vaccine – Prof G's MS Blog Archive

#COVID19MS: antibodies matter

Barts-MS rose-tinted-odometer: ★★★ (An ECTRIMS red Wednesday #e52330)

I am getting endless questions about when is it the best time to have the 3rd and/or booster dose of the COVID-19 vaccine in relation to ocrelizumab infusions, which is why I did an MS-Selfie Case Study on this topic on the weekend.

Unfortunately, until we have good evidence that shows people on ocrelizumab who seroconvert do better than those who don’t seroconvert after the COVID-19 vaccine there is no right or wrong answer. I think we just need to tell pwMS that they are likely not to seroconvert if they are on an anti-CD20 therapy (ocrelizumab, rituximab & ofatumumab) and still have peripheral B-cell depletion. However, if pwMS on anti-CD20 therapy want to optimise their immunity by seroconverting they will need to delay or miss infusions or injections until they B-cell reconstitute. The latter is more important for older patients and those with comorbidities, who are at higher risk of severe COVID-19 and dying from the infection.

The following vaccine study from Israel in this week’s NEJM tells us why antibodies are important post-vaccination. Breakthrough vaccine infections in healthcare workers who had been double vaccinated with the Pfizer-BionTech mRNA vaccine were much more likely in those with lower antibody titres. In summary breakthrough infections with SARS-CoV-2 is correlated with low neutralizing antibody titers during the peri-infection period. The good news is that most breakthrough infections were mild or asymptomatic, although persistent long-COVID-like symptoms did occur.

Can we extrapolate this to pwMS? Yes, definitely. Why would the biology of neutralizing anti-SARS-CoV-2 antibody protection be different in pwMS compared to people in the general population or in this case healthcare workers? This is why pwMS on anti-CD20 therapy who have not seroconverted after being fully vaccinated with a COVID-19 vaccine must consider themselves at-risk of breakthrough infections, which may be severe, particularly in older age groups and those with comorbidities and not to mention long-COVID.

Bergwerk et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021 Jul 28; NEJMoa2109072.

Background: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.

Methods: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.

Results: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

Conclusions: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

Conflicts of Interest

MS-Selfie Newsletter / MS-Selfie Microsite

Preventive Neurology

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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 and are not meant to be interpreted as personal clinical advice.

To get a booster or not

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.

Bar-On et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. NEJM September 15, 2021 DOI: 10.1056/NEJMoa2114255

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.

Conflicts of Interest

MS-Selfie Newsletter / MS-Selfie Microsite

Preventive Neurology

Twitter / LinkedIn / Medium

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.

Conflicts of Interest

Preventive Neurology

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Medium

#MSCOVID19 – AstraZenca Vaccine Update

Barts-MS rose-tinted-odometer: ★★

In response to a comment from one of our readers. We have not directly addressed the thrombosis AstraZeneca vaccine issue as we are not vaccinologists or haematologists. But as there seems to a lot of anxiety around this issue a short blog post about the potential risks may allay your fears.

I received the following email, from Professor Marcel Levy (Consultant Haematologist and CEO, UCLH), on the 19th of March that suggests the underlying thrombotic disorder that has been recognised in patients who have received the Oxford-AstraZenca COVID-19 vaccine may be quite specific and identifiable.

19th March

Dear Colleagues

I am taking a rather peculiar step but I think it is important to get this premature information out in the open for the potential benefit of patients.

We have found a strong clue about what is causing the rare thrombosis and thrombocytopenia in patients who received the COVID-19 vaccination. We have to be extremely careful because it is pending some more confirmation but there may be immediate implications for patients we cannot ignore. I know some others may be thinking in the same direction but are awaiting to publish the findings in a journal but we feel it takes too long and I think it is not responsible not sharing this with others as soon as possible.

We have identified three UK cases who developed rare (cerebral sinus vein) thrombosis in London after COVID-19 vaccination and Marie Scully of UCLH has identified a very strong anti-platelet factor 4 antibody response in those patients. They were not exposed to heparin before but you may realise Ted Warkentin has described incidental cases a few years ago (Warkentin TE, Basciano PA, Knopman J, Bernstein RA. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood. 2014 Jun 5;123(23):3651-4.). We feel it may be a good idea if others are confronted with these patients to do a HIT-ELISA and to withhold heparin until we know whether this is real or a false lead and awaiting further confirmation.

Just want to emphasise that we all realise this is extremely rare and should not be a reason to stop vaccination whatsoever. However, when confronted with a case, this may have consequences for their optimal treatment.

Please feel free to share this information within your communities as you may seem fit, as it might have implications for patients (once again, I think we need to be very careful of course before jumping to conclusions). I know we all want to be the first to publish, but we also have a responsibility for our patients.

All credits to Marie Scully who has done this test in these patients and is happy to share with everyone.

Best wishes, Marcel Levi
Prof. Marcel Levi MD PhD FRCP
Professor of Medicine, University College London
Professor of Medicine, University of Amsterdam
Consultant in Acute & Vascular Medicine and Haematology

Although we can’t be sure these thromboses are due to the AstraZenca vaccine it seems increasingly likely that they are as these sorts of thromboses have not been seen (yet) or described with the Pfizer-BionTech and other COVID-19 vaccines. According to the latest figures from the MHRA, there have been 22 reports of a blood clot or thrombosis in the brain called cerebral venous sinus thrombosis (CVST) accompanied by a low platelet count (as described in the letter above) as well as eight reports of other blood clotting problems with low platelets, among recipients of the AstraZeneca COVID-19 vaccine. Of these 30 reported cases, seven people have died. The denominator is over 18 million people who have received the vaccine. At the moment the rate of this complication is 1.7 people per million vaccinated and one death for every 2.6M people vaccinated. These estimates are likely to be under-estimates because of a reporting lag, but even if the risk increase by a factor of 2 or 3 they will still be relatively low. This risk needs to be compared to 1 in 1000 chance of dying from COVID-19 if you are aged between 40 and 50 years of age.

