Tag: anti-CD20

#MSCOVID19: anti-CD20 nuances

Barts-MS rose-tinted-odometer: ★★★

I had to have a detailed discussion with a patient this week about starting ocrelizumab during the COVID-19 pandemic. This patient was concerned about (1) the data showing an increased risk of COVID-19 in anti-CD20 treated patients, (2) an increasing number of cases not seroconverting when being infected with the coronavirus and (3) she will not be able to have a coronavirus vaccine when one emerges. 

All of these three concerns are not black-and-white, but very grey, and need explaining. 

1. The increased risk of COVID-19 and severe COVID-19 on anti-CD20 therapy

This finding has been reported by the Italian register, the Iranians, the Swedes and the MSIF’s Data Alliance initiative. There is also a similar signal in the US data and French data. However, despite the increased risk of COVID-19 it is not associated with increased mortality. In the Italian data there is a weak signal that the longer you have been on an anti-CD20 therapy, particularly more than 3 years, the greater the risk of COVID-19. 

One issue that is not adequately addressed is reporting bias, i.e. more severe COVID-19 cases get reported and the less severe ones don’t because they are not registered as having COVID-19. Reporting bias is likely to affect DMTs that require patients to attend hospitals, i.e. treatments that bring them into contact with HCPs and hence they have a chance to report symptoms, and those DMTs that are the most widely prescribed. It is clear that both of these factors play a role in anti-CD20 therapies. One clue in support of this is the fact that there is a similar signal of a greater COVID-19 and severe COVID-19 signal emerging with natalizumab, i.e. another DMT that requires frequent hospital visits (reporting bias) but is less prescribed than anti-CD20 so the signal is not quite significant yet. 

One way to address this issue is to study non-biased trial populations, which has to be the data gold-standard. Roche presented 51 COVID-19 cases in over 4,000 ocrelizumab exposed trial patients (1.3%) (see presentation below). There was clearly no link between COVID-19 and treatment duration (slide 6). Three patients out of 51 patients died (5.9%). The numbers are too small to make a call on whether this represents a higher mortality than the background rate. Another important factor is that COVID-19 was not linked to hypogammaglobulinaemia. This ‘gold-standard’ data challenges some of the dogma that has emerged around CD20 therapies and COVID-19 and alters my interpretation of the Italian data.   

(2) An increasing number of ocrelizumab-treated cases not seroconverting when being infected with the coronavirus

Although there are several cases of SARS-CoV-2 positive COVID-19 cases on ocrelizumab who have been reported that have not seroconverted (detectable antibodies) there are many more normal people who have have COVID-19 who haven’t seroconverted as well. Whether this observation is assay dependent, i.e. insensitive assays that don’t detect low level antibody, or true biology needs further investigation. The fact that these people, ocrelizumab-treated or normal people, recover from COVID-19 is telling us that an antibody response is not necessary to clear the virus and for recovery from COVID-19. It is likely these patients have very good cellular immune responses that will protect them from reinfection in the future.

These observations have implications for vaccine responses and hence we may have had the wool pulled over our eyes focusing on the easier to measure antibody responses. I suspect, as do many others, that it is not humoral, but cellular, immunity that will be important for  protective immunity against SARS-CoV-2. I am not saying antibody responses won’t be important, but it is likely the dominant protection will come from cellular immunity. 

(3) Not being able to have a coronavirus vaccine when one emerges

This is clearly not correct. Patients on ocrelizumab will be able to have DNA, RNA and component coronavirus vaccines. The only vaccines they may not be able to have are live attenuated vaccines and potentially vaccines using a live viral vector to deliver the immunogen. The question is whether or not ocrelizumab-treated patients will be able to mount an adequate protective immune response to these vaccines is a moot point, which is why I have been urging Roche to plan and set-up registry studies to see if ocrelizumab-treated patients develop adequate immune responses to these vaccines. It is important that these studies are well designed and include both antibody or humoral and cellular components. 

Another thing to remember is that no vaccine is likely to be 100% effective. Even if the vaccine is only 60% to 70% effective it will be sufficient to create herd immunity and stop the spread of coronavirus. Vaccines are about population health and not necessarily about individual health, which is why regulators are fixated on safety.

