The genomic epidemiology of hyperinvasive and carriage-associated lineages of Neisseria meningitidis

Thesis

Neisseria meningitidis is the bacterial pathogen responsible for meningococcal disease: 10% of cases result in death. Endemic disease is sporadic, with fewer than three cases per 100,000 population, but elevated incidence also occurs during hyperendemic and epidemic periods. Successful control of meningococcal disease is achieved via immunisation against capsular polysaccharides, however, no vaccine exists against serogroup B polysaccharide due to poor immunogenicity and safety concerns.

Recently, 'serogroup B-substitute vaccines' containing sub-capsular antigens have been developed: one such vaccine is to be introduced to UK infant immunization schedules from September 2015. Meningococcal populations are genetically diverse and arranged into clonal complexes that fluctuate in geotemporal prevalence. It is therefore essential to survey meningococcal populations in given locations to understand molecular evolution following vaccine introduction.

The advent of whole-genome sequencing presents an opportunity to investigate meningococcal populations at high genetic resolution. This thesis introduces the MRF Meningococcus Genome Library, a comprehensive collection of WGS data from national surveillance of meningococcal disease in England and Wales between the 2010/11-2012/13 epidemiological years. The utility of WGS data in routine surveillance was investigated.

Structuring of genomic variation revealed population-level lineages analogous to clonal complexes. Prevalent hyperinvasive lineages were composed of immunologically distinct sub-lineages that, when linked with patient data, were age-group associated: vaccines may affect age-groups differently. Sub-lineage specific core-genome and epigenetic DNA methylation variation was primarily in metabolic loci. Finally, genomic variation of an epidemic clone, generated by recombination, was great, and epidemiological data remains indispensible for investigating transmission. These findings provide insight into meningococcal evolution and are of importance in understanding the effects of new vaccines.

Authors: Hill, DMC

• DOI: 10.5287/ora-bpwbxvj4b
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English