vaccine readiness – Page 4 – Prof G's MS Blog Archive

#MSCOVID19: Why is cladribine so misunderstood?

Because cladribine and alemtuzumab are classified as immune reconstitution therapies (IRTs), and probably work in a similar way, they are tarnished with the same brush. However, cladribine’s immune depletion and reconstitution, and adverse event profile are very different to alemtuzumab’s and therefore cladribine should be considered on its own when weighing up the risks and benefits of treating highly-active MS during the COVID-19 pandemic. For example, the advice that pwMS need to shield after cladribine treatment is a very harsh call and in my opinion unnecessary. Why?

The following are the points concerning cladribine in the latest version (19-May-2020) of the ABN GUIDANCE ON THE USE OF DISEASE-MODIFYING THERAPIES IN MULTIPLE SCLEROSIS IN RESPONSE TO THE COVID 19 PANDEMIC

EXECUTIVE SUMMARY

5. The effect of DMTS on the risk of SARS-CoV2 infection and COVID 19 disease remains uncertain and we commend pwMS and MS teams to continue to submit data to the UK MS Register study of COVID 19. We recommend that patients are counselled on the effect of a DMT on their individualised risk of COVID 19 disease, taking into account its duration of action; any comorbidities; and also the DMT’s impact on the efficacy of any future SARS-CoV2 vaccine. Patients should be informed if their treatment choice requires shielding [especially cladribine and alemtuzumab].

11. Cladribine should be started cautiously on a case-by-case basis when the risk of SARS-CoV2 is very high. Re-treatment should be delayed until the risk of infection is level 3 or below.

14. pwMS with mild symptoms of COVID-19 should not stop first-line DMTs, but infusions [and cladribine administration] should be delayed until symptoms resolve.

C. THE RISK OF COVID-19 IN PEOPLE WITH MS [PWMS] ON DISEASE MODIFYING THERAPIES [DMTS]

11. There is very limited experience4 of pwMS on cladribine becoming infected with SARS-CoV2 and the SmPC warns of herpetic viral infections being “common”. However, it may be considered on a case-by-case basis. When and where the rate of SARS-CoV2 infection is very high, the risks of increased infection for three months after cladribine administration, and the advice to shield, may outweigh its benefits.

D. DMTS IN PwMS WITH ACTIVE COVID 19 INFECTION

14. pwMS with mild symptoms of COVID-19 should not stop a first line DMT, but infusions [and cladribine administration] should be delayed until symptoms resolve.

We know that anti-SARS-CoV-2 immunity requires innate immune responses (neutrophils and macrophages) and T-cell responses (predominantly CD8+ responses) to clear the virus. Cladribine does not deplete monocytes and neutrophils and has a modest impact on CD8+ve T-cells. Therefore t is unlikely to have a major impact on anti-SARS-CoV-2 immunity.

On cladribine, T lymphocytes are in general depleted by about 40% and the vast majority of patients don’t drop their counts below 500/mm3. In the T-cell compartment, the CD8+ T-cells are much less affected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections and explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme.

In the phase 3 programme about a quarter of patients had a transient grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts in year 1 had not yet recovered to above 800/mm3 (per-protocol dosing). We have used the trial data to model grade 3 and 4 lymphopaenia (<500/mm3), and estimate that less 7% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the cladribine redosing guidelines. This is important because most of the cases of zoster were in subjects who developed grade 3 or 4 lymphopaenia, which implies the risk of getting herpes zoster in real-life (post-marketing) is likely to be much lower than what we saw in the clinical trials.

Should we be so hung up about the lymphocyte count? When we explore the safety data of oral cladribine, from both the trial programme and post-marketing surveillance, we really don’t see a significant viral infection signal in cladribine-treated subjects. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. The following presentation is data that we recently presented at the AAN and EAN meetings and illustrates how uncommon viral infections are in pwMS treated with cladribine.

