vaccine readiness – Page 3 – Prof G's MS Blog Archive

#MSCOVID19: yes, have the vaccine

Barts-MS rose-tinted-odometer: ★★★★★

Despite the long blog post that I called CATCH-22 I am still getting numerous emails and questions from patients with MS about whether or not they should have a COVID-19 vaccine.

YES, you should have the vaccine when it is offered to you. Clearly, timely access to the vaccine will depend on where you live, how vulnerable you are and the local, regional and national guidelines in place in your own country.

The benefits of COVID-19 vaccination is time-sensitive and if you wait to be vaccine-ready you may inadvertently acquire the coronavirus infection and become really ill or when you are vaccine-ready the pandemic and the at-risk period may have passed.

In my opinion, some immunity is better than no immunity and the blunted vaccine immunity on some DMTs may be sufficient to prevent you from becoming infected with SARS-CoV-2, developing COVID-19 and more importantly developing severe COVID-19.

Are the vaccines safe? No vaccine is 100% safe, but the fact that the regulatory authorities have licensed these vaccines indicates that the benefits of the vaccine far outweigh the risks associated with the vaccine in the general population. At the moment the only relative contraindication to the Pfizer-BioNTech RNA vaccine is a history of severe atopy or allergies, i.e. people who carry around an epi-pen to prevent anaphylaxis in response to an environmental allergen.

If you have any questions please read the CATCH-22 blog post, and our new advice here. If these don’t answer your question(s) we will try and address them below.

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#MSCOVID19: CATCH-22

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

Bring back the experts

Barts-MS rose-tinted-odometer: ★★

“I think the people of this country have had enough of experts”, Michael Gove, June 2016.

Of the many positive things to come out of the COVID-19 pandemic and our response to it is the end of the era of denigrating the expert. Yes, expertise and in particular deep expertise really matters and that applies to the diagnosis and management of multiple sclerosis.

What is the difference between expertise and deep expertise? For example, I am registered by the General Medical Council in the UK as a neurologist and hence a medical expert in the practice of neurology. This means I can see, diagnose and manage anybody with a neurological problem. However, my sub-speciality is multiple sclerosis and related diseases (deep expertise). If you had a myopathy or a disease of muscles would really want me to be your treating neurologist. I suspect not; you would probably want to see a neurologist who specializes in muscle diseases. Although, I can quite easily read about the latest evidence and research into myopathies and give you an expert opinion, as I don’t have the day-to-day experience (deep expertise) in managing patients with myopathy you would not be given the best advice. Who knows if my self-directed rapid myopathy update would be good enough? Would I have enough insight and experience to only read the best most up-to-date evidence or would I be influenced by some whacky off-the-wall myologist (muscle expert)?

We need, more than ever, a serious pushback on ‘fake news sites’, ‘lobby groups with vested interests’, ‘social media groups without expert input’ and ‘anti-science movements with unsubstantiated conspiracy theories’ to name the most obvious.

We also need to understand and learn to live with and be comfortable with uncertainty. Yes, that means accepting that experts may disagree with each other. Science is not black-and-white and is usually grey and as more evidence emerges and innovations or ideas become adopted or accepted the colour or advice becomes closer to being black or white. Science and the acceptance of science take time.

This is where inspired leadership comes into play. In any field, there are leaders who have the necessary reputations and trust that people will follow their advice. These leaders are often good communicators and have the uncanny ability to provide a balanced view of the state of play when the evidence is not black-and-white and they can communicate uncertainty in a way that makes sense and is understandable to the general public. Dr Anthony Fauci, from the NIH, comes to mind with his level headed approach to the COVID-19 epidemic in the US. On the other hand, there are many examples of bad or poor leadership during this pandemic, which has resulted in squandering of political capital, confusion and lack of trust. I don’t think I need to give specific examples of poor leadership there are many obvious ones.

In the MS space, there is different advice being peddled by various groups about what to do about vaccinating people with MS on anti-CD20 therapies with the newly licensed or soon to be licensed coronavirus vaccines. I think there is broad consensus that a live replicating viral vaccine is a no-no in people on anti-CD20 therapies. However, this advice is irrelevant as the three coronavirus vaccines at the head of the queue are not live replicating virus vaccines. The Oxford-AstraZeneca vaccine uses a viral vector (chimpanzee adenovirus) to deliver the construct (nucleotide message) to express the immunogen, but it is a replication-deficient virus so is highly likely to be safe in people with MS on anti-CD20 therapies.

