Pre-vaccination biomarkers of enteric dysfunction, inflammation and nutritional status associate with seroconversion to oral cholera vaccine and are perturbed during natural infection

Abstract

Background Oral cholera vaccines (OCVs) show variable immunogenicity in endemic settings. Host factors including enteric dysfunction, systemic inflammation, and nutritional status may influence responses, yet their role in shaping OCV immune responses is not fully understood. This study examined associations between pre-vaccination biomarkers spanning these domains and vibriocidal seroconversion to an OCV, while characterizing how the same biomarker profiles are altered during acute natural V. cholerae infection. Methods We conducted a retrospective analysis of stored samples from two Zambian cohorts. The primary cohort comprised 225 adults vaccinated with Shanchol™ IN 2021.The comparator cohort included 38 individuals with acute V. cholerae infection during the 2023 outbreak. Eleven biomarkers were measured using the MEEDAT 11-plex ELISA, and vibriocidal antibodies were assessed. Associations with seroconversion were assessed using cross-fit partialling-out LASSO Poisson regression and quartile analysis. Biomarker profiles were compared between cohorts using Wilcoxon rank-sum and Spearman correlation tests. Results Quartile analysis showed higher seroconversion rates among participants with low to mid-range thyroglobulin levels, while the highest quartile had reduced responses (Inaba Q4: 36.2%; Ogawa Q4: 49.2%). In multivariable LASSO Poisson regression, higher baseline FGF-21 was independently associated with increased Inaba seroconversion (adjusted IRR 1.10, 95% CI 1.04-1.17, p=0.001). Compared with the pre-vaccination baseline, acutely infected individuals exhibited lower ferritin, IGF-1 and RBP4, and higher sTfR, CRP, AGP and FGF-21, together with a restructured inter-biomarker correlation network. Conclusion Selected pre-vaccination host biomarkers, particularly FGF-21 and thyroglobulin, are associated with OCV seroconversion. The profound multi-domain perturbation observed during acute infection underscores the importance of measuring these markers under stable baseline conditions when studying vaccine immunogenicity.