Distribution of capsule and O types in Klebsiella pneumoniae causing neonatal sepsis in Africa and Asia: meta-analysis of genome-predicted serotype prevalence and coverage to inform vaccine development

Klebsiella pneumoniae causes about 20% of sepsis in neonates, with about 40% mortality. A vaccine administered to pregnant women, protecting against greater than70% of K. pneumoniae infections, could avert about 400,000 cases and about 80,000 deaths annually, and formulations targeting the capsular (K) or O polysaccharides are in development. Global K. pneumoniae populations display extensive diversity of K and O types, necessitating a polyvalent vaccine design tailored to the specific types causing disease in the target setting. We investigated the prevalence of K and O types associated with neonatal sepsis in high burden settings in Africa and South Asia to inform maternal vaccine design.We analysed n=1930 K. pneumoniae isolated from the blood of neonates with suspected sepsis in 35 sites across 13 countries, from 13 different prospective surveillance studies. We used whole-genome sequences to predict K and O serotypes and correct for local transmission clusters, and Bayesian hierarchical meta-analysis to estimate K and O prevalence. Eighty-seven K loci were identified. Most common were KL2, KL102, KL25, KL15 and KL62, accounting for 49% of infections. We estimate the global top-20 K loci would cover 72.8% of infections , but with regional variation in coverage (Southern Africa, 76.4%; Eastern Africa, 71.7%; Western Africa, 50.5%; Southern Asia, 67.8%). An alternative set of 20 K loci, comprising the eight most prevalent per region, could cover 72.9% overall and greater than 70% per region.Neonatal sepsis is associated with diverse K and O types, with substantial geographic variation. A single 20-valent K vaccine could theoretically cover greater than 70% of infections in all target regions, although locally-targeted vaccines could achieve higher coverage with lower valency. In principle, very high coverage could be achieved with lower valency O-based vaccines, however protective efficacy of antibodies targeting the O antigen remains uncertain. Further research is needed on cross-reactivity, and stability of antigens over time, to better inform vaccine development.