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Objective: Several factors have been associated with altered risk of developing multiple sclerosis (MS). Epstein–Barr virus (EBV) is the critical risk factor for MS, but recent studies indicate that human herpesvirus 6A (HHV-6A) and cytomegalovirus (CMV) are involved in MS aetiopathogenesis. We recently reported an association between rubella virus (RV) envelope protein 1 (E1) seropositivity and the risk of developing MS. Here, we aimed to further explore this association.

Methods: Bio-banked blood samples collected before the onset of MS from 981 cases and 1278 matched controls were analysed for antibodies against RV envelope proteins 1 and 2 (E2), and serum-neurofilament light chain (S-NfL), a marker for axonal injury. The association between RV and MS was analysed with conditional logistic regression, calculating odds ratios (OR) with 95% confidence intervals (CI).

Results: Rubella E1 seropositivity was significantly associated with a higher risk of MS development, even when adjusting for EBV, CMV and HHV-6A serostatus (OR = 1.67, 95% CI 1.29–2.14, P < 0.001). We also observed an increase in seroreactivity against RV E1 before an increase in S-NfL in MS cases, indicating that increased RV E1 seroreactivity precedes axonal injury in the MS prodrome at group-level. There was no association between RV E2 serostatus and MS risk. The association between RV E1 serostatus and MS risk remained similar when the analysis was restricted to unvaccinated participants (OR = 1.78, 95% CI 1.07–2.98, P = 0.028).

Conclusions: Our results support a broadening of the viral hypothesis in MS, arguing for further studies on the neurotropic RV in MS aetiology.