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Vaccines Feb 2024is a leading cause of moderate-to-severe diarrhea globally, with young children most affected. The burden of shigellosis drops increasingly with age, inferring the...
BACKGROUND
is a leading cause of moderate-to-severe diarrhea globally, with young children most affected. The burden of shigellosis drops increasingly with age, inferring the acquisition of natural immunity. We tested the hypothesis that IgG antibodies elicited against O-specific polysaccharide (O-SP) are correlates of age-acquired immunity.
OBJECTIVES
We examined levels and determinants of serum IgG to LPS and the association with the incidence of shigellosis in Israeli children and adolescents.
METHODS
We analyzed 1096 serum samples from 0- to 19-year-olds collected in 2008-2015 for IgG anti- LPS levels by ELISA. Corresponding age-specific incidences of culture-proven shigellosis from 2008 to 2015 were obtained. We compared ecologically IgG levels, prevalence above a proposed protective threshold, and shigellosis incidence.
RESULTS
In a multivariable analysis model, children aged 1-4, 5-14, and 15-19 years were 6.71, 27.68, and 48.62 times more likely to have IgG anti- LPS above the threshold than those aged < 1 year, respectively ( < 0.001). Infants 0-3 months old had relatively high IgG anti- LPS levels of maternal origin that dropped thereafter. Children of low socioeconomic status had a 2.73 times higher likelihood of having IgG anti- LPS above the threshold ( < 0.001). A significant inverse correlation between age-specific IgG anti- LPS levels and shigellosis incidence was observed (Spearman rho= -0.76, = 0.028).
CONCLUSIONS
The study results support anti- LPS antibodies as correlates of protection that can inform vaccine development.
PubMed: 38543873
DOI: 10.3390/vaccines12030239 -
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 -
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 -
Open Forum Infectious Diseases Mar 2024is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting are in development, and phase 3 clinical trials are imminent to determine...
BACKGROUND
is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis.
METHODS
The Enterics for Global Health (EFGH) surveillance study is designed to determine the incidence of medically attended shigellosis in 6- to 35-month-old children in 7 resource-limited settings. Here, we describe the microbiological methods used to isolate and identify . We developed a standardized laboratory protocol for isolation and identification of by culture. This protocol was implemented across all 7 sites, ensuring consistency and comparability of results. Secondary objectives of the study are to determine the antibiotic resistance profiles of , compare isolation of from rectal swabs versus whole stool, and compare isolation of following transport of rectal swabs in Cary-Blair versus a modified buffered glycerol saline transport medium.
CONCLUSIONS
Data generated from EFGH using culture methods described herein can potentially be used for microbiological endpoints in future phase 3 clinical trials to evaluate vaccines against shigellosis and for other clinical and public health studies focused on these organisms.
PubMed: 38532949
DOI: 10.1093/ofid/ofad576 -
NPJ Vaccines Mar 2024Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested...
Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4β7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.
PubMed: 38459072
DOI: 10.1038/s41541-024-00822-2 -
Journal of Visualized Experiments : JoVE Feb 2024The human-adapted enteric bacterial pathogen Shigella causes millions of infections each year, creates long-term growth effects among pediatric patients, and is a...
The human-adapted enteric bacterial pathogen Shigella causes millions of infections each year, creates long-term growth effects among pediatric patients, and is a leading cause of diarrheal deaths worldwide. Infection induces watery or bloody diarrhea as a result of the pathogen transiting the gastrointestinal tract and infecting the epithelial cells lining the colon. With staggering increases in antibiotic resistance and the current lack of approved vaccines, standardized research protocols are critical to studying this formidable pathogen. Here, methodologies are presented to examine the molecular pathogenesis of Shigella using in vitro analyses of bacterial adherence, invasion, and intracellular replication in colonic epithelial cells. Prior to infection analyses, the virulence phenotype of Shigella colonies was verified by the uptake of the Congo red dye on agar plates. Supplemented laboratory media can also be considered during bacterial culturing to mimic in vivo conditions. Bacterial cells are then used in a standardized protocol to infect colonic epithelial cells in tissue culture plates at an established multiplicity of infection with adaptations to analyze each stage of infection. For adherence assays, Shigella cells are incubated with reduced media levels to promote bacterial contact with epithelial cells. For both invasion and intracellular replication assays, gentamicin is applied for various time intervals to eliminate extracellular bacteria and enable assessment of invasion and/or the quantification of intracellular replication rates. All infection protocols enumerate adherent, invaded, and/or intracellular bacteria by serially diluting infected epithelial cell lysates and plating bacterial colony forming units relative to infecting titers on Congo red agar plates. Together, these protocols enable independent characterization and comparisons for each stage of Shigella infection of epithelial cells to study this pathogen successfully.
