#MSCOVID19: immunosuppression & vaccine-readiness

It is always a good idea to learn from others. We have stressed that the uneventful recovery from COVID-19 involves two processes. Firstly, an appropriate antiviral response, which is needed to clear the virus and secondly an anti-inflammatory response to prevent the delayed immunological damage to the lung that triggers ARDS (acute respiratory distress syndrome), which is the main cause of death with COVID-19. There clearly is a balancing act as if you suppress the delay immune response too much you may prevent clearing of the virus and ongoing damage from viral replication. 

It is very heartening to see that patients with other immune-mediated inflammatory disorders that are on immunosuppressive therapies, predominantly biological therapies, are not at increased risk of severe COVID-19 (see Haberman et al below). This experience is mirroring our experience in MS. 

However, in the transplant field where the levels of immunosuppression are an order of magnitude more intense, the message is mixed. Liver transplant recipients seem to do fine (see D’Antiga below) but in kidney transplant recipients those with the greatest T-cell depletion, particularly those who receive ATG (anti-thymocyte globulin), do the worst and have high mortality from COVID-19 (see Akalin below). The reason for the difference between liver transplant recipients and ATG-treated kidney transplant recipients are T-cells. ATG is one of the most potent T-cell depleting agents we have and rendering someone severely deficient in T-cells puts them at high risk of viral, in particular severe viral, infections. The latter does not only include exogenous (outside the body) viral infections such as SARS-CoV-2 but endogenous (inside the body) latent viruses such as CMV and EBV. The ATG treated transplant patients are likely to be succumbing to uncontrolled SARS-CoV-2 infection rather than the delayed immunological reactions or ARDS. 

What this is telling us is that moderate immunosuppression, with reasonable T-cell counts and T-cell function, does not increase your risk of getting COVID-19 or severe COVID-19 and may reduce your risks of the latter. However, as soon as you drop your T-cell counts and profoundly suppress T-cell function you are increased risk of severe COVID-19, probably from uncontrolled viral replication. 

So how is this relevant to MS? As always it is a balancing act between being sufficiently immunosuppressed to prevent the immunological complications of SARS-CoV-2, but not too immunosuppressed that you can’t control the viral infection. In my opinion, in the MS space, the only treatments that we need to be concerned about are the acute effects of alemtuzumab and HSCT on the immune system in the depletion phase of treatment, i.e. the initial 3-6 months until total lymphocyte counts recover to a level that gives you adequate anti-viral responses. I have set the latter at above 500/mm3 in younger pwMS and above 800/mm3 on older people (older than 60 years of age). The reason for the latter is that as you get older and develop immunosenescence the proportion of your T-cells that are naive and able to respond to new viruses and antigens shrinks. This may explain why older people are at more risk of getting severe COVID-19, i.e. their immune systems are just not as good at responding to new viral infections. 

There is a third phase to SARS-CoV-2 and that is the delayed antibody response, which is B-cell dependent. The antibodies probably contribute to the tissue damage in the immune-mediated phase of COVID-19. However, you clearly don’t need B-cells and antibodies to recover from COVID-19. I base this on the case reports of two patients with agammaglobulinaemia from Italy who recovered from COVID-19. Please remember these patient don’t have B-cells. Another clue that B-cells are not needed is the fact that patients on anti-CD20 therapies tend to deal with viral infections, including novel or new viral infection, well and rarely get severe viral infections. The latter observation is borne out by how well anti-CD20 patients are weathering the COVID-19 storm. 

The one downside of anti-B-cell therapies, however, is that you may need anti-SARS-CoV-2 antibodies to prevent yourself from getting reinfected with the virus. The latter has major implications for when a SARS-CoV-2 vaccine arrives. Will pwMS on anti-CD20 therapies be able to respond to a vaccine? Based on the fact that the SARS-CoV-2 spike protein, the main immunogen in future vaccines, is heavily glycosylated and that anti-CD20 therapies block antibody responses to glycoproteins (proteins covered in sugar molecules) patients on anti-CD20 therapies are unlikely to be vaccine ready unless their dosing is interrupted to allow peripheral B-cell recovery. 

It is clear from social media activity and exchanges with my colleagues that many of us are now moving onto the next phase of preparedness for managing MS during COVID-19, i.e. how to ensure your patients are vaccine ready for a SARS-CoV-2  vaccine. The latter is something I have discussed before and is why I have added another column to my DMT table (version 4). 

Haberman et al. Covid-19 in Immune-Mediated Inflammatory Diseases — Case Series from New York. N Engl J Med 2020 Apr 29. doi: 10.1056/NEJMc2009567.

A better understanding of the implications of Covid-19 in patients with immune-mediated inflammatory disease and the effects of anti-cytokine and other immunosuppressive therapies is urgently needed to guide clinicians in the care of patients with psoriasis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, and related conditions. Although our analysis was limited in sample size, our data reveal an incidence of hospitalization among patients with immune-mediated inflammatory disease that was consistent with that among patients with Covid-19 in the general population in New York City reported by the New York City Department of Health and Mental Hygiene (35,746 of 134,874 patients [26%]) (Table S5). These findings suggest that the baseline use of biologics is not associated with worse Covid-19 outcomes.

Lorenzo D’Antiga. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplantation 20 March 2020. 

