I have been saying that based on its mode of action cladribine works as a semi-selective B-cell depleting agent similar to an anti-CD20 or anti-CD19 therapy. However, cladribine has an advantage as it is used as an IRT (immune reconstitution therapy) so is not associated with continuous immunosuppression. Cladribine is also CNS penetrant and hence targets CNS resident B-cells.
Another advantage of cladribine is that as it kills B-cells in the periphery new migrant naive cells are emerging from the bone marrow. Hence peripheral B-cell counts don’t drop to zero, which explains why pwMS treated with cladribine are vaccine ready and make good antibody and T-cell responses to the COVID-19 vaccines. Importantly, the latter seems to be independent of where in the cladribine treatment cycle vaccinations occur and appears to be independent of peripheral lymphocyte counts.
The following is the safety data I presented and ECTRIMS in relation to pwMS treated with cladribine who had COVID-19. Importantly, out of 503 cladribine-treated pwMS, there were only 3 fatalities (0.6%). This is an order of magnitude lower than that recently reported with ocrelizumab (Hughes et al. Mult Scler Relat Disord. 2021 Apr;49:102725.).
The list of other adverse events is self-explanatory.
Overall of the high-efficacy B-cell depleting DMTs, cladribine is emerging as the one DMT that seems to be the best tolerated with a low risk of severe COVID-19 and at the same time allowing to receive COVID-19 vaccinations with confidence. The fundamental difference is that cladribine is an IRT and many HCPs and pwMS don’t feel comfortable with the fact that after an IRT you have to play a wait-and-see game, i.e. no treatment until MS disease activity returns. If you are one of these people you need to ask yourself if you are not prepared to have an IRT could you please ask yourself how are we the MS community going to ever find a cure for MS?
Please note that I am the principal investigator on the oral cladribine phase 3 programme and have been involved with its development since 2002. I am therefore heavily conflicted so you may want to interpret anything I say that is positive about cladribine with caution.
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.
Barts-MS rose-tinted-odometer: ★★★ (a red-eyed Tuesday #FF0000)
I was doing a Q&A webinar with some US clinicians last night and they were asking whether or not pwMS should have a booster COVID-19 vaccine or not. The answer is simple, YES. The study below in 60+-year-old Israelis shows that people who had a booster or third dose of the Pfizer-BionTech RNA vaccine were 11.3x less likely to be infected with SARS-CoV-2 compared to people who had been double vaccinated. The more impressive finding is that severe COVID-19 was reduced by a factor of 19.5 in the boosted group compared to the non-boosted group.
The question is whether or not this study’s findings are relevant to pwMS. Of course, they are. Older people have immunosenescence which is a form of immunosuppression and hence if you have MS and are on immunosuppressive therapy you need to boost your immunity. The principles are very similar.
In the UK pwMS on immunosuppressive therapies are being called up for a third dose. Please go ahead with the booster. People on anti-CD20 therapy should be aware that if they have no B-cells in their peripheral blood they are unlikely to make an antibody response, but the booster should theoretically improve their anti-SARS-CoV-2 T-cell responses. If they want to make an antibody response they can ask their team if they can delay their next infusion to allow some B-cell reconstitution before being vaccinated. The question is whether or not this is necessary is a moot point.
Hopefully, real-life data will emerge comparing COVID-19 outcomes in pwMS who are seropositive post-vaccine with those who are seronegative.
If you are on an S1P-modulator, such as fingolimod, you don’t really have the luxury of delaying dosing. Therefore I suggest going ahead with the booster in the hope that it works. Stopping fingolimod, and or other S1P modulators, for a vaccine is risky because of rebound disease activity.
Booster responses for all other DMTs should be fine.
BACKGROUND: On July 30, 2021, the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) was approved in Israel for persons who were 60 years of age or older and who had received a second dose of vaccine at least 5 months earlier. Data are needed regarding the effect of the booster dose on the rate of confirmed coronavirus 2019 disease (Covid-19) and the rate of severe illness.
METHODS: We extracted data for the period from July 30 through August 31, 2021, from the Israeli Ministry of Health database regarding 1,137,804 persons who were 60 years of age or older and had been fully vaccinated (i.e., had received two doses of BNT162b2) at least 5 months earlier. In the primary analysis, we compared the rate of confirmed Covid-19 and the rate of severe illness between those who had received a booster injection at least 12 days earlier (booster group) and those who had not received a booster injection (non-booster group). In a secondary analysis, we evaluated the rate of infection 4 to 6 days after the booster dose as compared with the rate at least 12 days after the booster. In all the analyses, we used Poisson regression after adjusting for possible confounding factors.
RESULTS: At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the non-booster group by a factor of 11.3 (95% confidence interval [CI], 10.4 to 12.3); the rate of severe illness was lower by a factor of 19.5 (95% CI, 12.9 to 29.5). In a secondary analysis, the rate of confirmed infection at least 12 days after vaccination was lower than the rate after 4 to 6 days by a factor of 5.4 (95% CI, 4.8 to 6.1).
CONCLUSIONS: In this study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, we found that the rates of confirmed Covid-19 and severe illness were substantially lower among those who received a booster (third) dose of the BNT162b2 vaccine.
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.
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.
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.
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.
Barts-MS rose-tinted-odometer: zero-★s (Feeling ‘Kind of Blue’ for a Saturday, midnight blue #191970)
We have known for some time now that pwMS on DMTs who get COVID-19 seem to be at no greater risk of severe COVID-19 and death compared to the general population with the exception of pwMS on anti-CD20 therapies. This implies that anti-CD20 therapies either impact preexisting cross-reactive protective immunity from other community-acquired coronavirus infections and/or antibody responses during COVID-19, which have been now shown to prevent severe infection and death. I think there is now ample evidence to support both of these explanations.
People who had the original SARS in 2003 have been shown to have broad anti-coronavirus immunity and make very good neutralising antibodies to SARS-CoV-2, which is boosted to very high levels in response to COVID-19 vaccination. Similarly, immunoglobulin formulations made from the plasma of blood donors prior to COVID-19 is able to neutralise SARS-CoV-2. Therefore preexisting immunity to other coronaviruses is helpful and this will be blunted by being on an anti-CD20 therapy, particularly if you have been on the anti-CD20 therapy for a prolonged period of time. This observation goes beyond COVID-19 and explains why the risk of infections in people on long-term anti-CD20 therapy increases over time.
It has also recently been shown that the delayed development of neutralising anti-SARS-CoV-2 antibodies is strongly associated with death in patients with COVID-19 in intensive care (Lucas et al. Nat Med. 2021 Jul;27(7):1178-1186). Therefore contrary to original hypotheses that B-cell responses were not necessary for recovery from COVID-19, it is now clear that antibody responses to SARS-CoV-2 are important in protecting you against a poor COVID-19 outcome. This now explains why people on anti-CD20 therapies are more likely to have severe COVID-19 and I suspect more likely to succumb to the infection.
I discuss the clinical implications of this and other findings for the management of MS in my latest MS-Selfie Newsletter ‘Anti-CD20 Kool-Aid and COVID-19 vaccines’ (9-Sept-2021).
Kind of Blue: Please take some time off today to remember and reflect on the people who lost their lives in the 11-September-2001 attacks in New York and Washington and subsequently in the world’s response to these attacks. I am going to listen to Mile Davis’ album, ‘Kind of Blue’ when I do this.
Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.
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.
I heard last week that one of my patients sadly succumbed to COVID-19. This is not the first person with MS to die of COVID-19 but is a reminder of how fickle life can be. I have contacted my patient’s partner to say how sorry I am. The question I am asking myself is; could this death have been prevented? Yes, almost certainly. However, I suppose this answer applies to all COVID-19 related deaths.
Although the official global death toll from COVID-19 is 4.6m the unofficial estimate is 15.2m (95%CI 9.4m-18.2m), which means most of us will know someone who has died of COVID-19 (see The Economist; The pandemic’s true death toll, 5th Sept. 2021).
We should count ourselves lucky in the UK because we have a very high vaccination rate that has clearly reduced the number of people getting severe COVID-19 and dying from COVID-19. Sadly, however, being double-vaccinated is no guarantee of protection. Data from Public Health England (PHE) reveals that of all the people who died within 28 days of testing positive for the delta variant between 1 February and 19 July, 49% (224) had had two vaccine doses; almost all of these people, 220, were aged 50 or older (Public Health England. Investigation of SARS-CoV-2 variants of concern: technical briefings. 23 July).
What does this mean for pwMS? This means we are not out of the woods yet. Please remain vigilant and careful. This particularly applies to those of you who have not been vaccinated and those on an anti-CD20 or S1P-modulator, in whom vaccine responses are likely to be blunted. People with MS are being classified by the government as being vulnerable and hence you will be offered a booster dose later this year.
