#MSCOVID19: getting ready for the vaccine

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Informing patients about their potential coronavirus risks associated with anti-CD20 therapy is complicated and resulting in our patients being given different advice depending on who they see. The reason for this is that we don’t have the direct evidence to be able to dissect out why people on anti-CD20 therapy are at higher risk of COVID-19 and at higher risk of being admitted to hospital with severe COVID-19. 

I doubt this increased risk relates to increased exposure to the coronavirus. Why should someone on ocrelizumab who attends their healthcare facility be at increased risk of acquiring SARS-CoV-2 infection compared to someone for example on natalizumab who attends for their infusion every 4-6 weeks? 

The clue to the increased risk is in the detail of the data. It is apparent that the longer you have been on an anti-CD20 therapy the greater your risk; the risk of COVID-19 is particularly high if you have been on an anti-CD20 therapy for more than 3 years. This means that it must be due to prior exposures, i.e. exposures before the COVID-19 pandemic started.  

In the general population, it is now clear that some people have T-cells and antibodies that cross-react with SARS-CoV-2 and that these protect these people from developing COVID-19 or severe COVID-19. These cross-reactive immune responses are likely to have developed in response to infection or exposure to other circulating coronaviruses; the viruses that cause the common cold. 

My theory is that if you are on an anti-CD20 therapy with no B-cells and a poorly functioning antibody response and you get the common cold your immune system will not be able to make these protective cross-reactive anti-coronavirus antibodies. This would then reduce your chances of being protected from getting COVID-19 or getting only mild COVID-19 when you are infected with SARS-CoV-2. 

I have tried to illustrate this in the following slide showing that people on long-term anti-CD20 therapies are more likely to get symptomatic SARS-CoV-2 infection, i.e. COVID-19, and when they do get COVID-19 it is likely to be more severe. Severity in this context is requiring hospitalisation and potential intensive care and ventilation. 

What does this mean for you? It means that if you are about to start ocrelizumab, rituximab or ofatumumab then your chances of getting COVID-19 are unlikely to be different to another DMT, with the exception of interferon-beta that lowers your risk because of its antiviral effects. 

If you happen to be on ocrelizumab, rituximab or ofatumumab already there is little you can do, because these agents are not rapidly reversible and even if you stop the treatment and allow your B-cell compartment to reconstitute you are unlikely to develop the cross-reactive immunity from common coronaviruses. However, by stopping your anti-CD20 and allowing your B-cells to reconstitute you will be allowing your immune system to prepare itself for a coronavirus vaccine in the future.

At the beginning of the pandemic, I was a bit cynical about the chances of a successful coronavirus vaccine emerging, but the preliminary phase 2 results of several vaccines and the immunological insights above have made me much more optimistic that we will have an effective coronavirus vaccine quite soon. When I say soon I suspect we will have one ready for general consumption early next year. In all likelihood, one of the first vaccines will be the Oxford-AstraZeneca vaccine that happens to involve a live virus, which itself will have implications for some of the MS DMTs. 

If my predictions are correct the MS community may need to start getting vaccine ready or they can simply rely on herd immunity. With anti-CD20 therapy, this needs to be planned ahead and patients will need to miss one, two or possibly three infusions depending on their body size and individual B-cell reconstitution kinetics in order to prepare their immune systems for the vaccine. 

Some critics of this strategy are saying that patients on an anti-CD20 therapy will still make T-cell responses to the vaccine that will in all likelihood protect them. Yes, this may be the case, but then how do you explain the above observations that people on anti-CD20 therapy are at increased risk of COVID-19 and severe COVID-19? I would interpret this as them having blunted T-cell responses to cross-reactive common coronaviruses. If this is the case pwMS on an anti-CD20 will have blunted T-cell response to the vaccine. In support of the latter is the observation that several pwMS on ocrelizumab who have had swab-positive COVID-19 have failed to make an antibody response to the virus. Please remember that good quality antibody responses are T-cell dependent. These observations are telling me that in all likelihood being on anti-CD20 therapy will prevent you from developing protective immunity to coronavirus from a vaccine.

