#MSCOVID19: Interferon-beta and NABs

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Barts-MS rose-tinted-odometer: ★

It is always nice to see evidence supporting a hypothesis you had more than a decade ago see daylight. 

If you are on interferon-beta or have been on interferon-beta in the past this post is important to you. It is clear type 1 interferons, such as interferon-beta and alpha, are important antiviral cytokines and are critical in the body’s fight against coronaviruses. There are two papers in Science that show that people with errors in the interferon pathway or neutralizing anti-interferon antibodies are at high and serious risk of severe COVID-19. The reason for this is that their immune system can’t mount an appropriate antiviral response.  

Why is this important to pwMS? The problem is that people on interferon-beta may generate anti-drug antibodies (ADAs)  to interferon-beta that can inhibit its antiviral activity. The rate of anti-interferon-beta neutralizing antibody (NABs) production depends on the preparation of interferon-beta you are on or have been on in the past. The NAB rates vary from about 2% to 35% and higher. The reason for this is based on whether or not the interferon-beta aggregates in the vial and whether or not there are other impurities in the particular formulation that may make the interferon-beta more immunogenic (more likely to stimulate the immune system to make NABs). 

Please note even if you have been treated with interferon-beta many years ago you may still have NABs. NABs may persist for many years and these will continue to inhibit your own interferon-beta’s activity. 

We reported a single case, our index case (see below), who developed recurrent severe genital herpes that coincided with her developing NABs. The herpes was such a problem that this patient is now on continuous antiviral prophylaxis and has been so for about 8 years. Any attempt to stop the antiviral is followed by rapid recurrent herpetic lesions. 

Based on this I suspect that pwMS who have NABs to interferon-beta may be at increased risk of getting severe COVID-19. I would urge anyone with a cohort of such patients to screen them for NABs and test this hypothesis. 

It is now clear that overall pwMS on interferon-beta are at lower risk of COVID-19 and severe COVID-19 presumably because the antiviral effects of interferon are protecting them against the virus. Therefore being on interferon-beta may be a double-edged sword depending on whether or not you have NABs.

If you don’t know your NAB status ask your HCP for a test. 

Would knowing that someone with MS was NAB-positive change practice? Yes, based on the science you would recommend increased vigilance and possibly self-isolation if the background risk of coronavirus infection is high. 

Fine et al. Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways? Mult Scler Relat Disord 2015 Jan;4(1):88-91.

Introduction: Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNβ.

Clinical case: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNβ treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNβ; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNβ were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNβ to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses.

Conclusion: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNβ. This case highlights that NABs not only decreases exogenous IFNβ treatment efficacy but may also interfere with anti-viral properties of endogenous IFNβ. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans.

Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4585 DOI: 10.1126/science.abd4585

Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4570 DOI: 10.1126/science.abd4570.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

10 comments

  • Hi Prof G. Earlier thoughts during the pandemic were that people who’d done lemtrada within the past 5 years were likely to have a less severe covid due to being unable to produce the cytokine response which is believed to cause it. Does that change if someone has previously done interferon beta if they have the neutralising antibodies?

  • Thank you Prof G for this information. Can one know of NAB without a test? I was on Plegridy for 4 years. On the last year I gradually started to have stomach issues which was quite disturbing and led to discontinuation. Is such a reaction related to NABs or can it be some other reaction to the drug?
    Can a GP test for NABs related to plegridy or is it a special test?
    Thank you for these informative blogs.

      • It wasn’t a relapse though. Everytime after the injection I had stomach ache (weird feces, etc) for days. A biopsy showed inflammation of the gut but nothing specific. It stopped after I stopped the injections,, and started again once I restarted plegridy. That forced us to change dmt even though my ms was stable.

        If you know the name of the test that would be very helpful. Thank you.

  • How long do these antibodies last or are they permanent. I was on Rebif for three years and then seven years ago switched to medications. Would this still be an issue?

  • ‘Please note even if you have been treated with interferon-beta many years ago you may still have NABs. NABs may persist for many years and these will continue to inhibit your own interferon-beta’s activity.’

    I don’t recall being told Rebif would cause lasting changes to my bodies chemistry when was encouraged to take it. A bit galling since it did nothing to help my MS. How long do these effects last?

    I’ve been happily off it, (and all other ‘DMT’s, for 10 years) and still no sign of my “nice wheel chair”, but it still seems I may be at risk from this retched stuff 10 years later.

    Also, I took part in your NABs study in 2009 but I couldn’t find a record in my files of my results, were these ever sent out to the participants?

    • Once you have antibodies you will have them for life. Although you may not have beta interferon, I suspect your own beta interferon could keep the antibody producing cells in an active state for ever and so the NAbs could be persistent. However remember you have more types of interferon and beta is only one of them

      • Great…

        Any mention of NABs with me was in the context of them reducing the (already dubious) efficacy of Rebif. To quote the leaflet I was given as a participant in your 2009 study: “As you may be aware some patients develop antibodies to interferon and these reduce its beneficial effects” No mention here that this could affect my health for the rest of my life.

        The unforeseen consequences of taking these powerful, poorly understood drugs is the main reason I’ve avoided them, and done very well with other measures to keep me healthy. I have fewer symptoms and less disability than 10 years ago, and I strongly regret succumbing to the pressure the newly diagnosed are put under by prescribers.

        So Prof G thinks it’s ‘nice’ that his hypothesis, that a drug he prescribes can do lasting damage to our immune systems, has been shown to be correct? I’m (almost) lost for words. Surely a more appropriate response would be ‘Unfortunately a hypothesis I had more than a decade ago….’

  • Very interesting post and this is what I was afraid of as a patient who had been on interferon for 10 years.

    Do we have any anecdotal data at this time in MS patients besides the HSV example you mentioned? Wouldn’t this have popped up by now in the MS population if it was a serious risk?

    For those with neutralizing antibodies, do you think there is any benefit to going back on an interferon to try to balance things out would that be a futile exercise?

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