#MSCOVID19: T-cells and anti-CD20 therapy

Barts-MS rose-tinted-odometer: ★★★

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

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

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

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

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

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

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

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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.

Long-COVID

Barts-MS rose-tinted-odometer: ★★

If anyone who has any doubts on the debate of getting or not getting COVID-19 and taking your chances without being vaccinated needs to read the paper below in this week’s BMJ on long-COVID.

Long-COVID is a serious problem and should not be dismissed as something minor. Long-COVID is not simply post-viral fatigue. So if you are one of those people who is nervous about having the vaccine I would urge you to think again. There is no doubt in my mind getting COVID-19 is much worse and riskier than having any of the licensed COVID-19 vaccines. If you don’t have the vaccine you have to assume that at some point in the future you will get COVID-19; this virus is not going away it will become endemic.

So my message remains simple #StayCalm #BeRational #GetVaccinatedASAP

Ayoubkhani et al. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ 2021;372:n693

Objective: To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population.

Design: Retrospective cohort study.

Setting: NHS hospitals in England.

Participants: 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records.

Main outcome measures: Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity.

Results: Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).

Conclusions: Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.

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COVID-19 vaccine thrombosis update

Barts-MS rose-tinted-odometer: ★★

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

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

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

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

Please #StayCalm and #GetVaccinatedASAP.

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

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

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#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side.

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination.

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP.

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug. So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines.

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

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#MSCOVID19: T-cell response on ocrelizumab

Barts-MS rose-tinted-odometer: ★★★★★

As you know the vast majority of pwMS on anti-CD20 therapy who get COVID-19 or for that matter any other viral infection recover. In other words, their immune systems work despite blunted or absent B-cell or antibody responses. This study presented yesterday at the AAN meeting confirms that ocrelizumab-treated patients who get COVID-19 have good robust T-cell responses. Almost all of these patients also had antibody responses to the virus. The ocrelizumab-treated cases that fail to seroconvert may therefore represent a publication bias. However, as this study doesn’t include the 5% of subjects on ocrelizumab who succumb to COVID-19 we can’t assume this applies to all ocrelizumabers.

It will be interesting to see these results replicated with the COVID-19 vaccines. Although wild-type infection with SARS-CoV-2 is likely to provide a more robust immunological challenge than a COVID-19 vaccine, I can’t see why the vaccine won’t induce T-cell responses as well. The question will be how few patients fail to respond to the vaccine at both an antibody and T-cell level.

I am sure a large number of ocrelizumabers or anti-CD20ers and their HCPs will be relieved to see these results (or not).

Kister et al. Preliminary Results of Ongoing, Prospective Study of Antibody and T-Cell Responses to SARS-CoV-2 in Patients With MS on Ocrelizumab or Other Disease-Modifying Therapies. AAN 2021

Objective: 1. To assess SARS-CoV-2 seropositivity in 1,000 patients with multiple sclerosis (MS) and its association with demographic and disease-related characteristics, and disease-modifying therapy (DMT); 2. To evaluate the persistence of antibody and T-cell responses in a subset of these patients who were receiving ocrelizumab (OCR), other DMT or no DMT at the time of COVID-19 infection. Background: Since March 2020, ˜15% of patients attending NYU MS Care Center (NYUMSCC) in New York City had COVID-19. It is unknown whether DMTs affect the persistence of antibody and T-cell responses to SARS-CoV-2.

Design/Methods: Patients from NYUMSCC were invited to undergo serologic assessment using Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays of antibody responses to SARS-CoV-2 nucleocapsid and spike proteins. A subset of patients with or without COVID-19 history underwent a study of T-cell responses to SARS-CoV-2 spike protein using IFN-? enzyme-linked immunosorbent spot (Invitrogen) and TruCulture (Myriad RBM) spike protein assays and live virus immunofluorescence-based microneutralization assay.

Results: Since January 2021, 100 unvaccinated patients with MS were enrolled (mean 41 years; 63% female; 45% non-white; 35% on OCR; 26% had COVID-19). Antibody and T-cell results were available for 40 patients (26 on OCR; 17 had COVID-19, median 10 months before sampling). Of the 40, Elecsys Anti- SARS-CoV-2 assay identified all but 2 COVID-19+ patients, and multiplex bead-based assay identified all but 1 COVID-19+ patient as seropositive. Neither assay had false positives. T-cell activation based on induced IFN-gamma secretion was observed in 10/17 COVID-19+ patients and 1 patient without COVID-19 history who developed PCR-confirmed COVID-19 five days after sampling. Anti-SARS-CoV-2 antibody response was detected in 4/5 and T-cell response in 3/5 OCR-treated COVID-19+ patients.