Clearly getting more detailed population-level COVID-19 data in people with MS is very important. This is why we are trying to crowdfund our study to identify people who have antibodies to SARS-CoV-2. We will be able to use this resource to do nested immunological studies on pwMS on different DMTs to understand the cross-reactive immunology at both the T and B cell level to coronaviruses in general and test the hypotheses above. It will also allow us to study vaccine responses if and when the vaccines arrive. 

If you are prepared to help with a small donation it would be much appreciated. Thank you.

CoI: multiple

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.

28 comments

    • I don’t know, there is a data gap. It is clear that ocrelizumab-treated patients can make antibody responses to some vaccines. What we need are studies to address this when the vaccine or vaccines emerge. I suspect it won’t be black and white.

    • The question we should be asking is do people with MS need to be vaccinated against coronavirus and do they need to become immune to it? They could take their chances and rely on herd immunity, i.e. rely on the people around them to be vaccinated and to protect them.

      If you take this line of thinking there is no need to anything about your DMT. In low COVID-19 incidence country, this may be the best strategy to adopt, which protects you from your MS and COVID-19.

    • If it was me personally I would take my chances and continue as is and rely on herd immunity to protect me. MS is a bad disease and needs to be treated.

      • As a patient (can’t stand the PwMS moniker myself) I concur, so recently got a regular ocrelizumab infusion -slightly behind schedule but that was not really driven by covid.

      • Maybe so, but we have seen how well herd immunity worked for measles when some people decided not to get their children vaccinated… since about 30% Of people have said they won’t have a COVID vaccine, can we really rely on herd immunity?

        • That will depend on what the natural R-value is without social distancing. If it is somewhere near 6, which I estimate, then if 30% of the population are non-immune then it won’t be sufficient herd immunity. If the R-value is close to 3 which is the most commonly quoted figure then it will be okay.

  • I have just had an email from a patient on ocrelizumab who is now planning to take a drug holiday to wait for the vaccine. This is not what I am advising. I am trying to provide some context to the scientific issues raised by the data and the relatively urgent need to do research on (1) the vaccine(s) when it/they arrive and (2) the immunology of anti-CD20 therapy and coronavirus in general.

    When there is data vacuum the best thing to do is to do hypothesis-driven research to answer the questions.

  • If you were a HCP due second full dose (so 4th infusion) next month, and were a) desperate to return to on-call working and b) concerned about the risk of catching COVID-19 specifically over this first winter with all the unknowns, what would you do?

    Would you ask to delay by ?2-3-4 months to get back to work fully and be able to work normally over the winter then plan to have the next dose after that? This is what I have decided – am having MRI this week to check, and then neuro is supporting that decision. Otherwise very fit and well…

    I would be v appreciate of your opinion

    • There is no right or wrong answer here. At least in terms of ocrelizumab’s ability to tackle focal inflammatory activity (relapses and new lesion formation) you are fine missing one or two doses. But as I have said before this is not the real MS. When it comes to treating the real disease or smouldering MS you need continual treatment with ocrelizumab and possibly at higher doses. This is why I am so keen that Roche/Genentech does a double-dose study.

        • I think you need to be aware that although your risk of getting COVID-19 and severe COVID-19 are increased if you have been on anti-CD20 for some time, the data on mortality is not there yet. The reason I say this is there is still a theoretical chance that anti-CD20 therapy may protect you from the delayed antibody responses that are associated with ARDS or the severe lung disease. So the risk:benefit story is incomplete.

          • Thanks that is important information too. Hence I definitely don’t plan to delay indefinitely, only for a few months to get me over flu season in the NHS and see what it brings for covid. Hopefully not much new and I can carry on as planned….. 🙏🏼

  • This is very complicated, and I understand there are no right or wrong answers, but any decent answer would be helpful. I am a frontline HCP in the US. I have been on Rituximab for over three years. My immunoglobulin levels are low, specifically IgM and IgG. Additionally, for unknown reasons, my % CD8 levels are either low or borderline low normal. I have not returned to in-person care, but I obviously would like to. Without clear guidance, I am anxious to do so. Would you share your thoughts?

