The following is a summary of updated recommendations and new data on COVID-19 vaccination in MS patients. (See also DMTs and vaccine response in MS: the evidence to date, NeuroSens, July 27, 2021.)

Updated guidelines
The Canadian Network of MS Clinics (CNMSC) has posted an update of its January vaccine guidelines although few changes have been made. The recommendations are posted on the MS Society website rather than the CNMSC website (https://mssociety.ca/resources/news/article/covid-19-vaccine-guidance-for-people-living-with-ms?gclid=CjwKCAiAnO2MBhApEiwA8q0HYQBGoGfz5eQ2pIHjJP0YKYyLxN67ZVDcjfitFNbIj3stGcJhUMW5rRoCzqIQAvD_BwE).

• Injectables (interferons, glatiramer acetate): No dosing modification is required.
• Teriflunomide and dimethyl fumarate: No dosing modification is required. Further discussion may be warranted for patients with a low lymphocyte count.
• S1PR agonists (fingolimod, siponimod, ozanimod): Likely reduce immune response to vaccination (see below). No dosing modification is recommended. Treatment initiation should be delayed two weeks (formerly four) after vaccination.
• Natalizumab: Not expected to reduce the immune response to COVID-19 vaccine. No dosing modification is recommended for vaccination. Following vaccination, no delay to treatment initiation is required.
• Alemtuzumab: use with caution due to infection risk during the cell depletion phase. Delay vaccination for six months after last dose; a three-month delay may be acceptable if lymphocytes have recovered to near normal. The next cycle may be delayed to maximize vaccine response. Delay initiation for at least two weeks after vaccination.
• Cladribine (formerly included with alemtuzumab): The timing of vaccination relative to cladribine dosing is unlikely to make a difference in vaccine response (vaccine formerly advised 3-6 months after dosing). May start/resume dosing two weeks after vaccination.
• IV anti-CD20 agents (ocrelizumab, rituximab): Some evidence suggests susceptibility to more severe COVID-19 (see below). Delay vaccination as late as is reasonable (e.g. 4-6 months), and resume infusions at least four weeks after the second vaccination. Delay initiation at least two weeks (formerly four) after vaccination.
• Subcutaneous anti-CD20 agents (ofatumumab): Consider another agent or delay initiation. Start treatment at least two weeks (formerly four) after vaccination. Administer vaccine four weeks after ofatumumab injection and resume ofatumumab four weeks after the second vaccination.

Response to primary infection
The seroconversion rate following COVID-19 infection in untreated MS patients is reportedly 85%, suggesting that response to infection is generally not impaired (Jaber et al. ECTRIMS 2021; P671).

Vaccine response
Numerous studies have now reported a high seroconversion rate in MS patients receiving an injectable, dimethyl fumarate, teriflunomide and natalizumab (Weinstock-Guttman et al. ECTRIMS 2021; P630. Capuano et al. ECTRIMS 2021; P651. Karussis et al. ECTRIMS 2021; P940. Brill et al. ECTRIMS 2021; P781.). The Global Data Sharing Initiative now uses DMF and natalizumab as the reference values when analysing vaccine response (Simpson-Yap M. ECTRIMS 2021; 098).

Following an early report by Achiron and colleagues (Achiron et al. Ther Adv Neurol Disord 2021;14:17562864211012835), a number of studies have now reported a relatively low seroconversion rate (range 26% to 64%) with fingolimod (Weinstock-Guttman 2021. Capuano 2021. Karussis 2021). It is not known if the response is similarly impaired with other S1PR agents. One study reported a seroconversion rate of 50% with siponimod (Ziemssen et al. ECTRIMS 2021; P810).

It is now well established that anti-CD20 agents (rituximab, ocrelizumab) significantly attenuate the seroconversion rate following COVID-19 vaccination (range 23% to 55%;) (Weinstock-Guttman 2021. Capuano 2021. Karussis 2021. Disanto et al. ECTRIMS 2021; P961). It is unclear if a similar effect will be seen with the different dosing/scheduling of ofatumumab; studies are ongoing (Ziemssen et al. ECTRIMS 2021; P660).

Several small studies have reported no significant decrease in vaccine response during treatment with cladribine (Achiron 2021. Disanto 2021. Brill et al. ECTRIMS 2021; P780). In the Brill et al. study, the CoV-2 IgG response was not correlated with the timing of cladribine dosing or total dose administered.

