Looking in a crystal ball…Should we supply an anti-COVID-19 antibody response to Immunosuppressed people?

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We are reporting frequently on the lack of an antibody response in people treated with anti-CD20 and whilst we think about how we manipulate the biology to encourage B cell responses in B cell depleted individuals, there is another solution and that is to supply people with an antibody response. This can be in the form of convalescent sera (antibodies from people recovered from covid) or SARS-CoV-2 antibody cocktail. These could be selected to defend against the variants circulating. We know they work as they can be shown to prevent infection in animals

Some of these have been approved as a prophylactic against infections in homes for the unifected from the infected. This should have been tested in health care workers/high risk individuals as prohylactics against infection months ago, but perhaps in the post-vacination era it is too late. They can give antibody responses to people who don’t have them.

However, it in addition to protecting against infection in immunosuppressed individuals they may protect against escape mutants occuring in immunosupressed people that could stop the vaccines working, as we would not want the next delta, omega or andromeda strain to come from immunosupressed pwMS

Copin R et al. The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies. Cell. 2021;184(15):3949-3961.e11.

Remember the UK alpha variant is thought to come from someone immunosuppressed as it had serial mutations

Pan D et al. The new UK SARS-CoV-2 variant and lockdown – causes and consequences. Clin Med (Lond). 2021; 21:e295-e299.

and this can virus evolution has been seen

Avanzato VA et al. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020;183(7):1901-1912.e9.  

Other alternatives possible outcomes

Kemp SA et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021;592:277-282.

Would they work and be useful in CD20-depleted individuals? I don’t know but should be tested in a trial.

On the whole treating people after they have the virus and the results have been indifferent and when used late in hospitalisation they often don’t work. However here is an example of a study…it is clearly too small to be truely informative.

Successful treatment of COVID19 infection with convalescent plasma in B cell-depleted patients may promote cellular immunity.Kremer AE, Kremer AN, Willam C, Völkl S, Verhagen J, Achenbach S, van der Meijden ED, Lang V, Aigner M, Maier C, Tenbusch M, Korn K, Lutzny-Geier G, Spoerl S, Strauß R, Vetter M, Überla K, Neurath MF, Mackensen A, Schiffer M, Hackstein H.Eur J Immunol. 2021 Aug 4. doi: 10.1002/eji.202149277. Online ahead of print.

Treatment with convalescent plasma has been shown to be safe in COVID-19 infection, although efficacy reported in immunocompetent patients varies (Yep often it doen’t work). Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for haematological malignancies (and MS), lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analysed clinical course and inflammation markers of three B-cell depleted patients suffering from COVID-19 that were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR positive T-cells ex vivo and CD137 positive T-cells after in vitro stimulation with SARS-CoV-2 derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137 positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B cell-depleted patients and present data that suggests that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T cell responses.

I reiterate that this should be done as a trial and not self experiment.

I am rehearsing these arguments in public for a review paper. What do you think?

Would it give you more confidence in going out if you knew you have an protective antibody response? Having seen my own vaccination response on our blood spot test, I felt better for it? I would have been happier with the levels we found in a STORMCHASER (Had anti SARS-COV2 Ig) participant that we measured.

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

18 comments

  • As the pandemic is waning it is unlikely we will get data on this. What about the costs? There treatments are likely to be very expensive and NICE/NHS will therefore not cover the costs of prophylactic treatment, particularly when the risk from COVID-19 to pwMS on an anti-CD20 therapy is quite low; most recover without problems. Surely it is cheaper and easier to stop ocrelizumab and switch to another class of DMT?

    • Good point….So should we bin ocrelizumab? I wonder how many people think like you because it they do then the sales figures for ocrelizumab could plummet. As Roche make both antibodies maybe it is worth the confidence boost?
      They will be throwing it all away soon

      • I wouldn’t want to stop ocrevus, I was unable to walk for over 2.5 years pre Ocrevus and told by neuro they don’t rule recovery or until a year after relapse, I didn’t recover any ability until 2.5 years later and 7 months post starting ocrevus. I don’t want to risk going back to a wheelchair /crutches.
        I did test antibodies to vaccine privately and tested negative, I would’ve been happier to return to work if I knew I had antibodies.

      • or we just wait another view month until phase 3 data of AT-527 comes out.
        I have big hope that this is „game channging“ – so far phase 2 shows an 80% greater virus reduction after two days compared to placebo and two weeks after treatment 50% had no detectable coronavirus on swab (22% placebo arm).
        this antiviral pill + t cell protection from vaccine = no need to think about switching cd20 if you do well with it?
        what do you think dottore mouse?

        • Good point The MORNINGSKY trial…….50% had viral removal in phase II…what about the other 50% and this is another treat after the event it does give you protection so are you happier with a condom/IUD etc or the morning after approach?

