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Open Forum Infectious Diseases Mar 2024In 2002, the Centre pour le Développement des Vaccins du Mali (CVD-Mali) was established as a partnership between the Mali Ministry of Health and the University of...
BACKGROUND
In 2002, the Centre pour le Développement des Vaccins du Mali (CVD-Mali) was established as a partnership between the Mali Ministry of Health and the University of Maryland, Baltimore. Since its creation, CVD-Mali has been dedicated to describing the epidemiology of infectious diseases, supporting the development of vaccines, and training a team of local researchers. CVD-Mali participated in the Global Enteric Multicenter Study from 2007 to 2010 and the Vaccine Impact on Diarrhea in Africa study from 2015 to 2018, where the importance of as an enteric pathogen was established.
METHODS
In the Enterics for Global Health (EFGH) surveillance study, CVD-Mali will conduct surveillance at 4 health centers serving the population currently participating in a demographic surveillance system and will measure the local incidence of diarrhea and related outcomes in 6- to 35-month-old children. Antibiotic sensitivity patterns and the costs related to these cases will also be measured.
RESULTS
We anticipate reporting the number of diarrhea episodes that are positive by stool culture, the antibiotic susceptibility of these isolates, and the management and outcomes of these cases.
CONCLUSIONS
In Mali, the EFGH study will contribute valuable information to understanding the burden of in this population. These data will inform the evaluation of vaccine candidates.
PubMed: 38532954
DOI: 10.1093/ofid/ofae003 -
Frontiers in Immunology 2024is the etiologic agent of a bacillary dysentery known as shigellosis, which causes millions of infections and thousands of deaths worldwide each year due to 's unique...
INTRODUCTION
is the etiologic agent of a bacillary dysentery known as shigellosis, which causes millions of infections and thousands of deaths worldwide each year due to 's unique lifestyle within intestinal epithelial cells. Cell adhesion/invasion assays have been extensively used not only to identify targets mediating host-pathogen interaction, but also to evaluate the ability of -specific antibodies to reduce virulence. However, these assays are time-consuming and labor-intensive and fail to assess differences at the single-cell level.
OBJECTIVES AND METHODS
Here, we developed a simple, fast and high-content method named visual Adhesion/Invasion Inhibition Assay (vAIA) to measure the ability of anti-antibodies to inhibit bacterial adhesion to and invasion of epithelial cells by using the confocal microscope Opera Phenix.
RESULTS
We showed that vAIA performed well with a pooled human serum from subjects challenged with and that a specific anti-IpaD monoclonal antibody effectively reduced bacterial virulence in a dose-dependent manner.
DISCUSSION
vAIA can therefore inform on the functionality of polyclonal and monoclonal responses thereby supporting the discovery of pathogenicity mechanisms and the development of candidate vaccines and immunotherapies. Lastly, this assay is very versatile and may be easily applied to other species or serotypes and to different pathogens.
Topics: Humans; Bacterial Adhesion; Dysentery, Bacillary; Antibodies, Bacterial; Host-Pathogen Interactions; Shigella; Epithelial Cells; Shigella sonnei; Antibodies, Monoclonal; HeLa Cells
PubMed: 38680489
DOI: 10.3389/fimmu.2024.1374293 -
Open Forum Infectious Diseases Mar 2024is a leading cause of acute watery diarrhea, dysentery, and diarrhea-attributed linear growth faltering, a precursor to stunting and lifelong morbidity. Several...
BACKGROUND
is a leading cause of acute watery diarrhea, dysentery, and diarrhea-attributed linear growth faltering, a precursor to stunting and lifelong morbidity. Several promising vaccines are in development and field efficacy trials will require a consortium of potential vaccine trial sites with up-to-date diarrhea incidence data.
METHODS
The Enterics for Global Health (EFGH) surveillance study will employ facility-based enrollment of diarrhea cases aged 6-35 months with 3 months of follow-up to establish incidence rates and document clinical, anthropometric, and financial consequences of diarrhea at 7 country sites (Mali, Kenya, The Gambia, Malawi, Bangladesh, Pakistan, and Peru). Over a 24-month period between 2022 and 2024, the EFGH study aims to enroll 9800 children (1400 per country site) between 6 and 35 months of age who present to local health facilities with diarrhea. species (spp.) will be identified and serotyped from rectal swabs by conventional microbiologic methods and quantitative polymerase chain reaction. spp. isolates will undergo serotyping and antimicrobial susceptibility testing. Incorporating population and healthcare utilization estimates from contemporaneous household sampling in the catchment areas of enrollment facilities, we will estimate diarrhea incidence rates.
