Scientific Publications by FDA Staff

Tuberculosis 2020 Jan;120:101895

Whole genome profiling refines a panel of correlates to predict vaccine efficacy against Mycobacterium tuberculosis.

Kurtz SL, Gardina PJ, Myers TG, Ryden P, Elkins KL

New vaccines are needed to combat the public health threat posed by M. tuberculosis (M. tb), though optimal protective mechanisms of immunity for this pathogen are not clear. Using mouse models, our laboratory developed an in vitro system where M. tb-infected macrophages are co-cultured with TB-immune lymphocytes to evaluate control of intra-macrophage bacterial replication. When lymphocytes are derived from a panel of vaccines of varying efficacy, the degree of in vitro growth control by various immune cell populations reflected relative in vivo protection against lethal challenge. We hypothesized that genes upregulated in protective versus less or non-protective vaccines represent potential immune correlates, and in a targeted analysis found several mediators whose expression correlated with in vitro growth control. Here we furthered those findings by employing genome wide expression analyses to immune cells recovered from M.tb. co-culture to define genes whose expression correlate with protection. We initially screened splenocyte RNA by microarray and validated subsequent findings in splenocytes and peripheral blood lymphocytes to deliver a refined list of immune correlates that include Cxcl9, IFN-g, and Ccl5. These findings expand the knowledge of immune mechanisms that may underlie successful vaccination and provide a panel of relevant immune correlates to advance vaccine development.