Genetic characterization of M. tuberculosis isolates from participants in a Phase 2b randomized trial evaluating the M72/AS01E tuberculosis candidate vaccine

BACKGROUND: The efficacy and safety of the M72/AS01E tuberculosis (TB) candidate vaccine were evaluated in the phase 2b randomized, placebo-controlled trial NCT01755598. In the trial, participants with Mycobacterium tuberculosis sensitization by a positive interferon-gamma release assay received either M72/AS01E or placebo (randomized 1:1) and were followed for 3 years. In this descriptive study, we genetically characterized M. tuberculosis isolates from participants who developed pulmonary TB during the trial to assess variability among isolates and evaluate the possibility of preferential progression from infection to active TB by certain strains in M72/AS01E and placebo recipients. METHODS: M. tuberculosis isolates were recovered from sputum samples and underwent DNA extraction and sequencing to assess lineage, antibiotic resistance profile, genetic variation, and genomic clusters. RESULTS: One hundred isolates (37 M72/AS01E, 63 placebo) were genetically characterized from 50 participants who developed microbiologically confirmed active pulmonary TB during the trial (20 M72/AS01E, 30 placebo). Diverse M. tuberculosis lineages were identified in both M72/AS01E and placebo recipients. No multidrug-resistant strains were detected. Genetic sequences corresponding to the antigenic components of M72/AS01E, showed low variation in pepA and high variation in PPE18. However, no apparent preferential distribution of variants was observed in M72/AS01E or placebo recipients. Cluster analyses identified 10 genomic clusters with isolates from >1 participant, illustrating complex transmission dynamics and potential of co-infection by multiple strains within individuals. CONCLUSION: This descriptive analysis showed no apparent preferential distribution of local M. tuberculosis strains in M72/AS01E or placebo recipients. These results support the continued development of this candidate vaccine.