Genetically diverse CC and DO mouse models enable comprehensive assessments of novel tuberculosis vaccines

Development of a new vaccine for tuberculosis (TB) to replace the BCG vaccine has been hampered by the lack of a preclinical vaccine model that accurately reflects the genetic heterogeneity of the human population. We previously tested both Collaborative Cross (CC) and Diversity Outbred (DO) mice, which collectively reflect the genetic diversity of an outbred population, as models for preclinical vaccine testing. Using both CC and DO mice, we compared the ability of two different strategies to enhance BCG-mediated protection against Mycobacterium tuberculosis (Mtb). BCG::ESX-1^Mmar is genetically modified to express the esx-1 region of Mycobacterium marinum. In contrast, the BCG/ChAd:TB strategy relies on boosting BCG-induced immunity using a chimp adenoviral vectored vaccine expressing the mycobacterial antigens Ag85A, TB10.4, and RpfB administered by the intranasal route. Both BCG::ESX-1^Mmar and BCG/ChAd:TB vaccination strategies significantly protect mouse strains that were not well protected by BCG. Although both vaccination strategies were associated with reduced bacterial growth in CC and DO mice, bacterial control did not correlate with survival. Both BCG::ESX-1^Mmar and BCG/ChAd:TB induced immune signatures after Mtb challenge in the tested CC strains that were previously associated with protection in traditional inbred mouse strains. Our findings established the use of both CC and DO mice as robust platforms that incorporate host genetic diversity for the preclinical evaluation of TB vaccines.