Another bit of misinformation that is doing the rounds is that these vaccines will trigger MS relapses. This 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. 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 relapse. This in my opinion is not a reason to avoid having the coronavirus vaccine at present. This opinion may change if new data emerges to the contrary.

Another bit of grey advice that is being peddled as black or white is that people with MS (pwMS) on anti-CD20 therapy should delay their next infusion or miss one or two infusions to allow B-cell reconstitution before they have a coronavirus vaccine. What is the evidence for this? There is no definitive evidence. 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 so-called neoantigens or new antigens that the immune system has not seen before. However, this doesn’t mean these people haven’t developed immunity to the infection of 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. Do you then think this cellular immunity simply vanishes? Highly unlikely. Normal people who have COVID-19 and who lose their antibody responses still have 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. Whilst this is happening companies like Roche-Genentech (ocrelizumab & rituximab) and Novartis (ofatumumab) or the wider MS community should be funding studies to look at both antibody and cellular immunity to the coronavirus vaccines in pwMS on these therapies so that we can develop an evidence base. The data collected as part of these studies will not only be relevant to SARS-CoV-2 infections and vaccines but other infections and future vaccines.

In my opinion, it is more important for pwMS 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. If you have MS and would rather wait for data to emerge on the safety and efficacy of the vaccine in the MS population it will take another 6 to 12 months, and maybe longer, and then the evidence if not collected prospectively as part of a well-controlled trial may not answer the questions you have. Also in 6-12 months, the pandemic is likely to be over and hence these questions may never get answered.

So my gut feeling based on scientific principles is that all pwMS should be vaccinated. If the initial roll-out of vaccines means the vaccines may be rationed I would argue we prioritise pwMS (1) over the age of 50, (2) those with significant comorbidities, (3) those on immunosuppressive therapies, in particular, those on anti-CD20 therapies and natalizumab and (4) those pwMS doing essential jobs with significant face-to-face contact with the general public (healthcare workers, care workers, teachers, etc.) to get the vaccine first.

Disclaimer: As I am not a public health or vaccine expert you need to interpret my advice with care.

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#MSCOVID19: ABN Guidance Update

Barts-MS rose-tinted-odometer: ★★★

The ABN have updated their COVID-19 guidelines, which are beginning to move towards the evidence. However, the guidance on cladribine is not supported by the evidence nor the science, i.e. how cladribine actually works and its impacts the immune system.

The latest guidance states “the risk of severe COVID-10 disease is increased for many months after ocrelizumab and cladribine”. I am not sure there is evidence to support the statement about cladribine. Ocrelizumab and other anti-CD20 therapies are given continuously and hence the risk does not go away. However, cladribine is an immune reconstitution therapy and is reversible. Even in the depletion phase of treatment, the level of immunodepletion is modest, particularly for CD8+ T cells (see slide show below) and innate immunity is left intact. In our opinion, this pattern of immunodepletion is not sufficient to pose a risk to people with MS treated with cladribine and is supported by the emerging pharmacovigilance data.

The good news is that the guidelines state that for both ocrelizumab and cladribine “self-isolation for all that time is not appropriate except for individuals with multiple other risk factors”, which is compatible with our practice.

I am also reassured that their guidance has also softened for alemtuzumab; i.e. “we would anticipate pwMS being advised to strictly self-isolate for at least four weeks after an alemtuzumab administration”. This has been our practice since we started dosing alemtuzumab again. The rationale for the 4 week time period I assume is based on the impact of alemtuzumab on innate immunity and is supported by trial data; i.e. the viral infection risk falls rapidly after four weeks, presumably because monocyte counts recover.

The ABN is also recommending two weeks of self-isolation after high-dose steroids, which is pragmatic advice based on the risk of severe COVID-19 identified in the Italian registry studies.

The new guidance has also made a comment about vaccine readiness; “patients contemplating ocrelizumab should be advised that they may not be able to receive a future SARS CoV2 vaccine if it is a live vaccine, and they may not respond immunologically to a dead or inactivated vaccine. Consideration should be given to delaying ocrelizumab re-treatment”. It is interesting that none of the other DMTs is specifically mentioned when it comes to vaccine readiness. I am sure live viral vaccines will also be contraindicated in patients on S1P modulators (fingolimod and siponimod) and on some of the other immunosuppressive DMTs such as natalizumab and possibly even teriflunomide based on their current SmPCs.

The interesting thing about vaccine readiness is we don’t know about how important T-cell responses are in relation to these emerging vaccines and whether or not people on anti-CD20 therapies will mount an adequate protective T-cell response to the SARS-CoV-2 spike protein and other antigens. Everyone focuses on antibody responses when they may not be that important in protective anti-SARS-CoV-2 immunity.

