-
International Journal of Molecular... Nov 2023Shigellosis remains a global health concern, especially in low- and middle-income countries. Despite improvements in sanitation, the absence of a licensed vaccine for...
Shigellosis remains a global health concern, especially in low- and middle-income countries. Despite improvements in sanitation, the absence of a licensed vaccine for human use has prompted global health organizations to support the development of a safe and effective multivalent vaccine that is cost-effective and accessible for limited-resource regions. Outer Membrane Vesicles (OMVs) have emerged in recent years as an alternative to live attenuated or whole-inactivated vaccines due to their immunogenicity and self-adjuvating properties. Previous works have demonstrated the safety and protective capacity of OMVs against infection in mouse models when administered through mucosal or intradermal routes. However, some immunological properties, such as the cellular response or cross-protection among different strains, remained unexplored. In this study, we demonstrate that intradermal immunization of OMVs with needle-free devices recruits a high number of immune cells in the dermis, leading to a robust cellular response marked by antigen-specific cytokine release and activation of effector CD4 T cells. Additionally, functional antibodies are generated, neutralizing various serotypes, suggesting cross-protective capacity. These findings highlight the potential of OMVs as a promising vaccine platform against shigellosis and support intradermal administration as a simple and painless vaccination strategy to address this health challenge.
Topics: Animals; Humans; Mice; Shigella flexneri; Dysentery, Bacillary; Shigella Vaccines; Shigella; Cytokines; Antibodies, Bacterial
PubMed: 38069232
DOI: 10.3390/ijms242316910 -
Frontiers in Molecular Biosciences 2023Shigellosis is leading bacterial cause of diarrhea with high prevalence in children younger than 5 years in low- and middle-income countries, and increasing number of...
Shigellosis is leading bacterial cause of diarrhea with high prevalence in children younger than 5 years in low- and middle-income countries, and increasing number of reports of cases associated to anti-microbial resistance. No vaccines against are still licensed, but different candidates based on the O-antigen portion of lipopolysaccharides are in clinic. Generalized Modules for Membrane Antigens (GMMA) have been proposed as an alternative delivery system for the O-antigen, and a 4-component vaccine candidate (altSonflex1-2-3), containing GMMA from and 1b, 2a and 3a is being tested in a phase 1/2 clinical trial, with the aim to elicit broad protection against the most prevalent serotypes. Here, the 4-component GMMA vaccine candidate has been compared to a more traditional glycoconjugate formulation for the ability to induce functional antibodies in mice and rabbits. In mice, in the absence of Alhydrogel, GMMA induce higher IgG antibodies than glycoconjugates and stronger bactericidal titers against all serotypes. In the presence of Alhydrogel, GMMA induce O-antigen specific IgG levels similar to traditional glycoconjugates, but with a broader range of IgG subclasses, resulting in stronger bactericidal activity. In rabbits, GMMA elicit higher functional antibodies than glycoconjugates against , and similar responses to 1b, 2a and 3a, independently from the presence of Alhydrogel. Different O-antigen based vaccines against are now in clinical stage and it will be of particular interest to understand how the preclinical findings in the different animal models translate in humans.
PubMed: 38046812
DOI: 10.3389/fmolb.2023.1284515 -
Vaccine Mar 2024The global public health nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC,...
The global public health nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, from November 29 to December 1, 2022. This international gathering focused on cutting-edge research related to the development of vaccines against neglected diarrheal pathogens including Shigella, enterotoxigenic Escherichia coli (ETEC), Campylobacter, and non-typhoidal Salmonella. In addition to the conference's plenary content, the agenda featured ten breakout workshops on topics of importance to the enteric vaccine field. This unique aspect of VASE Conferences allows focused groups of attendees to engage in in-depth discussions on subjects of interest to the enteric vaccine development community. In 2022, the workshops covered a range of topics. Two focused on the public health value of enteric vaccines, with one examining how to translate evidence into policy and the other on the value proposition of potential combination vaccines against bacterial enteric pathogens. Two more workshops explored new tools for the development and evaluation of vaccines, with the first on integrating antigen/antibody technologies for mucosal vaccine and immunoprophylactic development, and the second on adjuvants specifically for Shigella vaccines for children in low- and middle-income countries. Another pair of workshops covered the status of vaccines against two emerging enteric pathogens, Campylobacter and invasive non-typhoidal Salmonella. The remaining four workshops examined the assessment of vaccine impact on acute and long-term morbidity. These included discussions on the nature and severity of intestinal inflammation; cellular immunity and immunological memory in ETEC and Shigella infections; clinical and microbiologic endpoints for Shigella vaccine efficacy studies in children; and intricacies of protective immunity to enteric pathogens. This article provides a brief summary of the presentations and discussions at each workshop in order to share these sessions with the broader enteric vaccine field.
