Before the availability of SARS-CoV-2 vaccines, MS patients with high Expanded Disability Status Scale (EDSS) scores and treated with anti-CD20 therapies had a significantly increased risk of severe COVID-19 complications. The introduction of mRNA vaccines raised concerns regarding their immunogenicity in MS patients receiving disease-modifying treatments (DMTs). While many DMTs, including natalizumab (NTZ), don't significantly impact immune response to mRNA vaccines, those treated with anti-CD20 or sphingosine-1-phosphate receptor modulators (S1P-RMs), such as ocrelizumab (OCR) and fingolimod (FNG), exhibit a weakened humoral response, and S1P-RMs also show impaired cellular response. Preliminary data indicated a higher risk of breakthrough COVID-19 infections and more severe courses in patients on OCR and S1P-RMs after two mRNA vaccine doses. Given this, the effectiveness of a third booster dose in these patients became crucial. This study aimed to investigate COVID-19 outcomes in MS patients treated with OCR and FNG after three mRNA vaccine doses, comparing them to patients on NTZ. The study also sought to evaluate differences in COVID-19 symptoms, duration, and medication needs across the three DMT groups.

Existing literature highlighted the increased risk of severe COVID-19 in MS patients on certain DMTs prior to vaccination. Studies focusing on the efficacy of mRNA vaccines in MS patients showed that most DMTs did not significantly affect the immune response. However, high-efficacy DMTs like anti-CD20 therapies and S1P-RMs demonstrated a blunted humoral response to the vaccines. Studies showed higher breakthrough infection rates and severe disease in patients on ocrelizumab (OCR) and S1P-RMs after two vaccine doses. The need for a third booster dose to improve the immune response in these patients was evident, though data on its effectiveness remained limited. This study aimed to fill this gap by evaluating the impact of a third booster dose on COVID-19 outcomes in MS patients on different high-efficacy DMTs.

This multicenter, longitudinal, observational study involved 17 Italian MS centers. Inclusion criteria included MS patients ≥18 years old, treated with either NTZ, OCR, or FNG without DMT changes since the first vaccine dose, and a COVID-19 diagnosis (molecular or antigenic test) at least 14 days after the third booster dose. Exclusion criteria included missing COVID-19 outcome data, steroid use within a month of any vaccine dose or COVID-19 diagnosis, and COVID-19 diagnosis before the third booster. Data collected from September 2021 to July 2022 included socio-demographic information (age, gender, MS onset, type, EDSS score, DMT start date, last OCR infusion date), comorbidities, mRNA vaccine dates and type (BNT162b2 or mRNA-1273), and COVID-19 details (diagnosis date, symptoms, medication, course, and outcomes). Statistical analysis using STATA version 14.0 included descriptive statistics, ANOVA/Fisher's exact test for comparing variables between groups, and linear/logistic regression to evaluate the impact of clinical-demographic variables and DMTs on COVID-19 course and outcomes. Hochberg and Benjamini correction addressed multiple comparisons. Two sensitivity analyses excluded patients with progressive disease and those treated with monoclonal antibodies against SARS-CoV-2.

Initially, 307 patients were enrolled, but 17 were excluded due to missing data, leaving 290 patients (79 NTZ, 126 OCR, 85 FNG) in the final analysis. Significant differences were observed across groups in age, EDSS score, MS phenotype, and treatment duration, reflecting the typical clinical profiles associated with each DMT. No differences were found in comorbidity rates. Patients on OCR had significantly longer COVID-19 symptom duration than those on NTZ. While some individual symptoms (sore throat, myalgia, loss of taste/smell, fever >38°C, cough, and dyspnea) were less frequent in the NTZ group, the overall proportion of symptomatic vs. asymptomatic cases did not significantly differ across groups. The use of NSAIDs, steroids, and monoclonal antibodies was lower in the NTZ group compared to OCR and FNG groups. Similarly, antibiotics and oxygen use were higher in the OCR group compared to the NTZ group. Hospitalization was higher in the OCR group than the NTZ group, but this difference wasn't significant after correcting for multiple comparisons. No COVID-19-related deaths were observed. Regression models showed that most differences in symptom duration, individual symptoms, medication use, and hospitalization were due to demographic and clinical characteristics, rather than the specific DMT. However, differences in the time elapsed between the third booster and COVID-19 diagnosis, loss of smell/taste, cough, and monoclonal antibody use remained significantly associated with the DMT used. Sensitivity analyses excluding patients treated with monoclonal antibodies or those with progressive MS yielded similar results.

This large multicenter study investigated COVID-19 outcomes after a third mRNA vaccine dose in MS patients on high-efficacy DMTs. The observed differences in patient characteristics across the DMT groups were expected, reflecting established clinical patterns. While OCR and FNG groups showed slightly more severe COVID-19 courses compared to the NTZ group, regression analysis indicated that these differences were mainly explained by factors such as age, sex, and EDSS, rather than the DMT itself. The lack of severe outcomes, including deaths, and the absence of significant differences in hospitalization after adjusting for confounders suggest the effectiveness of the third booster dose in preventing severe COVID-19 in patients on OCR and FNG. This aligns with previous findings demonstrating improved immune response after the third dose in these patients. The lower hospitalization rates might also be related to the predominance of the Omicron variant during the study period, known for milder outcomes. The higher use of monoclonal antibodies in OCR and FNG groups might reflect higher clinical concern due to their known effects on immune response to the vaccine.

This study demonstrates the effectiveness of a third mRNA vaccine booster dose in mitigating severe COVID-19 outcomes in MS patients treated with OCR and FNG, despite the known blunted immune response to vaccines in these populations. Future research could explore the optimal timing of booster doses for different DMTs, investigate humoral and cellular immune responses in relation to breakthrough infections, and examine the long-term effects of the third booster dose on COVID-19 severity.

The study's limitations include potential selection bias due to recruiting patients after COVID-19 diagnosis, potentially underrepresenting asymptomatic cases. Asymptomatic infections before the third booster could have also influenced the immune response. The study lacked a comparison group of patients with COVID-19 after the second dose, and it did not evaluate humoral and cellular immune responses in detail.