          Or it buy your 6 months supply of ocrelizumab and get you AT-527 (what shall we call it Rocheivir) as a 2 for 1:-)

          • fair enough BUT under economic reality i think this kind of „protection“ against severe course will make me feel safer – i dont know this phase 2 study on detail but can it be that 50% had NO virus and the other half LOWER virus load (+ t cell vaccine effect would still lower probability of severe covid?)
            i mean unfortunately there wont be a perfect solution and more variants coming…so infections will happen anyway?

          • From the company website

            AT-527’s SARS-CoV-2 potent antiviral activity was also observed in patients with higher baseline viral loads above the median of 5.26 log10 as compared to placebo. When evaluating a strict RT-qPCR threshold of 500 copies/mL with no detectable ribonucleic acid (RNA) virus (target not detected, TND), the AT-527 arm achieved SARS-CoV-2 clearance as early as Day 2 (in 6% of patients), Day 8 (in 7% of patients) Day 10 (in 33% of patients), and Day 12 (in 31% of patients) compared to 0% of patients in the placebo arm at the same timepoints. By Day 14 (last viral sampling study day) approximately 47% of patients in the AT-527 arm and 22% in the placebo arm had no detectable RNA virus (TND). Nasopharyngeal swabs were measured in a reverse transcription polymerase chain reaction test (RT-qPCR) for the quantitative detection of nucleic acid from SARS-CoV-2.

  • It’s a good idea! You can’t just bin ocrelizumab unless you had something better sooner what do you do with the thousands of people doing well on it that then risk a massive decline from dmd switch to one that – may not work as well for them

    Can we also speed up trial paperwork and approvals for hsct in the us and demyelination therapies all over? That would make it less risky for people to abandon cd 20 therapy.

    • “That would make it less risky for people to abandon cd 20 therapy”……out of all the DMTs, I believe rebound risk is on the lower side after stopping OCR.

      Unfortunately, there is not much data on this subject. However, as a regular reader of this blog you know how long it could take to repopulate (studies show anywhere between 5 months and 3yrs).

      My personal experience, 130lbs, 39yrs old, 3 full cycles, and it took about 10 months for my circulating cd-19 B cells to start repopulating after my last infusion. I started using TERI to “modulate” my B cells, which did effectively kept them below baseline levels until I was able to start CLAD. Plus the antiviral aspects of TERI were hopefully beneficial.

      CLAD is in someways very similar to OCR, but in my opinion is a bit more effective (small molecule, BBB penetration, kills memory B cells, etc.) and not needed to be taken forever.

      Also, I should note I was very happy to use OCR first line, as it “healed” several of my spinal lesions, which my doctors say prevented me from a faster decline than I am currently experiencing. Had to stop as I was part of the lucky 1% that becomes “allergic”to the drug with more exposure, or so that is what I was told caused my severe adverse events.

      • Im not a doctor but I would think it is easy to transitions from ocre to cladribeine without need for teri

        • Nor am I a doc….however I do agree with you MD that Teri is probably not needed to transition.

          Once my B cells were modulated by Teri and I did not have a major relapse, I washed out Teri, watched my B cell quickly accelerate past my pre Ocre baseline, then started Clad. No rebound or relapse. So probably not needed, but I was just so fearful of rebound activity that I wanted to do something! There is very little data on this subject so my neuros and I were essentially guessing at what would be the safest way to transition. Seem to work for me (sample size of 1).

  • I don’t know about all these studies of anti CD 20 therapies and coronavirus vaccine ab production. What is the prevalence of influenza in ocr treated patients who have received vaccine? Don’t we have a good idea of immune response from other vaccines in ocr/ritux patients?

  • I think many vaccine’s work poorly in anti-cd20 patients, which for some, is a big deal. The evidence is rather compelling that the MRNA’s don’t result in Ab’s but T-cell, maybe.
    Some suggest many anti-cd20 patients have a good recovey from primary covid infection yet I think it must be recognized that we still know quite little about long-haul covid. Loss of brain tissue has been reported even with mild covid. The US gave EUA to the Regen monoclonal antibody cocktail (and subcutaneous) for post exposure. Far better than nothing, especially if you get it quickly. 81% effective I believe.

    • crikey, can you imagine #longcovid on top MS??

      MS nurse thinks people on Ocrevus should be out and about, meeting friends and family and living their lives…..don’t know if anyone in that hospital knows that papers are out, (MOUSEDOCTOR) saying people on Ocrevus and Fingolimod likely don’t produce much of an immune response after the 2 covid jabs.

      • My matre was out and about at the weekend caught covid….now waiting to see what happens however they have vaccine response.

  • “Would it give you more confidence in going out if you knew you have an protective antibody response?”

    Was on O; stopped. Tested + for antibodies. Made me feel much more confident until Delta. Still know I won’t die, but want to avoid being really sick, and other variants are probably coming until this thing gets under control world-wide. I want my immune system functioning at full speed, especially because I live amongst the anti-vaxers. If I was 35, it would be a different story, I’m 63.

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