Management of Multiple Sclerosis in the Era of COVID-19 Pandemic - Episode 4

MS Immune Responses to COVID-19 Vaccines

An expert delves into the different types of immune responses a patient with MS can have to COVID-19 vaccines if they are also on DMTs.

Klaus Schmierer, MB BS, PhD, FRCP: When we’re talking about an immune response to vaccination in the context of disease-modifying treatment [DMT], we need to realize that the response itself contains broadly 2 elements. One is T-cell responses and the other is B-cell responses that ultimately lead to antibody generation. These elements are differently affected by the drugs you use. You can imagine that B-cell depleting compounds will have an impact on B-cell effects of the vaccination, or the response, while drugs that deplete both T as well as B-cells, will have an impact on both those elements of the system. So if we are looking at highly effective treatments, which include mepolizumab, ocrelizumab, ofatumumab, fingolimod, and cladribine, just to take these into account, we can clearly see that the response to vaccines is highly variable. That has been shown in a number of studies, one of them in our center, but also particularly the first studies that came out from Israel from…and her team, clearly showing that patients who are treated with the platform drugs, which include interferons, have essentially the same response as the normal population, or untreated people without DMT. The same applies for patients who are on cladribine.

But there is a very different effect in patients who are on B-cell depleting drugs. That is ocrelizumab and those on S1P [sphingosine-1-phosphate] modulators that lead to a depletion, essentially, in the peripheral blood of T as well as B-cells, where the antibody response or the serology response has been very weak. In fact it appeared in some of these experiments essentially nonexistent. Now, this is not entirely new or not entirely surprising because we have prior evidence from other viruses or immunizations that the response is imperfect or not present in all, but it is quite impressive when you look at differences between these compounds.

As I said, this is not the only part of immunity. We also have a T-cell response that appears to be present and strong in patients certainly on B-cell depleting drugs. But when we’re looking as these data become available now—there’s a very recent study from the team of Maria Pia Sormani, [PhD,] which has just been put on MetaArchive [Cooperative]—you do generate a higher risk with sustained B-cell depletion as it happens with those compounds that do that. The risk is well demonstrated because it’s so commonly used, and that obviously boosts numbers in studies, and the confidence intervals become very narrow, as shown for ocrelizumab. But I wouldn’t be surprised or don’t think there’s any significant difference compared to say rituximab.

I would also expect something similar with ublituximab if it becomes available, or ofatumumab, but the numbers are simply not there yet to make that call. I think ocrelizumab is the clearest. With fingolimod, it seems to be sort of in between, but again the risk is slightly increased, while the other compounds, particularly the immune reconstitution treatments, and the platform drugs, interferons, glatiramer acetate…Tecfidera [dimethyl fumarate], and teriflunomide, do not seem to be modulated very strongly by taking these compounds.

When we’re talking about timing of [COVID-19] vaccination, we obviously should take into account the timelines of how the compounds in question work. We have a constant immunomodulation or suppression with drugs like fingolimod or siponimod because they are given on a daily basis. With B-cell depleter [medications], the way they’re being taken every 6 months with ocrelizumab infusion, you will always have B-cell depletion with that constantly. With cladribine and alemtuzumab, it’s different because you have a brief stint or brief period of immune cell depletion, which is then followed by reconstitution such that the risk of those compounds certainly after a few months, and that applies particularly for alemtuzumab, subsides. As I already alluded to with cladribine, because it’s so selective for specific B-cell subsets, particularly memory B-cells, but not the new B-cells that come straight out of the bone marrow after the depletion has completed, there seems to be no relationship with the timing of those drugs. Theoretically, I would probably also give it 2 or 4 weeks after the treatment to vaccinate, but so far the data have not borne that out. In terms of B-cells depleters, I think it’s an interesting and challenging call because there is some preliminary evidence suggesting that if you dose ocrelizumab higher, you may have a better effect on disability. That is being assessed in the…trials, or the double dose study.

On the other hand, discard that argument for a moment and say, OK, we know that the B-cell depletion with ocrelizumab outlasts the 6-month interval at which we give this drug. You can also say, OK, If I want to generate a really effective immune response, we better wait 9 or 12 months where we know that at least 1% or 2% of B-cells are recovering, and that appears to be sufficient to produce an effective immune response. So I think this is something that we were hoping that the manufacturer would have addressed, and perhaps that will happen. I think also all these data of current practice will give us some clues to what the best strategy is. [We will learn] whether it’s better to lengthen the interval, or whether there’s an associated risk for resuming disease activity, or whether that has no impact on disease activity but will lead to a more effective immune response following vaccination.

This transcript has been edited for clarity.