Host genetic background is a barrier to vaccine-induced protection against infection

The heterogeneity of immune responses observed in humans is difficult to model in standard inbred laboratory mice. We used Collaborative Cross (CC) recombinant inbred strains to capture the diversity of outbred populations and better understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis. Using 24 CC strains, we show host genetics has a major role in determining whether BCG elicits protective immunity to M. tuberculosis. Only 54% of BCG-vaccinated CC strains had significantly reduced lung bacillary burdens after infection. Furthermore, BCG efficacy is dissociable from inherent susceptibility to TB. Like people, CC mice have diverse immunological responses after BCG vaccination and M. tuberculosis challenge. We define immunological signatures associated with BCG-induced protection other than canonical Th1 immunity. Like interferon-γ, lung homogenate levels of IL-17 correlated with disease. However, the presence of Th1/17 CD4 T cells were an immune feature that correlated with protection. CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.  ### Competing Interest Statement The authors have declared no competing interest.