Conclusions: Preliminary results suggest persistent humoral and T-cell immune memory to SARS-CoV-2 up to 10 months following infection even in B-cell depleted patients with MS. Updated results will be presented.

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

#MSCOVID19: antibody testing post-vaccine

Barts-MS rose-tinted-odometer: ★★★

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

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

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

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

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

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

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#MSCOVID19: adenoviral vector vaccines

Barts-MS rose-tinted-odometer: ★

You may have heard that the FDA has suspended dosing of the J&J COVID-19 vaccine as they have identified 6 cases of thrombosis in young woman similar to that described below with the Oxford-AstraZeneca vaccine (see articles below). It looks like the complication may therefore be due to the vectors, i.e. adenoviruses, rather than the SARS-CoV-2 spike protein. If this is the case there is likely to be similar cases identified with the Russian Sputnik V vaccine, which uses two different adenoviral vectors.

Please remember that this thrombotic complication is still very rare, i.e. likely to be less than 1 person affected in over 100,000 vaccinated people, which is why the EMA, MHRA and WHO have made it clear that the potential benefit of the Ox-AX vaccine outweighs the risk of thrombosis. In other words, the risk of getting COVID-19 is far worse than the risks associated with the vaccine. So our message remains the same; #GetVaccinatedASAP.

Thrombotic (blood clots) thrombocytopaenia (low platelets) is an immune-mediated condition, in which your own immune system makes antibodies against a protein called platelet factor 4 expressed on platelets. In other words, it is an antibody-mediated autoimmune disease. This will allow haematologists and vaccinologists to study the condition and work out why it is happening and then manage the risk or hopefully prevent it from happening in the future. For example, it could simply be due to molecular mimicry to a protein or stretch of protein in one of the adenoviral proteins that could be engineered out of the next generation of vaccines.

With my preventive medicine hat on I am concerned that this rare complication of the adenoviral vaccines will feed the anti-VAXX lobby and turn people off having the COVID-19 vaccine. This would be a great tragedy as it is the adenoviral vaccines that are going to save the world from this pandemic; they are relatively cheap and easy to manufacture and don’t have to be stored at -20 or -80. All these attributes make them the vaccines of choice for low and middle-income countries.

Please note I would not have a problem being vaccinated with a COVID-19 adenoviral vaccine nor would I have a problem recommending these vaccines to my family members.

Greinacher et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print.

Background: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

Methods: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.

Results: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity-purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

Conclusions: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

Schultz et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882. Online ahead of print.

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

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The aftermath

Barts-MS rose-tinted-odometer: ★★

I am increasingly being asked about what is going to happen to MS research and clinical services post-COVID-19. The question is being asked as if I am some kind of futurist or prophet. I am not. My response is let’s focus on the here and now. The following on the issues that need to be addressed this year:

Untreated or under-treated MS. There is has been a drop-off of about 30% of new-starts on DMTs. This means people with MS are waiting in queues to be diagnosed and offered treatment.
Far too few people with PPMS and SPMS have been through the screening pathways for potential treatment with ocrelizumab or siponimod, respectively. Some MS centres have yet to start their progressive treatment pathways.
Vaccine hesitancy: too many pwMS are refusing our offer for a COVID-19 vaccine. Why? What do we need to address vaccine hesitancy? The message #GetVaccinatedASAP is maybe too flippant and doesn’t take into account the complexity of the issues.
Neuro rehab: so many of my patients have deteriorated because their rehab services are on hold. Does the NHS have the capacity to deal with the backlog?
Mental health: so many of my patients have mental health issues as a result of lockdown. Who is managing this avalanche of depression and anxiety? What can we do about social isolation and loneliness?
Symptomatic therapies: where do I begin? The biggest one is bladder and muscle botox services. So many of my patients are waiting for these services to restart; they are in a desperate state with bladder problems and spasticity. Wheelchair services? Orthotics? Falls prevention? Bone health? Continence services? Swallowing assessments? Dietary advice? Comorbidity screening and management? Etc. It is not that these services are not running, however, many are running at half capacity and need really need to be face-2-face to be done properly.
Monitoring: so many patients are waiting for annual MRIs to assess treatment response? How many have EDA (evident disease activity) that is being missed? Cervical smears as part of cancer screening? Blood monitoring etc.?
Social services: how many people with MS are waiting for housing assessments or adaptions? How are we going to address social determinants of health? Poverty? Inequality? Addiction? Alcohol consumption has soared during the pandemic; pwMS are not exempt.

