RT Journal Article SR Electronic T1 Vaccine-specific immune responses against Mycobacterium ulcerans infection in a low-dose murine challenge model JF bioRxiv FD Cold Spring Harbor Laboratory SP 800250 DO 10.1101/800250 A1 Kirstie M. Mangas A1 Andrew H. Buultjens A1 Jessica L. Porter A1 Sarah L. Baines A1 Estelle Marion A1 Laurent Marsollier A1 Nicholas J. Tobias A1 Sacha J. Pidot A1 Kylie M. Quinn A1 David J. Price A1 Katherine Kedzierska A1 Weiguang Zeng A1 David C. Jackson A1 Brendon Y. Chua A1 Timothy P. Stinear YR 2019 UL http://biorxiv.org/content/early/2019/10/10/800250.abstract AB The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective BU 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 TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guérin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-γ produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres 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 experimental ER vaccine. In contrast, high titres of IL-6, TNF-α, IFN-γ and IL-10 in the DLN and low IFNγ titres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.