Innovative clinical trial designs to rationalize TB vaccine development

Introducing the ESAT-6 free IGRA, a companion diagnostic for TB vaccines based on ESAT-6

“…ESAT-6 based vaccines for TB are still far from implementation in vaccine programs; however, a tool to monitor infection in vaccinated individuals is urgently needed for trials exploring infection as a surrogate endpoint for TB disease. IGRA conversion occurs 10 times more frequently than disease, and prevention of infection (POI) trials can therefore be completed with less than a tenth of the sample size1011. The fact that BCG vaccination reduces the risk of IGRA conversion in children further supports that POI can be utilized as a marker of biological effect1112.…”

Design of tuberculosis vaccine trials under financial constraints

“…However, a focus on POI vaccines, aiming at avoiding that naive populations be infected would have considerable public health impact in the long term, given that infection be preventable even in the 10% of those who, if became infected, would go on to develop the disease [14]. Beyond the potential plausibility for the design of protective preinfection vaccines [14], these types of trials require smaller sample sizes and shorter duration in high-endemic countries [15], given that the forces of transmission are high and high conversion rates could be detectable by interferon-γ release assays [16].…”

“…The latter are the target population for the so-called prevention of recurrence (POR) studies, which represent a potentially efficient approach, given that trials could be done with relatively low-sample sizes. Given that 91% of recurrences might occur during the first year after TB treatment completion and a high proportion of recurrences in high-transmission settings, vaccine trials designs including just 450 participants per study group with 12-month follow-up could be deemed sufficiently powered [15]. However, identifying these patients and ensuring they fulfill the definition of 'cured' are issues that would also need to be addressed.…”

Human Biomarkers: Can they help us to Develop a new Tuberculosis Vaccine?

“…In endemic populations, the annual incidence of disease is typically 1-2% requiring large numbers and lengthy follow-up to obtain sufficient sample size for an immune correlates analysis with a TB disease end point. One alternative is to use infection as an end point for immune correlates studies (prevention of infection [POI]) [11]. The annual incidence of TB infection is approximately five to tenfold higher than that of TB disease, substantially reducing the size and length of a vaccine efficacy trial [11].…”

“…One alternative is to use infection as an end point for immune correlates studies (prevention of infection [POI]) [11]. The annual incidence of TB infection is approximately five to tenfold higher than that of TB disease, substantially reducing the size and length of a vaccine efficacy trial [11]. Although attractive, there are caveats to this approach.…”