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

AbstractImportanceAn 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.ObjectiveTo synthesize the available evidence concerning the effect of DMTs on COVID-19 vaccination immunogenicity and effectiveness.Data SourcesWe searched MEDLINE, Scopus, Web of Science, MedRxiv, and Google Scholar from January 2021 until January 2022.Study SelectionThe exclusion criteria included: not a primary investigation; retracted/withdrawn; no eligible participants – people with no history/evidence of previous COVID-19 and corticosteroid administration within two months of vaccination; no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 SynthesisEntries 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 MeasuresMain 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.ResultsData 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 RelevanceThe 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.