I also told this patient that there are many other factors at play. For one the death rate or mortality from COVID-19 is falling. This is happening for several reasons. Firstly, we now have approved treatments for COVID-19 and the circulating strains are likely less virulent than the initial strains. Based on simple evolutionary principles the more benign strains are out competing the virulent strains. Another factor that I have commented on before is that we may be nearing herd immunity in some areas of the country, for example in London. This is based on the observation that many people have cross-reactive cellular and humoral immunity, presumably from other coronaviruses, that are protecting them from getting COVID-19. Therefore the risks of getting COVID-19 are falling. Add to this sensible personal hygiene and social distancing and the risks remain low. The second surge is really happening in areas of the country with low herd immunity and amongst care-free populations who are not being adherent to the government’s guidelines; for example, University students. 

The bottom line is that if you are low risk of getting COVID-19 and you double that risk the risk remains low. I would also only cross the vaccination bridge when it arises. Trying to preempt when and what vaccine will emerge first is really a guessing game. What is not a guess is that this patient has active MS, with a relatively poor prognostic profile (spinal cord disease) and needs treatment. She does not have highly-active MS therefore the only high-efficacy DMT available to her first-line on the NHS is ocrelizumab. She could select a platform therapy, which has also been offered to her, and to then see how she does, but as she is very well informed and understands the concept of ‘flipping the pyramid’ and that ‘time is brain’ doesn’t want to take a chance on a lower efficacy DMT. The outcome from our discussion is that she has decided to go ahead with ocrelizumab after she has had her pneumococcal and seasonal influenza vaccines. 

As you can see the COVID-19 anti-CD20 data is quite complex with a lot of nuances, which makes it difficult to communicate to patients. But if you take time to explain it to patients, not only do you allay their fears, but you end-up with a well informed patient who knows what they are signing up for. 

CoI: multiple

Twitter: @gavinGiovannoni             Medium: @gavin_24211

#MSCOVID19: good news

Barts-MS rose-tinted-odometer: ★★★★★

The late late-breaking session at the MSVirtual2020 meeting, which covered COVID-19 has already received a lot of air-time on social media. The big-data alliance confirmed the Italian data, i.e. that people with MS (pwMS) on anti-CD20 are at higher risk of getting COVID-19 and severe COVID-19 (hospitalisation, intensive care admission and/or ventilation) compared to pwMS on dimethyl fumarate. Importantly there was no mortality signal, i.e. pwMS on anti-CD20 don’t appear to be at higher risk of dying from COVID-19 and its complications. This is very good news! 

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However, the Big-Data alliance couldn’t confirm what the Italians have shown that treatment duration on an anti-CD20 is a risk factor. A clue to the latter is the observation that the COVID-19 risk was higher with rituximab compared to ocrelizumab in the Big-Data alliances graphs. As it is likely that rituximab-treated pwMS have been on treatment longer than ocrelizumab-treated patients would support this. Ocrelizumab has only recently been licensed and hence most people on ocrelizumab are likely to have been on it for a shorter period of time compared to rituximab-treated patients. 

Is all this good news? Yes, very good news. 

It clearly shows that people on anti-CD20 therapy have the ability to mount a robust immune response and recover from coronavirus infections, despite having a reduced B-cell and antibody response. This means that innate immunity and adaptive cellular immune responses are all that is required to recover from coronavirus and other viral infections. It will be important to study how robust the T-cell memory responses are post-COVID-19 in these patients as this will have implications for studying vaccine response when vaccines arise. What this means is that even if pwMS on an anti-CD20 don’t make an antibody response to a SARS-CoV-2 vaccine they may still have protective cellular immunity. This will also be good news. I sincerely hope Roche-Genentech and Novartis are planning to study vaccine responses in ocrelizumab- and ofatumumab-treated patients when the vaccines arrive. 

The observation that the longer you have been on an anti-CD20 the greater your chances of getting COVID-19 and severe COVID-19 implies the risk may be related to hypogammaglobulinaemia and blunting of past cross-reactive immunity from being exposed to other circulating community-acquired coronaviruses. I illustrate this in the following slide. In short pwMS on anti-CD20 therapy are shifted to the right and are less likely to have asymptomatic infections and more likely to have severe infections. 