… the available data on past and present coronavirus outbreaks suggest that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not develop severe coronavirus pneumonia, regardless of their immune status, although they get infected and can, therefore, spread the infection. The risk factors for severe disease remain old age, obesity and its complications, other comorbidities, and male sex. Although the surveillance of this particular group of patients should continue, there are no reasons to postpone lifesaving treatments, such as transplantation or chemotherapy for cancer, during coronavirus outbreaks both in children and in adults.

Akalin et al. Covid-19 and Kidney Transplantation. N Engl J Med. 2020 Apr 24.

In conclusion, at our institution, kidney-transplant recipients with Covid-19 had less fever as an initial symptom,3 lower CD3, CD4, and CD8 cell counts,4 and more rapid clinical progression than persons with Covid-19 in the general population. The number of our patients with very low CD3, CD4, and CD8 cell counts indirectly supports the need to decrease doses of immunosuppressive agents in patients with Covid-19, especially in those who have recently received antithymocyte globulin, which decreases all T-cell subsets for many weeks. Our results show a very high early mortality among kidney-transplant recipients with Covid-19 — 28% at 3 weeks as compared with the reported 1% to 5% mortality among patients with Covid-19 in the general population who have undergone testing in the United States and the reported 8 to 15% mortality among patients with Covid-19 who are older than 70 years of age.

CoI: multiple

21 thoughts on “#MSCOVID19: immunosuppression & vaccine-readiness”

  1. As pwMS – would we absolutely have to have the vaccine? Or will we be able to make that choice if we’d rather continue on our stronger ‘blunting’ DMT’s?

  2. Thank you for your continual updates on this developing situation. If we are due to have our next Ocrelizumab infusions in August in London this year, and have a ‘stable’ MRI result to date with EDSS of 2.0, would it be wise to delay the next infusion to allow our B-cell count to recover in readiness for a vaccine (should one be ready early 2021) and then re-commence treatment once vaccinated?

  3. Why does B-cell depletion affect antibody response to glycoproteins more than simple proteins?

    1. It has to do with hardcore immunology and the way the immune system processes antigens. Proteins tend to be stripped of their sugars before being classically processed and presented to the immune system. It is well known that viral glycoproteins are heavily glycosylated by N- and O- linked glycans, which creates a so-called glycan shield, The shield decrease antibody binding affinity to the protein and facilitates evasion of neutralizing antibodies. I am sure viruses have evolved glycosylation to evade immune detection. It is well known from empirical studies that antibody responses to glycoproteins are poor and often of low affinity. The ocrelizumab antibody response to Pneumovax or pneumococcal polysaccharide vaccine, which includes purified preparations of pneumococcal capsular polysaccharide is poor. Based on this I am predicting that the vaccine or antibody response to the SARS-CoV-2 spike protein, which is heavily glycosylated will be poor as well. However, the proof will be in the pudding. Let’s see if patients on ocrelizumab who get COVID-19 seroconvert and if they do seroconvert will they make high titre neutralizing antibody?

      1. I have asked Roche to study this ASAP so that we can incorporate this knowledge into our thinking when deciding on what to do with our patients in anticipation of a SARS-CoV-2 vaccine.

    1. Yes and no! MD2 is correct the Oxford vaccine is using an adenovirus vector to carry the immunogen into human cells. Other vaccines will be naked DNA vaccine and component vaccines. Who knows we may be spoilt for choice.

    1. I doubt it. The B-cell repopulation of kinetics post-ofatumumab will change with time, i.e. bone marrow and deep tissue B cell depletion will increase over time, and hence the B-cell reconstitution may be delayed as well. As I have said before on this blog I suspect you need CNS penetration with anti_CD20 therapies to target CNS B cells. I suspect ocrelizumab 600mng and higher is better than doing this than ofatumumab at a 10th of the dose.

      1. What about individuals who experience adverse reactions to ocrelizumab at 600mng? Could one theorize that after 3-4 cycles of ocrelizumab, b-cells in the CNS have been sufficiently depleted, and switching to ofatumumab at a lower dose would provide similar efficacy with less risk of adverse drug reactions. Also, possibly less risk of developing anti-drug anti-bodies.

      2. Is cns penetration different from intrathecal administration? I believe that was tried but it did not work

  4. Thanks for this Prof G!

    How long does it take B cells to reconstitute approximately? I have had 2 rounds of ocrelizumab and the next is due in Sept 2020. If I plan to delay this in order to get a vaccine, I wonder when would be a good idea to restart?

    Also I am happy to be a guinea pig for people on ocrelizumab to check for seroconversion as I (think) has covid in March. Wonder who would be interested!

    1. The median (middle) is between 60 and 70 weeks for B cells to recover after 3 and 4 doses. There is no guarantee there is going to be a vaccine until next year. At present Oxford vaccine is a live virus and this may be contra indicated.

      We would be interested, once we can get back in the lab.

  5. Does this also mean that if a patient is on a B-cell depletor they will not gain any natural immunity from catching and recovering from Covid-19? In the same way that a vaccine may not work properly?

    1. It will gain sum as T cells will get immunity and with SARS this was get long lasting. However the interpretation is that there could be an issue for B cells to make a proper vaccine response

      1. The science is beyond me. Does this mean that it is likely that ‘naturally’ catching and recovering if on a b-cell depletor will not confer the immunity being discussed for people otherwise ‘normal’?

      2. Imunity its about many diferent cell types working together

        Not just one type

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