I am sure we haven’t heard the last on MS DMTs and vaccine readiness. This is why I would urge all the DMT manufacturers to do the necessary studies to provide us with the necessary evidence-base to make clinical decisions.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Barts-MS Journal Club: vaccine responses on ocrelizumab

Dr Ide Smets discusses the Veloce study and its implications for managing MS.

CoI: multiple

#MSCOVID19: woods for the trees

Barts-MS rose-tinted-odometer: ★★★★

I am sure you know the term “I can’t see the woods (or the forest) for the trees”. This means you are unable to understand a situation clearly because you are too involved in it. I think this is what has happened to the MS community when it comes to managing multiple sclerosis during the coronavirus pandemic.

We are so fixated on the potential risks associated with DMTs and COVID-19 that we are ignoring the elephant in the room, age and comorbidities. It is now clear that moderate immunosuppression from some of the MS disease-modifying therapies (DMTs) does not increase one’s risk substantially of getting COVID-19, severe COVID-19 or dying from COVID-19. The real risk factors for getting severe COVID-19 are age, progressive or advanced disease, which is closely associated with age, and the presence of comorbidities.

I presented the ocrelizumab COVID-19 data at a satellite symposium on day-1 of our fourth triMS.online conference and it was clear to me that the risk associated with anti-CD20 therapies are trumped by age and comorbidities. It is also clear that the pharmacovigilance data for ocrelizumab has to be biased in that patients on infusion therapies and those with more severe disease needing hospitalisation, ITU admission, ventilation and sadly those who die from the infection, are more likely to be reported. People with MS who have mild or even moderate COVID-19 are clearly less likely to be reported by their HCPs. Therefore, the current data is likely to be the worst-case scenario.

Another factor that is not being captured in this data is the fact that the outcome for COVID-19 has been improving. As treatments for COVID-19 and medical know-how, for example, how to manage ventilation and thrombotic complications of SARS-CoV-2 infection, have improved the mortality from COVID-19 has almost halved.

The issue of vaccine-readiness, which also raises its head frequently, is like the greasy pig; you may be able to catch the pig but it is almost impossible to hold on to. This is why I suggest batting vaccine readiness into the long grass and addressing the issue if and when a vaccine finally arrives. It has also become apparent as the immunology of coronavirus infection has become better understood that T-cell immunity, in particular CD8+ T-cell immunity, is likely to be the dominant player in driving immunity from primary infection and reinfection. Even if people who have been infected and do not seroconvert or lose their antibodies quickly, are highly likely to be immune to reinfection. Even if they are reinfected with the SARS-CoV-2 virus that causes COVID-19 they are likely to get asymptomatics infection or mild disease. Please note reinfection rates at present are very rare and get much more air-time than is warranted.

In my talk, I concluded that MS is a bad disease and we should manage it as we would have managed it prior to COVID-19. I think untreated or under-treated multiple sclerosis is a bigger problem than COVID-19 for people with MS at present.

I also stressed that prehabilitation is really important for people with MS and remains so. If you can, you need to do everything possible, to optimise your general health so that if you get COVID-19 you give yourself the best chance of recovering without complications.

To quote from Chalie Mackesy’s bestseller “The Boy, The Mole, The Fox and The Horse”, when the boy asks the horse “What’s the best thing you have learned about storms?”. “That they end”, said the horse.

This quote not only sums up my optimism but has also made me realise that the storm clouds have lightened, the thunder and lightning have moved over the horizon, the rain is not as hard as it was at the beginning of the storm and the winds have dropped in intensity. I get a sense that the storm will pass over very soon.

I must compliment and thank Roche for releasing the ocrelizumab data to the MS community. The only other company that has attempted to do the same has been Merck in relation to their cladribine data. However, the data for cladribine is a lot less robust because of the smaller number of patients who have had cladribine and have subsequently gotten COVID-19.

The ocrelizumab and cladribine data are what they are. Having the data in the public domain, however, puts us in a much better place. We can quote the data to our patients, reassure them about the potential risks, which are small, and use it as part of the decision-making process to manage their MS as best we can during the pandemic.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: anti-CD20 nuances

Barts-MS rose-tinted-odometer: ★★★

I had to have a detailed discussion with a patient this week about starting ocrelizumab during the COVID-19 pandemic. This patient was concerned about (1) the data showing an increased risk of COVID-19 in anti-CD20 treated patients, (2) an increasing number of cases not seroconverting when being infected with the coronavirus and (3) she will not be able to have a coronavirus vaccine when one emerges.