For those of you who have lost a loved one to COVID-19, there is a very good series of articles in this week’s BMJ on grief and grieving, which I recommend you read. Lucy Selman’s essay touched a raw nerve when I read it and many of the issues she discusses are particularly pertinent to how I am feeling this morning. It is hard, harder than you think, being a healthcare professional during the pandemic.
……. For people working in healthcare, grief brings home the ultimate futility of medicine as a lifesaving endeavour. Despite the best efforts of doctors, we all eventually die. Grief teaches us that medicine is about so much more than extending life.
…… Accommodating the ubiquity of sadness, loss, and grief makes some separation and compartmentalisation seem inevitable, even a useful coping strategy, for those who practise medicine.
……. Clinicians are often encouraged or required, overtly or implicitly, to disregard and not talk about their own grief in the name of efficient patient care. Despite evidence of significant grief among clinicians, patient deaths are often not discussed.
…… But sequestering grief into the “private” realm outside of medical practice can have unintended negative consequences for clinicians and patients and their families, rendering us all more alone. Denying grief, hiding it away, hiving it off to a personal self, distinct from the professional, is to deny its place in life and to deny our humanity. In the context of a pandemic in which colleagues, patients, and loved ones have died, leaving no room at the table for grief renders life inauthentic.
…… Working with death and grief elides professional barriers. It urges us to bring our vulnerability with us, meeting the patient as a person but also, crucially, bringing our own person with us. That does not mean burdening patients with our own suffering or failing to maintain helpful boundaries. Rather, responding with compassion towards patients requires us to understand and respect our own need to process emotions.
……. Grief prompts us to consider how we treat ourselves as well as how we treat the person in front of us professionally. Being open about our own experiences of grief, and showing the strength of vulnerability, is a powerful statement to patients, carers, and colleagues that can help shift society’s attitude to grief. Individually, this can bring about a deepening and maturity of medical practice. Bringing the insights that grief affords into our professional and personal lives could have huge personal and societal benefits.
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.
Barts-MS rose-tinted-odometer: ★ (Black & White Friday)
As the delta variant of SARS-CoV-2 is surging it is putting residents of Whitechapel at serious risk of getting COVID-19.
This is important because the vaccination rate in Whitechapel is so low; less than 30% of adults have both dose of the COVID-19 vaccine.
Why is the uptake of vaccines so low in our local community?
Vaccine hesitancy is very high in Whitechapel and the reason are complex. If you can do anything to encourage people to get vaccinated please do. We in Barts Health NHS Trust and the Royal London Hospital are bracing ourselves for another surge of COVID-19 admissions, but the knock-on effects on other services, including our MS service, will take its toll on staff and people with MS.
The following are a some answers to questions that vaccine hesitators may ask. if you are a hesitator are there any questions I have missed out?
The following Questions and Answers have been adapted from the Quinn & Andrasik perspective in this week’s NEJM.
How did these trials move so quickly?
Researchers used existing clinical trial networks. Manufacturing started while the clinical trials were still underway. Adenoviral and mRNA vaccines are faster to produce than traditional vaccines. Other sponsors use platforms that have proven successful in the development of vaccines. The studies included more participants than a typical study and disease transmission rates were high, enabling researchers to determine efficacy in a short time. The MHRA prioritized review, authorization, and recommendation of Covid-19 vaccines.
Were vaccines tested on people like me?
Yes. Vaccine trials included all adults >18 yr of age. It was mandated that a large number (~20-25%) of participants in most trials had to be >65 yr of age. Study participants included ~25% of people with common health problems such as high blood pressure, diabetes, HIV, and cancer. There were no exclusions for diseases or medications, except immunosuppression. Vaccine studies did not include pregnant people.
Do these vaccines work for all races/ethnic groups?
Yes. There is strong evidence that the vaccines work well for all people, regardless of their genetic background. What types of reactions have been reported after vaccination? Common reactions: Sore arm, headache, aches, fever may appear within 48 hours. These are similar to reactions seen after shingles and influenza vaccines. Rare reaction: anaphylaxis, blood clots Current recommendation: 15 minutes of observation after injection If you have a history of severe allergies or an anaphylactic reaction to a vaccine, it’s recommended that you discuss vaccination with your provider and undergo 30 minutes of observation after receiving the vaccine. Most people with a history of allergies or anaphylaxis have received a vaccine with no issues.
