Immune signature against Klebsiella pneumoniae proteins in a mother-baby cohort from Blantyre, Malawi

Summary

Klebsiella pneumoniae (Kpn) is one of the most frequent causes of neonatal sepsis and neonatal deaths in low- and middle-income countries (LMICs). Amongst Kpn, resistance against beta-lactams is driven by acquisition of beta-lactamase enzymes that can degrade the antimicrobial (ESBLs). Bacterial isolates encoding ESBL enzymes have increased from 12% to >90% in healthcare settings in many parts of sub-saharan Africa (SSA) in the last decade. Given the lack of access to alternative antimicrobials in SSA, these infections are de facto untreatable. Approaches to preventing neonatal sepsis like vaccines are urgently needed.

Our aim is to identify robust protein targets for a maternally administered protein-based vaccine to protect neonates from sepsis by Kpn. We leverage an existing mother-baby cohort study which includes cases (babies develop neonatal sepsis caused by Kpn) and controls (no infection) in Malawi, one of the poorest countries on earth where Kpn neonatal sepsis is a severe risk for newborns. 

Project Outcomes

Our collaborative team has developed a first generation Klebsiella pneumoniae proteome microarray that can be used for profiling specific antibody immune responses to pathogen subclinical and clinical sequelae such as colonization and sepsis, respectively. An understanding of the proteins expressed by the pathogen that are surface exposed and that elicit a strong and protective host immune response, despite the large polysaccharide capsule of K. pneumoniae, is a critical step in the pathway to vaccine discovery and towards development of novel vaccines that may protect infants against the significant moribidity and mortality caused by Klebsiella infections in the first stages of life.

Our findings have shown that a significant number of predicted extracellular and outer membrane proteins indeed seem to be surface located / secreted and expressed at times relevant for host recognition (as opposed to e.g. only in lab settings or when living outside a host), as they are recognized by the human systemic and mucosal immune response. We furthermore show that these antibodies are transferred to newborn infants by placental transfer or passively through ingestion of mother’s milk. Furthermore, an analysis of the overall immune response against reactive Klebsiella proteins shows a profile that separates mothers with children that had Klebsiella infection from mothers with infants that remained uninfected. These antigens may be further studied for functional immune responses and associations with protection in other cohorts, and the most promising of these antigens may be excellent candidates for a protein-based vaccine against Klebsiella.