You have to realise that when you are vaccinating the whole adult population shit is still happening in the background; i.e. people will be getting DVTs, pulmonary emboli, myocardial infarctions, pneumonia, Bell’s palsy, strokes, CVSTs, etc. Life and biology continue as normal and all that has changed is that a vaccine is added to the mix. So when the EMA and MHRA say the benefits of these vaccines, including the AstraZeneca vaccine, outway the risks they mean it and their advice is based on safety data from tens of millions of vaccinated adults and a risk:benefit analysis. The latter is a judgment call they make on the impact of COVID-19 at a population level vs. the population benefits of vaccination. Their message can’t be any clearer: #GetVaccinatedASAP and these #VaccinesAreSafe. I think these figures speak for themselves and I fear we are literally throwing the baby out with the bathwater by dismissing the AstraZeneca vaccine as being too risky to use in certain population groups.

If you have any doubts about the benefits of being vaccinated or not being vaccinated just look at what is happening in France and Germany at the moment compared to the UK. My question is how many extra deaths are going to have happened because of delayed vaccinations in these countries? I suspect orders of magnitude more people will die from COVID-19 than from the rare complications of the COVID-19 vaccines. Do you agree?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: transverse myelitis

Barts-MS rose-tinted-odometer: ★★

How do you distinguish transverse myelitis that is not MS-related from spinal cord involvement in MS?

Yesterday after reporting the possible and likely link between the Oxford-AstraZenca vaccine and transverse myelitis (TM) and possibly MS you asked how do neurologists differentiate TM from CIS or MS.

Idiopathic or post-infectious/vaccine-related TM tends to be more extensive, i.e. involve multiple segments of the spinal cord compared to CIS/MS. This is often referred to as longitudinally-extensive TM. In addition, typical non-MS TM tends to involve the whole cord and not particular areas of the spinal cord. In comparison, CIS/MS tends to have discrete lesions that may involve the back or a segment of the spinal cord and extend over one or two segments.

CIS/MS myelitis tends to fit the demographic profile of MS, i.e. more common in females, youngish age of onset (20-40 years) and is more common in regions of the world with a high MS prevalence. In addition, there are often other lesions in the brain and/or spinal cord that look like MS and CSF analysis usually shows oligoclonal IgG band and the cell counts in the spinal fluid are lower.

Non-MS related TM can occur in any age group, occurs in both sexes and its quite common in Asian, African, Afro-Caribbean and African-American populations. Brain imaging is usually normal; the exception being some patients with NMO. CSF analysis is OCB negative and the cell count is often raised. Interestingly, it is not uncommon in acute TM to find some neutrophils and occasionally eosinophils in the spinal fluid that does not happen in MS-related myelitis.

An important clue is that non-MS related TM may have obvious precipitating factors of a recent viral or bacterial infection or vaccination.

Saying all this it is sometimes very hard to differentiate the two and then time becomes the best diagnostician, i.e. you have to wait to see if someone goes onto to develop recurrent events. This is why medicine and neurology remain as much an art as a science.

Worryingly the number of TM cases post-COVID-19 in the literature is quite high considering we are only 6-9 months into this pandemic. This would indicate that SARS-CoV-2 and its proteins may be the triggering factor for TM and/or MS and this will make this adverse event from this vaccine a real problem and we are likely to see more cases emerge. This does not mean the vaccine won’t be effective it simply means that some people with have to suffer harm to protect the many or the herd. This is the basic premise that population health is based on.

CoI: multiple

Twitter: @gavinGiovannoni / Medium: @gavin_24211

#MSCOVID19: vaccine readiness

Will Prof G have to eat his proverbial hat?

I have been telling people that an effective SARS-CoV-2 vaccine is a long way away and that we shouldn’t expect a commercially available vaccine for another 12-18 months. Maybe I am wrong. The Moderna phase 1 results were published by the NEJM yesterday and are more impressive than I expected. These results are so important because the vaccine is based on RNA technology, which is relatively easy to scale-up in terms of production, unlike recombinant protein vaccines or inactivated viral vaccines. Therefore this vaccine may be with us before the end of the year.

The Moderna RNA vaccine carries the code for S-2P antigen, consisting of the SARS-CoV-2 glycoprotein. The vaccine is given as two doses (Day 1 and Day 29) into the deltoid or shoulder muscle. The RNA then uses the molecular machinery of the deltoid muscle to make the immunogen that then stimulates the immune response to the antigen, which will hopefully prevent wild-type SARS-CoV-2 infection and prevent COVID-19.

This has potential implications for how we treat MS. It increases the likelihood of a successful vaccine to prevent COVID-19 and increases the chances of pwMS having to be vaccine-ready in a 6-9 month time scale rather than a 12-18 months period. Clearly this has implications for how we manage patients on DMTs that have been shown to blunt or prevent protective vaccine responses, in particular, pwMS on anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab) or S1P-modulators (fingolimod, siponimod, ozanimod, ponesimod).

Will Prof G have to eat humble pie or his hat? The market response to the data below suggests he will. What will be the implications for the MS DMT market? I suspect an effective coronavirus vaccine will hit the anti-CD20 market the most, which means ofatumumab’s MS launch will be a damp squib.

Jackson et al. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. NEJM July 14, 2020 DOI:10.1056/NEJMoa2022483

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.

METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.

RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

CONCLUSIONS: The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461

CoI: multiple