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Clinical Infectious Diseases : An... Apr 2023We evaluated the burden of Shigella spp from children aged 0-59 months with medically attended moderate-to-severe diarrhea and matched controls at sites in Mali, The...
BACKGROUND
We evaluated the burden of Shigella spp from children aged 0-59 months with medically attended moderate-to-severe diarrhea and matched controls at sites in Mali, The Gambia, and Kenya participating in the Vaccine Impact on Diarrhea in Africa (VIDA) study from 2015 to 2018.
METHODS
Shigella spp were identified using coprocultures and serotyping in addition to quantitative polymerase chain reaction (qPCR). Episode-specific attributable fractions (AFe) for Shigella were calculated using Shigella DNA quantity; cases with AFe ≥0.5 were considered to have shigellosis.
RESULTS
The prevalence of Shigella was determined to be 359 of 4840 (7.4%) cases and 83 of 6213 (1.3%) controls by culture, and 1641 of 4836 (33.9%) cases and 1084 of 4846 (22.4%) controls by qPCR (cycle threshold <35); shigellosis was higher in The Gambia (30.8%) than in Mali (9.3%) and Kenya (18.7%). Bloody diarrhea attributed to Shigella was more common in 24- to 59-month-old children (50.1%) than 0- to 11-month-old infants (39.5%). The Shigella flexneri serogroup predominated among cases (67.6% of isolates), followed by Shigella sonnei (18.2%), Shigella boydii (11.8%), and Shigella dysenteriae (2.3%). The most frequent S. flexneri serotypes were 2a (40.6%), 1b (18.8%), 6 (17.5%), 3a (9.0%), and 4a (5.1%). Drug-specific resistance among 353 (98.3%) Shigella cases with AMR data was as follows: trimethoprim-sulfamethoxazole (94.9%), ampicillin (48.4%), nalidixic acid (1.7%), ceftriaxone (0.3%), azithromycin (0.3%), and ciprofloxacin (0.0%).
CONCLUSIONS
A high prevalence of shigellosis continues in sub-Saharan Africa. Strains are highly resistant to commonly used antibiotics while remaining susceptible to ciprofloxacin, ceftriaxone, and azithromycin.
Topics: Child; Infant; Humans; Child, Preschool; Infant, Newborn; Dysentery, Bacillary; Azithromycin; Ceftriaxone; Shigella; Anti-Bacterial Agents; Ciprofloxacin; Diarrhea; Mali; Microbial Sensitivity Tests
PubMed: 37074444
DOI: 10.1093/cid/ciac969 -
Clinical Infectious Diseases : An... Apr 2023The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces...
Exploring Survey-Based Water, Sanitation, and Animal Associations With Enteric Pathogen Carriage: Comparing Results in a Cohort of Cases With Moderate-to-Severe Diarrhea to Those in Controls in the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018.
BACKGROUND
The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study.
METHODS
In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged <5 years with moderate-to-severe diarrhea and their matched controls (diarrhea-free in prior 7 days) via the TaqMan Array Card and surveyed caregivers about household drinking water and sanitation conditions and animals living in the compound. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using modified Poisson regression models, stratified for cases and controls and adjusted for age, sex, site, and demographics.
RESULTS
Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold <35) in the 4840 cases and 6213 controls. In cases, unimproved sanitation (RR, 1.56; 95% CI, 1.12-2.17), as well as cows (RR, 1.61; 95% CI, 1.16-2.24) and sheep (RR, 1.48; 95% CI, 1.11-1.96) living in the compound, were associated with Shiga toxin-producing Escherichia coli. In controls, fowl (RR, 1.30; 95% CI, 1.15-1.47) were associated with Campylobacter spp. In controls, surface water sources were associated with Cryptosporidium spp., Shigella spp., heat-stable toxin-producing enterotoxigenic E. coli, and Giardia spp.
CONCLUSIONS
Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children.
Topics: Case-Control Studies; Diarrhea; Water Supply; Sanitation; Gastrointestinal Microbiome; Feces; Humans; Animals; Cattle; Child; Cholera Vaccines
PubMed: 37074442
DOI: 10.1093/cid/ciac918 -
Clinical Infectious Diseases : An... Apr 2023Diarrheal disease is heterogeneous, including watery diarrhea (WD) and dysentery, some cases of which become persistent diarrhea (PD). Changes in risk over time...
Etiology, Presentation, and Risk Factors for Diarrheal Syndromes in 3 Sub-Saharan African Countries After the Introduction of Rotavirus Vaccines From the Vaccine Impact on Diarrhea in Africa (VIDA) Study.
BACKGROUND
Diarrheal disease is heterogeneous, including watery diarrhea (WD) and dysentery, some cases of which become persistent diarrhea (PD). Changes in risk over time necessitate updated knowledge of these syndromes in sub-Saharan Africa.
