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Epstein–Barr virus is now regarded as the critical risk factor for multiple sclerosis. However, Cytomegalovirus and human herpesvirus 6A have also been associated with altered multiple sclerosis risk, suggesting a multifactorial aetiology. Here, we present the first large-scale study of the association between human herpesvirus 7 and the risk of developing multiple sclerosis. A nested case-control study was performed by crosslinking Swedish registries and biobanks, identifying blood samples from 981 cases who later developed multiple sclerosis and 1278 matched controls. Serological testing was performed with a multiplex immunoassay. The association between viral serostatus and the risk of developing multiple sclerosis was analysed with conditional logistic regression, calculating an odds ratio with 95% confidence interval. Interactions between antibodies against human herpesvirus 7 and the Epstein–Barr virus nuclear antigen 1 regarding multiple sclerosis risk were analysed on the additive scale. Serological evidence of human herpesvirus 7 infection was associated with a higher risk of developing multiple sclerosis: odds ratio = 2.2 (95% confidence interval = 1.8–2.7), P < 0.001. The results remained similar when adjusting for cytomegalovirus, Epstein–Barr virus and human herpesvirus 6A serostatus. Synergistic interactions between human herpesvirus 7 and Epstein–Barr virus nuclear antigen 1 seroreactivity were observed: attributable proportion due to interaction = 0.51 (95% confidence interval = 0.34–0.68). These results suggest that human herpesvirus 7 could be a contributing factor in multiple sclerosis aetiology.

Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting.

Methods: In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression.

Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9).

Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.