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Vaccine Nov 2023Shigella is the leading bacterial cause of diarrhoea and the second leading cause of diarrhoeal mortality among all ages. It also exhibits increasing levels of...
Shigella is the leading bacterial cause of diarrhoea and the second leading cause of diarrhoeal mortality among all ages. It also exhibits increasing levels of antibiotic resistance. The greatest burden is among children under five in low- and middle-income countries (LMICs). As such, a priority strategic goal of the World Health Organization (WHO) is the development of a safe, effective and affordable vaccine to reduce morbidity and mortality from Shigella-attributable dysentery and diarrhea, including long term outcomes associated with chronic inflammation and growth faltering, in children under 5 years of age in LMICs. In addition, a safe and effective Shigella vaccine is of potential interest to travellers and military both to prevent acute disease and rarer, long-term sequelae. An effective Shigella vaccine is also anticipated to reduce antibiotic use and thereby help diminish further emergence of enteric pathogens resistant to antimicrobials. The most advanced vaccine candidates are multivalent, parenteral formulations in Phase 2 and Phase 3 clinical studies. They rely on O-antigen-polysaccharide protein conjugate technologies or, alternatively, outer membrane vesicles expressing penta-acylated lipopolysaccharide that has been detoxified. Other parenteral and oral formulations, many delivering a broader array of Shigella antigens, are at earlier stages of clinical development. These formulations are being assessed in alignment with the WHO Preferred Product Characteristics, which call for a 1 to 2 dose primary immunization series given during the first 12 months of life, ideally starting at 6 months of age. This 'Vaccine Value Profile' (VVP) for Shigella is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the Shigella VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.
Topics: Child, Preschool; Humans; Diarrhea; Dysentery, Bacillary; Escherichia coli Infections; Shigella; Shigella Vaccines; Infant
PubMed: 37827969
DOI: 10.1016/j.vaccine.2022.12.037 -
Infection and Immunity Nov 2023There are no licensed vaccines for , a leading cause of children's diarrhea and a common etiology of travelers' diarrhea. To develop a cross-protective vaccine, in this...
There are no licensed vaccines for , a leading cause of children's diarrhea and a common etiology of travelers' diarrhea. To develop a cross-protective vaccine, in this study, we constructed a polyvalent protein immunogen to present conserved immunodominant epitopes of invasion plasmid antigens B (IpaB) and D (IpaD), VirG, GuaB, and Shiga toxins on backbone protein IpaD, by applying an epitope- and structure-based multiepitope-fusion-antigen (MEFA) vaccinology platform, examined protein ( MEFA) broad immunogenicity, and evaluated antibody function against invasion and Shiga toxin cytotoxicity but also protection against lethal challenge. Mice intramuscularly immunized with MEFA protein developed IgG responses to IpaB, IpaD, VirG, GuaB, and Shiga toxins 1 and 2; mouse sera significantly reduced invasion of , serotype 2a, 3a, or 6, and type 1 and neutralized cytotoxicity of Shiga toxins of and Shiga toxin-producing . Moreover, mice intranasally immunized with MEFA protein (adjuvanted with dmLT) developed antigen-specific serum IgG, lung IgG and IgA, and fecal IgA antibodies, and survived from lethal pulmonary challenge with or serotype 2a, 3a, or 6. In contrast, the control mice died, became unresponsive, or lost 20% of body weight in 48 h. These results indicated that this MEFA protein is broadly immunogenic, induces broadly functional antibodies, and cross-protects against lethal pulmonary challenges with or serotypes, suggesting a potential application of this polyvalent MEFA protein in vaccine development.
Topics: Humans; Child; Animals; Mice; Shigella sonnei; Shigella flexneri; Diarrhea; Travel; Antigens, Bacterial; Shigella; Shigella Vaccines; Lung; Shiga Toxins; Immunoglobulin G; Immunoglobulin A; Antibodies, Bacterial; Dysentery, Bacillary
PubMed: 37795982
DOI: 10.1128/iai.00316-23 -
Microbiology Spectrum Dec 2023Shigellosis is endemic to low- and middle-income regions of the world where children are especially vulnerable. In many cases, there are pre-existing antibodies in the...
