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According to the 2015 Global Burden of Disease Study, diarrhea ranked ninth among causes of death for all ages, and fourth among children under 5 years old, accounting for an estimated 499,000 deaths in this young age group. It was also the second most common cause of years lived with disability (2.39 billion YLDs). The goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhea (GAPPD) is to reduce deaths from diarrhea in children under 5 years of age to less than 1 per 1000 live births, by 2025. Development of new and improved vaccines against diarrheal infections is a fundamental element of the strategy towards achieving this goal. Enterotoxigenic Escherichia coli (ETEC) and Shigella are enteropathogens that cause significant global mortality and morbidity, particularly in low- and middle-income countries. In 2016, WHO’s Product Development for Vaccines Advisory Committee (PDVAC) recommended that the WHO’s Initiative for Vaccine Research (IVR) engage in this area, based on PDVAC’s criteria of prioritizing the development of vaccines against pathogens that will address a major unmet public health need, and for which clinical candidates with a good probability of technical success are in the pipeline. As a first step, WHO’s IVR convened global subject matter experts to discuss the current global ETEC and Shigella disease burden estimates, including the current understanding of the long-term indirect effects of ETEC and Shigella infection, and how these data may affect future decision making on vaccine development for both pathogens. The available global burden estimates for ETEC and Shigella differ with respect to the relative importance of these two pathogens. The mortality estimates vary between iterations published by the same group, as well as between estimates of different groups, although the uncertainty intervals are broad and overlapping. These variances are attributable to differences in the data available and incorporated in the models; the methods used to detect the pathogens; the modelling methodologies; and, to actual changes in the total number of diarrheal deaths over time. The changes in the most recently reported mortality estimates for these pathogens, as compared to previous iterations, has led to debate as to whether investment in development of stand-alone vaccines, rather than combined vaccines, is warranted from cost-effectiveness and vaccine impact perspectives. Further work will be needed to understand better the variances and uncertainties in the reported mortality estimates to support investment decision making, and ultimately policy recommendations for vaccine use. In addition, a comprehensive assessment of the value proposition for vaccines against these pathogens is needed and will be strengthened if the long-term health consequences associated with diarrhea and dysentery due to these pathogens are better defined.

Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study. We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18–45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 μg (cohort 1) and 10 μg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed. Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 μg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 μg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 μg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045). SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations. The European Union Seventh Framework Programme.

We conducted a controlled before-and-after trial to evaluate the impact of an onsite urban sanitation intervention on the prevalence of enteric infection, soil transmitted helminth re-infection, and diarrhea among children in Maputo, Mozambique. A non-governmental organization replaced existing poor-quality latrines with pour-flush toilets with septic tanks serving household clusters. We enrolled children aged 1–48 months at baseline and measured outcomes before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. Despite nearly exclusive use, we found no evidence that intervention affected the prevalence of any measured outcome after 12 or 24 months of exposure. Among children born into study sites after intervention, we observed a reduced prevalence of Trichuris and Shigella infection relative to the same age group at baseline (<2 years old). Protection from birth may be important to reduce exposure to and infection with enteric pathogens in this setting.

Shigellosis is a clinical syndrome caused by invasion of the epithelium lining the terminal ileum, colon, and rectum by Shigella species. Although infections occur globally, and in people of all ages, endemic infections among children aged 1–4 years living in low-income and middle-income settings constitute most of the disease burden. The versatile manifestations of these highly contagious organisms range from acute watery diarrhoea to fulminant dysentery characterised by frequent scant bloody stools with fever, prostration, and abdominal cramps. A broad array of uncommon, but often severe, intestinal and extraintestinal complications can occur. Despite marked reductions in mortality during the past three decades, there are roughly 164 000 annual deaths attributable to shigellosis. Intercontinental dissemination of multiresistant shigella strains, facilitated by travellers and men who have sex with men, has prompted new recommendations for antibiotic therapy. Awareness of disease burden and the emerging threats posed by shigella have accelerated interest in development of shigella vaccines, many of which are being tested in clinical trials.

