Carmen A. Contreras

Background/Objectives: The efficacy and safety profiles of CYD-TDV and TAK-003 are established, but multiple publications may derive from the same randomized trial population and therefore not represent independent evidence. We evaluated efficacy, immunogenicity, and safety while distinguishing independent trials from overlapping follow-up reports and interpreting absolute effects within each programme. Methods: We conducted a PRISMA 2020 systematic review and meta-analysis of randomized trials and follow-up reports from five databases. Outcomes included virologically confirmed dengue, hospitalization, severe dengue, serotype-specific efficacy, immunogenicity, and safety. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated; immunogenicity and safety were synthesized narratively. RoB 2 and GRADE were applied. Results: Nine reports were included. CYD-TDV reduced virologically confirmed dengue (RR = 0.41; 95% CI: 0.35–0.48) and hospitalization (RR = 0.41; 95% CI: 0.25–0.67). Across two independent CYD-TDV trials, absolute reductions were 23.2 virologically confirmed dengue cases per 1000 participants (NNV = 44) and 12.0–50.0 hospitalizations per 1000 (NNVs = 84–20). In the primary TIDES report, TAK-003 reduced virologically confirmed dengue (RR = 0.28; 95% CI: 0.22–0.35) and hospitalization (RR = 0.10; 95% CI: 0.05–0.18), with absolute reductions of 23.6 and 12.9 per 1000 (NNVs = 43 and 78). Later TIDES reports extended follow-up of the same population. Conclusions: Both vaccines reduced dengue outcomes within their respective trial programmes. Absolute effects should be interpreted according to baseline risk and trial context, not as direct between-vaccine comparisons. The synthesis distinguishes extended follow-up from independent replication.

Introduction. Enteropathogenic Escherichia coli (EPEC) strains pose a significant threat as a leading cause of severe childhood diarrhoea in developing nations. EPEC pathogenicity relies on the type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE), facilitating the secretion and translocation of bacterial effector proteins. Gap Statement. While the regulatory roles of PerC (plasmid-encoded regulator) and GrlA (global regulator of LEE-activator) in ler expression and LEE gene activation are well-documented in the EPEC prototype strain E2348/69, understanding the variability in LEE gene expression control mechanisms among clinical EPEC isolates remains an area requiring further investigation. Aim. This study aims to explore the diversity in LEE gene expression control mechanisms among clinical EPEC isolates through a comparative analysis of secretion profiles under defined growth conditions favouring either PerC- or GrlA-mediated activation of LEE expression. Methodology. We compared T3SS-dependent secretion patterns and promoter expression in both typical EPEC (tEPEC) and atypical EPEC (aEPEC) clinical isolates under growth conditions favouring either PerC- or GrlA-mediated activation of LEE expression. Additionally, we conducted promoter reporter activity assays, quantitative real-time PCR and Western blot experiments to assess gene expression activity. Results. Significant differences in T3SS-dependent secretion were observed among tEPEC and aEPEC strains, independent of LEE sequence variations or T3SS gene functionality. Notably, a clinical tEPEC isolate exhibited increased secretion levels under repressive growth conditions and in the absence of both PerC and GrlA, implicating an alternative mechanism in the activation of Ler (LEE-encoded regulator) expression. Conclusion. Our findings indicate that uncharacterized LEE regulatory mechanisms contribute to phenotypic diversity among clinical EPEC isolates, though their impact on clinical outcomes remains unknown. This challenges the conventional understanding based on reference strains and highlights the need to investigate beyond established models to comprehensively elucidate EPEC pathogenesis.