A recent retrospective analysis of data from the MAGNIFY-MS study¹ indicates that people with multiple sclerosis (MS) treated with cladribine are able to mount a protective immune response after influenza and varicella zoster vaccination, regardless of the timing of the vaccine relative to the cladribine dose and independent of lymphocyte counts. According to MAGNIFY-MS steering committee member Professor Klaus Schmierer, this data and emerging real world evidence indicates that vaccine efficacy is maintained in patients taking cladribine.

Professor Klaus Schmierer is Professor of Neurology at Queen Mary University of London and Royal London Hospital UK. He is a member of the steering committee for MAGNIFY-MS¹ and Chief Investigator for the CHARIOT-MS study.²

Professor Schmierer explained that the impetus for the analysis was the need for urgent vaccination data to better manage people with multiple sclerosis (MS) during the COVID-19 pandemic. Disease modifying therapies (DMTs) may increase the risk of infections and alter vaccine efficacy³ and there are efforts to understand how these therapies will impact on a patient’s vaccine readiness for COVID-19 vaccination. “This was an analysis triggered by the pandemic,” said Professor Schmierer.

The authors of a recently-published international expert consensus⁴ on DMTs and COVID-19 vaccination in MS conclude, “In summary, currently available data show that vaccinations do not exacerbate MS, provoke a relapse, or prevent DMTs from being effective. Inactivated vaccines are considered safe in patients treated with any disease-modifying drugs, although in some cases may be less effective. In any case, it is not recommended to discontinue or modify DMTs to improve vaccine efficacy as the risk of disease reactivation and progression outweighs the potential benefit. At the same time, a reduced response is likely to be better than none. Knowledge of vaccine responses on DMTs and a careful risk/benefit assessment is mandatory. If at all possible, vaccinations clearly should be recommended and administered to people with MS.”

New data indicates vaccine readiness in people treated with cladribine

The MAGNIFY-MS study² is being conducted to determine the onset of action of cladribine in patients with highly active relapsing multiple sclerosis. Some patients enrolled in the study received vaccinations during the course of the study as part of standard of care, which presented the opportunity to investigate the vaccine response in a retrospective analysis.¹

Blood samples were taken and analysed from 15 patients who had either received varicella zoster vaccine (VZV) before starting cladribine therapy (n=3) or had received the seasonal influenza vaccine (n=12) after therapy had commenced. Two control blood samples were taken: one just before taking cladribine, and another just before vaccination. In addition, two post-vaccination blood samples (closest samples available after vaccination) were examined. Antibody titres in response to the VZV and the seasonal influenza vaccine were measured via assay.

In the samples analysed for VZV antibodies, seroprotective VZV titres were maintained over 6 months post-initiation of cladribine tablets, despite lymphocyte depletion.  With respect to seasonal influenza, the majority of patients had seroprotective antibody titres even before receiving the vaccination. Post-vaccination, nine out of 12 patients exhibited a two-fold or greater titre increase (and four patients exhibited a four-fold or greater increase) for at least one strain of influenza for up to six months.

Seroprotection, or an increase in seasonal influenza titres, occurred in patients who were vaccinated soon after cladribine (1.5–6 months in Year 1 of cladribine or 1–4.5 months in Year 2), and also in those who were vaccinated relatively late after cladribine (8.5 to 10.5 months after cladribine in Year 1).  Seroprotection was also maintained or increased irrespective of lymphocyte count.

In summarising their findings, the analysis authors say, “In this small retrospective investigation, vaccination close to cladribine tablet initiation in Year 1 and in Year 2 provided protective immunity against varicella zoster virus and seasonal influenza,”. They add, “Seroprotective antibody levels against varicella zoster and seasonal influenza were maintained or increased for at least 6 months independent of lymphocyte counts measured at the time of vaccination in Year 1 or 2 of cladribine tablets treatment.”¹

Professor Schmierer explained the clinical significance of the findings: “One can conclude in this relatively small retrospective investigation that vaccination close to cladribine initiation in year one and in year two that vaccines provide protective immunity against VZV and against seasonal influenza. A key finding is that protection was independent of the degree of lymphocyte depletion in these patients…These findings suggest that patients treated with cladribine are ready for vaccination at any time, apart from a very small window where we didn’t test – the first six weeks after cladribine therapy.”

Additional retrospective data supports MAGNIFY-MS findings

Professor Schmierer referred to additional data from a substudy of the CLOCK-MS⁵ study, in which three patients with relapsing remitting MS had received at least one dose of cladribine before receiving an influenza vaccine. Protective antibody levels were increased at four weeks-post vaccination in all three patients. Two of the patients were experiencing lymphopenia at the time of vaccination, having received cladribine tablets two to four months beforehand. “Although this is a very small sample, the trends are clearly in line with what we found in MAGNIFY-MS: that patients developed an effective immune response irrespective of lymphocyte count and irrespective of the timing of the vaccine,” Professor Schmierer said.

Real world evidence from Israel ‘underpins hypothesis’ that cladribine does not blunt vaccine response

The MAGNIFY-MS analysis provides some reassurance that patients taking cladribine continue to remain able to mount and maintain effective vaccine responses, said Professor Schmierer. Additionally, recently published real world data from Israel has found that cladribine does not impair humoral responses to COVID-19 vaccination.⁶

The authors measured the IgG response to the Pfizer mRNA vaccine (BNT162b2-COVID-19 vaccine) one month after the second vaccination dose in 125 people with MS who were either untreated, or receiving treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects who had also been vaccinated served as control.

The authors report healthy subjects (n=47) had a protective humoral immunity of 97.9% after vaccination.

The authors conclude, “Cladribine treatment does not impair humoral response to COVID-19 vaccination.

Commenting on this data, Professor Schmierer said, “The data seems to underpin what we hypothesised based on the MAGNIFY-MS and CLOCK-MS data: that the response to SARS CoV-2 vaccination is very effective and indistinguishable between patients treated with cladribine and patients on no disease modifying therapy or healthy controls.”

He added, “There is also a very robust distinction [in the humoral response to vaccination] between cladribine and some other disease modifying therapies that we use in routine clinical practice.”

References

1. 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) https://n.neurology.org/content/94/15_Supplement/1487
2. Roy S et al. Analysis of influenza and varicella zoster virus vaccine antibody titers in patients with relapsing multiple sclerosis treated with cladribine tablets. P059. ACTRIMS Virtual Forum 2021. 25-27 February 2021 https://medical.emdserono.com/content/dam/web/health-care/biopharma/web/USMI/congress-presentations/Analysis-of-Influenza-and-Varicella-Zoster-Virus-Vaccine-Antibody-Titers-in-Patients-with-Relapsing-Multiple-Sclerosis-Treated-with-Cladr.pdf
3. Zrzavy T et al. Vaccination in multiple sclerosis: friend or foe? Front Immunol DOI: 10.3389/fimmu.2019.01883 https://pubmed.ncbi.nlm.nih.gov/31440255/
4. Centonze D et al. Disease-modifying therapies and SARS-CoV-2 vaccination in multiple sclerosis: an expert consensus. J Neurol doi:10.1007/s00415-021-10545-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038920/
5. Wu G.F et al. Evaluating The Impact Of Cladribine Tablets On The Development Of Antibody Titres: Interim Results from the CLOCK-MS Influenza Vaccine Sub-Study. Presented at ACTRIMS 2021 Forum, February 2th, 2021. https://www.abstractsonline.com/pp8/#!/9245/presentation/104
6. 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 https://journals.sagepub.com/doi/full/10.1177/17562864211012835