Table 4. Conduct of Shigella-CHIMs in different population settings.

CHIM setting	Pros	Cons
Traditional - in Shigella naïve subjects	Well controlled clean system, potentially increasing reproducibility Immunologically unprimed Has potential to be predictive of target populations	Minimal co-morbidities which would be present in endemic setting Differences in genetic background compared to target population
Next-generation - in Shigella exposed subjects	Closer representation of target population environmental variables Accounts for population genetics Accounts for the impact of prior exposure/immunologic priming/ baseline immunity May help to better define protection/efficacy and true CoP Cost-benefit Acceleration of interventions Capacity building	Availability of representative circulating strains as inoculum Sensitivity of the model to overcome pre-existing and variable immunity, potentially decreasing reproducibility Low AR, impacting ability to draw meaningful conclusions Differentiating vaccine efficacy from background immunity Infrastructure, clinical/ containment