting’ after an OCR infusion, so generally I am telling my patients to just get the vaccine as soon as it is offered rather than trying to ‘time’ it around OCR infusions. Like you say, the benefits of the vaccine are highest right now! And likely driven significantly by T-cell immunity, not B-cell.

    • You seem to be correct on dosing Schedule

      Benefits driven by T cells not B cell,s but hard to think B cells are totally unimportant, therefore it is important to collect data to properly inform.

  • My next ocrelizumab is due on 5th Jan and I’ve had the call offering me the vaccination next week. My concern is that I need to leave 6 weeks before or after my infusion when timing the vaccinations and I’m now concerned with the 12 week delay in the 2nd dose. I cannot go 18 weeks without my treatment.
    Does anyone know more about the 12 week delay for the 2nd dose?

    • An update on my situation.

      Had my last ocrevus on 5th having declined the vaccine on 4th after discussing this with my MS nurse amid confusion re timings of vaccination and infusions.

      Spoken to my new MS nurse and current advice is to have 1st vaccine 6-12 weeks after infusion then 2nd after 12 weeks and next infusion at least 2 weeks later. I’ve also been advised that my neurologist prefers Pfizer for her patients on ocrevus given it’s higher efficacy.

      • If two doses are 99% effective as claimed in Israel they we all want it, but this may not be an option depending on where you live, it may not be true depending on the virus variant you have and in the case of the UK we need to see how the EU row plays out.

        The vaccine 6-12 weeks means blunted B cell response likely based on veloce and boost at 12 weeks and then infuse 2-3 weeks later. This is very similar to first dose few weeks before infusion (here you may get antibody respose) and then dose again 6-12 weeks after infusion (You are boosting T and plasma cell response that should not be inhibited by anti-CD20. There is no clear knowledge. If people sign up to Barts blood spots we will get this knowledge….We expect to find out sooner rather than later with you help

        • Where do I sign up for the Barts blood spots? I appreciate that more studies are needed before we will know what’s best so here’s hoping for more knowledge for any subsequent annual doses. I’m happy to give my blood for any research.

          • You can email: mscovid19ab@qmul.ac.uk This was set up for People in care of BartsMS but I know DrRuth is on the case of spreading the wings you need to be consented and then packs can be sent in the post.

          • Thanks MD, I’ve sent an email. If anyone knows of any other studies, I’d be more than willing to participate.

  • Is there a site where we can check the secondary effects reported with Pfizer and Moderna?

    Is there a MS observational study going on with the people that are already getting the vaccine?

    My problem is that there is not enough data. How do you know if a vaccine is safe if you didn’t test it in a particular group?. They tested the vaccines on healthy individuals. So, people with chronic conditions should be monitored carefully, so we can know for sure. Is this being done?

    Contraindications exist but the info is so minimal right now that we don’t know them yet.

    In my case, I’ll wait until more info is available.

    • The details of each vaccine is given on the MHRA website for each vaccine, search on the blog, under “Blurb” and you should find the links. The secondary effects are injection site reactions and alergeies.

      Is there an MS observational study ongoing…yes it is called “vaccinating people with MS”.

      How much time do you wait for enough data?
      There is less than a years worth of Pfizer data yet probbably over 50 million people have had it..How long do you want to wait?

      How do you know it is safe in asubgroup…You dont but how doyou know it is unsafe…You dont.

      They vaccine was tested in a variety of people how many people do you want to e tested to show it is safe…Shout come on TeamG and the rest of the world do a study to show it is safe…who is going to be a pioneer? I think I know.r

      I will wait for more info, is that until the pandemic it over and then you can come out of shielding?

      As some point people had to try these things, they will be monitored, there already brave MSers who have taken the risk..

      What evidence do you need and do you think you can get it. More people have takrn the covid-19 vaccine than I suspect many people have taken other vaccines. If you have to take one to go on holiday, you do itwithoutthought,so what is the difference here?

      It is important to know. There is a significant anti-vaxer movement in the world, If we do not stop transmission this is going to be around forever……I would like to see my parents before they are dead…at this rate I wonder.

      • Is there a site where we can check the secondary effects reported with Pfizer and Moderna?

        Is there a MS observational study going on with the people that are already getting the vaccine?

        My problem is that there is not enough data. How do you know if a vaccine is safe if you didn’t test it in a particular group?. They tested the vaccines on healthy individuals. So, people with chronic conditions should be monitored carefully, so we can know for sure. Is this being done?

        Contraindications exist but the info is so minimal right now that we don’t know them yet.

        In my case, I’ll wait until more info is available.

      • Thanks a lot for the info. I will check the site and the study.

        I’m not an antivaxer. I even ha my tetanus this 2021. However, I’m not very confident with the support I will get if something happen.

        I have seizures with my first avonex shot and the doctor didn’t care. I have talked to him once in three years. No MRI or controls in that time. So, I have read a lot of articles in that time.

        When I mean wait I was talking the end of the year. I don’t clasify in the priority groups. So, I have to wait either way

        So, it’s difficult. Maybe a third world country issue

        • Time for new neurologist?. If you have MS you will be in one of the priority group probably tier 4 or 6 in the UK, Not in the UK then I a sorry I dont know, we are lucky that the UK government was pro active and one of the few things they doing better thn some countries. I guess there are some unpleasant lessons we are learning about ourseles and our partners

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