Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Abstract

Importance: An evidence-based appraisal of the COVID-19 vaccination policies among people with multiple sclerosis (pwMS) with respect to disease-modifying therapies (DMT) is important for our understandings and their further management. Objective: To synthesize the available evidence concerning the effect of DMTs on COVID-19 vaccination immunogenicity and effectiveness. Data Sources: We searched MEDLINE, Scopus, Web of Science, MedRxiv, and Google Scholar from January 2021 until January 2022. Study Selection: The exclusion criteria included: not a primary investigation; retracted/withdrawn; no eligible participants - people with no history/evidence of previous COVID-19 and corticosteroid administration within two months of vaccination; no eligible exposures - all nine DMT classes; and no eligible comparators - DMT-unexposed at the time of vaccination. Data Extraction and Synthesis: Entries were assessed independently by two reviewers for eligibility and quality. Dichotomized data was extracted by two reviewers in accordance with Cochrane guidelines, and were pooled using either Peto fixed-effects or Inverse-variance random-effects methods. Main Outcomes and Measures: Main outcomes were i) B-cell response, measured by seroconversion odds ratio (OR); ii) T-cell response, measured by interferon-gamma release response OR, and CD4+/CD8+ activation-induced marker+ OR. Further outcomes including immunity waning speed and breakthrough COVID-19 incidence/severity were synthesized narratively. Results: Data from 28 studies (5,025 pwMS and 1,635 healthy participants) after COVID-19 vaccination suggests mildly-lower B-cell responses in teriflunomide- and alemtuzumab-treated, extensively-lower B-cell responses in sphingosine-1-phosphate receptor modulator (S1PRM)- and anti-CD20 (aCD20)-treated, and lower T-cell responses in interferon-, S1PRM-, alemtuzumab- and cladribine-treated pwMS. Every ten-week increase in aCD20-to-vaccine period is associated with a 1.94-time (95%CI: 1.57, 2.41, P<0.00001) increase in odds of seroconversion. B-cell-depleting therapies seem to accelerate post-vaccination humoral waning, and booster immunogenicity is predictable with the same factors affecting the priming vaccination. Furthermore, comparatively-increased breakthrough COVID-19 incidence and severity is being observed only among S1PRM- and anti-CD20-treated pwMS - i.e., among the pwMS with extensively-blunted B-cell response, despite adequate T-cell responses in the aCD20-treated. To date, pwMS on only-T-cell-blunting DMTs have not shown increased susceptibility to breakthrough COVID-19. Conclusion and Relevance: The implemented vaccination strategy to date has been effective for pwMS on all DMTs other than S1PRM and aCD20. As B-cell immunity seems to be a more important predictor of vaccine effectiveness than T-cell immunity, optimization of humoral immunogenicity and ensuring its durability among pwMS on DMTs are the necessities of an effective COVID-19 vaccination policy.

Hybrid and vaccine‐induced immunity against SAR‐CoV‐2 in MS patients on different disease‐modifying therapies

“…Some of the disease‐modifying therapies (DMTs) for MS suppress the immune system, which results in reduced immune responses to vaccinations 1–25 . In a meta‐analysis of COVID‐19 vaccine studies in MS, post‐vaccine seroconversion rates were 13‐fold lower among patients on B‐cell depleting anti‐CD20 therapies (aCD20) and eightfold lower with S1P receptor modulators (S1P) as compared to patients not on a DMT 24 . Post‐vaccine T‐cell activation post‐vaccine is suppressed with S1P 18,21,22,25 but largely intact with B‐cell depleting therapies even in the absence of antibody responses 4,6,8,10,16–18,21,22,25–27 …”

Self-Reported safety of the BBIBP-CorV (Sinopharm) COVID-19 vaccine among Iranian people with multiple sclerosis

“…This issue is of crucial value given the documented hindering effect of some DMTs—namely sphingosine 1-phosphate receptor (S1PR) modulators and anti-CD20 therapies (aCD20) – on proper immunization against COVID-19. 20 , 21–27 Accordingly, the limited available evidence pointed toward lower clinical efficacy of mRNA 28 and BBIBP-CorV 29 vaccines in pwMS on S1PR modulators and aCD20, however, further replications are required to validate these findings.…”

Hybrid and vaccine-induced immunity against SARS-CoV-2 in MS patients on different disease-modifying therapies

“…We demonstrated that PI markedly enhances post-vaccine humoral and, and, to a lesser extent, cellular responses across DMTs, i.e. that the immunologic benefits of PI extended to patients on DMT classes -aCD20 and S1P -that are associated with attenuated postinfection [41][42][43] and post-vaccination responses 24,25 . Thus, vaccinated MS patients on aCD20 and S1P therapies who had prior COVID-19 infection -and these currently comprise the majority of patients in the US -likely have significantly better immune protection than would be expected based on published studies of vaccination-only immune responses 24,25,56 .…”

“…that the immunologic benefits of PI extended to patients on DMT classes - aCD20 and S1P - that are associated with attenuated post-infection 41-43 and post-vaccination responses 24, 25 . Thus, vaccinated MS patients on aCD20 and S1P therapies who had prior COVID-19 infection - and these currently comprise the majority of patients in the US – likely have significantly better immune protection than would be expected based on published studies of vaccination-only immune responses 24, 25, 56 . Moreover, our results suggest that it may be possible to improve humoral and cellular immune response defenses following repeated exposure to virus-specific antigens even in patients whose immune system has been partially compromised by medications.…”

“…Some of the disease-modifying therapies (DMTs) for MS suppress the immune system, which results in reduced immune responses to vaccinations 1-25 . In a meta-analysis of COVID-19 vaccine studies in MS, post-vaccine seroconversion rates were 13-fold lower among patients on B-cell depleting anti-CD20 therapies (aCD20) and 8-fold lower with S1P receptor modulators (S1P) as compared to patients not on a DMT 24 . Post-vaccine T-cell activation post-vaccine is suppressed with S1P 18, 21, 22, 25 but largely intact with B-cell depleting therapies even in the absence of antibody responses 4, 6, 8, 10, 16-18, 21, 22, 25-27 .…”