Scientific Publications by FDA Staff

Clin Vaccine Immunol 2016 Jul 5;23(7):638-47

Induction of unconventional T cells by a mutant BCG strain formulated in cationic liposomes correlates with protection against M. tuberculosis infections of immunocompromised mice.

Derrick SC, Yabe I, Morris S, Cowley S

Earlier studies aimed at defining protective immunity induced by BCG immunization have largely focused on the induction of anti-tuberculosis CD4+ and CD8+ T cell responses. Here we describe a vaccine consisting of a BCG¿mmaA4 deletion mutant formulated in dimethyl dioctadecyl ammonium bromide (DDA) with D(+) trehalose 6,6 dibehenate (TDB) (DDA/TDB) adjuvant (A4/Adj) that protected TCRd-/- mice depleted of CD4+, CD8+ and NK1.1+ T cells against an aerosol challenge with Mycobacterium tuberculosis These mice were significantly protected relative to mice immunized with nonadjuvanted BCG¿mmaA4 (BCG-A4) and nonvaccinated controls at 2 months and 9 months post-vaccination. In the absence of all T cells following treatment with anti-Thy1.2 antibody, the immunized mice lost the ability to control the infection. These results indicate an unconventional T cell population was mediating protection in the absence of CD4+, CD8+, NK1.1+ and TCR¿d T cells and could exhibit memory. Focusing on CD4-CD8- double negative (DN) T cells, we found that the frequency of these cells accumulated in the lungs post-challenge significantly greater in A4/Adj immunized mice and induced significantly greater frequencies of pulmonary IFN-¿ producing cells than seen in nonvaccinated or the nonadjuvanted BCG control groups. Moreover, pulmonary DN T cells from the A4/Adj group exhibited significantly higher IFN-¿ iMFI values than seen in the control groups. We also show that DN T cells enriched from mice immunized with A4/Adj could control mycobacterial growth in vitro significantly better than naïve whole spleen cells. These results suggest that formulating BCG in DDA/TDB adjuvant confers superior protection in immunocompromised mice and likely involves the induction of long-lived memory DN T cells.