The
neglected tropical disease Buruli ulcer (BU) is an
infection of subcutaneous tissue with Mycobacterium ulcerans There is no effective
vaccine. Here, we assessed an experimental prime-boost
vaccine in a low-dose murine tail
infection model. We used the enoyl
reductase (ER) domain of the M. ulcerans
mycolactone polyketide synthases electrostatically coupled with a previously described
Toll-like receptor 2 (TLR-2) agonist-based
lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14 to 20 CFU of a bioluminescent strain of M. ulcerans Mice receiving either the experimental ER
vaccine or Mycobacterium bovis bacillus Calmette-Guérin (BCG) were equally protected, with both groups faring significantly better than nonvaccinated animals (P < 0.05). To explore potential correlates of protection, a suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were used to interrogate the immune response data to develop disease-prognostic models. High levels of
interleukin 2 (IL-2) and low
gamma interferon (IFN-γ) produced in the spleen best predicted control of
infection across all
vaccine groups. Univariate logistic regression revealed
vaccine-specific profiles of protection. High titers of ER-specific
IgG serum
antibodies together with
IL-2 and
IL-4 in the draining lymph node (DLN) were associated with protection induced by the ER
vaccine. In contrast, high titers of
IL-6,
tumor necrosis factor alpha (TNF-α), IFN-γ, and
IL-10 in the DLN and low IFN-γ titers in the spleen were associated with protection following BCG vaccination. This study suggests that an effective BU
vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of
infection.