Splosh, Splosh Splosh, the drips are increasing Vaccination and fingolimod and anti CD20 are like oil and water…Not mixing

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Today we have the first interim analysis of vaccination data from Italy they have looked at over 700 people on their way to studying 2000 people. So I think we can safely say in terms of anti-CD20 and fingolimod, that they are problem children in terms of the antibody response

Effect of SARS-CoV-2 mRNA Vaccination in MS Patients Treated With Disease Modifying Therapies. Sormani et al. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3886420

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.

Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech, Inc or mRNA-1273, Moderna Tx, Inc). A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics).

Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p<0·001), fingolimod (26-fold decrease, p<0·001) and rituximab (17-fold decrease, p<0·001) were significantly reduced as compared to untreated patients. mRNA-1273 vaccine resulted in a systematically 3·5-fold higher antibody level than the BNT162b2 vaccine (p<0·001).

Interpretation: In pwMS, therapy with anti-CD20 and fingolimod led to a reduced humoral response to SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·5-higher antibody titers than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 or fingolimod. Since it is still unknown the role of T-cells vaccine response, further information is required about the role of cellular immunity triggered by vaccination to better define the most appropriate strategy to vaccinate pwMS under specific DMTs.

So supports what I have said if you are interested in an antibody response Moderna *RNA-1273 gives the highest titre.

The percentage of patients on fingolimod, ocrelizumab and rituximab with antibody levels above the cutoff of
202 positivity was 100% (21/21), 61% (14/23) and 71% (5/7) respectively among those vaccinated with mRNA203 1273 vs 90.6% (58/64), 40.5% (53/131) and 61% (11/18) among those vaccinated with BNT162b2. So you can see the assay used may influence your positivitiy But as you can see the antibody levels low the scale is log 1=10, 2= 100 3 = 1000 4 10,000 so more people with moderna give about 8000 but the median for ocrelizumab = 10-20, In our assay this is essentially negative

As I have said you can see you may need to get a response if antibodies are important you can see most other DMT not influenced…but there were no astrazeneca users

With rituximab 9 months may be useful but ocrelizumab we dont know . Look at dot between 21 and 24 so nearly 2 years out and not much of a response for one person with ocrelizumab.

Anyway I am sure Dr Ruth will be adding to what is becoming a lake than a drip, more of that by next week. The question is what does a 10 U/mL antibody response mean?

But it is important

Why are antibody levels important, because they may affect your risk of infection. In this study in health care workers about 4% of people got infected after being double jabbed. Those who showed COVID-19 had lowever antibody levels. Now it is not possible to compare the graph below with the one above but the reduced level in the infected individuals is small compared to the more marked drop in anti-body levels after anti CD20.

Bergwerk et al.

Bergwerk et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers NENg J MedDOI: 10.1056/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.

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 titres and N gene cycle threshold 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 titres 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 titres were associated with lower infectivity. 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 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.

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

A Oberhardt et al. Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine. Nature

SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as 10 days post prime vaccination, when neutralizing antibodies are hardly detectable (Just as I said over a year and a half ago) . Vaccine-induced CD8+ T cells may thus be the main mediators of protection at this early stage  (Part as I said a year and half ago. They have forgotten about the innate cells/macrophages). The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood (etc etc). We show on a single epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after BNT162b2 prime vaccination when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable (Just like seen with other vaccines and given that the vaccines are 90%+ effective says they are important. Therefore good needs that they are induced in people treated with ant-CD20). Boost vaccination induced a robust expansion generating highly differentiated effector CD8+ T cells (NSS); however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared to natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

10 comments

    • Yes DrRuth will put the paper online this weekend so you can have our splash next week but as a sneak preview n=400-500

        • Don’t expect too much opinion….I didnt write the paper;-). That is down to DrRuth and our Friends in Cardiff….Yes we are not competing but have joined forces in the Best of British Collaborative Spirit indeed the neuros have been sharing data across a number of groups for a number of months

  • So the million dollar question: how can we get people on anti cd 20 protected so they don’t live in isolation forever. We know that going off your treatment is bad for MS but losing all your social capital as everyone goes places without you is just as bad for MS.

    I know some very smart people are working on the answers, can’t come soon enough!

    • It is evident that people on anti-CD20 get the important protection from T cells via vaccination, profG the optimist thinks that this is enough, but this is opinion but no evidence

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