    • Prof G and DrRuth as doing a webinar on shielding next week i will be making up the number…your case scenario would be a good one to discuss, they have a similar one planned

    • In terms of risk factors for infection we have neutropenia, lymphopenia and hypogamma globulinaemia (low IgM, IgG), in the recent rituximab verse ocrelizumab…low immunoglobulin increased infection risk.

      Therefore this is a risk factor for catching covid and appears to double your risk. In the ocrelizumab trial at 5 years the IgM levels were down by 50% and the IgG levels by about 20%. At about 2 years the IgG levels were about the same but IgM was down. IgM is a first line protection against infection.

      CD8 T cells express CD2 and are depleted. They are typically anti-viral cells.

      We know that anti-CD20 gives you a small risk of increased infection so it would not be surprsing if you there is small increase risk of COVID. Within the literature there is evidence of COVID infection in over 500 people on ocrelizumab and/or rituximab. The vast majority indeed most people recover.

      • I registered for the Trimsx webinar. Thank you, and I much appreciate your response here, but I suppose some of these are the kinds of answers that baffle me. I understand the immune physiology behind the diminished immunoglobulins and I understand what that potentially means as far as posing a risk factor. But, when doctors (and I say this being one) say things like “but the vast majority of people with MS and COVID recover”, there is a small part of me that wants to scream. Because although the vast majority might be recovering, there is still a percentage that DIE. Who wants to be in that number no matter how small? Until you can explain what definitely differentiates those people from the majority that recover, then I think it’s difficult to make any blanket statements. That’s obviously just my opinion. Even the healthiest of my young patients without risk factors in this pandemic who otherwise would be expected to do well suffered long term consequences, and yes, some died, without any good explanation. Trying to diminish the mortality sometimes fuels the fear, I think. Sometimes, it’s ok to say, there is so much about this virus we don’t know in general and not just about MS but the virus as a whole. Again, I am just a frustrated human and physician that has watched my entire healthcare system fail our country and its people in so many ways.

        • I dont have the answer sorry. However when this things started many were going to die and anyone on a DMT would likely suffer the consequences.

          The vast majority of people with MS who die I believe are they type of people who die without MS are the people who die due to risk factors associated with COVID-19 such as age, obesity, race, sex hypertension, cardac issues, kidney issues, put into the mix disability which probably leads to co-morbidities. I would also add viral load. If you get infected with a lot of virus and perhaps this is where healthcare workers suffered. I suspect it is a senile macrophage thing. I know of one odd one which was about a 31 year old person with rituximab from france. They were apparently obese. Then the question is do you have enough immunity from cold-causing coronavirus, do your DMT block this from generating, do they get rid of what you made

          I agree the healthy young people can be affected but I get the feeling that the youth have had enough and dont see that they are at major risk, hence they dont give a stuff about social distancing and wearing masks..they will get infected and do OK…but perhaps when they give the virus to their grans they wont do so well. A hundred years ago that youth walked towards machine guns. I wonder if ProfG wears a mask when he is off running…the grosses thing that has happend to me was when I was sweated-on by a female jogger when they had the whole field, but abit of wind can carry droplets a long way.

  • Have read the first 9 comments & replies for today 8/27 and appreciate the discussions so far. To what extent are your MS vs COVID-19 hypotheses generalizable to all forms of MS vs more selectively to relapsing or to progressive forms–in terms of (1) inherent severity risk with COVID-19 (2) estimated time for B cell/memory cell repopulation and (3) inherent risk of allowing untreated MS to relapse/progress?

    • Based on published data people with advanced EDSS seem to be at increased risk. This is not surprsing as people with advanced EDSS may be older (due to longer disease duration) and they may have more co-morbidities.

      In terms of B cell repopulation I suspect it is similar in RR and PPMS but I have seen no data for repopulation in PPMS. In the phase II extension period the B cells appeared to be still depleted 18 months later in based on the median response, no doubt some people repopulate quicker than than that

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