Should I get a vaccine now or “wait and see”?
You should be vaccinated as soon as possible. You are not the first: Over 1 billion people have received COVID-19 vaccines Immunity takes time to develop and you are only maximally covered against the new variants of the virus about 2 weeks after your second or booster dose of the vaccine. Please note the new Covid-19 strains are more contagious and cause more severe disease than the old variants.
Does mRNA and adenovirus DNA change your DNA?
No; mRNA and adenoviral DNA is a signal to your cell. It stays in the outer part of the cell and does not enter the nucleus where your nuclear DNA is located. The mRNA and adenoviral DNA in the vaccine is present in the body for only 1–3 days; then it degrades and the immune system is primed and ready.
I’ve heard that the vaccines ….?
No, it will not give you Covid-19. No, it does not affect women’s fertility. No, it does not contain fetal tissue, microchips, or any other devices.
Which vaccine is the best?
All the vaccines are very good at preventing severe disease, so they will greatly reduce rates of severe disease progression, hospitalization, and death. When you are offered a vaccine, you should take it. Because the adenoviral vaccines are associated with rare blood clots, which is mainly in younger people (<30), it is recommended that young people have the mRNA vaccines (Pfizer or Moderna).
Why do I have to wear a mask after getting immunized against Covid-19?
The vaccines prevent Covid-19 disease, severe disease, and death. We know much less about whether vaccines prevent asymptomatic infection, as this question was not studied. Until we know that, we must assume that vaccinated people might get Covid-19 and not know it. Masks, social distancing and handwashing are still required until we have more information.
Is one dose of vaccine as effective as two doses?
The data are very clear that the best protection from Covid-19 disease happens after the second (booster) dose. The first dose starts the immune response, and the second dose boosts it to make high antibody levels.
How long does vaccine immunity to Covid-19 last?
We don’t know. Covid-19 is a brand-new human disease, and we will need more time to determine how long vaccine responses last.
How will viral mutations affect Covid-19 vaccines?
Current vaccines work well against the variant originally identified in the UK. There seems to be some reduced efficacy for the variants originally identified in South Africa, Brazil and India. The vaccines are still highly effective in preventing severe disease (reducing risk of being hospitalised, requiring supplemental oxygen, needing a ventilator) and death. The vaccines may not prevent you from getting mild symptoms, but they will prevent severe disease.
Please get out there and become a pro-vaccine warrior. The sooner we flatten the tail of this pandemic with vaccine immunity and not herd immunity form wild-type infection the lower the risk of immune escape variants and the fewer deaths.
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.
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.
📣Roll-up, roll-up! Or should we say ‘walk-in, walk-in’! 🚶🏽 🚶🏼♀️ 🚶🏿♀️ 🚶
We’re offering Pfizer vaccine 1st doses on a walk-in basis at our centre on The Street @westfieldstrat, 8:30am–7pm.
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.
Barts-MS rose-tinted-odometer: ★ (a very Black & Red Monday)
I received an email from Laura, a young woman with very active MS, who had been on natalizumab (Tysabri) for 7 years and had recently seroconverted to being high-index JCV seropositive. She was put onto natalizumab extended interval dosing (EID), i.e an infusion every 8 weeks, to derisk PML and to reduced the number of infusions she required during the COVID-19 pandemic. Before starting her switch therapy she was told she needed to be vaccinated with the COVID-19 vaccine. Her natalizumab was stopped and whilst she was waiting for vaccine immunity to develop she developed natalizumab-rebound. This is her story.
“I’m Laura, a pwMS in the UK and I also work in the MS field. Currently, I’m not able to work due to recent rebound disease of MS, following discontinuation of Tysabri, to switch to another DMT. I believe the decision to delay the new treatment, to try to ensure I made antibodies to the second COVID-19 vaccination, was perhaps the wrong decision to be made on my behalf (I did not have any contribution to the decision, I was informed of the decision).
To risk rebound disease is not a small matter and I would urge conversations around this prior to the switch from Natalizumab (Tysabri) or Fingolimod (Gilenya) and potentially other S1P modulators (siponimod, ozanimod and ponesimod). I was in hospital for several weeks and much more disabled than I usually am; even during a typical relapse. It was a frightening and traumatic experience, and one I thought I would never endure. My mental health has also suffered as a direct result from the rebound relapse. I’m now trying to recover at home, to increase my strength and stamina sufficiently to be able to go back to driving again, working and being a Mum to two autistic boys. Independence.