METHODS
The Vaccine Impact on Diarrhea in Africa (VIDA) study was an age-stratified, case-control study of moderate-to-severe diarrhea among children <5 years old in The Gambia, Mali, and Kenya (2015-2018). We analyzed cases with follow-up of about 60 days after enrollment to detect PD (lasting ≥14 days), examined the features of WD and dysentery, and examined determinants for progression to and sequelae from PD. Data were compared with those from the Global Enteric Multicenter Study (GEMS) to detect temporal changes. Etiology was assessed from stool samples using pathogen attributable fractions (AFs), and predictors were assessed using χ2 tests or multivariate regression, where appropriate.
RESULTS
Among 4606 children with moderate-to-severe diarrhea, 3895 (84.6%) had WD and 711 (15.4%) had dysentery. PD was more frequent among infants (11.3%) than in children 12-23 months (9.9%) or 24-59 months (7.3%), P = .001 and higher in Kenya (15.5%) than in The Gambia (9.3%) or Mali (4.3%), P < .001; the frequencies were similar among children with WD (9.7%) and those with dysentery (9.4%). Compared to children not treated with antibiotics, those who received antibiotics had a lower frequency of PD overall (7.4% vs 10.1%, P = .01), and particularly among those with WD (6.3% vs 10.0%; P = .01) but not among children with dysentery (8.5% vs 11.0%; P = .27). For those with watery PD, Cryptosporidium and norovirus had the highest AFs among infants (0.16 and 0.12, respectively), while Shigella had the highest AF (0.25) in older children. The odds of PD decreased significantly over time in Mali and Kenya while increasing significantly in The Gambia.
CONCLUSIONS
The burden of PD endures in sub-Saharan Africa, with nearly 10% of episodes of WD and dysentery becoming persistent.
Topics: Infant; Child; Humans; Child, Preschool; Rotavirus Vaccines; Case-Control Studies; Cryptosporidiosis; Cryptosporidium; Diarrhea; Dysentery; Risk Factors; Kenya; Anti-Bacterial Agents
PubMed: 37074436
DOI: 10.1093/cid/ciad022 -
Clinical Infectious Diseases : An... Apr 2023To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli...
Epidemiology of Enteroaggregative, Enteropathogenic, and Shiga Toxin-Producing Escherichia coli Among Children Aged <5 Years in 3 Countries in Africa, 2015-2018: Vaccine Impact on Diarrhea in Africa (VIDA) Study.
BACKGROUND
To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya.
METHODS
Between May 2015 and July 2018, children aged 0-59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection.
RESULTS
Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged <23 months, aEPEC was similar across age strata, and STEC increased with age. No association between nutritional status at follow-up and DEC pathotypes was found. DEC coinfection with Shigella/enteroinvasive E. coli was more common among cases (P < .01).
CONCLUSIONS
No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease.
Topics: Child; Humans; Escherichia coli Infections; Shiga-Toxigenic Escherichia coli; Coinfection; Diarrhea; Enteropathogenic Escherichia coli; Kenya
PubMed: 37074433
DOI: 10.1093/cid/ciad035 -
Clinical Infectious Diseases : An... Apr 2023Diarrheal diseases remain a health threat to children in low- and middle-income countries. The Vaccine Impact on Diarrhea in Africa (VIDA) study was a 36-month,...
BACKGROUND
Diarrheal diseases remain a health threat to children in low- and middle-income countries. The Vaccine Impact on Diarrhea in Africa (VIDA) study was a 36-month, prospective, matched case-control study designed to estimate the etiology, incidence, and adverse clinical consequences of moderate-to-severe diarrhea (MSD) in children aged 0-59 months. VIDA was conducted following rotavirus vaccine introduction at 3 censused sites in sub-Saharan Africa that participated in the Global Enteric Multicenter Study (GEMS) ∼10 years earlier. We describe the study design and statistical methods of VIDA and where they differ from GEMS.
METHODS
We aimed to enroll 8-9 MSD cases every 2 weeks from sentinel health centers in 3 age strata (0-11, 12-23, 24-59 months) and 1 to 3 controls matched by age, sex, date of case enrollment, and village. Clinical, epidemiological, and anthropometric data were collected at enrollment and ∼60 days later. A stool specimen collected at enrollment was analyzed by both conventional methods and quantitative PCR for enteric pathogens. For the matched case-control study, we estimated the population-based, pathogen-specific attributable fraction (AF) and attributable incidence adjusted for age, site, and other pathogens, and identified episodes attributable to a specific pathogen for additional analyses. A prospective cohort study nested within the original matched case-control study allowed assessment of (1) the association between potential risk factors and outcomes other than MSD status and (2) the impact of MSD on linear growth.
