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.

2014-01-01·Journal of innate immunity2区 · 医学

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

2区 · 医学

ArticleOA

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

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 Bacillus anthracis, 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.

100 项与 Mycobacterium ulcerans vaccine(Swiss Tropical and Public Health Institute) 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
恶性疟	临床1期	-	Swiss Tropical & Public Health Institute	-
恶性疟	临床1期	-	Telormedix SA	-
非结核分枝杆菌感染	临床1期	瑞士	-	-
皮肤溃疡	临床1期	-	Telormedix SA	-
皮肤溃疡	临床1期	-	Swiss Tropical & Public Health Institute	-
溃疡	临床1期	-	Swiss Tropical & Public Health Institute	-
溃疡	临床1期	-	Telormedix SA	-