This cross-reactive immunity to other coronaviruses may be the silver lining to the ominous grey clouds that have been hanging over us for months. It seems that between 40-60% of people in the general population have T-cell responses to SARS-CoV-2 without a history of having had COVID-19 and without an anti-SARS-CoV-2 antibody response. It now seems that these cellular memory responses protect these individuals from getting COVID-19. If this proves to be the case then herd immunity might be much higher than we realise and this could explain why the second surge in places like London and New York are much lower than other places that had smaller peaks during the initial wave of COVID0-19. 

If this background cross-reactive coronavirus immunity hypothesis, backed by the observations we see in pwMS on anti-CD20 therapy, turns out to be true we may have already reached herd immunity in London and are not far off it in other areas of the country. New models by Gomes and colleagues, at the University of Strathclyde, and Lourenco and colleagues, at the University of Oxford, suggest herd immunity may occur at levels of exposure of 20% or lower. If this is the case then we will see it first in London. So please watch the London COVID-19 numbers if they stay low this will be very good news. 

Gomes et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold. MedRxIV doi: https://doi.org/10.1101/2020.04.27.20081893

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, the susceptible subpopulation is depleted causing the incidence of new cases to decline. Variation in individual susceptibility or exposure to infection exacerbates this effect. Individuals that are more susceptible or more exposed tend to be infected earlier, depleting the susceptible subpopulation of those who are at higher risk of infection. This selective depletion of susceptibles intensifies the deceleration in incidence. Eventually, susceptible numbers become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) is reached. Although estimates vary, simple calculations suggest that herd immunity to SARS-CoV-2 requires 60-70% of the population to be immune. By fitting epidemiological models that allow for heterogeneity to SARS-CoV-2 outbreaks across the globe, we show that variation in susceptibility or exposure to infection reduces these estimates. Accurate measurements of heterogeneity are therefore of paramount importance in controlling the COVID-19 pandemic.

Lourenco et al. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2. MedRxIV doi: https://doi.org/10.1101/2020.07.15.20154294

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

My position on anti-CD20 therapies has been criticised, why?

Barts-MS rose-tinted-odometer: ★★★★★

I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. 

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study. 

In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia. 

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the  NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list). 

The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions.  If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

#MSCOVID19: getting ready for the vaccine

Informing patients about their potential coronavirus risks associated with anti-CD20 therapy is complicated and resulting in our patients being given different advice depending on who they see. The reason for this is that we don’t have the direct evidence to be able to dissect out why people on anti-CD20 therapy are at higher risk of COVID-19 and at higher risk of being admitted to hospital with severe COVID-19. 

I doubt this increased risk relates to increased exposure to the coronavirus. Why should someone on ocrelizumab who attends their healthcare facility be at increased risk of acquiring SARS-CoV-2 infection compared to someone for example on natalizumab who attends for their infusion every 4-6 weeks? 

The clue to the increased risk is in the detail of the data. It is apparent that the longer you have been on an anti-CD20 therapy the greater your risk; the risk of COVID-19 is particularly high if you have been on an anti-CD20 therapy for more than 3 years. This means that it must be due to prior exposures, i.e. exposures before the COVID-19 pandemic started.  

In the general population, it is now clear that some people have T-cells and antibodies that cross-react with SARS-CoV-2 and that these protect these people from developing COVID-19 or severe COVID-19. These cross-reactive immune responses are likely to have developed in response to infection or exposure to other circulating coronaviruses; the viruses that cause the common cold. 

My theory is that if you are on an anti-CD20 therapy with no B-cells and a poorly functioning antibody response and you get the common cold your immune system will not be able to make these protective cross-reactive anti-coronavirus antibodies. This would then reduce your chances of being protected from getting COVID-19 or getting only mild COVID-19 when you are infected with SARS-CoV-2. 

I have tried to illustrate this in the following slide showing that people on long-term anti-CD20 therapies are more likely to get symptomatic SARS-CoV-2 infection, i.e. COVID-19, and when they do get COVID-19 it is likely to be more severe. Severity in this context is requiring hospitalisation and potential intensive care and ventilation. 