Based on these data I really don’t think it is necessary to for pwMS to shield during the current pandemic. All they need to do is maintain social distancing, practice good personal hygiene and avoid contact with potentially infectious people. This means that pwMS working in high-risk professions (healthcare and care sector workers with direct patient contact) who are treated with cladribine should not have direct patient-facing activities until they have recovered their lymphocyte counts to a safe level (>500/mm3 in people less than 60 years of age and >800/mm3 in those older than 60 years).

Although, cladribine is a remarkably good depleter of B-cells the B-cell numbers return quite quickly. The reconstituted B-cells are initially naive B-cells, which come from the bone marrow and are not memory B-cells. This is important for vaccine-readiness if a SARS-CoV-2 vaccine does emerge.

In comparison to cladribine, ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia, which is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.

The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.

Another advantage of cladribine is that as a small molecule it penetrates the CNS; cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.

I think cladribine is a very misunderstood DMT and has been hard done by in the COVID-19 treatment guidelines which in general are not evidence-based nor are they necessarily based on basic immunological principles.

As the COVID-19 pandemic is likely to have a long tail with a vaccine 18 to 24 months away I think we the MS community should reconsider our position on oral cladribine as cladribine addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.

Please note that I am not saying cladribine is safe; no DMT is safe. However, cladribine has a very well-defined risk-benefit profile that is less risky than what is been suggested in the ABN guidelines. The risk-benefit profile of cladribine simply allows you to counsel patients with highly-active MS about their treatment options during the COVID-19 pandemic and cladribine deserves to be part of that discussion.

CoI: multiple, but in particular I was the principal investigator on the oral cladribine phase 3 trial and have been involved with the development of oral cladribine as a treatment for MS since 2002.

#MSCOVID19: ostrich

Do you want to know if you have been infected with SARS-CoV-2 the coronavirus strain that causes COVID-19? With 25-50% of infections being asymptomatic or very mild you will need an antibody test to find out.

If you are found to have antibodies to SARS-CoV-2 would you not want to know the titre or amount of antibody in your blood? And whether or not these antibodies are so-called neutralizing and capable of preventing reinfection with SARS-CoV-2?

Answering these questions is critical and underpins the strategy of allowing people to receive a so-called “COVID-19 passports”. The passport will state that you have immunity to the virus and hence you can rejoin the herd and get on with your life.

As an MS researcher, I am also interested to know what happens to the antibody response to SARS-CoV-2 in pwMS on different DMTs. For example, are people on rituximab and ocrelizumab less likely to develop an antibody response after COVID-19 and if they do is the antibody response good quality, i.e. capable of neutralizing the virus and preventing reinfection? What about the antibody responses in people on natalizumab? On fingolimod? Post-cladribine or post-alemtuzumab?

My predictions are that the IRTs (cladribine and alemtuzumab) and possibly natalizumab will come out on top both in term of qualitatively (neutralizing antibodies) and quantitatively (overall titre) in terms of anti-SARS-CoV-2 antibody responses. Anti-CD20s (rituximab, ocrelizumab and ofatumumab) and the S1P-modulators (fingolimod, siponimod and ozanimod) will come out on the bottom. Please note this is a hypothesis and as with all hypotheses they need to be tested in well-designed and appropriately powered studies.

Barts-MS has therefore proposed doing an antibody study of this kind, but it looks like pharma is chicken to collaborate with us. I suspect they don’t want to know the answer to the questions above. I call this the “ostrich syndrome”; you can put our head in the sand for as long as you like, but eventually, a rabid dog will come and “bite your arse”.

As the MS community gears up for ensuring their patients are “vaccine ready”, who if they are SARS-CoV-2 antibody-negative (no previous infection) will want to be on a DMT that blunts or prevents an adequate vaccine response. Why take a chance if you don’t have to particularly as there are several suitable alternative DMTs? However, if the above hypotheses are disproved then most of us will be happy with the status quo.

All these arguments above are predicated on the assumption that we will get an effective SARS-CoV-2 vaccine or vaccines. Please note there is no guarantee that this will happen. I would estimate the chances of getting an effective vaccine in the next 18-24 months as being close to 80%. Optimistic? Yes, but at the same time, I am trying to be realistic.

CoI: nil

#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