Clinical development of human vaccine candidates against Shigella flexneri: a systematic review of clinical trials.

Shigella flexneri remains a leading cause of shigellosis, particularly in low- and middle-income countries, where it contributes substantially to childhood morbidity, mortality, and the growing burden of antimicrobial resistance. Despite decades of vaccine research, no licensed vaccine against S. flexneri is currently available. This systematic review aimed to summarize and critically evaluate the clinical evidence regarding the safety, immunogenicity, and efficacy of human S. flexneri vaccine candidates. A comprehensive literature search was conducted in major electronic databases following PRISMA guidelines to identify clinical studies evaluating S. flexneri vaccines. Twenty-four eligible clinical trials were included, encompassing live-attenuated, glycoconjugate, protein-based, generalized modules for membrane antigens (GMMA), and inactivated whole-cell vaccine platforms. Overall, most candidates demonstrated acceptable safety profiles and induced measurable systemic and, in several studies, mucosal immune responses. Glycoconjugate vaccines consistently generated durable humoral immunity, while live-attenuated vaccines elicited broader mucosal and cellular responses. However, considerable heterogeneity existed in vaccine formulations, dosing schedules, immunological endpoints, and follow-up periods, limiting direct comparisons across studies. Only one Phase III trial assessed clinical efficacy, highlighting the limited progression of vaccine candidates to advanced clinical evaluation. Collectively, the available evidence supports the continued development of several vaccine platforms. Large multicenter efficacy trials, standardized immunological outcome measures, and multivalent vaccine strategies will be essential to accelerate the development of an effective S. flexneri vaccine.