What does this mean for you? It means that if you are about to start ocrelizumab, rituximab or ofatumumab then your chances of getting COVID-19 are unlikely to be different to another DMT, with the exception of interferon-beta that lowers your risk because of its antiviral effects. 

If you happen to be on ocrelizumab, rituximab or ofatumumab already there is little you can do, because these agents are not rapidly reversible and even if you stop the treatment and allow your B-cell compartment to reconstitute you are unlikely to develop the cross-reactive immunity from common coronaviruses. However, by stopping your anti-CD20 and allowing your B-cells to reconstitute you will be allowing your immune system to prepare itself for a coronavirus vaccine in the future.

At the beginning of the pandemic, I was a bit cynical about the chances of a successful coronavirus vaccine emerging, but the preliminary phase 2 results of several vaccines and the immunological insights above have made me much more optimistic that we will have an effective coronavirus vaccine quite soon. When I say soon I suspect we will have one ready for general consumption early next year. In all likelihood, one of the first vaccines will be the Oxford-AstraZeneca vaccine that happens to involve a live virus, which itself will have implications for some of the MS DMTs. 

If my predictions are correct the MS community may need to start getting vaccine ready or they can simply rely on herd immunity. With anti-CD20 therapy, this needs to be planned ahead and patients will need to miss one, two or possibly three infusions depending on their body size and individual B-cell reconstitution kinetics in order to prepare their immune systems for the vaccine. 

Some critics of this strategy are saying that patients on an anti-CD20 therapy will still make T-cell responses to the vaccine that will in all likelihood protect them. Yes, this may be the case, but then how do you explain the above observations that people on anti-CD20 therapy are at increased risk of COVID-19 and severe COVID-19? I would interpret this as them having blunted T-cell responses to cross-reactive common coronaviruses. If this is the case pwMS on an anti-CD20 will have blunted T-cell response to the vaccine. In support of the latter is the observation that several pwMS on ocrelizumab who have had swab-positive COVID-19 have failed to make an antibody response to the virus. Please remember that good quality antibody responses are T-cell dependent. These observations are telling me that in all likelihood being on anti-CD20 therapy will prevent you from developing protective immunity to coronavirus from a vaccine.

Clearly getting more detailed population-level COVID-19 data in people with MS is very important. This is why we are trying to crowdfund our study to identify people who have antibodies to SARS-CoV-2. We will be able to use this resource to do nested immunological studies on pwMS on different DMTs to understand the cross-reactive immunology at both the T and B cell level to coronaviruses in general and test the hypotheses above. It will also allow us to study vaccine responses if and when the vaccines arrive. 

If you are prepared to help with a small donation it would be much appreciated. Thank you.

JustGiving

CoI: multiple

A false sense of security?

Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine. 

There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS? 

Image from supplementary material N Engl J Med 2020; 383:546-557.

It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a critically important one. In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis). 

So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.

Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo). 

Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.

Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding.

Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma. 

Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity. 

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383:546-557.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. 

METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. 

CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).

CoI: multiple

#MSCOVID19: vaccine readiness

Will Prof G have to eat his proverbial hat?

I have been telling people that an effective SARS-CoV-2 vaccine is a long way away and that we shouldn’t expect a commercially available vaccine for another 12-18 months. Maybe I am wrong. The Moderna phase 1 results were published by the NEJM yesterday and are more impressive than I expected. These results are so important because the vaccine is based on RNA technology, which is relatively easy to scale-up in terms of production, unlike recombinant protein vaccines or inactivated viral vaccines. Therefore this vaccine may be with us before the end of the year.

The Moderna RNA vaccine carries the code for S-2P antigen, consisting of the SARS-CoV-2 glycoprotein. The vaccine is given as two doses (Day 1 and Day 29) into the deltoid or shoulder muscle. The RNA then uses the molecular machinery of the deltoid muscle to make the immunogen that then stimulates the immune response to the antigen, which will hopefully prevent wild-type SARS-CoV-2 infection and prevent COVID-19. 

This has potential implications for how we treat MS. It increases the likelihood of a successful vaccine to prevent COVID-19 and increases the chances of pwMS having to be vaccine-ready in a 6-9 month time scale rather than a 12-18 months period. Clearly this has implications for how we manage patients on DMTs that have been shown to blunt or prevent protective vaccine responses, in particular, pwMS on anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab) or S1P-modulators (fingolimod, siponimod, ozanimod, ponesimod). 

