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.