Does early childhood BCG vaccination improve survival into adulthood in a population with a low tuberculosis prevalence? Quasi-experimental evidence on non-specific effects from 39 Swedish birth cohorts

The Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis (TB) is widely used globally. Many high-income countries discontinued nationwide vaccination policies as the TB prevalence decreased. However, there is continued interest in whether the general childhood immunity boost conferred by the BCG vaccination impacts adult health and mortality in low-TB contexts (known as non-specific effects) and whether BCG vaccination should be continued as a population policy. While recent studies found evidence of an association between BCG vaccination and later-life survival, it is unclear whether these associations are causal or driven by unobserved characteristics of those who chose to voluntarily vaccinate. We use the abrupt discontinuation of mandatory BCG vaccination in Sweden in 1975 as a natural experiment to estimate the causal non-specific effect of the BCG vaccine on long-term cohort survival. Applying two complementary study designs, we find no evidence that survival to age 30 was affected by the discontinuation of childhood BCG vaccination. The results are consistent in the male and female subpopulations and are robust to several sensitivity and falsification tests. Overall, despite interest and prior correlational studies suggesting large non-specific effects, we do not find any population-level evidence for a non-specific effect of the BCG vaccine discontinuation on long-term survival in Sweden. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at the Human Mortality Base ([mortality.org][1]) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced will be made available online at a data repository after the publication of the article in a peer- reviewed journal. [1]: https://mortality.org