#MSCovid19. The importance of B cells


I have been looking at the immune response and how it is used to deal with the virus and how it may be involved in the adverse effects.

Today we look at the B cells. Whilst I have made the case that in at least some people that the virus is dealt with before the antibody response kicks in. However, the antibody response is important as it can cause some protection and this is shown by taking peoples blood and injecting this into other people. This is the “Outbreak” (Film with Dustbin Hoffman) bleeding the Monkey to save the World Approach.

People who recover from COVID make and antibody response to the virus that provides immunity from re-infection. In China they bleed people who recovered and injected this into severely ill people and this seemed to do go, implying that the antibody response is beneficial. Therefore you dont want to deplete your B cell response, but most MS treatments deplete your B cells. I have argued this is why they work. However to make a new immune response yo want to spare your immature and mature/naive B cells to recover, this occurs quickly with alemtuzumab withina few months and abit longer with cladribine. Ocrelizumab keeps B cells low and so it is more difficult to make an anti-vaccine response. With alemtuzumab they come back quickly. Whilst the data below says that the B cell or an anti-viral B cells responsel is beneficial, it has also been suggested that anti-COVID antibody responses can be associated with a more severe disease. This does not surprise me because if any viral proteins are left on the cell surface after infection and it could be a target for antibody induced damage. When people with COVID-19 have been bled there is IgG1 and IgG3 response and we know that IgG1 and particularly IgG3 is very good at punching holes in their target by a process called complement fixation, so it could be damaging. This has been seen in other lower respiratory diseases, where sometimes the anti-viral response is damaging. Now in this study it was seen to beneficial, it may not always be. There is little IgG4 anti-COVID being made, so one images companies are making thes antibodies as fast as we can say COVID19 as these do not cause complement fixation. There is a trial doing the same in France and this should have finished. Hopefully we will get real life experience of what happens in people on ocrelizumab who are COVID infected to see where the good-bad balance lies.

UPDATE IN RESPONSE TO COMMENTS: Now so you know. CD20 is not expressed on the antibody making B cells and so once you make an antibody response then the plasma cells are not going to be initially touched by ocrelizumab, rituximab, ofatumumab, etc, etc,. Likewise despite being on ocrelizumab and depleting all your B cells in the blood, only about 2% of your B cells are in the blood. You still have B cells in your lymph nodes and this is were antibodies will be formed. Now it is true that ocrelizumab treatment will inhibit your capacity to make vaccine responses, it is the case that you still can make vaccine responses. The data is on NCT02545868. It seems like putting this easily findable in the public domain in approrpriate.


Deployment of convalescent plasma for the prevention and treatment of COVID-19. Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, van Buskirk C, Grossman BJ, Joyner M, Henderson JP, Pekosz A, Lau B, Wesolowski A, Katz L, Shan H, Auwaerter PG, Thomas D, Sullivan DJ, Paneth N, Gehrie E, Spitalnik S, Hod E, Pollack L, Nicholson WT, Pirofski LA, Bailey JA, Tobian AA.J Clin Invest. 2020 Apr 7. pii: 138745. doi: 10.1172/JCI138745. [Epub ahead of print]

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e. “convalescent”) plasma refers to plasma that is collected from individuals, following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy to confer immediate immunity to susceptible individuals. There are numerous examples, where convalescent plasma has been used successfully as post-exposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East Respiratory Syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads and improved survival. Globally, blood centers have robust infrastructure to undertake collections and construct inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, from evidence of benefit, regulatory considerations, logistical work flow and proposed clinical trials, as scale up is brought underway to mobilize this critical resource.  .

Duan K et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients.PNAS first published April 6, 020 https://doi.org/10.1073/pnas.2004168117

COVID-19 is currently a big threat to global health. However, no specific anti-viral agents are available for its treatment. In this work, we explore the feasibility of convalescent plasma (CP) transfusion to rescue severe patients. The results from 10 severe adult cases showed that one dose (200 mL) of CP was well tolerated and could significantly increase or maintain the neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3 d. Radiological examination showed varying degrees of absorption of lung lesions within 7 d. These results indicate that CP can serve as a promising rescue option for severe COVID-19, while the randomized trial is warranted.

Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L.JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4783. [Epub ahead of print]


All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2-specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion.

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  • What would you estimate the time frame for this being used in UK ICU units? Presumably not within this first surge?

    • Not sure it will pass health and safety…..however the French trial should have finishised, however without an antibody test you does know the best people to bleed.

  • So are you hypothesising that ocrelizumab patients are still not at increased risk of severe disease, but that we won’t be able to mount any kind of antibody response? So not only will we never know that we have had it, but we also will get it over and over again. Depressing news this morning!