Shigella is a leading cause of diarrhea and dysentery in children in low-resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. The aim of the study was to quantify the reduction in Shigella attributable diarrhea, all diarrhea, and antibiotic use in the first 2 years of life that could be prevented by a Shigella vaccine. We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, a birth cohort study that followed 1,715 children with twice weekly surveillance for enteric infections, illnesses, and antibiotic use for the first 2 years of life from November 2009 to February 2014 at 8 sites. We estimated the impact of 2 one-dose (6 or 9 months) and 3 two-dose (6 and 9 months, 9 and 12 months, and 12 and 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. We used Monte Carlo simulations to estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use comparing each vaccination scenario to no vaccination. We analyzed 9,392 diarrhea episodes and 15,697 antibiotic courses among 1,715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100 child-years. A Shigella vaccine with a mean vaccine efficacy of 60% against severe disease given at 9 and 12 months prevented 10.6 (95% CI [9.5, 11.5]) Shigella diarrhea episodes of any severity per 100 child-years (relative 34.5% reduction), 3.0 (95% CI [2.5, 3.5]) F/M courses for Shigella treatment per 100 child-years (relative 35.8% reduction), and 5.6 (95% CI [5.0, 6.3]) antibiotic courses of any drug class for Shigella treatment per 100 child-years (relative 34.5% reduction). This translated to a relative 3.8% reduction in all diarrhea, a relative 2.8% reduction in all F/M courses, a relative 3.1% reduction in F/M exposures to bystander pathogens, and a relative 0.9% reduction in all antibiotic courses. These results reflect Shigella incidence and antibiotic use patterns at the 8 MAL-ED sites and may not be generalizable to all low-resource settings. Our simulation results suggest that a Shigella vaccine meeting WHO targets for efficacy could prevent about a third of Shigella diarrhea episodes, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use are expected to be modest (<5%).

Berberine (BBR), an isoquinoline alkaloid, has a long history of clinical use in treating dysentery. However, its precise mechanism has not been fully elucidated. This study aimed to investigate the intestinal protective mechanisms of BBR against Shigella flexneri (S. flexneri)-induced dysentery in mice. We found that BBR significantly upregulated the intestinal barrier proteins ZO-1, occludin, and E-cadherin, enhancing intestinal mucosal integrity to inhibit S. flexneri invasion. Moreover, BBR effectively attenuated M1 macrophage polarization and restored the Th1/Th17/Treg balance to reduce inflammatory injury upon S. flexneri infection. Specifically, BBR reduced both the populations of Th1 and Th17 cells and their production of inflammatory cytokines IFN-γ and IL-17A. Concurrently, it enhanced Treg cell populations and the secretion of anti-inflammatory cytokines IL-10 and TGF-β1. Additionally, the intestinal protective effect of BBR was further augmented by an increase in secretory IgA (sIgA). Collectively, our findings demonstrate that BBR protects against S. flexneri-induced dysentery by enhancing the intestinal barrier and inflammatory responses, providing support for its clinical use.

Background. Shigella, a major diarrheal disease pathogen worldwide, is the target of vaccine development. The Global Enteric Multicenter Study (GEMS) investigated burden and etiology of moderate-to-severe diarrheal disease in children aged <60 months and matched controls without diarrhea during 3 years at 4 sites in Africa and 3 in Asia. Shigella was 1 of the 4 most common pathogens across sites and age strata. GEMS Shigella serotypes are reviewed to guide vaccine development. Methods. Subjects' stool specimens/rectal swabs were transported to site laboratories in transport media and plated onto xylose lysine desoxycholate and MacConkey agar. Suspect Shigella colonies were identified by biochemical tests and agglutination with antisera. Shigella isolates were shipped to the GEMS Reference Laboratory (Baltimore, MD) for confirmation and serotyping of S. flexneri; one-third of isolates were sent to the Centers for Disease Control and Prevention for quality control. Results. Shigella dysenteriae and S. boydii accounted for 5.0% and 5.4% respectively, of 1130 Shigella case isolates; S. flexneri comprised 65.9% and S. sonnei 23.7%. Five serotypes/subserotypes comprised 89.4% of S. flexneri, including S. flexneri 2a, S. flexneri 6, S. flexneri 3a, S. flexneri 2b, and S. flexneri 1b. Conclusions. A broad-spectrum Shigella vaccine must protect against S. sonnei and 15 S. flexneri serotypes/subserotypes. A quadrivalent vaccine with O antigens from S. sonnei, S. flexneri 2a, S. flexneri 3a, and S. flexneri 6 can provide broad direct coverage against these most common serotypes and indirect coverage against all but 1 (rare) remaining subserotype through shared S. flexneri group antigens.

Shigella is a Gram-negative, facultative intracellular, gastric acid-resistant bacterium of the Enterobacteriaceae family, which includes four serogroups: Shigella dysenteriae, Shigella sonnei, Shigella flexneri, and Shigella boydii. Globally, shigellosis is the most common cause of invasive bloody diarrhoea in children younger than 5 years. Humans are the only natural reservoir and an inoculum of only 10–100 organisms is required for infection. Rising antibiotic resistance rates increasingly reduce the ability to adequately treat severe disease. The prevention of infection with vaccination and sanitation strategies remains a crucial step in reducing worldwide morbidity and mortality.

