Early signals of vaccine driven perturbation seen in pneumococcal carriage population genomic data

Abstract

36Pneumococcal conjugate vaccines (PCV) have reduced pneumococcal diseases glob-37 ally. Despite this, much remains to be learned about their effect on pathogen pop-38 ulation structure. Here we undertook whole genome sequencing of 660 pneumococ-39 cal strains from asymptomatic carriers to investigate population restructuring in 40 pneumococcal strains sampled before and after PCV13 introduction in a previously 41 vaccine-naïve setting. We show substantial decreasing frequency of vaccine-type (VT) 42 strains and their strain diversity post-vaccination in the vaccinated but not unvacci-43 nated age groups indicative of direct but limited or delayed indirect effect of vaccina-44 tion. Clearance of identical VT serotypes associated with multiple lineages occurred 45 regardless of their genetic background. Interestingly, despite the increasing frequency 46 of non-vaccine type (NVT) strains through serotype replacement, the serotype diver-47 sity was not fully restored to the levels observed prior to vaccination implying lim-48 ited serotype replacement. The frequency of antibiotic resistant strains was low and 49 remained largely unchanged post-vaccination but intermediate-penicillin-resistant 50 lineages were reduced in the post vaccine population. Significant perturbations marked 51 by changing frequency of accessory genes associated with diverse functions especially 52 mobile genetic elements and bacteriocin activity were detected. This phylogenomic 53 analysis demonstrates early vaccine-induced pneumococcal population restructuring 54 not only at serotype but also accessory genome level. 55 Author summary 56 Different formulations of PCVs have been effective in reducing the invasive pneu-57 mococcal disease burden globally. Clinical trials have started to indicate high im-58 pact and effectiveness of PCV13 in Sub Saharan Africa (SSA) but there is limited 59 understanding of how the introduction of PCVs alters the population structure of 60 pneumococcal strains at serotype and genomic level. Here we investigated this using 61 pneumococcal strains sampled pre-and post-PCV13 introduction from a previously 62 vaccine naïve setting in Northern Malawi. Our findings reveal decrease in frequency 63 of VT serotypes and their associated lineages in the largely vaccinated under-five 64 population but not older individuals indicating a direct but limited or delayed in-65 direct protection. The diversity of serotypes also decreased post-vaccination in VT 66 strains in the under-fives but there was no change in NVT strains suggesting incom-67 plete serotype replacement. At the genomic level, logistic regression revealed chang-68 ing frequency of accessory genes largely associated with mobile genetic elements but 69 2 such changes did not include any antibiotic resistance genes. These findings show 70 significant perturbations at serotype and accessory genome level in carried pneumo-71 coccal population after two years from PCV13 introduction but the pneumococcal 72 population was still perturbed and had not returned to a new e...