All of these three concerns are not black-and-white, but very grey, and need explaining.

1. The increased risk of COVID-19 and severe COVID-19 on anti-CD20 therapy

This finding has been reported by the Italian register, the Iranians, the Swedes and the MSIF’s Data Alliance initiative. There is also a similar signal in the US data and French data. However, despite the increased risk of COVID-19 it is not associated with increased mortality. In the Italian data there is a weak signal that the longer you have been on an anti-CD20 therapy, particularly more than 3 years, the greater the risk of COVID-19.

One issue that is not adequately addressed is reporting bias, i.e. more severe COVID-19 cases get reported and the less severe ones don’t because they are not registered as having COVID-19. Reporting bias is likely to affect DMTs that require patients to attend hospitals, i.e. treatments that bring them into contact with HCPs and hence they have a chance to report symptoms, and those DMTs that are the most widely prescribed. It is clear that both of these factors play a role in anti-CD20 therapies. One clue in support of this is the fact that there is a similar signal of a greater COVID-19 and severe COVID-19 signal emerging with natalizumab, i.e. another DMT that requires frequent hospital visits (reporting bias) but is less prescribed than anti-CD20 so the signal is not quite significant yet.

One way to address this issue is to study non-biased trial populations, which has to be the data gold-standard. Roche presented 51 COVID-19 cases in over 4,000 ocrelizumab exposed trial patients (1.3%) (see presentation below). There was clearly no link between COVID-19 and treatment duration (slide 6). Three patients out of 51 patients died (5.9%). The numbers are too small to make a call on whether this represents a higher mortality than the background rate. Another important factor is that COVID-19 was not linked to hypogammaglobulinaemia. This ‘gold-standard’ data challenges some of the dogma that has emerged around CD20 therapies and COVID-19 and alters my interpretation of the Italian data.

(2) An increasing number of ocrelizumab-treated cases not seroconverting when being infected with the coronavirus

Although there are several cases of SARS-CoV-2 positive COVID-19 cases on ocrelizumab who have been reported that have not seroconverted (detectable antibodies) there are many more normal people who have have COVID-19 who haven’t seroconverted as well. Whether this observation is assay dependent, i.e. insensitive assays that don’t detect low level antibody, or true biology needs further investigation. The fact that these people, ocrelizumab-treated or normal people, recover from COVID-19 is telling us that an antibody response is not necessary to clear the virus and for recovery from COVID-19. It is likely these patients have very good cellular immune responses that will protect them from reinfection in the future.

These observations have implications for vaccine responses and hence we may have had the wool pulled over our eyes focusing on the easier to measure antibody responses. I suspect, as do many others, that it is not humoral, but cellular, immunity that will be important for protective immunity against SARS-CoV-2. I am not saying antibody responses won’t be important, but it is likely the dominant protection will come from cellular immunity.

(3) Not being able to have a coronavirus vaccine when one emerges

This is clearly not correct. Patients on ocrelizumab will be able to have DNA, RNA and component coronavirus vaccines. The only vaccines they may not be able to have are live attenuated vaccines and potentially vaccines using a live viral vector to deliver the immunogen. The question is whether or not ocrelizumab-treated patients will be able to mount an adequate protective immune response to these vaccines is a moot point, which is why I have been urging Roche to plan and set-up registry studies to see if ocrelizumab-treated patients develop adequate immune responses to these vaccines. It is important that these studies are well designed and include both antibody or humoral and cellular components.

Another thing to remember is that no vaccine is likely to be 100% effective. Even if the vaccine is only 60% to 70% effective it will be sufficient to create herd immunity and stop the spread of coronavirus. Vaccines are about population health and not necessarily about individual health, which is why regulators are fixated on safety.

I also told this patient that there are many other factors at play. For one the death rate or mortality from COVID-19 is falling. This is happening for several reasons. Firstly, we now have approved treatments for COVID-19 and the circulating strains are likely less virulent than the initial strains. Based on simple evolutionary principles the more benign strains are out competing the virulent strains. Another factor that I have commented on before is that we may be nearing herd immunity in some areas of the country, for example in London. This is based on the observation that many people have cross-reactive cellular and humoral immunity, presumably from other coronaviruses, that are protecting them from getting COVID-19. Therefore the risks of getting COVID-19 are falling. Add to this sensible personal hygiene and social distancing and the risks remain low. The second surge is really happening in areas of the country with low herd immunity and amongst care-free populations who are not being adherent to the government’s guidelines; for example, University students.