Background Shigellosis continues to pose a significant public health problem in Africa; however, there is a lack of comprehensive knowledge regarding its prevalence, serogroup distribution, and antimicrobial resistance profiles. Therefore, the objective of this systematic review and meta-analysis was to determine the overall prevalence of Shigella , the distribution of species, and the patterns of antimicrobial resistance across Africa. Methods Following PRISMA guidelines, a systematic search strategy was conducted using the PubMed, Web of Science and Scopus databases from January 31, 2024 to February 10, 2024. The study quality was assessed using the Joanna Briggs Institute checklist, and data were analyzed using the R statistical language and the R package ‘meta’. The random effects model was employed to estimate the pooled prevalence, while heterogeneity was assessed using the I 2 statistic and prediction interval. Results A total of 116 studies from 29 African countries were included in this meta-analysis, involving the examination of 99,510 samples. The overall pooled estimate of Shigella prevalence was determined to be 5.9% (95% CI: 4.9 – 7.0%). Regional prevalence showed prevalences of Southern Africa (6.9 [95% CI: 3.0 – 12.2%]), Northern Africa (6.7% [95% CI: 4.1 – 9.8%]), Eastern Africa (6.2% [95% CI: 4.9 – 7.6%]), Central Africa (4.5% [95% CI: 2.6 – 6.8%]) and Western Africa (4.0% [95% CI: 2.5 – 5.9%]). Shigella prevalence was found to be higher in children (6.6%, 95% CI: 3.2 – 11.1%) than in adults (3.6%, 95% CI: 1.6 – 6.3%). The most prevalent species was S. flexneri (53.6%, 95% CI: 46.1%—61.0%), followed by S. sonnei (11.5%, 95% CI: 7.7%—15.7%), S. dysenteriae (10.1%, 95% CI: 6.2 – 14.5%) and S. boydii (7.7%, 95% CI: 4.7 – 11.1%). Among the currently recommended first-line antibiotics, ciprofloxacin and ceftriaxone showed resistance prevalences of 10.0% (95% CI: 4.5%—16.9%) and 8.5% (95% CI: 2.4—16.9%) respectively. Conclusion This review highlights the burden of shigellosis in Africa. S. flexneri remains the most prevalent species associated with shigellosis cases with S. sonnei being the second most dominant. The antimicrobial resistance patterns observed in the study suggest local antimicrobial patterns in choosing antibiotics for the treatment of Shigellosis. Recommendation There is the need to explore alternative treatments for shigellosis with particular focus on vaccine development. There is also the need for more genomic epidemiology studies exploring the dissemination and risk of drug-resistant S. sonnei clones in Africa.

Increasing antimicrobial resistance poses a serious challenge for the treatment of Shigella infections, and there is an urgent need for alternative antibacterial treatments. We conducted a clinical trial to investigate the efficacy of oral tebipenem pivoxil, compared to intravenous ceftriaxone, in Bangladeshi children with shigellosis. Using demographic data of 2249 Bangladeshi children with suspected shigellosis, population pharmacokinetic (PK) simulations were conducted to simulate tebipenem PK profiles in children with the proposed dosing regimen. Subsequently, the model predictions estimated each virtual participant's fraction of time over the 3‐day treatment period during which simulated free tebipenem plasma concentration was above the minimum inhibitory concentration (fT > MIC). Variability associated with the prevalence of different Shigella species in Bangladeshi children and the MIC distributions were incorporated. Shigella treatment effect was assumed for participants that had fT > MIC for at least 40% of the 3‐day treatment period (40% fT > MIC). The probability of achieving 40% fT > MIC was 86.4% for 4 mg/kg tebipenem pivoxil three times daily (TID) dosing and 92.4% with 3 mg/kg tebipenem pivoxil four times daily (QID) dosing. Lastly, the probability of tebipenem pivoxil being non‐inferior to ceftriaxone, in a clinical trial containing 66 participants per arm, was evaluated for two dosing regimens. Three levels of ceftriaxone resistance were simulated to examine how dynamic ceftriaxone resistance may impact the trial outcome. Our findings suggest that more frequent tebipenem pivoxil dosing may increase the chance of producing treatment effects, contribute valuable insights to inform dosing strategy selection, and demonstrate a workflow that can be adapted to other drugs and diseases. Study Highlights What is the current knowledge on the topic? ○Shigella infection is the second leading cause of diarrheal mortality worldwide and disproportionately affects children under five. Treatment options are increasingly limited due to the global rise in broad‐spectrum antimicrobial resistance, underscoring the need for alternative therapies for shigellosis. What question did this study address? ○This study evaluated the predicted efficacy of tebipenem pivoxil compared with ceftriaxone for treating shigellosis in Bangladeshi children under five, incorporating demographic factors and resistance patterns specific to this high‐burden population. What does this study add to our knowledge? ○This study provided the first prediction of tebipenem pivoxil efficacy for treating shigellosis in Bangladeshi children—a population disproportionately affected by the disease and distinct from many others due to high rates of malnutrition, elevated antimicrobial resistance, and limited healthcare resources How might this change clinical pharmacology or translational science? ○The study shows that treatment success can be shaped by population demographics, prevalence of Shigella species, evolving antimicrobial resistance, and dosing strategies. The modeling workflow can be adapted to generate population‐specific efficacy predictions for other antimicrobials and infectious diseases, supporting more targeted and context‐appropriate decisions.