I do not know of course if I will ever go back to my previous baseline. It saddens me that this was potentially avoidable; that we need to be mindful that rebound disease, by its very definition, is more severe than what has previously been experienced, and although COVID-19 vaccination is of course very important, I would have preferred to reduce my risk of rebound disease as the priority. It is my brain and spine after all. And as we know the more lesions we acquire the less reserve we have for the future. Perhaps rebound disease should be a never event, as when managed carefully it can be avoided.”
Laura’s story is tragic and should never have happened. We know enough about natalizumab rebound to prevent it from happening. It is more likely to occur in patients who have high disease activity and a high level of disability prior to starting natalizumab (see paper below). It also occurs around month 3-4 after the last infusion of natalizumab and probably slightly earlier in patients like Laura on 8-weekly EID when the steady-state levels of natalizumab are likely to lower.
There is also no scientific evidence to suggest pwMS on natalizumab will make lower antibody responses to the COVID-19 vaccine whilst on natalizumab. In our centre, this patient will have been on 6-weekly and not 8-weekly EID. She would have had all her vaccine doses whilst on natalizumab. On the day of her last natalizumab infusion, she would have had an MRI and lumbar puncture to exclude subclinical or asymptomatic PML. Provided these were negative she would have been switched to her next DMT approximately 3-4 weeks later. If for some unforeseen reason a delay was going to occur we would have given her another infusion of natalizumab. In short, we have seen too many catastrophic rebound associated relapses and would want to prevent this from happening; we know how to prevent rebound relapses so why not?
Laura, if you are reading this blog post, thank you for agreeing to allow us to publish your story and I sincerely hope you make a good recovery from your relapse. If anything can be learnt from Laura is that please don’t let vaccine-readiness delay starting a natalizumab-switch therapy.
Laura’s case illustrates my biggest fear during COVID-19 that untreated or undertreated MS is more of a concern than COVID-19. The good news is that we should be getting a definitive answer on whether or not EID is as effective as standard interval dosing (SID) in the near future from the NOVA study (ClinicalTrials.gov Identifier: NCT03689972)
Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting.
Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse.
Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation.
Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.
The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.
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.
Barts-MS rose-tinted-odometer: ★★★ (a blueish-green Thursday; looking forward to being a weekend warrior #0d98ba )
My heart sank when I saw the latest COVID-19 UK case numbers. Here we go again? I don’t think so simply because the vaccines are working as well as the protective immunity induced by wild-type SARS-CoV-2 infection. I just wish the Government would take a pragmatic approach to the science and allow people who have been vaccinated (double-dose) and with confirmed previous SARS-CoV-2 infection to get back to normal.
It is clear from Israel that people who have had COVID-19 are as immune as vaccinated people to (re)infection with the virus. This will almost certainly apply to the circulating variants that as yet are not immune escape variants, i.e. capable of reinfecting large numbers of people who are meant to be immune to SARS-CoV-2.
The biggest concern with the current Indian or Delta SARS-CoV-2 variant is that it is more transmissible and more virulent, which means people who are not vaccinated are taking a big risk. This is very relevant to the East end of London where the vaccination rates in adults are below 50% because of significant vaccine hesitancy in the local population. We are therefore at high risk of a significant fourth wave of infections, which will have implications for our hospital and other services, including the MS service. We really need some respite from fighting and dealing with COVID-19 so that we can get back to normal or at least near normal. So please think carefully about resisting vaccination; you are not only putting yourself at risk but are impacting the health of others.
Please remember that COVID-19 and SARS-CoV-2 are going nowhere soon and will almost certainly become endemic, i.e. the virus and its variants will remain with us forever. So if you have not been vaccinated you will at some point in time get exposed to SARS-CoV-2 and get COVID-19. The risks of COVID-19 and its consequences, including long-COVID, are orders of magnitude worse than the risks of the vaccine. Therefore please #GetVaccinatedASAP. In my opinion there really are very few reasons to say no! Do you agree?
Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncontrolled leads many states to the dilemma whether or not to vaccinate previously infected persons. Understanding the level of protection of previous infection compared to that of vaccination is critical for policy making. We analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Vaccination was highly effective with overall estimated efficacy for documented infection of 92·8% (CI:[92·6, 93·0]); hospitalization 94·2% (CI:[93·6, 94·7]); severe illness 94·4% (CI:[93·6, 95·0]); and death 93·7% (CI:[92·5, 94·7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94·8% (CI:[94·4, 95·1]); hospitalization 94·1% (CI:[91·9, 95·7]); and severe illness 96·4% (CI:[92·5, 98·3]). Our results question the need to vaccinate previously-infected individuals.
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.
Barts-MS rose-tinted-odometer: ★★★ (It feels like a sky blue rainy Friday = #87ceeb)
“Prof G how many of my monthly ofatumumab injections should I miss to guarantee that I will have an adequate antibody response to the COVID-19 vaccine?”
This was the gist of one of the direct messages I received on Twitter from a person with MS living in the US.
I really don’t know. However, I have tried extrapolating data from the repopulation kinetics of ofatumumab given 3-monthly and the modelling data below on ocrelizumab and rituximab. For ocrelizumab and rituximab to have 80% confidence it requires at least 9 months from the last infusion to the first vaccination to have a >50% chance of seroconversion in response to an RNA-based COVID-19 vaccine. This equates to missing close to one dose of ocrelizumab or rituximab as you have to wait 9 months then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommencing your 6-monthly infusions. i.e. ~11 months after your last infusion. Although Mike Famulare has treated rituximab and ocrelizumab as being equipotent in his modelling I suspect he is wrong and the gap for ocrelizumab may in fact have to be substantially longer. I predict that the average person will need to wait about 11-12 months post their last infusion of ocrelizumab to be confident of an antibody response.
As ofatumumab, is a lower dose anti-CD20, with more rapid B-cell repopulation kinetics than ocrelizumab or rituximab (see figure below). I estimate that you will need to wait about 6 months from your last injection before being vaccinated and you would then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommending your monthly injections. i.e. ~8 months later. As this is all based on modelling I suspect in real life you will simply need to wait for peripheral blood B-cell reconstitution to occur before being vaccinated. The problem with the latter is how high do your peripheral B-cells have to be before being vaccinated; more than 3, 5, 10, 20, 50 or 80 CD19+ B-cells per mm3? Clearly, this is something that needs further study and I would urge Pharma or one of the MS groups interested in answering this question to do the study. Let’s call it the ‘Peripheral B-cell Threshold Vaccine Study‘ or the ‘PerBeC Vax Study‘.
I want to reiterate that vaccine immunity is not only about B-cell and antibody immunity, T-cells also have an important role to play. Granted that if you don’t make antibodies it indicates that your follicular T-helper cells memory may not be that great, but this does not tell you about other CD4+ and CD8+ T-cell memory responses. Therefore, please be patient until these data emerge.
My message remains the same; #GetVaccinatedASAP. During this phase of the pandemic, some immunity is better than no immunity. The risk associated with getting COVID-19, particularly if you are on a B-cell depleting agent, far outweighs the risks associated with vaccination.
Seroconversion rate following complete COVID-19 vaccination vs. time since most recent b-cell depleting therapy (BCDT). Best fit, 80%, and 95% confidence interval shows logistic regresssion model of seroconversion probability over time.
B-cell depleting therapies (BCDT) such as ocrelizumab and rituximab used for the management of multiple sclerosis are associated with reduced seroconversion rates following COVID-19 vaccination. In this note, I reanalyze data from the literature to examine how the probability of seroconversion depends on the time interval between the last BCDT dose and the first vaccine dose. While uncertainty is high due to limited data, the results show that the seroconversion probability increases with time. Under a Bayesian interpretation of logistic regression, I estimate with 80% confidence that it requires at least 9 months from last BCDT to first vaccination to have a >50% chance of seroconversion following complete mRNA vaccination, with large uncertainty on when higher confidence of seroconversion can be expected. Among subjects who do seroconvert following vaccination, anti-Spike IgG levels correlate with time since last BCDT. Limited data indicate that levels comparable with immunocompetent response can be achieved with intervals of 12 or more months between BCDT and vaccination. With combined data from multiple sources, I argue that time development of the seroconversion probability and antibody response parallels that of CD19+ and naive B-cell repopulation following BCDT, suggesting that monitoring B-cell repopulation will be useful at the individual level for optimizing vaccine response while maintaining adequate MS control.
Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.
Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).
Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.
Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.
Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.
Classification of evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.
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.
