Kind of Blue


Barts-MS rose-tinted-odometer: zero-★s (Feeling ‘Kind of Blue’ for a Saturday, midnight blue #191970)

We have known for some time now that pwMS on DMTs who get COVID-19 seem to be at no greater risk of severe COVID-19 and death compared to the general population with the exception of pwMS on anti-CD20 therapies. This implies that anti-CD20 therapies either impact preexisting cross-reactive protective immunity from other community-acquired coronavirus infections and/or antibody responses during COVID-19, which have been now shown to prevent severe infection and death. I think there is now ample evidence to support both of these explanations.

People who had the original SARS in 2003 have been shown to have broad anti-coronavirus immunity and make very good neutralising antibodies to SARS-CoV-2, which is boosted to very high levels in response to COVID-19 vaccination. Similarly, immunoglobulin formulations made from the plasma of blood donors prior to COVID-19 is able to neutralise SARS-CoV-2. Therefore preexisting immunity to other coronaviruses is helpful and this will be blunted by being on an anti-CD20 therapy, particularly if you have been on the anti-CD20 therapy for a prolonged period of time. This observation goes beyond COVID-19 and explains why the risk of infections in people on long-term anti-CD20 therapy increases over time.

It has also recently been shown that the delayed development of neutralising anti-SARS-CoV-2 antibodies is strongly associated with death in patients with COVID-19 in intensive care  (Lucas et al. Nat Med. 2021 Jul;27(7):1178-1186). Therefore contrary to original hypotheses that B-cell responses were not necessary for recovery from COVID-19, it is now clear that antibody responses to SARS-CoV-2 are important in protecting you against a poor COVID-19 outcome. This now explains why people on anti-CD20 therapies are more likely to have severe COVID-19 and I suspect more likely to succumb to the infection.

I discuss the clinical implications of this and other findings for the management of MS in my latest MS-Selfie Newsletter ‘Anti-CD20 Kool-Aid and COVID-19 vaccines’ (9-Sept-2021). 

Kind of Blue: Please take some time off today to remember and reflect on the people who lost their lives in the 11-September-2001 attacks in New York and Washington and subsequently in the world’s response to these attacks. I am going to listen to Mile Davis’ album, ‘Kind of Blue’ when I do this.  

Lucas et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med. 2021 Jul;27(7):1178-1186. 

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.

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. 

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.


  • sad to hear that u lost a patient because of covid 😔
    can u say whether there were unfavorable preconditions and of older age?
    would you then reccomend an early intervention with regeneron or likes as standard for cd20 treated patients?
    thank you!

  • Given the risks of anti-CD20 treatments with regard to Covid, do you think other treatments i.e. Cladribine will be approved as a first-line for RRMS? At the moment it seems a like the options are, take beta interferons and risk worsening or anti-CD20 and risk Covid

  • This saddens me. Been NEDA for 3+ years on rituximab, but am now working as a teacher in elementary school. Double jabbed pfizer, probably no antibodyresponse. Fearful for my future now, Even tho i’m,young, late twenties. Do i stop working or stop anti-CD20. Or do i take the risks? Currently I’m doing the latter, but probably shouldn’t?
    Also, has there still not emerged any data on the clinical effects of the observed T cell responses in anti cd20 treated patients?

    • Yes, at the moment the T-cell responses are lab results and don’t necessarily tell us whether or not they will be effective in reducing the chances of getting severe COVID-19.

  • Please read the article again. They say ” Together, these data indicate that clinical trajectories and outcomes do not correlate with the levels of NAb produced over the disease course but with the timing of NAb production.” So production and levels of antibodies does not play a role but those with worse outcome seem to develop antibodies later. This is just an association and the reason is not known. Neverthelles, antibody kinetics of people on anti-cd20 are not in the study as they will not produce antibodies neither early or late, so this study is interesting but irrelevant for people on B cell depleting treatment.