Topics: Child; Humans; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Shigella; Diarrhea; Shigella Vaccines; Salmonella; Oligopeptides
PubMed: 38036392
DOI: 10.1016/j.vaccine.2023.11.045 -
Vaccine Mar 2024The global nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, on November... (Review)
Review
The global nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, on November 29 to December 1, 2022. With a combination of plenary sessions and posters, keynote presentations, and breakout workshops, the 2022 VASE Conference featured key updates on research related to the development of vaccines against neglected diarrheal pathogens including Shigella, enterotoxigenic Escherichia coli (ETEC), Campylobacter, and Salmonella. The presentations and discussions highlighted the significant impact of these diarrheal pathogens, particularly on the health of infants and young children in low- and middle-income countries, reflecting the urgent need for the development and licensure of new enteric vaccines. Oral and poster presentations at the VASE Conference explored a range of topics, including: the global burden and clinical presentation of disease, epidemiology, and the impact of interventions; the assessment of the value of vaccines against enteric pathogens; preclinical evaluations of vaccine candidates and models of enteric diseases; vaccine candidates in clinical trials and human challenge models; host parameters and genomics that predict responses to infection and disease; the application of new omics technologies for characterization of emerging pathogens and host responses; novel adjuvants, vaccine delivery platforms, and immunization strategies; and strategies for combination/co-administered vaccines. The conference agenda also featured ten breakout workshop sessions on topics of importance to the enteric vaccine field, which are summarized separately. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2022 VASE Conference.
Topics: Humans; Diarrhea; Dysentery, Bacillary; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Oligopeptides; Shigella; Shigella Vaccines
PubMed: 38030421
DOI: 10.1016/j.vaccine.2023.11.031 -
Frontiers in Immunology 2023Shigellosis is common worldwide, and it causes significant morbidity and mortality mainly in young children in low- and middle- income countries. To date, there are not...
Shigellosis is common worldwide, and it causes significant morbidity and mortality mainly in young children in low- and middle- income countries. To date, there are not broadly available licensed vaccines. A novel type of conjugate vaccine candidate, SF2a-TT15, was developed against serotype 2a (SF2a). SF2a-TT15 is composed of a synthetic 15mer oligosaccharide, designed to act as a functional mimic of the SF2a O-antigen and covalently linked to tetanus toxoid (TT). SF2a-TT15 was recently shown to be safe and immunogenic in a Phase 1 clinical trial, inducing specific memory B cells and sustained antibody response up to three years after the last injection. In this manuscript, we advance the study of B cell responses to parenteral administration of SF2a-TT15 to identify SF2a LPS-specific B cells (SF2a+ B cells) using fluorescently labeled bacteria. SF2a+ B cells were identified mainly within class-switched B cells (SwB cells) in volunteers vaccinated with SF2a-TT15 adjuvanted or not with aluminium hydroxide (alum), but not in placebo recipients. These cells expressed high levels of CXCR3 and low levels of CD21 suggesting an activated phenotype likely to represent the recently described effector memory B cells. IgG SF2a+ SwB cells were more abundant than IgA SF2a + SwB cells. SF2a+ B cells were also identified in polyclonally stimulated B cells (antibody secreting cells (ASC)-transformed). SF2a+ ASC-SwB cells largely maintained the activated phenotype (CXCR3 high, CD21 low). They expressed high levels of CD71 and integrin α4β7, suggesting a high proliferation rate and ability to migrate to gut associated lymphoid tissues. Finally, ELISpot analysis showed that ASC produced anti-SF2a LPS IgG and IgA antibodies. In summary, this methodology confirms the ability of SF2a-TT15 to induce long-lived memory B cells, initially identified by ELISpots, which remain identifiable in blood up to 140 days following vaccination. Our findings expand and complement the memory B cell data previously reported in the Phase 1 trial and provide detailed information on the immunophenotypic characteristics of these cells. Moreover, this methodology opens the door to future studies at the single-cell level to better characterize the development of B cell immunity to .
Topics: Child, Preschool; Humans; Healthy Volunteers; Immunoglobulin A; Immunoglobulin G; Lipopolysaccharides; Memory B Cells; Serogroup; Shigella; Shigella flexneri; Shigella Vaccines; Vaccines, Synthetic; Clinical Trials, Phase I as Topic
PubMed: 38022674
DOI: 10.3389/fimmu.2023.1291664 -
PLoS Medicine Nov 2023Shigella 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...
BACKGROUND
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.
METHODS AND FINDINGS
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.
CONCLUSIONS
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%).
Topics: Humans; Infant; Dysentery, Bacillary; Anti-Bacterial Agents; Cohort Studies; Shigella; Diarrhea; Dysentery; Vaccines
PubMed: 37992134
DOI: 10.1371/journal.pmed.1004271 -
PloS One 2023Shigella sonnei is a gram-negative bacterium and is the primary cause of shigellosis in advanced countries. An exceptional rise in the prevalence of the disease has been...
Vaccinomics-aided next-generation novel multi-epitope-based vaccine engineering against multidrug resistant Shigella Sonnei: Immunoinformatics and chemoinformatics approaches.
