A clinically parameterized mathematical model of <i>Shigella</i> immunity to inform vaccine design

<div><p>We refine and clinically parameterize a mathematical model of the humoral immune response against <i>Shigella</i>, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two <i>Shigella</i> EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against <i>Shigella′s</i> lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against <i>Shigella</i> and to predict which humoral immune components should be elicited to create a protective vaccine against <i>Shigella</i>. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against <i>Shigella′s</i> LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by <i>Shigella</i> bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that <i>Shigella</i> migrates into the lamina propria or epithelium, 2) the rate that memory B cells (B_M) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the <i>Shigella</i>-specific B_M carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective <i>Shigella</i> vaccine.</p>