T cell response to vaccination
There is conflicting evidence on the T cell response in patients receiving anti-CD20 therapy. The Philadelphia group reported a robust T cell (CD4+ subsets, CD8+) response following COVID-19 vaccination in 20 MS patients (Apostolidis et al. Nat Med 2021;27:1990-2001). Indeed, there was greater expansion of CD8+ cells after a second vaccination in anti-CD20-treated MS patients compared to healthy controls. This finding has led to the suggestion that vaccination will provide some measure of protection in patients during anti-CD20 therapy.

However, the Swiss RituxiVac study examined the humoral and cellular response to vaccination in 96 patients with various medical conditions (primarily autoimmune disorders, 5% MS) with prior rituximab exposure (Moor et al. Lancet Rheumatol 2021;3:E789-E797). Median cumulative dose was 2.8 g; median time from last treatment was 1.07 years. Most (59%) had also received concomitant immunosuppressants. Overall, anti-Spike IgG antibodies were detected in 49% after the second vaccination and 20% had a T cell response. Only 14% had both a B and T cell response fully one year after stopping anti-CD20 therapy.

While a T cell response during anti-CD20 therapy may provide some measure of reassurance, there does appear to be an impaired T follicular helper (Tfh) response (Apostolidis 2021), which is required for germinal centre formation and an efficient B cell response (Crotty S. Immunity 2014;41:529-542). Fingolimod also profoundly suppresses Tfh subsets, which is likely due to S1PR blockade; other agents, such as DMF, do not appear to affect Tfh levels even during periods of lymphopenia (Huber et al. J Immunol 2020;204:1101-1110).

An intact T cell and innate immune response may be sufficient for most patients to recover adequately from COVID-19 infection despite treatment with an anti-CD20 agent or fingolimod. However, there remains an increased risk of severe COVID-19 outcomes and mortality (in part due to the populations treated) with anti-CD20 agents compared to other DMTs (Simpson-Yap M. ECTRIMS 2021; 098). As some authors have noted, patients receiving an anti-CD20 therapy may be able to clear the primary infection, but would be less likely to achieve sterilizing immunity, leaving them more susceptible to repeat infection (Giovannoni et al. Mult Scler Relat Disord 2021;53:103155).

Timing of anti-CD20 therapy
Recent studies have reported an improved humoral response to vaccination if the next ocrelizumab dose is delayed >6 months (Disanto 2021. Karussis 2021). The CovaXiMS study reported a more robust antibody response if vaccination is administered at least 143 days (20 weeks) after the last ocrelizumab infusion (Sormani M. ECTRIMS 2021; 099).

Booster vaccination
A preliminary study reported an increase in breakthrough infections (not necessarily severe) in the general population >4 months after completing a two-dose vaccine regimen (Mizrahi et al. medRxiv preprint, July 31, 2021).

The MS Society and the CNMSC are now advocating for a booster shot for patients expected to have an inadequate response to vaccination; this includes patients receiving an anti-CD20 therapy (ocrelizumab, rituximab, ofatumumab), an S1PR agonist (fingolimod, ozanimod, ponesimod), or a cell-depleting agent (cladribine, alemtuzumab)  (https://mssociety.ca/resources/news/article/ms-society-advocates-for-covid-19-vaccine-boosters-for-immunocompromised-individuals-with-ms?gclid=CjwKCAiAv_KMBhAzEiwAs-rX1ADqKX7YeFVcPWiPFqIe8N4_9OEcLGxvpGIFhSXRGS_oBV0RUz_SNhoCdZIQAvD_BwE). While this is consistent with recent recommendations from the National Advisory Committee on Immunization for immunocompromised individuals (www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/statement-september-10-2021-additional-dose-covid-19-vaccine-immunocompromised-following-1-2-dose-series.html), it is unclear at present if all provinces will extend access to booster vaccines to MS patients.

The U.S. National MS Society has made similar recommendations but includes siponimod and ponesimod and excludes cladribine from its list of drugs (www.nationalmssociety.org/About-the-Society/News/COVID-19-Vaccine-Additional-Doses-Boosters-and-MS). A booster injection is advised at least three months after the last infusion of an anti-CD20 therapy (insufficient data for ofatumumab) (Beard et al. J Neurol Sci 2021;430:120034). A booster shot with an mRNA vaccine is preferred. The Moderna vaccine is reported to produce a somewhat more robust response than the Pfizer vaccine (Sormani 2021).