Use of M. tuberculosis genome sequencing to determine relapse and reinfection in a phase 2 prevention of recurrent tuberculosis vaccine trial
A M Cabibbe(1) V Batignani(1) F Di Marco(1) D M Cirillo(1) The POR TB Consortium(2)
1:San Raffaele Scientific Institute; 2:Statens Serum Institut
Whole genome sequencing (WGS) of M. tuberculosis (MTB) can distinguish relapse (same strain) from reinfections (different strains) in clinical studies, by comparing single-nucleotide polymorphism (SNP) distances between first and subsequent tuberculosis (TB) episodes. Here we assess strain identity by WGS for TB recurrence (relapses/reinfections) within a phase 2b prevention of recurrent (POR) TB vaccine trial and describe the phylogenetic features of the MTB study collection.
831 participants with active TB were enrolled from 6 sites in South Africa (SA) and Tanzania, randomized to receive H56:IC31 vaccine or placebo after successful treatment, and monitored for 12 months for recurrence. Sputum samples were provided for culture and Illumina sequencing at baseline and when TB symptoms occurred.
MTB genotyping data available for 631 (82%) baseline samples plus 30 recurrences showed significant associations (P ≤0.05) between MTB lineage (L) and geographic location: L3 in Tanzania, L4 and L2 at sites in Gauteng and Western Cape (SA), respectively. Recent transmission index was 14.4%. Recurrence was due to relapse in 17/30 (57%) events with average 0.46 SNP acquisition rate per 1 person-year, compared to 13/30 events (43%) suggestive of reinfection (average 678 SNP distance). Drug resistance shifting was not observed in relapses. L3 showed 8.2% relapse rate (P >0.05).
This trial is among the first to perform systematic WGS-based assessment of recurrence following a first TB episode in Sub-Saharan Africa and showed diverse MTB populations and modest transmission rates at trial sites, and higher relapse than reinfection within 1 year follow up.