    • I think I may have had it – dry cough and wheeze for ten days but it was 5-15th March back when nobody was getting tested unless they had travelled to China or Italy or been in contact with a known case (none applied to me). So I carried on as if it was a ‘normal cough’. Now I think it must have been and I had travelled to Birmingham 4 days before it started on the train.
      Anyway I will never know – even if an antibody test comes I won’t be positive as I’m on ocrevus!

      • No necessarily true…You can make antibody responses and anti-CD20 is not on plasma cells and so they will survive for some time, it takes months before the IgG levels start to drop. If we can ever get back in the lab we have planned to make a test.

    • Not an immunologist but my reading is that ocrelizumab blunts immune responses (otherwise vaccines would never work) rather than preventing them altogether.

      • Yes they do blunt the vaccine response but do not prevent them. I wrote to Amit Bar Or three weeks ago to ask if they were going to publish this data….They presented the data in 2018 so they have had 3 years to publish this. This is a very good reason why ECTRIMS needs to change its policy and have every pharma poster online and under their control of ECTRIMS not pharma. This poster is hard to find. The data is sat in clinical trials.gov and I will extract and publish this as a review. Therefore Roche please write to us ASAP and tell us if there is a paper, this is vitally important information to have at hand as it reassurres people with MS that they can make a vaccine response even if on full dosing.

  • Plasma transfer

    Wont make your immune system mount an immune response?

    After those antibodies fade away you have to get another shot?


  • One striking feature of the data from both of the convalescent plasma studies is that the patients treated had reasonably high antibody levels *before* receiving the plasma. In Shen et al., the geometric mean titer of the recipients pre-transfusion is 10,439 for RBD-specific IgG and 25,140 for RBD-specific IgM — the numbers for the *donors* are just 5,400 for both! The recipients did have lower neutralizing titers, but not terrible — 70 for recipients, 193 for donors.

    Meanwhile, in Duan et al., the recipients had neutralizing titers of 346 (geometric mean of dilution level) *before* receiving the convalescent plasma. This did rise to 640 on average after treatment, but half the patients were already at that level beforehand and saw no measured increase. Strange. Also, Duan et al. makes a lot of the fact that the measured viral load becomes negative after transfusion. However, the measured viral load is *already* at a very low level before transfusion. Based on their arbitrary cutoffs (less than 38 is “positive,” above 40 is “negative,” in between is ambiguous), 2/10 patients were in that ambiguous zone to begin with. There just isn’t a big change in viral load — it goes from very low to lower.

    What I’m left wondering, then, is if the claimed mechanism here (antibodies in the plasma get rid of the virus) is really operating. Perhaps plasma exchange by itself, with no special antibodies, could improve the conditions of some patients, and that’s what’s driving the results. There have been some case reports describing the use of plasmapheresis for ARDS in other diseases, but nothing too solid.

    • Interesting view point thanks for this, There is laos a study that should have finished in france by now, and also I believe Takeda who manufacture IvIG are collecting convalencent sera, as I woul dbe rath uncomforatble using sera, even if it has been UV light treated as COVID may not be the only disease we have to worry about/

      • I don’t understand where you stand? Are you in favor or not of using convalescent sera in critically ill patients? I think the better approach will be convalescent serum as a prophylactic and plasmapheresis in critically ill. What do you think.

        • I am not in favour of putting human blood into human blood, or cows eating cows, it was not good for BSE. You can take the the sera and do more processing to make it much more safe. The experiment has been done and it appears that there is some benefit…We have been here before with other lower respiratory tract infections but when you get adverse events, this is what will can the approach. Zenaca spent $0.45 billion. However if I was on a venilator and my chance of death is 50:50, I think I would be willing to take the 5% chance or less of an adverse effect.


          • Ok I see Prof G. But I am still confuse. Isn’t that an overload of antibodies gives a worst outcome as you wrote in a past entry in your blog about a suggestion of being lucky if being in a DMT? I understood that the last phase in critically ill patients will be the removal of infected cells by antibodies. So in critically ill patients, even if convalescent sera administered is more purified it could also lead to a worst outcome?
            I believe that purified antibodies will be better as a prophylactic measure not as treatment for the critically ill. This as you showed it was seen in the relationship between higher titres of antibodies and worst outcome. There are several health systems that thinks this is going to be the key of low mortality in the outbreak, giving thos critically ill patients purified antibodies from convalescent plasma.

  • Not sure it will pass health and safety…..however the French trial should have finishised, however without an antibody test you does know the best people to bleed.

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