CONCLUSIONS
GEMS and VIDA together comprise the largest and most comprehensive assessment of MSD conducted to date in sub-Saharan Africa populations at highest risk for morbidity and mortality from diarrhea. The statistical methods used in VIDA have endeavored to maximize the use of available data to produce more robust estimates of the pathogen-specific disease burden that might be prevented by effective interventions.
Topics: Child; Humans; Infant; Prospective Studies; Case-Control Studies; Diarrhea; Africa South of the Sahara; Rotavirus Vaccines
PubMed: 37074428
DOI: 10.1093/cid/ciac968 -
Human Vaccines & Immunotherapeutics Dec 2023The ongoing COVID-19 pandemic highlights that complications and mortality associated with infectious diseases increase with age. Various vaccines are recommended for... (Review)
Review
The ongoing COVID-19 pandemic highlights that complications and mortality associated with infectious diseases increase with age. Various vaccines are recommended for adults, but coverage rates remain suboptimal. Although co-administration would improve vaccine uptake and timely immunization, this is not routine practice in adults. We review key data on co-administration of vaccines in children and adults to reassure healthcare providers about its safety and advantages. In European countries and the United States, combined tetanus, diphtheria, and acellular pertussis boosters as well as meningococcal and human papillomavirus vaccines are recommended for healthy adolescents and adults of certain ages. Vaccination against influenza (annually), pneumococcal disease, and herpes zoster is recommended for older adults and specific risk groups. While co-administration is well established in children, it is less common in adults. Travelers can also receive multiple co-administered vaccines. Pediatric and travel vaccine co-administration has a well-established positive benefit-risk profile and is an efficient and cost-saving strategy to improve coverage. Healthcare providers could more often recommend and practice vaccine co-administration; this would not risk patient safety and health, would improve protection against vaccine-preventable diseases, and would help comply with national vaccination calendars. Recommending bodies may consider revising vaccination schedules to reduce the number of visits.
Topics: Adolescent; Humans; Child; United States; Aged; Vaccination Coverage; Pandemics; COVID-19; Vaccination; Tetanus Toxoid; Diphtheria-Tetanus-acellular Pertussis Vaccines
PubMed: 37039318
DOI: 10.1080/21645515.2023.2195786 -
MSphere Jun 2023is responsible for high burdens of diarrhea and dysentery globally. Children living in areas of endemicity are the most affected, and currently, there are no licensed...
is responsible for high burdens of diarrhea and dysentery globally. Children living in areas of endemicity are the most affected, and currently, there are no licensed vaccines to prevent shigellosis. Vaccine approaches have traditionally targeted the bacterial lipopolysaccharide as a protective antigen. O-polysaccharide (OPS) conjugated to recombinant Pseudomonas aeruginosa exotoxin A (rEPA) or tetanus toxoid (TT) is advanced in clinical evaluation. Adequate efficacy of these vaccines, particularly in the infant target group, remains to be demonstrated. A major limitation of the OPS-glycoconjugate concept is its limited coverage, since immunity to the O antigen is serotype specific, and there are multiple disease-causing serotypes. Another concern is the use of protein carriers already included in multiple other childhood vaccines. This study reports a novel OPS conjugate vaccine that uses the invasion plasmid antigen B (IpaB) as the carrier protein. IpaB is a virulence factor component of the type III secretion system and highly conserved among serotypes. It is robustly immunogenic and a protective antigen. IpaB and IpaB containing nonnative amino acids (nnAA) were produced at large scale using cell-free protein synthesis. Incorporation of nnAA enabled site-specific conjugation of IpaB to Shigella flexneri 2a OPS using click chemistry, yielding OPS-IpaB glycoconjugate. Parenteral immunization of mice with the OPS-IpaB vaccine resulted in high levels of OPS- and IpaB-specific serum IgG and robust protection against lethal S. flexneri 2a or Shigella sonnei challenge. The OPS-IpaB vaccine is a promising new vaccine candidate with the capacity to confer broad protection against clinically relevant serotypes. Diarrhea caused by species results in long-term disability and mortality globally, disproportionally affecting younger children living in poor countries. Although it is treatable by antibiotics, the rapid and widespread emergence of resistant strains and the highly contagious nature of the disease compel the development of preventive tools. Currently, several OPS conjugate vaccines are being evaluated in clinical studies, but these rely exclusively on immunity against the bacterial O antigen, which limits their coverage to only the immunizing serotype; multivalent vaccines are needed to protect against the most prevalent serotypes. This is the first report of a novel OPS-conjugate vaccine that uses IpaB as a carrier and protective antigen. This vaccine, administered parenterally, elicited robust immunity and protected mice against lethal infection by S. flexneri 2a or S. sonnei. The OPS-IpaB vaccine is a promising candidate for evaluation in vulnerable populations.