Topics: Humans; Child; Agar; Congo Red; Shigella; Epithelial Cells; Dysentery, Bacillary; Diarrhea
PubMed: 38407235
DOI: 10.3791/66426 -
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 -
International Journal of Molecular... Jan 2024Shigellosis, an acute gastroenteritis infection caused by species, remains a public health burden in developing countries. Recently, many outbreaks due to...
Shigellosis, an acute gastroenteritis infection caused by species, remains a public health burden in developing countries. Recently, many outbreaks due to multidrug-resistant strains have been reported in high-income countries, and the lack of an effective vaccine represents a major hurdle to counteract this bacterial pathogen. Vaccine candidates against are under clinical development, including a Generalized Modules for Membrane Antigens (GMMA)-based vaccine. The mechanisms by which GMMA-based vaccines interact and activate human immune cells remain elusive. Our previous study provided the first evidence that both adaptive and innate immune cells are targeted and functionally shaped by the GMMA-based vaccine. Here, flow cytometry and confocal microscopy analysis allowed us to identify monocytes as the main target population interacting with the 1790-GMMA vaccine on human peripheral blood. In addition, transcriptomic analysis of this cell population revealed a molecular signature induced by 1790-GMMA mostly correlated with the inflammatory response and cytokine-induced processes. This also impacts the expression of genes associated with macrophages' differentiation and T cell regulation, suggesting a dual function for this vaccine platform both as an antigen carrier and as a regulator of immune cell activation and differentiation.
Topics: Humans; Monocytes; Shigella sonnei; Antigens, Bacterial; Vaccines; Blood Group Antigens; Gastroenteritis; Methylmethacrylates
PubMed: 38256189
DOI: 10.3390/ijms25021116 -
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 -
Microbial Pathogenesis Mar 2024Shigella is one of the major causes of dysenteric diarrhea, which is known shigelosis. Shigelosis causes 160,000 deaths annually of diarrheal disease in the global scale...
BACKGROUND
Shigella is one of the major causes of dysenteric diarrhea, which is known shigelosis. Shigelosis causes 160,000 deaths annually of diarrheal disease in the global scale especially children less than 5 years old. No licensed vaccine is available against shigelosis, therefore, efforts for develop an effective and safe vaccine against Shigella as before needed. The reverse vaccinology (RV) is a novel strategy that evaluate genome or proteome of the organism to find a new promising vaccine candidate. In this study, immunogenicity of a designed-recombinant antigen is evaluated through the in silico studies and animal experiments to predict a new immunogenic candidate against Shigella.
METHODS
In the first step, proteome of Shigella flexneri was obtained from UniProtKB and then the outer membrane and extracellular proteins were predicted. In this study TolC as an outer membrane protein was selected and confirmed among candidates. In next steps, pre-selected protein was evaluated for transmembrane domains, homology, conservation, antigenicity, solubility, and B- and T-cell prediction by different online servers.
RESULT
TolC as a conserved outer membrane protein, using different immune-informatics tools had acceptable scores and was selected as the immunogenic antigen for animal experiment studies. Recombinant TolC protein after expression and purification, was administered to BALB/c mice over three intraperitoneal routes. The sera of mice was used to evaluate the IgG1 production assay by indirect-ELISA. The immunized mice depicted effective protection against 2LD of Shigella. Flexneri ATCC12022 (challenge study).
CONCLUSION
Therefore, the reverse vaccinology approach and experimental test results demonstrated that TolC as a novel effective and immunogenic antigen is capable for protection against shigellosis.
Topics: Humans; Child; Animals; Mice; Child, Preschool; Shigella flexneri; Protein Subunit Vaccines; Shigella Vaccines; Proteome; Shigella; Dysentery, Bacillary; Recombinant Proteins; Vaccines, Synthetic; Membrane Proteins; Antibodies, Bacterial
PubMed: 38211835
DOI: 10.1016/j.micpath.2024.106539