Will Prof G have to eat humble pie or his hat? The market response to the data below suggests he will. What will be the implications for the MS DMT market? I suspect an effective coronavirus vaccine will hit the anti-CD20 market the most, which means ofatumumab’s MS launch will be a damp squib. 

Jackson et al. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. NEJM July 14, 2020 DOI:10.1056/NEJMoa2022483

BACKGROUND:  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.

METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.

RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

CONCLUSIONS: The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461

CoI: multiple

#T4TD when it comes to Anti-CD20 therapy body size counts

Did you know that if you are a large person standard dose ocrelizumab is not as effective as it is in a small person? 

When looking at the efficacy of anti-CD20 therapies such as ocrelizumab you shouldn’t bother looking at relapses and focal MRI activity (Gd-enhancing lesions or new T2 lesions) when comparing effectiveness between doses and competing products. Relapses and MRI lesions are ultrasensitive to the effects of anti-CD20 therapies and are suppressed, to almost zero, at relatively low doses. In scientific measurement-speak we refer to this as a floor effect; in other words, you can’t go lower than zero or near-zero. 

However, when you look at disability progression (the real MS) there is clearly a dose effect, i.e. the higher the dose of ocrelizumab relative to body size, the greater the B-cell depletion and the less likely you are to progress. Most commentators miss this insight and are lulled into a false sense of security by seeing the relapse and MRI data when the real MS may be smouldering away and shredding your brain unabated. 

For this reason, we really need to do studies with higher doses of ocrelizumab and almost certainly higher doses of rituximab and ofatumumab. The observation that rituximab, at relatively low doses, doesn’t prevent the majority of pwMS becoming secondary progress is not surprising when it seems we need more intensive and not less intensive B-cell depletion. 

There are two hypotheses that could explain the dose-effect of ocrelizumab: (1) CNS penetration and the need to scrub the brain free of B-cells, or (2) really deep tissue B-cell depletion. Higher doses of ocrelizumab may achieve both of these. The real question is what is it about B-cells that is driving MS?

Those of you who are up to speed with safety and vaccine readiness data will argue that higher dose ocrelizumab will come with a price. Yes and no. Until we do the studies we won’t know. In relation to vaccine responses, I suspect there will be little difference between low and high dose ocrelizumab as both will almost certainly ablate germinal centre function. 

In terms of long-term safety, I suspect we may not need to use high-dose or very high-dose anti-CD20 therapy long term; we may get away with using it as an induction therapy followed by a maintenance therapy. 

Does this have implications for you as an individual? Yes, don’t accept your neurologist saying your disease is under control simply because you are relapse and MRI activity free; remember smouldering MS is the real disease. There are now compelling reasons why we need to do the double-dose ocrelizumab trial or DODO study and other add-on studies to target smouldering MS. Do you agree?

#T4TD = Thought for the Day

CoI: multiple

#MSCOVID19: COVAX or Coronavirus Ocrelizumab Vaccination Study

Anti-CD20 therapy not only increases your chances of getting COVID-19 but also increases your chances of developing severe COVID-19 and having to be admitted to hospital for treatment. I have argued that the likely mechanism is to be due to anti-CD20 therapies blunting important cross-reactive anti-coronavirus immune response acquired from other community-acquired coronaviruses. If this is correct it means that people with MS (pwMS), and other diseases, on anti-CD20 therapies, will be unlikely to mount protective immune responses to ane effective SARS-CoV-2 vaccine. 

Based on the questions I have been asked on social media and recent COVID-19 related webinars vaccine readiness is clearly playing on the minds of many HCPs and pwMS. To provide some perspective we have recently written a review paper on vaccine readiness to highlight this topic and to how to mitigate this issue. 

It seems likely that pwMS on anti-CD20 therapies are going to have to take a drug holiday to allow peripheral blood B-cell reconstitution before being vaccinated. What I don’t know is whether or not this hypothesis is correct and if correct what level of B-reconstitution will be necessary to allow an adequate vaccine response. I, therefore, propose testing this in a clinical trial where we compare antibody and T-cell responses to the SARS-CoV-2 vaccine when it emerges with different levels of peripheral B-cell reconstitution. The idea will be to vaccinate patients at different time points after early and late (above normal) peripheral blood B-cell reconstitution. I have called this trial the COVAX Study or the “Coronavirus Ocrelizumab VA(X)ccination Study”.

