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Vaccine development

Studies in different geographic regions and ethnic populations have produced disparate estimates of protection conferred by BCG against TB. BCG efficacy is estimated to be greater than 75% in some populations. In contrast, no significant protection is detected in regions where TB remains endemic. Such variable efficacy could be due to differences in the BCG strain, its preparation, the environment, or the host genetic background. While the role of genetic variation in BCG strains and previous exposure to environmental mycobacteria have been investigated extensively, the role of host genetic variation has been more difficult to quantify. Many studies find that the immunological response to mycobacterial infection and BCG vaccination is heritable. However, the relationship between these immunological markers and vaccine efficacy is unknown and difficult to address in natural populations. Using the CC panel, we have identified host genetic diversity as crucial factor that affects BCG efficacy. As in human meta-analyses of BCG efficacy, when these genetically diverse mice were considered as a single population, BCG has a modest protective effect. However, when assessed by genotype, we found some lines to be protected, others that were not protected, and a few in which vaccination exacerbated disease. These observations indicate that host genetic variation limits BCG efficacy, and suggests that current efforts to develop vaccines that are effective in C57BL/6 mice (e.g., a single genotype), could fail in a genetically diverse population. Thus, this project seeks to determine the genetic and immunological determinants of vaccine-induced immunity in genetically diverse populations with the ultimate goal of improving the mouse model for pre-clinical vaccine development.