Topics: Animals; Mice; Vaccines, Conjugate; Serogroup; Antibody Formation; Shigella; Shigella Vaccines; Lipopolysaccharides; O Antigens; Pseudomonas aeruginosa Exotoxin A
PubMed: 37017547
DOI: 10.1128/msphere.00019-23 -
Journal of Personalized Medicine Mar 2023CpG is a widely used adjuvant that enhances the cellular immune response by entering antigen-presenting cells and binding with receptors. The traditional physical mixing...
CpG is a widely used adjuvant that enhances the cellular immune response by entering antigen-presenting cells and binding with receptors. The traditional physical mixing of the antigen and CpG adjuvant results in a low adjuvant utilization rate. Considering the efficient delivery capacity of nanovaccines, we developed an attractive strategy to covalently load CpG onto the nanovaccine, which realized the co-delivery of both CpG and the antigen. Briefly, the azide-modified CpG was conjugated to a bioconjugate nanovaccine (NP-OPS) against through a simple two-step reaction. After characterization of the novel vaccine (NP-OPS-CpG), a series of in vitro and in vivo experiments were performed, including in vivo imaging, lymph node sectioning, and dendritic cell stimulation, and the results showed that more CpG reached the lymph nodes after covalent coupling. Subsequent flow cytometry analysis of lymph nodes from immunized mice showed that the cellular immune response was greatly promoted by the nanovaccine coupled with CpG. Moreover, by analyzing the antibody subtypes of immunized mice, NP-OPS-CpG was found to further promote a Th1-biased immune response. Thus, we developed an attractive method to load CpG on a nanovaccine that is simple, convenient, and is especially suitable for immune enhancement of vaccines against intracellular bacteria.
PubMed: 36983689
DOI: 10.3390/jpm13030507 -
Brazilian Journal of Microbiology :... Jun 2023Shigellosis remains a worldwide health problem due to the lack of vaccines and the emergence of antibiotic-resistant strains. Shigella (S.) dysenteriae has rigid...
Shigellosis remains a worldwide health problem due to the lack of vaccines and the emergence of antibiotic-resistant strains. Shigella (S.) dysenteriae has rigid peptidoglycan (PG), and its tight regulation of biosynthesis and remodeling is essential for bacterial integrity. Lytic transglycosylases are highly conserved PG autolysins in bacteria that play essential roles in bacterial growth. However, their precise functions are obscure. We aimed to identify, clone, and express MltC, a unique autolysin in Escherichia (E.) coli C41 strain. The purification of recombinant MltC protein was performed using affinity chromatography and size-exclusion chromatography methods. The PG enzymatic activity of MltC was investigated using Zymogram and Fluorescein isothiocyanate (FITC)-labeled PG assays. Also, we aimed to detect its localization in bacterial fractions (cytoplasm and membrane) by western blot using specific polyclonal anti-MltC antibodies and its probable partners using immunoprecipitation and mass spectrometry applications. Purified MltC showed autolysin activity. Native MltC showed various locations in S. dysenteriae cells during different growth phases. In the Lag and early stationary phases, MltC was not found in cytoplasm and membrane fractions. However, it was detected in cytoplasm and membrane fractions during the exponential phase. In the late stationary phase, MltC was expressed in the membrane fraction only. Different candidate protein partners of MltC were identified that could be essential for bacterial growth and pathogenicity. This is the first study to suggest that MltC is indeed autolysin and could be a new drug target for the treatment of shigellosis by understanding its biological functions.
Topics: Humans; Peptidoglycan Glycosyltransferase; Shigella dysenteriae; N-Acetylmuramoyl-L-alanine Amidase; Dysentery, Bacillary; Escherichia coli; Recombinant Proteins; Peptidoglycan
PubMed: 36973582
DOI: 10.1007/s42770-023-00957-9 -
International Journal of Molecular... Feb 2023Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children... (Review)
Review
Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children under 5 years of age. In the last decades, has become even more worrisome because of the onset of antimicrobial-resistant strains (AMR). Indeed, the WHO has listed as one of the priority pathogens for the development of new interventions. To date, there are no broadly available vaccines against shigellosis, but several candidates are being evaluated in preclinical and clinical studies, bringing to light very important data and information. With the aim to facilitate the understanding of the state-of-the-art of vaccine development, here we report what is known about epidemiology and pathogenesis with a focus on virulence factors and potential antigens for vaccine development. We discuss immunity after natural infection and immunization. In addition, we highlight the main characteristics of the different technologies that have been applied for the development of a vaccine with broad protection against .
Topics: Child; Humans; Child, Preschool; Shigella Vaccines; Dysentery, Bacillary; Shigella; Virulence Factors; Anti-Infective Agents
PubMed: 36902092
DOI: 10.3390/ijms24054649