The bottom line is that if you are low risk of getting COVID-19 and you double that risk the risk remains low. I would also only cross the vaccination bridge when it arises. Trying to preempt when and what vaccine will emerge first is really a guessing game. What is not a guess is that this patient has active MS, with a relatively poor prognostic profile (spinal cord disease) and needs treatment. She does not have highly-active MS therefore the only high-efficacy DMT available to her first-line on the NHS is ocrelizumab. She could select a platform therapy, which has also been offered to her, and to then see how she does, but as she is very well informed and understands the concept of ‘flipping the pyramid’ and that ‘time is brain’ doesn’t want to take a chance on a lower efficacy DMT. The outcome from our discussion is that she has decided to go ahead with ocrelizumab after she has had her pneumococcal and seasonal influenza vaccines.

As you can see the COVID-19 anti-CD20 data is quite complex with a lot of nuances, which makes it difficult to communicate to patients. But if you take time to explain it to patients, not only do you allay their fears, but you end-up with a well informed patient who knows what they are signing up for.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: getting ready for the vaccine

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

#MSCOVID19 two swallows don’t make a summer

As you know I have had to backpedal with my SARS-CoV-2/COVID-19 advice in relation to anti-CD20 therapies. I have now had to reinterpret data on the role of immunoglobulins in protecting people from developing COVID-19 and severe COVID-19.

I have been using the two Italian cases of X-linked agammaglobulinaemia who got COVID-19 and make a recovery as an argument that you don’t need B-cells and immunoglobulins to recover from SARS-CoV-2 infection. I now think I am wrong. Both these patients were being managed with immunoglobulin replacement therapy or IVIG (intravenous immunoglobulin therapy). IVIG is essentially a mix of immunoglobulins from blood donors from the general population. The assumption I made was that as SARS-CoV-2 was a new virus there would be no antibodies in the general population that would neutralize the SARS-CoV-2. However, the study below shows that pooled immunoglobulin therapies are able to neutralise SARS-CoV-2 (see Díez et al. below). Therefore I can’t assume, based on these two cases, that you don’t need immunoglobulins to make a recovery from COVID-19. This observation of neutralizing anti-SARS-CoV-2 activity in IVIG is also compatible with the emerging data that rituximab and by implication other anti-CD20 therapies now appear to increase your chances of getting COVID-19 and severe COVID-19.

I suspect anti-CD20 therapies increase your chances of getting COVID-19 by reducing your chances of having an asymptomatic SARS-CoV2 infection. The immune responses to other human coronaviruses, the ones that cause the common cold, cross-react and help neutralise SARS-CoV-2, which explains why some people get asymptomatic or mild SARS-CoV-2 infections (see Shen et al. below). However, if you are B-cell depleted when getting the common cold, due to coronavirus, your immune system isn’t able to make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting COVID-19.

In support of this the case study published last week of a person with MS on ocrelizumab who failed to seroconvert to having anti-SARS-CoV-2 antibodies despite having confirmed SARS-CoV-2 COVID-19 (see Conte. case report below). This particular patient had mild hypogammaglobulinaemia as a result of ocrelizumab treatment. The failure to seroconvert could be an assay problem, i.e. low sensitivity, or is more likely to be due to the blunted B-cell response from being treated with ocrelizumab. Clearly this case report is going to be very important in shaping our thinking in terms of doing further anti-SARS-CoV-2 seroprevalence studies in people with MS and preparing our patients for a potential SARS-CoV-2 vaccine. The latter gets more pressing as most countries have now abandoned herd immunity as a strategy to deal with COVID-19.

Díez et al. Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins. BioRxiv doi: https://doi.org/10.1101/2020.06.19.160879

Background: There is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy.

Methods: The neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT50) in the PFU assay and the half maximal inhibitory concentration (IC50) in the cytopathic/cytotoxic method (calculated as the minus log10 dilution which reduced the viral titer by 50%).

Results: All IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV.

Conclusion: In cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management.

Conte. Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab with hypogammaglobulinemia. MSARDS June 20, 2020.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

#MSCOVID19: rituximab & vaccine readiness

The following is a short YouTube vlog on Rituximab, COVID-19 and vaccine readiness. This is a brief update to my presentation on anti-CD20 therapies and COVID-19 to iWiMS webinar on the 20-May-2020.

What is your opinion on vlogging vs. blogging? Is there a need for both?

CoI: multiple