T-cells – Prof G's MS Blog Archive

Zoster

Barts-MS rose-tinted-odometer: ★ (Bank Holiday Monday morning blues)

The next marketing battle in terms of MS DMTs will be herpes zoster and how we manage it. Shingles is quite common in the general population, but it is much more common in pwMS. Why? Probably because of the immunosuppression associated with MS DMTs and the use of high-dose steroids to treat relapses and prevent infusion reactions. Put simply Zoster comes with the territory of managing MS. The following figure is from a meta-analysis I have recently done on the rate of zoster reactivation on current MS DMTs relative to other DMTs and compared to what is expected in the background population. Do you find the results surprising?

The two reported case studies below of severe shingles/herpes-zoster in two pwMS on dimethyl fumarate demonstrates two things. Firstly, contrary to what most people think DMF is an immunosuppressive compound. Even if we derisk DMF and switch treatments if the total lymphocyte counts drop below 880/mm3 or 500/mm3 there can still be quite a profound CD8+ T-cell lymphopaenia. Secondly, the cases below actually had relatively normal total lymphocyte counts despite low CD8+ T-cell counts. These cases make me wonder if we should be monitoring T-cells subset counts in our patients on DMF.

The relative sensitivity of CD8+ T-cells to DMF must be a clue to how the drug is working from an immunological perspective. Despite this, the exact mode of action of DMF in MS remains a mystery.

For several years I have been asking whether or not boosting cytotoxic CD8+ T-cell immunity against the herpes zoster virus with the new Shringex vaccine, prior to starting DMTs, would lower the risk of shingles on treatment. Which brave Pharma company will do this study in the current environment? I suspect a few might take the plunge as vaccine readiness or vaccine responsiveness is now uppermost in the minds of MS experts and their patients. The latter is being driven by the COVID-19 vaccine studies and the demonstration that people on antiCD20 therapies and fingolimod of blunted antibody responses to the vaccines.

So in summary vaccines, vaccine readiness and derisking infectious complications, in particular herpes zoster, will be the next marketing battleground in the MS DMT wars. Did your HCP discuss the zoster risk with you prior to start you on a DMT?

Anagnostouli et al. Aggressive Herpes Zoster in Young Patients With Multiple Sclerosis Under Dimethyl Fumarate: Significance of CD8 + and Natural Killer Cells. Neurol Neuroimmunol Neuroinflamm. 2021 May 28;8(4):e1017.

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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.

Anti-CD20 more than just B-cell depletion

Barts-MS rose-tinted-odometer: ★★ (amber; a sleep deprived colour somewhere between yellow and orange)

It has become clear that the anti-CD20 therapies are more than just anti-B-cell therapies. Minority populations of both CD4+ and CD8+ T-cells and NK-cells express CD20 and are depleted after both rituximab and ocrelizumab treatment.

It looks as if ocrelizumab may be more effective in deleting this population of cells and may explain why herpes zoster or shingles is more common after ocrelizumab, compared to rituximab, than what you would expect based on its putative B-cell only targeting effect. The mild depletion of this population of cells may also explain why pwMS on ocrelizumab are at higher risk of getting COVID-19 and severe COVID-19.

The study below shows that this population of cells express a so-called CTL or cytotoxic phenotype that fits in with the zoster and COVID-19 data. This also raises concerns that just maybe peripheral tumour immune surveillance is also compromised on anti-CD20 therapies. The tumour signal however is likely to be small as a large secondary cancer signal would likely have emerged already on the anti-CD20s.

More topical is the role these CD20-expressing T-cells play in vaccine responses. If they are important in vaccine immunity then patients with MS on anti-CD20 therapies who lack this population of T-cells may not develop adequate T-cell immunity in response to vaccination. We won’t have long to wait for the latter data as many immunology laboratories are busy trying to get their T-cell vaccine data out as soon as possible.

So yes there is much more to the immunology of anti-CD20 therapy than simple B-cell depletion. Could the T-cell compartment targeted by anti-Cd20 therapies be as important or more important than the B-cell compartment? There is so much more to learn about how MS DMTs really work, in particular the anti-CD20 therapies.

Boldrini et al. Cytotoxic profile of CD3+CD20+ T cells in progressive multiple sclerosis. Mult Scler Relat Disord. 2021 May 7;52:103013.

Recently, it was shown that highly effective anti-CD20 therapies used for MS patients not only deplete CD20+ B cells, but also a small subset of T cells expressing CD20 surface marker (CD3+CD20+ T cells). Here we demonstrated that, in progressive MS patients, CD3+CD20+ T cells share the ability to express cytotoxic factors such as perforin and serine-protease granzyme-B (GzmB), classically associated with CD8+ T cells functionality. Beyond it, cluster analyses show that a set of activation markers and transcriptional factors related with CD8 effector program are also expressed in CD3+CD20+ T cells. Further characterization of surface and functional markers from CD3+CD20+ T subsets may be helpful for development of new therapeutic strategies mainly for progressive MS patients, as well as for assessing pathophysiological effects of highly effective anti-CD20 therapies.

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#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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Stay calm and get vaccinated

Barts-MS rose-tinted-odometer: ★★★

We can speculate until the cows come home, but speculation remains guesswork. Until a similar study to the one below on T-cell responses to the COVID-19 vaccine is done in people with MS on different DMTs we can’t be confident that people who don’t seroconvert after the vaccine have adequate or protective anti-SARS-CoV2 spike protein T-cell responses.

However, my message remains the same around vaccinations. The COVID-19 vaccines are safe and we don’t have any reason to suspect the vaccines have any effect on your MS in the long term. Apart from transient worsening of symptoms, which are reversible, in response to the flu-like symptoms from the vaccine pwMS seem to be tolerating the vaccine without any problems. The latter is more common in patients with advanced disability and can be managed with prophylactic paracetamol and/or ibuprofen.

Good things come to communities who are patient. My advice would be to stay calm and #GetVaccinatedASAP.

Painter et al. Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. bioRxiv 2021 doi: https://doi.org/10.1101/2021.04.21.440862

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naive subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.

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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.