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New data on COVID vaccination in multiple sclerosis (MS) patients has shown a reduced humoral response in patients treated with the anti-CD20 antibodies ocrelizumab or rituximab, but not in those receiving the similar product, ofatumumab.

The results also show a reduced response to COVID vaccination in some patients on fingolimod.

The data come from a new series of vaccinated MS patients from Madrid, Spain, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress being held virtually October 13-15.

Presenting the data, Celia Oreja-Guevara, MD, Hospital Clínico San Carlos, .25 finasteride Madrid, Spain, concluded that: “Currently approved COVID-19 vaccines appear safe in MS patients and are effective in most patients. However, vaccine strategy in patients treated with anti-CD20 and S1P inhibitors (such as fingolimod) need further study.”

“We showed that patients on ocrelizumab or rituximab had a very low or no antibody response to COVID vaccination,” she added. “However, some previous studies have shown some T cell response to vaccination in these patients, and we are looking at that now.”

For the current study, the researchers analyzed the antibody response to COVID-19 vaccination at week 3, week 6, and month 3 after the first dose in 165 MS patients and 200 healthy controls.

Of the MS patients, 120 received both doses of mRNA vaccine and 42 received the AstraZeneca vaccine. The mean age of the MS patients was 45 years and 46 years in the healthy controls.

Adverse events were similar in the two groups, and no increase in relapse activity was seen in the MS patients.

Mean antibody titres were slightly lower in the MS patients versus the healthy controls. At 3 weeks, mean titres were 7910 AU/mL in the MS patients and 9397 in the healthy controls. At 6 weeks, mean levels were 16,347 AU/mL in the MS patients and 18,120 in the healthy controls.

MS patients treated with interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, and natalizumab who received mRNA vaccines developed a similar postvaccination humoral response as the healthy controls at each of 3, 6, and 12 weeks after the first dose.

MS patients receiving the AstraZeneca vaccine mounted a lower humoral response than those receiving the mRNA vaccine, but this same effect was also seen in the healthy controls.

However, patients on the anti-CD20 drugs ocrelizumab or rituximab showed a lower humoral response to COVID vaccination. Only 3 of 20 patients who had been treated with ocrelizumab developed antibodies, but these patients had longer washout periods (at least 6 months) between receiving ocrelizumab and the COVID vaccine. All 6 patients treated with rituximab had no antibody response to the COVID vaccination.

Oreja-Guevara also suggested that ocrelizumab-treated patients may have a worse outcome after COVID-19 infection. “In the first wave of infection in Madrid, we recorded 5 patients on ocrelizumab with COVID-19, 4 of whom were hospitalized,” she noted.

“In patients on ocrelizumab we need to try and have a long interval between giving this drug and giving the COVID vaccine. The longer the wash out period, the more antibodies are seen,” she said.

She noted that two patients in the study received the COVID vaccine 1 year after ocrelizumab administration and had a normal humoral response, similar to the healthy controls.

The new anti-CD20 drug, ofatumumab, did not seem to affect the COVID vaccine antibody response as much as ocrelizumab or rituximab. In the current study, four of five patients treated with ofatumumab had an antibody response.

Oreja-Guevara suggested that this was probably because the depletion of B cells is not so strong with ofatumumab. “This drug is dosed every 4 weeks and it doesn’t deplete all the B cells and they are replaced quite quickly,” she noted.

Fingolimod is another MS drug that seems to affect the antibody response to COVID-19 vaccination.

Oreja-Guevara described the response to COVID vaccination in patients on fingolimod as “very variable.” Of 16 patients treated with fingolimod, four failed to develop a humoral response, seven had a low antibody response, and five had a similar response to that seen in the healthy controls (three of these patients had also had a previous COVID-19 infection). The response to vaccination in fingolimod-treated patients did not appear to be related to lymphopenia.  

Cellular Response Also Impaired With Fingolimod

These data are consistent with those from another cohort from Israel reported previously.

In that study, which was published earlier this year, a team led by Anat Achiron, MD, Sheba Medical Center, Tel-Aviv, Israel, analyzed humoral immunity in 125 MS patients 1 month after the second dose of the Pfizer COVID vaccine. A group of healthy people similarly vaccinated served as control.

Results showed that protective humoral immunity occurred in 97.9% of the control group after vaccination compared with 100% in untreated MS patients and 100% in MS patients treated with cladribine but in just 22.7% of those treated with ocrelizumab and only 3.8% of those taking fingolimod.

For ocrelizumab-treated patients, the failure to mount appropriate IgG immune response was regardless of the absolute lymphocyte counts that were in the normal range or to the time-interval from the last ocrelizumab treatment dose that ranged from 3.1 to 8.9 months, “suggesting the need to postpone the next dosing to enable an effective post-vaccination humoral response,” the authors say.

They note that the majority of the fingolimod-treated patients in the study had a low lymphocyte count (< 1000 cells/mm3), which may be the cause for failing to mount an immune response. But even in the small group of fingolimod-treated MS patients with an absolute lymphocyte count > 1000 cells/mm3, no humoral response was detected.

At the ECTRIMS meeting, Achiron presented further results from this study on memory B cell and T cell responses to the COVID vaccine in these patients.

The results showed that COVID-specific B and T cell responses were only present in about half of healthy subjects, untreated MS patients, and those treated with cladribine.

While the B cell response was almost completely impaired in the ocrelizumab patients, the T cell response was present to the same extent as in the control group. But fingolimod patients showed no B or T cell responses.

Achiron concluded that patients on ocrelizumab should wait at least 9 months following the last dose before receiving COVID vaccination, and that patients taking fingolimod should consider a switch to a different medication.

But she pointed out that, despite the lack of humoral cellular responses in the fingolimod group, in this study there does not seem to have been an increase in COVID infection in patients taking fingolimod in a large registry study.

“This leads us to the idea that maybe lymphopenia is not the only story, and maybe innate immunity is playing a role. We still don’t really know the answer for that.”

Achiron said she was also surprised to see that even untreated and healthy subjects did not develop complete B cell and T cell responses after double COVID vaccination. And similar results have been seen in patients who have recovered from natural COVID infection, where the B cell response is “not 100%,” she added.

“This points to the suggestion that everyone might need a third vaccination, MS patients or not,” she concluded.   

European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress. Presented October 13.

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