Siblings reduce multiple sclerosis risk by preventing delayed primary Epstein-Barr virus infection.

Epstein-Barr virus infection, and perhaps almost exclusively delayed Epstein-Barr virus infection, seems a prerequisite for multiple sclerosis development. Siblings provide protection against infectious mononucleosis by occasionally preventing delayed primary Epstein-Barr virus infection with its associated high risk of infectious mononucleosis. Each additional sibling provides further protection according to the age difference between the index child and the sibling. The closer in age, the higher protection and with younger siblings being more protective against infectious mononucleosis than older siblings. If the hypothesis that delayed Epstein-Barr virus infection is necessary for the development of multiple sclerosis is true, then the relative risk of multiple sclerosis as a function of sibship constellation should mirror the relative risk of infectious mononucleosis as a function of sibship constellation. Such an indirect hypothesis test is necessitated by the fact that age at primary Epstein-Barr virus infection will be unknown for practically all people not having experienced infectious mononucleosis. In this retrospective cohort study using nation-wide registers, we followed all Danes born in 1971-2018 (n = 2,576,011) from 1977 through 2018 for hospital contacts with an infectious mononucleosis diagnosis (n = 23,905) or a multiple sclerosis diagnosis (n = 4,442), defining two different end points. Relative risks (hazard ratios) of each end point as a function of sibship constellation were obtained from stratified Cox regression analyses. The hazard ratios of interest for infectious mononucleosis and multiple sclerosis could be assumed identical (test for homogeneity P = 0.19), implying that having siblings especially of younger age may protect a person against multiple sclerosis through early exposure to Epstein-Barr virus. The maximum protection per sibling was obtained by having a 0-2 years younger sibling, corresponding to a hazard ratio of 0.80 with 95% confidence interval (0.76-0.85). The corresponding hazard ratio from having an (0 to 2 years) older sibling was 0.91 (0.86-0.96). Our results suggest that it may be possible to essentially eradicate multiple sclerosis by an Epstein-Barr virus vaccine administered before teenage years. Getting there would require both successful replication of our study findings and if so elucidation of why early Epstein-Barr virus infection usually will not trigger the immune mechanisms responsible for the association between delayed Epstein-Barr virus infection and multiple sclerosis risk.