A recent analysis suggests that the immune repopulation pattern in people treated with cladribine (Mavenclad) may contribute to the ability to mount an immune response to infection and develop protective antibodies upon vaccination.1 The limbic spoke with Professor David Baker, Professor of Neuroimmunology at London’s Queen Mary University, about the relevance of cladribine’s mechanism of action and lymphocyte repopulation dynamics to vaccine readiness during the COVID-19 pandemic.
At the beginning of the COVID-19 pandemic there were concerns around the potential for multiple sclerosis (MS) disease modifying therapies (DMTs) to increase the risk of infection with the SARS-CoV-2 virus, as well as the risk of developing severe COVID-19 complications.2 Professor Baker explains, “When COVID-19 materialised, we noticed that the people who were doing badly had low levels of white blood cells. Therefore there was a big concern because most of the multiple sclerosis drugs target white blood cells.”
Despite this early concern, it was subsequently found that people with MS taking DMTs were at no greater risk of COVID-19 than the general population. “I think the problem is that [low white blood cell counts] was a consequence [of COVID-19] and not the cause,” says Prof Baker.
Innate immunity is responsible for eliminating SARS-CoV-2
In a review article published during the early months of the pandemic in 20203 Prof Baker and colleagues examined the biology that underpins immunity to the SARS-CoV-2 virus and the pathology related to COVID-19, in order to determine the potential implications of MS treatment with DMTs.
The authors concluded that elements of the innate immune system were responsible for eliminating the virus and noted, “In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD 8 T cells to limit protection against COVID-19.”
Speaking to the limbic, Prof Baker explains, “The major part of the biology of getting rid of SARS-CoV-2 is first your innate immune system, and MS drugs do not target the innate immune system. And then it’s your CD8 T cells, which are important because they’re designed to get rid of viral infections. And most of the MS drugs actually don’t target the CD8 cells to any great level.”
When the innate system does not eliminate the virus, infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion, a cytokine storm and vascular pathology all contribute to Acute Respiratory Distress Syndrome.3
Listen to the full interview with Professor David Baker here:
Cladribine does not impair antibody response to vaccination: analyses
While B-cell depletion may not necessarily expose people to severe COVID-19, there continues to be concerns that it may inhibit protective immunity following vaccination. However, clinical trial and real-world data have shown that people taking cladribine are able to mount and maintain effective vaccine responses.4,5
A real-world study conducted in Israel4 found that patients who had taken cladribine were able to generate antibodies following a COVID mRNA vaccine administered one month after the last cladribine dosing. The antibody response was similar to the comparison group of MS patients not receiving immunomodulatory treatments and also similar to healthy controls.
Similarly, analysis of data from the MAGNIFY-MS6 study has shown that people treated with cladribine were able to mount responses to influenza and varicella zoster vaccines, irrespective of lymphocyte count.5
Cladribine repopulation dynamics the key to vaccine responsiveness
The clue to vaccine responsiveness in people treated with cladribine might be found in the immune repopulation pattern that occurs after therapy. In further analysis of data from the MAGNIFY-MS1 study, reduction of memory B cells occurred as early as one month after cladribine initiation with lowest levels sustained for up to 12 months, while naïve B-cells, which are typically required for the generation of antibody responses following vaccination, began recovering immediately.1
“Because of the repopulation kinetics, the immature cells can come back quickly and therefore they can respond to the vaccines, whereas the memory cells don’t. So your MS is controlled and if the drug’s [eliminated] when those B cells encounter the antigen, they make memory cells that become plasma cells…the plasma cells are the key in part of getting the vaccine response,” explains Prof Baker.
Professor Baker believes that cladribine is well-suited for the COVID-19 pandemic era. “The beauty of the cladribine is the biology actually just worked out perfectly because you’re not targeting the innate immune system so you can make an antiviral response, you’re not getting rid of your T-cells out of existence so they can make an antiviral response…and because those memory cells are kept at a low level, your MS is kept in check,” he says.
This article was sponsored by Merck. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Mavenclad product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.
- Wiendl H et al. Characterization of peripheral immune cell dynamics and repopulation patterns in the first 12 months of cladribine tablets treatment: MAGNIFY-MS Study (2235). Neurol 2021;96(15).
- Berger JR et al. COVID-19 and MS disease-modifying therapies. Neurol Neuroimmunol Nueroinflamm 2020;7:e761.
- Baker D et al. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic. Mult Scler Relat Disord 2020; 43.
- Achiron A et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021;14:1–8
- Roy S et al. Analysis of influenza and varicella zoster virus vaccine antibody titers in patients with relapsing multiple sclerosis treated with cladribine tablets. ACTRIMS Virtual Forum 2021. 25-27 February 2021
- de Stefano N et al. A 2-year study to evaluate the onset of action of cladribine tablets in subjects with highly active relapsing multiple sclerosis: results from MAGNIFY-MS baseline analysis (1487). Neurology 2020;94 (15 Suppl)