Development of a TB vaccine trial site in Africa and lessons from the Ebola experience.

Tuberculosis is the deadliest infection of our time. In contrast, about 11,000 people died of Ebola between 2014 and 2016. Despite this manifest difference in mortality, there is now a vaccine licensed in the United States and by the European Medicines Agency, with up to 100% efficacy against Ebola. The developments that led to the trialing of the Ebola vaccine were historic and unprecedented. The single licensed TB vaccine (BCG) has limited efficacy. There is a dire need for a more efficacious TB vaccine. To deploy such vaccines, trials are needed in sites that combine high disease incidence and research infrastructure. We describe our twelve-year experience building a TB vaccine trial site in contrast to the process in the recent Ebola outbreak. There are additional differences. Relative to the Ebola pipeline, TB vaccines have fewer trials and a paucity of government and industry led trials. While pathogens have varying levels of difficulty in the development of new vaccine candidates, there yet appears to be greater interest in funding and coordinating Ebola interventions. TB is a global threat that requires similar concerted effort for elimination.

Chest Radiographs for Pediatric TB Diagnosis: Interrater Agreement and Utility.

The chest radiograph (CXR) is considered a key diagnostic tool for pediatric tuberculosis (TB) in clinical management and endpoint determination in TB vaccine trials. We set out to compare interrater agreement for TB diagnosis in western Kenya. A pediatric pulmonologist and radiologist (experts), a medical officer (M.O), and four clinical officers (C.Os) with basic training in pediatric CXR reading blindly assessed CXRs of infants who were TB suspects in a cohort study. C.Os had access to clinical findings for patient management. Weighted kappa scores summarized interrater agreement on lymphadenopathy and abnormalities consistent with TB. Sensitivity and specificity of raters were determined using microbiologically confirmed TB as the gold standard (n = 8). A total of 691 radiographs were reviewed. Agreement on abnormalities consistent with TB was poor; k = 0.14 (95% CI: 0.10-0.18) and on lymphadenopathy moderate k = 0.26 (95% CI: 0.18-0.36). M.O [75% (95% CI: 34.9%-96.8%)] and C.Os [63% (95% CI: 24.5%-91.5%)] had high sensitivity for culture confirmed TB. TB vaccine trials utilizing expert agreement on CXR as a nonmicrobiologically confirmed endpoint will have reduced specificity and will underestimate vaccine efficacy. C.Os detected many of the bacteriologically confirmed cases; however, this must be interpreted cautiously as they were unblinded to clinical features.