Systemic and mucosal immunity to enterotoxigenic Escherichia coli: evidence from natural infection and vaccination.

Enterotoxigenic Escherichia coli (ETEC) is a major contributor to diarrheal morbidity and mortality, especially among children under 5 years of age in low- and middle-income countries (LMICs). Development of an effective ETEC vaccine has been impeded by the pathogen's antigenic complexity and lack of well-defined immune correlates of protection. This review synthesizes evidence from human infection and vaccination studies to summarize current knowledge on systemic and mucosal immune responses to ETEC, the assays employed to measure them, and the factors affecting immune outcomes, providing a critical synthesis of systemic and mucosal immune measures. Most studies reviewed assessed systemic immune responses despite ETEC being an enteric pathogen, highlighting challenges in measuring mucosal immune responses. Substantial progress has been made in assay technologies, from basic singleplex Enzyme-Linked Immunosorbent Assays (ELISAs) to robust multiplex and microarray platforms that enable profiling of responses to multiple antigens and immunogenic antigen discovery. The evidence shows that multiple immune pathways, including humoral, cellular, and mucosal components, contribute to overall protection. The review further highlights the need for assay standardization to facilitate cross-study comparisons and uniform interpretation of immunogenicity and efficacy data. ETEC immunity is complex and is impacted by host, pathogen, and environmental factors. Standardizing immunological assays and defining measurable correlates of protection is critical for the accurate evaluation and optimization of ETEC vaccine candidates.