If you are on ocrelizumab would you volunteer to participate in this study?

Baker et al. COVID-19 vaccine-readiness for ocrelizumab and other anti-CD20-depleting therapies in multiple sclerosis and other autoimmune diseases. Authorea. June 23, 2020. DOI: 10.22541/au.159292858.82650822

Although most autoimmune diseases are considered to be CD4 T-cell or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab that is used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities, notably multiple sclerosis, where ofatumumab is in late stage development and ocrelizumab is approved for use. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of multiple sclerosis and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B-cell subset inhibition that controls multiple sclerosis and other autoimmunities, would not influence innate and CD8 T-cell responses, which are central to SARS-CoV-2 elimination, nor the hyper-coagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority (mortality rate n=~5/392) of SARS-CoV-2 infected, CD20-depleted people with multiple sclerosis have recovered. However, protective neutralising-antibody and vaccination responses are predicted to be blunted, until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control in MS and other autoimmune diseases, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

CoI: multiple

#MSCOVID19 two swallows don’t make a summer

As you know I have had to backpedal with my SARS-CoV-2/COVID-19 advice in relation to anti-CD20 therapies. I have now had to reinterpret data on the role of immunoglobulins in protecting people from developing COVID-19 and severe COVID-19.

I have been using the two Italian cases of X-linked agammaglobulinaemia who got COVID-19 and make a recovery as an argument that you don’t need B-cells and immunoglobulins to recover from SARS-CoV-2 infection. I now think I am wrong. Both these patients were being managed with immunoglobulin replacement therapy or IVIG (intravenous immunoglobulin therapy). IVIG is essentially a mix of immunoglobulins from blood donors from the general population. The assumption I made was that as SARS-CoV-2 was a new virus there would be no antibodies in the general population that would neutralize the SARS-CoV-2. However, the study below shows that pooled immunoglobulin therapies are able to neutralise SARS-CoV-2 (see Díez et al. below). Therefore I can’t assume, based on these two cases, that you don’t need immunoglobulins to make a recovery from COVID-19. This observation of neutralizing anti-SARS-CoV-2 activity in IVIG is also compatible with the emerging data that rituximab and by implication other anti-CD20 therapies now appear to increase your chances of getting COVID-19 and severe COVID-19. 

I suspect anti-CD20 therapies increase your chances of getting COVID-19 by reducing your chances of having an asymptomatic SARS-CoV2 infection. The immune responses to other human coronaviruses, the ones that cause the common cold, cross-react and help neutralise SARS-CoV-2, which explains why some people get asymptomatic or mild SARS-CoV-2 infections (see Shen et al. below). However, if you are B-cell depleted when getting the common cold, due to coronavirus, your immune system isn’t able to make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting COVID-19. 

In support of this the case study published last week of a person with MS on ocrelizumab who failed to seroconvert to having anti-SARS-CoV-2 antibodies despite having confirmed SARS-CoV-2 COVID-19 (see Conte. case report below). This particular patient had mild hypogammaglobulinaemia as a result of ocrelizumab treatment. The failure to seroconvert could be an assay problem, i.e. low sensitivity, or is more likely to be due to the blunted B-cell response from being treated with ocrelizumab. Clearly this case report is going to be very important in shaping our thinking in terms of doing further anti-SARS-CoV-2 seroprevalence studies in people with MS and preparing our patients for a potential SARS-CoV-2 vaccine. The latter gets more pressing as most countries have now abandoned herd immunity as a strategy to deal with COVID-19.

Díez et al. Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins. BioRxiv doi: https://doi.org/10.1101/2020.06.19.160879

Background: There is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy. 

Methods: The neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT50) in the PFU assay and the half maximal inhibitory concentration (IC50) in the cytopathic/cytotoxic method (calculated as the minus log10 dilution which reduced the viral titer by 50%). 

Results: All IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV. 

Conclusion: In cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management. 