    • Yes, but it doesn’t change my interpretation of the data. It is clear that the COVID-19 mortality rate of people on anti-CD20 therapies is looking much higher than that in pwMS in other treatments. Yes, Roche-Genentech says this is due to reporting bias, i.e. only the more severe cases get reported. However, this should affect other DMTs as well. The company data on the other DMTs show a much lower mortality rate; if it was reporting bias they would have as high a mortality rate as that reported with ocrelizumab. I must congratulate Roche on being so open and transparent with their data; the other MS pharma companies have not been that proactive in making their data available rapidly.

      • Replyiing to anon: if I recall correctly, the factor 2 is for pwms who have reached the progressive stage, whether on DMTs or not (and most are not), and taking into consideration all other confounding factors.

        In other words those of us who have reached this exalted status have approx 2 times the risk of someone similar in the gen popn.

  • Where does this leave the early vs escalation debate? Given the uncertainty of both progression and risk from Covid-19, has the balance tipped in favour of a more cautious approach?

    • No way.

      If your young, like when most people with MS are diagnosed, covid only has a small chance of ending up in hospital even smaller chance of death. That’s if you even get any symptoms at all

      Your MS should have priority over a covid virus that you may never catch

      • While I agree that treating MS should have priority (still makes me wonder if anti cd20 is a good approach though), it is fairly unlikely that you won’t catch delta at some point.

  • I have been double vaccinated 4 months ago and now about to start on ocrevus , should I think about delaying this or not having it at all?

  • Does convalescent plasma therapy provide patients on B cell depleting mabs for malignancies or neuroinflammation have benefits or is it transitory?

  • I know you report some moons ago about X-linked agammaglobulinemia patients did recover from covid-19

    So those patients never had mature b cell(antibodies )in their life so how come they do not die from covid-19?

    Also how do expalin this

    Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

    We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained.

    “A painting is music you can see, and music is a painting you can hear.”
    ― Miles Davis

    • Re: “So those patients never had mature b cell(antibodies )in their life so how come they do not die from covid-19?”

      Both these patients were on high-dose IVIG replacement therapy. We now know that IVIG contains cross-reactive anti-SARS-CoV-2 antibodies. So they might have not had B-cells, but they had some immunoglobulins. Another thing to point out is that both of these patients were critically ill.

    • Re: “Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection”

      This makes sense if you can make neutralizing antibody, which is the point I am making. People on anti-CD20 don’t make neutralizing antibodies and hence are more likely to get symptomatic infection, severe infection and die from the infection. This is not rocket science. Then throw in waning immunity and new variants and it is easy to see why being chronically immunosuppressed puts you at high risk. You don’t have to worry; having had AHSCT your immune system is now reconstituted and ready to mount vaccine and anti-viral responses.

      • Yep you only need 3% of nab´`s in the conv . serum

        Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7–24 months posttransplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pretransplant plasma cells

        Yep only in the first the first 6 months

      • Forgot to say that with only 3% nab ´s needed in conv. serum for 50% protection from severe disease other mechanisms must be at play…T cell or maybe innate imunity

  • Kind of Blue…….thank you Prof. G

    I was stationed at RAF Fairford for six months during the war in 2003 and found the local pubs to be friendly and (most) people to be very welcoming.

    I saw this clip today of Welsh Guard Soldiers performing the U.S. national anthem during the British memorial to 9/11. The show of respect and underlying message of unity is heart warming.

  • Prof. G. Thanks for keeping us updated. Ocrevus patient here (37yo, no comorbidities, on Ocrevus for 3 years). I had covid on March 2020 (mild symptoms), then got vaccinated (pfizer on April 2021). In both cases detectable no anti-bodies. I took Ocrevus 3 weeks ago (my neuros told me it is not worth to delay it to wait for a 3rd vaccine boost). Should I feel in danger – I am a teacher, and thus constantly exposed to infection risk- or having gone through natural infection ´+ vaccination should make me feel confident I will overcome Delta (that I am pretty sure at some point will knock at my door)? Many thanks!

By Prof G



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