Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system, that leads to disability accrual through two different mechanisms: relapse associated worsening (RAW) and progression independent of relapse activity (PIRA) (Portaccio et al., 2022; Lublin et al., 2022; Tur et al., 2023).

Disease modifying treatments (DMTs) are effective to prevent both relapses and disability progression. Clinical trials (Hauser et al., 2017; Hauser et al., 2020; Cohen et al., 2012, 2019, 2010) and observational studies (He et al., 2020; Brown et al., 2019; Iaffalodano et al., 2021; Harding et al., 2019) have demonstrated that highly effective treatments (HETs) are more efficacious than platform therapy in preventing confirmed disability progression (CDP), when used early.

EAN-ECTRIMS guidelines recommend “Offering a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of disease activity” (Montalban et al., 2018).

There is an increasing consensus on the early use of HETs as a first MS treatment, following the publication of clinical trials and observational studies comparing HETs to platform therapy.

Unfortunately, there is still no consensus on the definition of HETs (Samjoo et al., 2021). Monoclonal antibodies (natalizumab, alemtuzumab, ocrelizumab, ofatumumab, ublituximab) are widely considered as highly effective treatments, while sphingosine-1-phospathe receptor modulators (S1PRM, i.e., fingolimod, siponimod, ozanimod, ponesimod) and cladribine are considered as intermediate efficacy treatment. Injectables, teriflunomide, and dimethyl-fumarate are categorized as platform therapy.

On the other hand, infections may complicate the use of HETs, and their prevention is crucial to ensure the safety of people with MS (pwMS) during the treatment. Vaccination could be a safe and effective way to prevent infections in pwMS on HETs.

The COVID-19 pandemic represents a large-scale model of novel infection, allowing us to observe vaccine effectiveness in people treated with DMTs.

In this scenario, anti-CD20 treatments (anti-CD20) have been shown to increase the risk of COVID-19 infection, even after vaccination (breakthrough infection) (Schiavetti et al., 2022; Spierer et al., 2023; Novak et al., 2023). Indeed, antibody titers after vaccination are reduced in pwMS treated with anti-CD20 DMTs and S1PRM therapy compared to other treatments (Sormani et al., 2022). Furthermore, the cell-mediated immune response to vaccination is also reduced in pwMS treated with S1PRM (Tortorella et al., 2022).

Long-term real-world data from comprehensive database that include all hospitalization due to COVID-19 are scanty.

The aim of the present study is to describe the effect of MS DMTs on COVID-19 vaccination and the risk of breakthrough infection in a cohort of pwMS followed from January 2021 to September 2023 using a database comprehensive of all the patients’ hospitalizations.