Conte. Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab with hypogammaglobulinemia. MSARDS June 20, 2020.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

#MSCOVID19: an anti-CD20 backpedal

Science is not a religion and hence scientific advice, unlike beliefs, change as new evidence emerges. When the COVID-19 pandemic started we had to formulate advice on DMT use and their impact on SARS-CoV-2 infection and COVID-19 based on scientific principles and evidence of other viral infections. I created a table to summarise my opinions and as evidence has emerged I have updated the table accordingly. I have also added in new columns for example on advice about shielding/quarantine and on vaccine readiness. I have just updated the table for a sixth time changing the risk category of rituximab and other anti-CD20 therapies with a warning that it appears that this class of therapy increases your chance of getting COVID-19 and possibly severe COVID-19. This change is based on data from the Swedish MS registry and the survey below done in Iran. In short being on rituximab doubles your risk of getting COVID-19 and there is a suggestion that it increases your risk of getting severe COVID-19. At the moment there is not enough evidence to be firm about the latter or to comment on mortality risk. 

How rituximab increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. The latter seems most likely and is meanable to study.

It now seems that immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. So just maybe having had that common cold last winter or the year before has given you some built-in protection against getting COVID-19 and severe COVID-19.  However, if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19. Please note this is a hypothesis, but it can be tested by studying people with MS and other condition on anti-CD20 therapies and screening them for antibodies against coronaviruses and comparing them to age-matched controls and patients on other DMTs. I am prepared to bet you the anti-CD20ers don’t have these cross-reactive antibodies or if they do they are at a lower level (titre) and are non-neutralizing. 

Another possibility is that anti-SARS-CoV-2 antibody responses, in particular IgM antibodies, help clear the virus and aid in a more rapid recovery from COVID-19 and milder disease. Therefore, if your anti-SARS-CoV-2 antibody response is delayed or blunted by being on an anti-CD20 therapy this will increases your chances of getting more severe COVID-19.  Whether this contributes to you being less likely to have asymptomatic SARS-CoV-2 infection is unknown, but again this can be studied in carefully designed studies. 

Should this emerging data on rituximab change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies it takes months to years to reconstitute your peripheral B-cell pool. This is why I am now recommending that if you are on an anti-CD20 therapy you be extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments). The good news is that the risk to individuals is low as a result of acquiring SARS-CoV-2 infection falls rapidly in most countries where anti-CD20 therapies are widely used to treat MS. I am still not recommending shielding because even though there is about a doubling of the risk of getting severe COVID-19 (hospitalization) the affected people with MS have been making a good recovery. The main determinants of death from COVID-19 in people with MS are older age, advanced disease and comorbidities and not the DMT they are on.

What about starting an anti-CD20 therapy? The decision to do this must be individualised and weighed against the risk of getting COVID-19. In countries where this risk is very low anti-CD20 therapies will be safe. The other issue that is emerging is vaccine readiness, i.e. having a peripheral immune system that is ready to respond to a SARS-CoV-2 vaccine if and when one emerges.

We know that people who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response will be poor. For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? I would not recommend this until a vaccine emerges; only cross bridges when they are built and if you need to cross them. There is still a relatively high chance that all of the 100+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

At the moment the data we have from the Swedish registry and Iran is limited to rituximab but is likely to be relevant to ocrelizumab, ofatumumab and other anti-CD20 therapies. If you are conservative you may want to wait for the evidence base for these other anti-CD20 therapies to mature before incorporating the emerging evidence into your clinical decision-making. The good news is that there are several big data initiatives underway and we should report out within the next 1-2 months to confirm if this is a real signal, how robust the signal is and whether or not it applies to ocrelizumab and potentially other anti-CD20 therapies.  

Does this have implications for other infectious diseases? I don’t know but I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns may emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic that is only months away. The scary thought is what will happen if next season’s flu strain is a bad one? The impact of a more virulent flu strain on top of the tail of a SARS-CoV-2 pandemic is a scenario that makes me shudder. Do black swans ever emerge as twins?  

Safavi et al B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. MSARDS Published:May 12, 2020.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

Addendum

The following slides show some of the data I refer to above:

If you want to watch the iWiMS Webinar it is on YouTube; the relevant section starts at about 21 minutes.

CoI: multiple

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