CONCLUSIONS
This multicountry surveillance network will provide key incidence data needed to design vaccine trials and strengthen readiness for potential trial implementation. Data collected in EFGH will inform policy makers about the relative importance of this vaccine-preventable disease, accelerating the time to vaccine availability and uptake among children in high-burden settings.
PubMed: 38532963
DOI: 10.1093/ofid/ofad664 -
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 -
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 -
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 -
Frontiers in Immunology 2024Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however,...
BACKGROUND
Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however, limited data available to define the appropriate timing for vaccine administration in this age group. Information on antibody responses following natural infection, proxy for exposure, could help guide vaccination strategies.
METHODS
We undertook a retrospective analysis of antibodies to five of the most prevalent serotypes among children aged <5 years in Kenya. Serum samples from a cross-sectional serosurvey in three Kenyan sites (Nairobi, Siaya, and Kilifi) were analyzed by standardized ELISA to measure IgG against and 1b, 2a, 3a, and 6. We identified factors associated with seropositivity to each serotype, including seropositivity to other serotypes.
RESULTS
A total of 474 samples, one for each participant, were analyzed: Nairobi ( = 169), Siaya ( = 185), and Kilifi ( = 120). The median age of the participants was 13.4 months (IQR 7.0-35.6), and the male:female ratio was 1:1. Geometric mean concentrations (GMCs) for each serotype increased with age, mostly in the second year of life. The overall seroprevalence of IgG antibodies increased with age except for 6 which was high across all age subgroups. In the second year of life, there was a statistically significant increase of antibody GMCs against all five serotypes ( = 0.01-0.0001) and a significant increase of seroprevalence for 2a ( = 0.006), 3a ( = 0.006), and ( = 0.05) compared with the second part of the first year of life. Among all possible pairwise comparisons of antibody seropositivity, there was a significant association between 1b and 2a (OR = 6.75, 95% CI 3-14, < 0.001) and between 1b and 3a (OR = 23.85, 95% CI 11-54, < 0.001).
CONCLUSION
Children living in low- and middle-income settings such as Kenya are exposed to infection starting from the first year of life and acquire serotype-specific antibodies against multiple serotypes. The data from this study suggest that vaccination should be targeted to infants, ideally at 6 or at least 9 months of age, to ensure children are protected in the second year of life when exposure significantly increases.
Topics: Infant; Child; Humans; Male; Female; Child, Preschool; Kenya; Serogroup; Immunoglobulin G; Retrospective Studies; Seroepidemiologic Studies; Cross-Sectional Studies; Shigella; Dysentery, Bacillary; Vaccination
PubMed: 38361949
DOI: 10.3389/fimmu.2024.1340425 -
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 -
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 -
PloS One 2024B memory (BM) cell responses were evaluated using peripheral blood mononuclear cells that were collected and cryopreserved during a Phase 1 trial of two live Shigella...
B memory (BM) cell responses were evaluated using peripheral blood mononuclear cells that were collected and cryopreserved during a Phase 1 trial of two live Shigella sonnei vaccine candidates WRSs2 and WRSs3. An ELISpot assay was used to measure IgG+ and IgA+ BM cell responses against S. sonnei LPS, IVP and IpaB antigens. Analysis of BM cell responses at baseline, and on days 28 and 56 post vaccination indicate that after a single oral dose of WRSs2 and WRSs3, both groups of vaccinees induced IgG+ and IgA+ BM cell responses that were variable in magnitude among subjects and reached significance to IVP and IpaB at several doses. The responses generally peaked at d28 after vaccination. The baseline as well as post-vaccination levels of IgA+ BM cells were relatively higher than IgG+ BM cells, but the maximum fold-increase at d28/d56 over baseline was greater for IgG+ than IgA+ BM cell responses. Furthermore, at the three highest vaccine doses, >60-90% of subjects were considered responders indicating a ≥2-fold higher IgG+ BM cell responses to IVP and IpaB post vaccination, while fewer subjects indicated the same level of response to LPS.
Topics: Humans; Antibodies, Bacterial; Antigens; Bacterial Proteins; Immunoglobulin A; Immunoglobulin G; Leukocytes, Mononuclear; Lipopolysaccharides; Shigella sonnei; Shigella Vaccines; Vaccination; Vaccines, Attenuated; Clinical Trials, Phase I as Topic
PubMed: 38232106
DOI: 10.1371/journal.pone.0290987