Designing sero-epidemiological studies to explore immune markers associated with a reduced risk of invasive Klebsiella pneumoniae disease.

Klebsiella pneumoniae (Kpn) is a leading cause of neonatal invasive bacterial disease especially in low- and middle-income countries (LMICs), with 20-30% of culture-confirmed neonatal sepsis caused by Kpn. This, coupled with the rapid emergence of multidrug-resistant strains, calls for additional therapeutic options. Maternal vaccination represents a promising strategy to confer protection to neonates through transplacental transfer of antibodies, with modelling suggesting a vaccine of moderate efficacy (~70%) could avert over 80,000 neonatal deaths annually. Advancing Kpn vaccine development requires identification and validation of serological thresholds of risk reduction (SToRR), or immune markers associated with a reduced risk of invasive Kpn disease (IKpnD). However, no standardized framework currently exists for this purpose. Drawing on lessons from other pathogens, this review outlines key methodological considerations for designing rigorous sero-epidemiological studies to establish such markers. We address three critical domains: (i) study design and population selection, including the rationale for nested case-control designs within birth cohorts enriched for high-risk neonates; (ii) statistical approaches for threshold estimation, including covariate-adjusted logistic regression and Bayesian frameworks; and (iii) laboratory standardization and assay validation, encompassing binding and functional antibody assays. Addressing these considerations systematically will accelerate the development and deployment of a Kpn vaccine capable of reducing neonatal mortality globally.