Shigellosis is endemic to low- and middle-income regions of the world where children are especially vulnerable. In many cases, there are pre-existing antibodies in the local population and the effect of prior exposure should be considered in the development and testing of vaccines against infection. Our study shows that L-DBF-induced immune responses are not adversely affected by prior exposure to this pathogen. Moreover, somewhat different cytokine profiles were observed in the lungs of vaccinated mice not having been exposed to , suggesting that the immune responses elicited by infection and L-DBF vaccination follow different pathways.
Topics: Child; Animals; Mice; Humans; Antigens, Bacterial; Bacterial Proteins; Dysentery, Bacillary; Serogroup; Shigella Vaccines; Shigella; Vaccines; Antibodies, Bacterial
PubMed: 37787548
DOI: 10.1128/spectrum.00062-23 -
Frontiers in Immunology 2023Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease,...
Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. 's primary virulence factor is its type III secretion system (T3SS), which is a specialized nanomachine used to manipulate host cells. A fusion of T3SS injectisome needle tip protein IpaD and translocator protein IpaB, termed DBF, when admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from enterotoxigenic was protective using a murine pulmonary model. To facilitate the production of this platform, a recombinant protein that consisted of LTA-1, the active moiety of dmLT, and DBF were genetically fused, resulting in L-DBF, which showed improved protection against challenge. To extrapolate this protection from mice to humans, we modified the formulation to provide for a multivalent presentation with the addition of an adjuvant approved for use in human vaccines. Here, we show that L-DBF formulated (admix) with a newly developed TLR4 agonist called BECC438 (a detoxified lipid A analog identified as Bacterial Enzymatic Combinatorial Chemistry candidate #438), formulated as an oil-in-water emulsion, has a very high protective efficacy at low antigen doses against lethal challenge in our mouse model. Optimal protection was observed when this formulation was introduced at a mucosal site (intranasally). When the formulation was then evaluated for the immune response it elicits, protection appeared to correlate with high IFN-γ and IL-17 secretion from mucosal site lymphocytes.
PubMed: 37744341
DOI: 10.3389/fimmu.2023.1194912 -
Frontiers in Nutrition 2023Obesity is often associated with glucolipid and/or energy metabolism disorders. extract (seaweed extract, SE) and extract (tea extract, TE) have been reported to...
OBJECTIVES
Obesity is often associated with glucolipid and/or energy metabolism disorders. extract (seaweed extract, SE) and extract (tea extract, TE) have been reported to promote positive metabolic effects through different mechanisms. We investigated the effects of SE and TE on metabolic homeostasis in diet-induced obese mice and discussed their functional characteristics.
METHODS
Male C57BL/6J mice fed with high-fat diets for 8 weeks were established as obese models and subsequently divided into different intervention groups, followed by SE, TE, and their joint interventions for 10 weeks. Body weight and food intake were monitored. Fasting glucose and oral glucose tolerance tests were interspersed during the experiment. After the intervention, the effects on obesity control were assessed based on body composition, liver pathology section, blood lipids and glucose, respiratory exchange ratio (RER), energy expenditure (EE, EE, and EE), inflammatory factors, lipid anabolism enzymes, and gut flora of the obese mice.
RESULTS
After continuous gavage intervention, the mice in the intervention groups exhibited lower body weight (lower ~4.93 g, vs. HFD 38.02 g), peri-testicular fat masses (lower ~0.61 g, vs. HFD 1.92 g), and perirenal fat masses (lower ~0.21 g, vs. HFD mice 0.70 g). All interventions prevented diet-induced increases in plasma levels of glucose, adiponectin, leptin, and the inflammatory factors IL-1β and TNF-α. The RER was modified by the interventions, while the rhythm of the RER was not. Blood lipids (total cholesterol, triglycerides, and LDL) decreased and were associated with lower lipid anabolism enzymes. In addition, the SE and TE interventions altered the structure and abundance of specific flora. Different interventions inhibited the growth of different genera positively associated with obesity (, etc.) and promoted the growth of and , thus affecting the chronic inflammatory state.
