The major pathogen Haemophilus influenzae experiences pervasive recombination and purifying selection at local and global scales

Haemophilus influenzae is a major opportunistic human pathogen which causes both non-invasive and invasive disease. The H. influenzae type b (Hib) vaccine has led to a significant reduction of invasive Hib disease, but offers no protection against colonisation or disease by non-typeables (NT) or non-b serotypes, and H. influenzae remains a public health burden worldwide, with increasing reports of multi-drug resistance (MDR). Despite this, there is no comprehensive understanding of the species’ global population structure. Here, we wholegenome sequenced >4,000 isolates of H. influenzae from an unvaccinated paediatric carriage and pneumonia cohort from northwestern Thailand. Despite no Hib immunisation, serotype b was uncommonly found, while 91.7% of isolates were NT. We identified a large number of nearly pan-resistant lineages and discovered that no lineages were enriched among disease samples, suggesting the ability to cause invasive disease is not restricted to any subpopulation. Population genetic analyses of our data combined with nearly 6,000 published genomes revealed a highly admixed population structure, low core genome nucleotide diversity, and evidence of pervasive negative selection. Global isolates confirm that MDR lineages are not confined to our newly-sequenced dataset, and their establishment globally is an urgent concern.