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

Abstract

Abstract Epstein–Barr virus infection, and perhaps almost exclusively delayed Epstein–Barr virus infection, seems to be a prerequisite for the development of multiple sclerosis. 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 the siblings are in age, the higher the protection, 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 is unknown for practically all people who have not experienced infectious mononucleosis. In this retrospective cohort study using nationwide registers, we followed all Danes born during the period 1971–2018 (n = 2 576 011) from 1977 to 2018 for hospital contacts with an infectious mononucleosis diagnosis (n = 23 905) or a multiple sclerosis diagnosis (n = 4442), 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 to be 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 the Epstein–Barr virus. Maximum protection per sibling was obtained by having a 0–2 years younger sibling, corresponding to a hazard ratio of 0.80, with a 95% confidence interval of 0.76–0.85. The corresponding hazard ratio from having an (0–2 years) older sibling was 0.91 (0.86–0.96). Our results suggest that it may be possible essentially to eradicate multiple sclerosis using an Epstein–Barr virus vaccine administered before the teenage years. Getting there would require both successful replication of our study findings and, if so, elucidation of why early Epstein–Barr virus infection does not usually trigger the immune mechanisms responsible for the association between delayed Epstein–Barr virus infection and multiple sclerosis risk.