Immunological Outcomes of New Tuberculosis Vaccine Trials: WHO Panel Recommendations

The mechanisms of immune protection against human TB, a disease that causes 2 million deaths world-wide each year, are not fully known. T cell immunity is critical for protection [1,2]; therefore, the current TB vaccine, bacille Calmette-Guérin (BCG), and most new vaccines under development aim to induce this immunity. Most of these developmental vaccines [1–4] are designed to boost pre-existing immunity induced by BCG; however, some candidates aim to ultimately replace BCG as the priming vaccine. Following phase I/IIa trials of the vaccines, safety and immunogenicity results will be critical to decide which vaccine candidates should move into efficacy trials. For this choice, the ability to compare immunogenicity would be an important asset. Potential comparisons are confounded by variation in individual laboratory approaches, logistics, and the diverse populations studied in vaccine trials. Some comparison may be achieved by harmonisation of assays (see below); however, even then, antigen components of vaccines and therefore antigens in assays may differ. Further, the desired character of induced immunity may differ according to vaccine candidate, making choice of an assay to be harmonised difficult. To tackle this problem, the WHO Initiative for Vaccine Research sponsored three meetings of experts representing current TB vaccine development efforts to discuss the requirements for and challenges in harmonising assays for new TB vaccine trials. The primary focus was on phase I and IIa trials; other principles may apply to phase IIb and III trials because of their larger sample sizes and because resources in settings of these trials may differ. In this article, we describe advantages and disadvantages of multiple assay approaches and make recommendations for using specific assay approaches in phase I/IIa trials.