CONCLUSION
SE and TE both have synergistic effects on weight control and glucolipid metabolism regulation by improving insulin sensitivity and reducing lipid synthesis-related enzyme expression, whereas the combination of SE and TE (3:1) has a better effect on regulating energy metabolism and inhibiting chronic inflammation.
PubMed: 37693249
DOI: 10.3389/fnut.2023.1242157 -
Gut Pathogens Sep 2023Bacterial ghost cells (BGCs) are cells were drained of their genetic and cytoplasmic components. This work aimed to develop vaccine candidates against the Shigella...
BACKGROUND
Bacterial ghost cells (BGCs) are cells were drained of their genetic and cytoplasmic components. This work aimed to develop vaccine candidates against the Shigella flexneri (S. flexneri) 2b serotype using the BGCs approach. For the first time, (S. flexneri) 2b serotype BGCs vaccine was prepared by incubation with Triton X-100 (TX100) for only 12 h. Its safety and immunogenicity were compared to another vaccine produced using a previously used surfactant, namely Tween 80 (TW80). Scanning electron microscopy (SEM), cellular DNA, protein contents measurements, and ghost cell re-cultivation were used to confirm the successful generation of the BGCs. Immunogenicity was assessed through mice's intraperitoneal (IP) immunization followed by infection with S. flexneri ATCC 12022. Finally, histopathological examination was carried out.
RESULTS
Viable colony forming units (CFUs) of S. flexneri were counted from stool samples as well as homogenized colon tissues of the non-immunized challenged group. Immunized mice sera showed a significant increase in serum bactericidal activity of both preparations (TX100 = 40% and TW80 = 56%) compared to the non-immunized challenged group (positive control). The IgG levels of the bacterial ghost-vaccinated groups were four and three times greater for the TX100 and TW80 ghost vaccines, respectively, compared to that of the positive control; both bacterial ghost vaccines (BGVs) were safe and effective, according to the results of the safety check tests and histopathological analysis.
CONCLUSIONS
When comparing the BGVs prepared using TX100 and TW80 methods, the use of TX100 as a new chemical treating agent for BGC production attained robust results in terms of shorter incubation time with the targeted cells and a strong immune response against S. flexneri 2b serotype ATCC 12022 in the IP challenge test. However, a clinical study is needed to confirm the efficacy and total safety of this novel vaccine.
PubMed: 37679798
DOI: 10.1186/s13099-023-00568-7 -
NPJ Vaccines Sep 2023Shigellosis is a leading cause of diarrheal disease in low-middle-income countries (LMICs). Effective vaccines will help to reduce the disease burden, exacerbated by...
Shigellosis is a leading cause of diarrheal disease in low-middle-income countries (LMICs). Effective vaccines will help to reduce the disease burden, exacerbated by increasing antibiotic resistance, in the most susceptible population represented by young children. A challenge for a broadly protective vaccine against shigellosis is to cover the most epidemiologically relevant serotypes among >50 Shigella serotypes circulating worldwide. The GMMA platform has been proposed as an innovative delivery system for Shigella O-antigens, and we have developed a 4-component vaccine against S. sonnei, S. flexneri 1b, 2a and 3a identified among the most prevalent Shigella serotypes in LMICs. Driven by the immunogenicity results obtained in clinic with a first-generation mono-component vaccine, a new S. sonnei GMMA construct was generated and combined with three S. flexneri GMMA in a 4-component Alhydrogel formulation (altSonflex1-2-3). This formulation was highly immunogenic, with no evidence of negative antigenic interference in mice and rabbits. The vaccine induced bactericidal antibodies also against heterologous Shigella strains carrying O-antigens different from those included in the vaccine. The Monocyte Activation Test used to evaluate the potential reactogenicity of the vaccine formulation revealed no differences compared to the S. sonnei mono-component vaccine, shown to be safe in several clinical trials in adults. A GLP toxicology study in rabbits confirmed that the vaccine was well tolerated. The preclinical study results support the clinical evaluation of altSonflex1-2-3 in healthy populations, and a phase 1-2 clinical trial is currently ongoing.
PubMed: 37670042
DOI: 10.1038/s41541-023-00725-8 -
Gastroenterology Research and Practice 2023To estimate gastroenteritis disease and its etiological agents in children under the age of 5 years living in South Africa. (Review)
Review
OBJECTIVE
To estimate gastroenteritis disease and its etiological agents in children under the age of 5 years living in South Africa.
