Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS), characterized by focal neurologic deficits that can lead to physical and cognitive disability.¹ Patients with MS are treated with a number of approved disease-modifying therapies (DMTs) that effectively decrease disease activity, mainly by reducing the number of clinical relapses and the formation of new CNS magnetic resonance imaging (MRI) lesions.²

It is known that DMTs suppress the immune response in patients with MS in various ways, resulting in an increased risk of infection. For instance, interferon-beta (IFN-β) and glatiramer acetate downregulate the production of pro-inflammatory cytokines and upregulate the production of anti-inflammatory and immunoregulatory cytokines. Dimethyl fumarate and teriflunomide reduce the number of immune cells or switch them to an anti-inflammatory phenotype. In addition, the sphingosine 1-phosphate (S1P) receptor modulator fingolimod interferes with T-cell trafficking. Natalizumab, a widely used monoclonal antibody (mAb) to human α4 integrin, inhibits white blood cells from crossing the blood-brain barrier, whilst anti-CD20 mAbs including rituximab and ocrelizumab promote B-cell depletion.¹

Therefore, with COVID-19 vaccination spreading around the world, it is critical to assess the ability of patients with MS treated with DMTs to mount an appropriate immune response to COVID-19 vaccines, and to ensure that vaccines are safe.

Moreover, all three studies found that patients treated with B-cell depletion therapies, such as rituximab and ocrelizumab, failed to develop a sufficient antibody response to the vaccines.^3-5 The study conducted in Israel further reported that SARS-CoV-2-specific B- and T-cell responses were also substantially decreased in patients treated with ocrelizumab or fingolimod.⁵ The time interval between receiving ocrelizumab or rituximab and receiving the vaccine was shown to substantially impact vaccine success, with a longer time interval resulting in an improved antibody response.^3-5
The study from Israel reported that patients treated with fingolimod had low lymphocyte counts and failed to develop appropriate immune responses⁵. Absolute lymphocyte count was shown to significantly correlate with post-vaccination SARS-CoV-2 antibody levels in these patients (p=0.028). However, the Spanish study reported more variable humoral responses in this patient population and did not find a correlation between low SARS-CoV-2 antibody levels and lymphopenia.³
Conversely, patients with MS receiving other DMTs including IFN-β, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab and cladribine developed an antibody response similar to healthy controls.^3-5

In the Italian dataset, there were 11 breakthrough COVID-19 infections in fully vaccinated patients, and these were exclusively in patients treated with ocrelizumab (6), fingolimod (3), rituximab (1), and in one untreated patient. No patient required hospitalization.
Interestingly, this study also showed that vaccination with Moderna led to a 3.5-fold higher antibody level than with the Pfizer-BioNTech vaccine.⁴

Although a longer clinical follow-up is required to define COVID-19 vaccination guidelines in the context of DMTs and MS, the present data demonstrates the safety of these vaccines in MS and strongly supports delaying vaccination from the time of last infusion in patients treated with ocrelizumab and rituximab. For these patients, it might also be beneficial to offer a third booster dose to help increase antibody levels. In addition, it is essential to inform these patients that they are not protected against COVID-19 infection and that they should maintain social distancing measures.

Prof. Achiron spoke on this topic at the ECTRIMS congress 2021:

“It is a really complicated question because we don’t want to harm their immune-modulating treatment – it is protecting them from disease progression and from relapses, but on the other hand if they want to get vaccinated what should we do? Should we switch them to another more vaccination-safe therapy? One option is to stop treatment for 4-6 weeks to increase the lymphocyte counts and then to vaccinate them.”

Written by Elitsa Kamberska

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