Short summary

A series of studies conducted in Africa indicate that BCG, a live vaccine against tuberculosis, is associated with marked beneficial effects on overall health.

In a study from Denmark, there was in addition a marked effect on the risk of death from neurological diseases of having received BCG at school. In a large cohort, we will further examine these effects, both for all-cause outcomes and esspecially for neurological diseases such as multiple sclerosis.

Rationale

A Danish study provides interesting clues of BCG's effects. Until the end of the 1970s, BCG was provided to all children at school entry, after which BCG was phased out due to low tuberculosis prevalence. The Danish birth cohorts born from 1965-76 thus experienced the phase out of BCG; coverage went down from almost 100% to ~25%.

This natural experiment provides a unique opportunity to study the long-term consequences of BCG in the Copenhagen School Health Record Register (CSHRR). The case-cohort study encompassed 5,316 individuals and compared BCG at school entry vs no BCG, following participants to 2010, when members of the cohort were 34-45 years old. BCG reduced mortality risk from natural causes by 42% (15% to 61%).

The natural causes of death were subdivided in major disease categories and BCG and/or vaccinia was associated with a 77% (7% to 94%) reduction in the risk of death from neurological diseases - several of the deaths were due to epilepsy and MS.

The indications from epidemiological data, murine studies, RCT data and ecological data suggestive of BCG-induced protection against neurological diseases and multiple sclerosis (MS) merits further investigation. If BCG vaccination reduces the risk of MS, then it could have marked consequences, since the vaccine is associated with very few and mild side-effects.

Hypotheses

Receiving BCG vaccine in childhood is associated with:

1) reduced long-term all-cause mortality and morbidity up to 55 years of age

2) reduced long-term mortality and morbidity from neurological diseases

3) reduced risk of developing MS and reduced MS severity

4) improved offspring health outcomes, including reduced risk of neurological diseases such as MS

Description of the cohort

The project is based on a unique cohort of 47,622 schoolchildren born between 1965-76 that are registered in the Copenhagen School Health Regard Register (CSHRR). We will follow the cohort from their first school health examination to 2020, where the youngest in the cohort will be 44 years old. The cohort grew up when BCG was phased out and the data for a sub-cohort of 13% has been fully digitalized which has enabled case-control studies that have examined associations between childhood vaccinations and subsequent long-term health outcomes.

Data and biological material

We will use no biological material in this study.

We will link the CSHRR cohort with the Danish Multiple Sclerosis Registry. The registry contains data on all Danes who have been diagnosed with MS after 1921 and includes information about sex, date of birth, time of onset and diagnosis, the onset of symptoms, disease course, treatment, selected clinical variables and date of death. The project will therefore both evaluate the effect of BCG on the risk of acquiring MS and on the severity and course of the disease. It will be evaluated also whether there are differences in BCG effects on the three types of MS (MS with periodic attacks, primary progressive and secondary progressive). We will also link the CSHRR to the Danish Civil Registration System to assess vital status, the Danish Register of Causes of Death (updating data regarding cohort deaths that occurred between 2010 to 2021), the National Patient Register for morbidity outcomes and the CPR registry to identify offspring from the cohort. Morbidity outcomes will be reported by the same major disease groups (cancers, cardiovascular, infectious, neurological, autoimmune, other) as in the previous paper. We will furthermore assess BCG effects on the risk of specific diseases with a special focus on MS.

Collaborating researchers and departments

Neurocentret, Rigshospitalet

• Professor Melinda Magyari

University of Copenhagen

• Professor Naja Hulvej Rod

Bandim Health Project, Department of Clinical Research

• Professor Christine Stabell Benn