METHODS
A mini literature review of pertinent articles published in ScienceDirect, PubMed, GoogleScholar, and Scopus was conducted using search terms: "Gastroenteritis in children," "Gastroenteritis in the world," Gastroenteritis in South Africa," "Prevalence of gastroenteritis," "Epidemiological surveillance of gastroenteritis in the world," and "Causes of gastroenteritis".
RESULTS
A total of 174 published articles were included in this mini review. In the last 20 years, the mortality rate resulting from diarrhea in children under the age of 5 years has declined and this is influenced by improved hygiene practices, awareness programs, an improved water and sanitation supply, and the availability of vaccines. More modern genomic amplification techniques were used to re-analyze stool specimens collected from children in eight low-resource settings in Asia, South America, and Africa reported improved sensitivity of pathogen detection to about 65%, that viruses were the main etiological agents in patients with diarrhea aged from 0 to 11 months but that , followed by sapovirus and enterotoxigenic had a high incidence in children aged 12-24 months. In addition, co-infections were noted in nearly 10% of diarrhea cases, with rotavirus and being the main co-infecting agents together with adenovirus, enteropathogenic , , or .
CONCLUSIONS
This mini review outlines the epidemiology and trends relating to parasitic, viral, and bacterial agents responsible for gastroenteritis in children in South Africa. An increase in sequence-independent diagnostic approaches will improve the identification of pathogens to resolve undiagnosed cases of gastroenteritis. Emerging state and national surveillance systems should focus on improving the identification of gastrointestinal pathogens in children and the development of further vaccines against gastrointestinal pathogens.
PubMed: 37663241
DOI: 10.1155/2023/1906782 -
Vaccine: X Dec 2023is the leading bacterial cause of diarrheal mortality in children and can cause long-term effects on growth and development. No licensed vaccines currently exist but...
BACKGROUND
is the leading bacterial cause of diarrheal mortality in children and can cause long-term effects on growth and development. No licensed vaccines currently exist but several promising candidates are in development and could be available in the next five years. Despite being a well-known public health target of the World Health Organization for decades, given current burden estimates and competing preventable disease priorities in low-income settings, whether the availability of an effective vaccine will lead to its prioritization and widespread introduction among countries at highest risk is unknown.
METHODS
We conducted a mixed-methods study of national stakeholders and healthcare providers in five countries in Asia and Africa and regional stakeholders in the Pan American Health Organization to identify preferences and priorities for forthcoming vaccines.
RESULTS
In our study of 89 individuals, diarrhea was the most frequently mentioned serious health concern for children under five years. Antimicrobial resistance (AMR) was more often considered very concerning than diarrhea or stunting. awareness was high but not considered a serious health concern by most stakeholders. Most participants were willing to consider adding a new vaccine to the routine immunization schedule but expressed reservations about a vaccine because of lower perceived burden relative to other preventable diseases and an already crowded schedule; interest was highest among national stakeholders in countries receiving more financial support for immunization. The priority of a vaccine rose when participants considered vaccine impacts on reducing stunting and AMR. Participants strongly preferred oral and combination vaccines compared to injectable and a single-antigen presentations, citing greater perceived community acceptability.
CONCLUSIONS
This study provides a critical opportunity to hear directly from country and regional stakeholders about health priorities and preferences around new vaccines. These findings should inform ongoing vaccine development efforts and eventual vaccine introduction and implementation planning.
PubMed: 37636544
DOI: 10.1016/j.jvacx.2023.100368 -
The Journal of Infectious Diseases Apr 2024Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera.
METHODS
AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies.
RESULTS
Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella.
CONCLUSIONS
Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment.
CLINICAL TRIALS REGISTRATION
NCT03130114.
Topics: Humans; Infant; Anti-Bacterial Agents; Azithromycin; Bacteria; Bacterial Infections; Cryptosporidiosis; Cryptosporidium; Diarrhea; Dysentery; Pathology, Molecular; Shigella
PubMed: 37405406
DOI: 10.1093/infdis/jiad252