The other elephant in the room is the manpower shortage. Many NHS workers are taking early retirement because of burn-out. Yes, many of us are simply tired, depressed and worn out. How are we going to do more, much more, with less staff? This is not unique to MS but applies to the NHS in general.

Clearly, there is MS research that needs addressing. Many trials were halted or even terminated early because of COVID-19. Can we resuscitate these studies? Who is going to cover the funding shortfall to cover the extension costs of these trials?

I am told that charities are down about 40% in their fundraising. Less fundraising less priming of research ideas, less innovation.

At least the pandemic has driven a rapid adoption and investment in new technologies, which is likely to increase productivity in the future. I see no reason why the productivity gains won’t have a positive impact on MS services and research output.

One of the advantages of the pandemic is that I have had quite a bit of time to reflect on things and will come out of the COVID-19 more focused. I have learnt to say no and will continue to say no to many things related to MS. My time left to make a difference to MS research is relatively short and I want to make a real difference, which is why my focus is going to be on EBV, the viral aetiology of MS and MS prevention.

Please don’t get blinkered about the impact of DMTs on COVID-19 and vaccines; these ‘micro issues’ are really tiny relative to the ‘macro issues’ highlighted above. We seem to be missing seeing the forest for the trees. Yes, the mountain looks big and impossible to scale, but unless we start climbing it today we will never reach its summit.

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Should we abandon the ADIOS study?

Barts-MS rose-tinted-odometer: ★★★

If you have been on ocrelizumab for two years would you be prepared to participate in the ADIOS (adaptive dosing ocrelizumab study)? One of the study arms would mean that you would not receive any ocrelizumab until you had a relapse or new MRI activity. In other words, we would be using ocrelizumab like we use alemtuzumab or cladribine, i.e. as an immune reconstitution therapy (IRT).

Some of our colleagues doubt whether people with MS would volunteer for such a study. I personally think they being affected by their own preconceived biases. We don’t know if we can use ocrelizumab or other anti-CD20 therapies as an IRT, which means we have equipoise. It is clear that using anti-CD20 therapy in this way will be safer, i.e. you would be less likely to develop hypogammaglobulinaemia and infections as a complication of continuous therapy. Similarly, the risk of secondary malignancies should be lower and you will be vaccine ready. The latest paper below shows that the time from the last dose of an anti-CD20 therapy predicts seroconversion after a COVID-19 vaccination; i.e. the longer you wait after a dose of rituximab, and probably ocrelizumab, the more likely you are to seroconvert after having the COVID-19 vaccine. I suspect going forward people on anti-CDC20 therapy may have to take drug holidays anyway to make sure they respond to vaccines. In fact, I was on a Medscape recording yesterday with a colleague from UCSF and a vaccinologist and they both said that most MSologists and rheumatologists in North America are already doing this. At the moment I have been saying get #GetVaccinatedASAP and cross the vaccine-readiness bridge when the boosters arrive. We will also have evidence, such as below, to guide us in the future.

Deepak P et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. MedRxiv https://doi.org/10.1101/2021.04.05.21254656.

The following data from Anat Achiron will hopefully be out as a pre-publication this week.

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

Conflicts of Interest

Preventive Neurology

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#MSCOVID19: triMSx-online

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

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

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

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

Tag: COVID-19

#MSCOVID19: T-cells and anti-CD20 therapy

Long-COVID

COVID-19 vaccine thrombosis update

#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

#MSCOVID19: T-cell response on ocrelizumab

#MSCOVID19: antibody testing post-vaccine

#MSCOVID19: adenoviral vector vaccines

The aftermath

Should we abandon the ADIOS study?

#MSCOVID19: triMSx-online

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

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

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

8 and 9 April 202119:00–19:45 BST I 14:00–14:45 EDT I 20:00–20:45 CEST

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