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Title: Population genomics of pneumococcal strains from a high disease African setting
Author: Chaguza, Chrispin
ISNI:       0000 0004 7428 6689
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Streptococcus pneumoniae, the pneumococcus, is an α-haemolytic pathogenic bacterium, which kills over one million children and causes over fifteen million disease episodes annually globally. While mild forms of pneumococcal infections are common, other forms invasive disease are life-threatening such as pneumonia, sepsis and meningitis. Globally, the pneumococcal disease burden is especially high in low-income countries such as in sub-Saharan African countries for example in Malawi where HIVcoinfections exacerbates the burden and until recently, no pneumococcal vaccine was available to prevent serotypes that cause majority of the invasive diseases. However, despite such a high disease burden in African settings, there is limited understanding of the pneumococcal genomic epidemiology and evolution in these vulnerable populations compared to industrialised countries where majority of the pneumococcal clones have been characterised and the epidemiological trends are expertly monitored using advanced surveillance systems. Pneumococcal vaccines have been in use for decades and the first vaccines to be introduced the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the early 1980s and the 7-valent pneumococcal conjugate vaccines (PCV7) in the early 2000s. The PCVs have widely replaced the use of PPSV23 especially in children where the invasive pneumococcal disease (IPD) burden is the highest while the use of PPSV23 has been mainly limited to the elderly. Since the introduction of PCV7 and subsequent higher valent vaccines including PCV10 and PCV13, these has been a significant decline of the IPDs especially those cause by the vaccine-type (VT) serotypes although in carriage there has been serotype replacement whereby the clearance of the VT serotypes has induced an increase of non-vaccine type (NVT) serotypes to claim the vacated ecological nasopharyngeal niche possibly because of reduced within-species strain competition. Because of this, it has become important to fully understand the pneumococcal population in term of its composition, epidemiology and evolution preand post-introduction of the PCVs to fully understand the impact of the vaccines and where possible to predict and monitor post-vaccination changes to inform the design of clinical interventions such as the design of higher valent PCVs targeting more serotypes. In this thesis, nearly two thousand pneumococcal whole genome sequences obtained from human nasopharyngeal carriage and IPD in Malawi were analysed to determine population structure, serotype and clonal dynamics, and evolution of pneumococcal strains re- and post-PCV introduction. A combination of genomic and phylogenetic analysis approaches was used to compare the strains. This analysis revealed the distribution of serotypes and lineages and their temporal trends in prevalence, antibiotic resistance and sequence diversity, and capsule switching and genomic evolution of different lineages. Overall, there was stability in serotype frequency pre-vaccination except for serotypes 1 and 5 despite the fact that there was a significant reduction in the IPD incidence prior to vaccination largely attributed to the scale-up of anti-retroviral therapies (ART) for HIV. Serotype 1, which decreased in prevalence, whilst serotype 5 increased in prevalence in 2010 potentially due to a local outbreak in Blantyre, Malawi. Serotype 1 particularly ST217 (PMEN27) was the most dominant lineage prevaccination and in contrast to the expectation that rarely carried serotypes should have lower resistance rates, serotype 1 strains showed the highest antibiotic resistance rate than any serotype in Malawi. Serotype 5 ST289 (PMEN19) was another common serotype whose frequency appeared to change in some years but unlike serotype 1 it was associated with lower resistance rates. Despite the observation of high capsule (serotype) switching in other serotypes, no capsule-switched was detected involving serotype 1 and 5 strains possibly reflecting infrequent genomic recombination for these lineages. Further genomic analysis of the serotype 1 PMEN27 (ST217) clone showed high phylogeographic structure whereby PMEN27 strains from different countries clustered predominantly by their country of origin although both limited short and long distance spread of PMEN27 clone were identified between countries within Africa and between Africa and Asia. Furthermore, PMEN27 strains from different countries exhibited variable antibiotic resistance rates with strains from Malawi showing high resistance rates whereas strains from West Africa showed lower resistance to chloramphenicol due to the deletion of the chloramphenicol acetyltransferase gene in the mobile genetic element (Tn5253) that harbours the gene. Additional genomic analysis of the serotype 5 PMEN19 (ST289) strains showed that the increased prevalence of these strains was due to clonal expansion of a single sub-clade but this sub-clade did not acquire any novel recombination events or virulence factors that may have promoted its upsurge in 2010 in Malawi. Additional analysis revealed that serotype-specific recombination rates between different pneumococcal lineages from Malawi are highly variable and interestingly lineages that are known to be carried for longer duration in the nasopharynx, which also possess thicker outer cell wall polysaccharide capsule and are highly invasive, showed higher rates of recombination. Finally, there has been an increased reduction of the invasive pneumococcal disease incidence post-introduction of PCV13 in Malawi due to decreasing prevalence of the VT serotypes across across different pneumococcal lineages in both IPD and carriage. There has been a pronounced decrease of the prevalence of the VT serotypes in children than in adults where only few VT serotypes have decreased slightly, which potentially suggests a high direct but limited indirect effect of the vaccine three years postvaccination. Moderate serotype replacement was evident particularly due to serotypes 12F, 13 and 35B but there was no evidence of replacement due to clonal expansion of capsule-switched strains already in circulation prior to vaccination. Furthermore, antibiotic resistance rates have decreased post-vaccination for multiple antibiotics such as tetracycline and chloramphenicol whose resistance rates were higher among VT than NVT serotypes specially in IPD. Resistance rates for penicillin, erythromycin and ceftriaxone resistance have increased post-vaccination, which is a concern because these remain the most effective last resort antibiotics for treating IPD in Malawi. In conclusion, this thesis provides comprehensive genetic and epidemiological description of the pneumococcal population in Malawi, a setting with high IPD and carriage. By using a combination of whole genome sequencing and traditional molecular typing methods, high resolution insights regarding the genomic diversity, epidemiology and evolution of the pneumococcal strains in Malawi were observed. This study highlights the remarkable stability in genetic diversity and prevalence of serotypes prior to PCV13 implementation in Malawi, temporal evolution rates of common serotypes, high rates of genomic recombination and capsule-switching, and evidence of the population impact of PCV13 on the pneumococcal disease incidence, serotype prevalence and antibiotic resistance rates post-vaccination. Continued diligent clinical surveillance coupled 'omics' approaches such as whole genome sequencing as demonstrated in this thesis is required to fully understand the population changes particularly monitoring serotypes with higher antibiotic resistance and potential for replacement post-vaccination sto inform decision makers on pneumococcal infection prevention and control strategies in Malawi.
Supervisor: Everett, Dean ; Bentley, Stephen ; Hanage, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral