ABSTRACT A Mycobacterium ulcerans human challenge model has the potential to fundamentally advance our understanding of early human immune responses to infection, while rapidly evaluating vaccines and other therapeutic interventions. Here, using a murine tail infection model, we tested a very well-characterized working cell bank of the proposed challenge isolate M. ulcerans JKD8049 in naïve and Mycobacterium bovis bacille Calmette–Guérin (BCG)-vaccinated BALB/c mice. All 10 naïve mice were successfully infected with 20 colony-forming units (CFU) of M. ulcerans [95% confidence interval (CI) 17–22 CFU] with a mean time to visible lesion of 86 days (95% CI 79–92 days). In the 10 vaccinated mice, there was a significant delay in the mean time to lesion compared to the naïve controls of 24 days ( P = 0.0003), but all mice eventually developed ulcerative lesions. This study informs a future human infection model by demonstrating the successful application of the challenge agent in this in vivo model and highlights both the promise and the problems with trying to induce protective immunity against M. ulcerans . IMPORTANCE In preparation for its proposed use in a controlled human infection model (CHIM), this study reports the successful infection of BALB/c mice using a carefully characterized, low-dose inoculum of Mycobacterium ulcerans JKD8049 (our proposed CHIM strain). We also demonstrate that Mycobacterium bovis bacille Calmette–Guérin delays the onset of disease but cannot alter the course of illness once a lesion becomes apparent. We also validate the findings of previous low-dose challenges that used less accurate methods to determine the inoculum, but our presented methodology is practical, accurate, and anticipated to be reproducible.

01 Jan 2014·Journal of Innate ImmunityQ2 · MEDICINE

Innate Immune Protection against Infectious Diseases by Pulmonary Administration of a Phospholipid-Conjugated TLR7 Ligand

Q2 · MEDICINE

ArticleOA

Author: Guiney, Donald G. ; Julander, Justin G. ; Cottam, Howard B. ; Corr, Maripat ; Chan, Michael ; Wu, Christina C. N. ; Sabet, Mojgan ; Tawatao, Rommel I. ; Smee, Donald F. ; Carson, Dennis A. ; Yao, Shiyin ; Hayashi, Tomoko ; Lao, Fitzgerald S. ; Crain, Brian

Pulmonary administration of Toll-like receptor (TLR) ligands protects hosts from inhaled pathogens. However, systemic side effects induced by TLR stimulation limit clinical development. Here, a small-molecule TLR7 ligand conjugated with phospholipid, 1V270 (also designated TMX201), was tested for innate immune activation and its ability to prevent pulmonary infection in mice. We hypothesized that phospholipid conjugation would increase internalization by immune cells and localize the compound in the lungs, thus avoiding side effects due to systemic cytokine release. Pulmonary 1V270 administration increased innate cytokines and chemokines in bronchial alveolar lavage fluids, but neither caused systemic induction of cytokines nor B cell proliferation in distant lymphoid organs. 1V270 activated pulmonary CD11c+ dendritic cells, which migrated to local lymph nodes. However, there was minimal cell infiltration into the pulmonary parenchyma. Prophylactic administration of 1V270 significantly protected mice from lethal infection with <i>Bacillus anthracis</i>, Venezuelan equine encephalitis virus and H1N1 influenza virus. The maximum tolerated dose of 1V270 by pulmonary administration was 75 times the effective therapeutic dose. Therefore, pulmonary 1V270 treatment can protect the host from different infectious agents by stimulating local innate immune responses while exhibiting an excellent safety profile.

01 Nov 2011·Human Vaccines

Buruli ulcer

Review

Author: Huygen, Kris ; Einarsdottir, Thorbjorg

Buruli Ulcer (BU) is a neglected, necrotizing skin disease, caused by M. ulcerans, that can leave patients with prominent scars and lifelong disability. M. ulcerans produces a diffusible lipid toxin, mycolactone, essential for bacterial virulence. Prevention is difficult as little is known about disease transmission and there is no vaccine. There have been several recent advances in the field. These include sequencing of the bacterial genome and of the giant plasmid responsible for mycolactone synthesis, better understanding of the bacterial lifecycle and of the mechanism of action of the toxin. This work has revealed a number of possible vaccine candidates, some of which are shared with other mycobacteria, e.g. M. tuberculosis, while other targets are unique to M. ulcerans. In this review, we discuss several M. ulcerans vaccine targets and vaccination methods, and outline some of the gaps in our understanding of the bacterium and the immune response against it.

100 Deals associated with Mycobacterium ulcerans vaccine(Swiss Tropical and Public Health Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Mycobacterium Infections, Nontuberculous	Phase 2	CH	-	-
Malaria, Falciparum	Phase 1	-	Telormedix SA	-
Malaria, Falciparum	Phase 1	-	Swiss Tropical & Public Health Institute	-
Skin Ulcer	Phase 1	-	Swiss Tropical & Public Health Institute	-
Skin Ulcer	Phase 1	-	Telormedix SA	-
Ulcer	Phase 1	-	Telormedix SA	-
Ulcer	Phase 1	-	Swiss Tropical & Public Health Institute	-

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