Mycobacterium leprae infection causes leprosy, a dermatological and neurological disease that is among the leading causes of non-traumatic disfigurements and disabilities worldwide. Although multidrug therapy (MDT) has reduced reported case numbers, leprosy persists and new intervention strategies are required to maintain and promote further reductions. We have developed a defined subunit vaccine, called LepVax, which is capable of reducing M. leprae burden when provided prophylactically to mice. Using experimental infection in armadillos, we have shown that post-exposure prophylaxis with LepVax alleviates and delays the neurologic disruptions caused by M. leprae infection. A recently completed Phase 1 clinical trial in the US indicated that the vaccine is safe in humans. Preliminary data from the Phase 1 trial demonstrate robust induction of vaccine-specific IgG antibodies. The studies proposed here will enable additional immunogenicity assessments to be completed for this first-in-human study by characterizing magnitude and quality of vaccine-specific humoral and cellular responses. The remaining proposed activities will allow us to optimally prepare for evaluations of vaccine- induced responses in a funded Phase 1b trial in being conducted in target populations in an endemic region (Brazil). First, we will optimize four key immunogenicity assays, including ELISA, IFN?-ELISpot, intracellular cytokine staining, and a cytokine multiplex assay, for use with the LepVax antigen. Next, we will perform assay validation studies to ensure that the methods are specific and produce reliable data. Finally, we will evaluate several exploratory assays that have been used in the tuberculosis field for utility as biomarkers for leprosy disease status. In multiple disease fields, biomarkers have proved useful in measuring disease status and in providing immune correlates of vaccine efficacy that can enable proof of concept studies and accelerate vaccine development. Using in-house specimens collected during treatment of leprosy patients and healthy contact controls, we will evaluate three assays including a serum protein multiplex assay, an immunophenotyping panel, and a mycobacterial growth inhibition assay. By completing the immunogenicity characterization from the first- in-human trial, these studies will serve to advance a promising new leprosy vaccine candidate into clinical testing in endemic countries and exposed individuals. The validation studies will ensure that the data from the Phase 1b trial is robust and reliable for informing dose selection in target populations. Lastly, we will leverage our experience in tuberculosis to screen and rank assays that have been successful elsewhere for inclusion in future studies as potential disease status biomarkers, which could be a transformative tools for the broader leprosy field.
Despite the provision of free multidrug therapy by the World Health Organization, leprosy remains a public health problem and disease elimination will likely require a vaccine. We have developed LepVax, a new leprosy vaccine that provides effective pre-exposure and post-exposure protection in animal models and demonstrated safety in a Phase 1 clinical trial. The studies proposed here will characterize immune responses elicited by LepVax, validate assays to ensure data robustness going forward, and develop exploratory assays to maximize output from the next clinical trials in target populations.
