Publication date: Sep 01, 2025

Although disease-modifying therapies (DMTs) may suppress coronavirus disease 2019 (COVID-19) vaccine responses in people with multiple sclerosis (pwMS), limited data are available on the cumulative effect of additional boosters. Maturation of Spike immunoglobulin G (IgG) to target a greater diversity of SARS-CoV-2 variants, especially past the BA. 1 variant, has not been reported. In addition, the prediction of variant-specific protection, given that Spike antibody testing is not performed routinely, remains a challenge. We, therefore, evaluated whether additional vaccine doses improved the breadth of cross-variant recognition to target emerging SARS-CoV-2 variants. Machine learning-based models were designed to predict variant-specific protection status. In a prospective observational cohort (n = 442), Spike IgG titers and live virus neutralization against D614, BA. 1, BA. 2, BA. 5, XBB. 1.1, XBB. 1.5, and EG. 5.1 variants were determined in 1,011 serum samples (0-12 months after 2-4 doses). Predictive protection models were developed by K-fold cross-validation on training and test data sets (random split 70:30). After primary vaccination, pwMS on immunosuppressive disease-modifying therapy (IMM-DMT) had 10-fold and 7. 2-fold lower D614 Spike IgG titers than pwMS on low-efficacy (LE)-DMT and cladribine (p < 0. 01). After 4 doses, pwMS on IMM-DMT had significantly lower Spike IgG titers, compared with pwMS on low-efficacy disease-modifying therapy, for D614 (p < 0. 05), as well as BA. 1, BA. 2, BA. 5, XBB. 1, XBB. 1.5, and EG. 5.1(p < 0. 01). The breadth of Spike IgG to recognize variants other than the cognate antigen increased after 4 doses of all DMTs. Although pwMS on IMM-DMT displayed reduced cross-variant recognition, a fourth dose resulted in a 2-4-fold increase in protection against newer variants and a reduction in two-thirds of pwMS without protective Spike IgG (p < 0. 0001). Tixagevimab and cilgavimab did not induce additional cross-variant protection. Variant-specific predictive models of vaccine protection were influenced by treatment, time since primary vaccination, and age, with high sensitivity (99. 4%, 95% CI 96. 8-99. 99) and specificity (72. 0%, 95% CI 50. 6-87. 9) for XBB. 1.5/EG. 5.1 variants. Despite not eliciting adequate antibody response in pwMS on IMM-DMT, COVID-19 boosters improve the breadth of the humoral response against SARS-CoV-2 emerging variants. Vaccine protection can be predicted by statistical modeling.

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