Shigella sonnei is a gram-negative bacterium and is the primary cause of shigellosis in advanced countries. An exceptional rise in the prevalence of the disease has been reported in Asia, the Middle East, and Latin America. To date, no preventive vaccine is available against S. sonnei infections. This pathogen has shown resistances towards both first- and second-line antibiotics. Therefore, an effective broad spectrum vaccine development against shigellosis is indispensable. In the present study, vaccinomics-aided immunoinformatics strategies were pursued to identify potential vaccine candidates from the S. sonnei whole proteome data. Pathogen essential proteins that are non-homologous to human and human gut microbiome proteome set, are feasible candidates for this purpose. Three antigenic outer membrane proteins were prioritized to predict lead epitopes based on reverse vaccinology approach. Multi-epitope-based chimeric vaccines was designed using lead B- and T-cell epitopes combined with suitable linker and adjuvant peptide sequences to enhance immune responses against the designed vaccine. The SS-MEVC construct was prioritized based on multiple physicochemical, immunological properties, and immune-receptors docking scores. Immune simulation analysis predicted strong immunogenic response capability of the designed vaccine construct. The Molecular dynamic simulations analysis ensured stable molecular interactions of lead vaccine construct with the host receptors. In silico restriction and cloning analysis predicted feasible cloning capability of the SS-MEVC construct within the E. coli expression system. The proposed vaccine construct is predicted to be more safe, effective and capable of inducing robust immune responses against S. sonnei infections and may be worthy of examination via in vitro/in vivo assays.
Topics: Humans; Shigella sonnei; Dysentery, Bacillary; Proteome; Escherichia coli; Cheminformatics; Molecular Docking Simulation; Bacterial Vaccines; Vaccines, Subunit; Epitopes, T-Lymphocyte; Molecular Dynamics Simulation; Computational Biology; Epitopes, B-Lymphocyte
PubMed: 37992050
DOI: 10.1371/journal.pone.0289773 -
Current Opinion in Immunology Dec 2023Shigella spp. are major causative agents of bacillary dysentery, a severe enteric disease characterized by destruction and inflammation of the colonic epithelium... (Review)
Review
Shigella spp. are major causative agents of bacillary dysentery, a severe enteric disease characterized by destruction and inflammation of the colonic epithelium accompanied by acute diarrhea, fever, and abdominal pain. Although antibiotics have traditionally been effective, the prevalence of multidrug-resistant strains is increasing, stressing the urgent need for a vaccine. The human-specific nature of shigellosis and the absence of a dependable animal model have posed significant obstacles in understanding Shigella pathogenesis and the host immune response, both of which are crucial for the development of an effective vaccine. Efforts have been made over time to develop a physiological model that mimics the pathological features of the human disease with limited success until the recent development of genetically modified mouse models. In this review, we provide an overview of Shigella pathogenesis and chronicle the historical development of various shigellosis models, emphasizing their strengths and weaknesses.
Topics: Animals; Mice; Humans; Dysentery, Bacillary; Shigella; Inflammation; Disease Models, Animal; Vaccines
PubMed: 37952487
DOI: 10.1016/j.coi.2023.102399 -
Cancers Oct 2023Colorectal cancer (CRC) is a significant global health concern. Microbial dysbiosis and associated metabolites have been associated with CRC occurrence and progression....
Colorectal cancer (CRC) is a significant global health concern. Microbial dysbiosis and associated metabolites have been associated with CRC occurrence and progression. This study aims to analyze the gut microbiota composition and the enriched metabolic pathways in patients with late-stage CRC. In this study, a cohort of 25 CRC patients diagnosed at late stage III and IV and 25 healthy participants were enrolled. The fecal bacterial composition was investigated using V3-V4 ribosomal RNA gene sequencing, followed by clustering and linear discriminant analysis (LDA) effect size (LEfSe) analyses. A cluster of ortholog genes' (COG) functional annotations and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to identify enrichment pathways between the two groups. The findings showed that the fecal microbiota between the two groups varied significantly in alpha and beta diversities. CRC patients' fecal samples had significantly enriched populations of , , , , , , , , Family XIII_AD3001 Group, , , , , , , and (Q < 0.05). The enriched pathways identified in the CRC group were amino acid transport, signaling and metabolism, membrane biogenesis, DNA replication and mismatch repair system, and protease activity (Q < 0.05). These results suggested that the imbalance between intestinal bacteria and the elevated level of the predicated functions and pathways may contribute to the development of advanced CRC tumors. Further research is warranted to elucidate the exact role of the gut microbiome in CRC and its potential implications for use in diagnostic, prevention, and treatment strategies.
PubMed: 37894386
DOI: 10.3390/cancers15205019 -
The Lancet. Global Health Nov 2023Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in... (Review)
Review
Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.
Topics: Child; Humans; Shigella Vaccines; Developing Countries; Dysentery, Bacillary
PubMed: 37858591
DOI: 10.1016/S2214-109X(23)00421-7