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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 -
Vaccine Jul 2023There is a need for vaccines effective against shigella infection in young children in resource-limited areas. Protective immunity against shigella infection targets the...
There is a need for vaccines effective against shigella infection in young children in resource-limited areas. Protective immunity against shigella infection targets the O-specific polysaccharide (OSP) component of lipopolysaccharide. Inducing immune responses to polysaccharides in young children can be problematic, but high level and durable responses can be induced by presenting polysaccharides conjugated to carrier proteins. An effective shigella vaccine will need to be multivalent, targeting the most common global species and serotypes such as Shigella flexneri 2a, S. flexneri 3a, S. flexneri 6, and S. sonnei. Here we report the development of shigella conjugate vaccines (SCV) targeting S. flexneri 2a (SCV-Sf2a) and 3a (SCV-Sf3a) using squaric acid chemistry to result in single point sun-burst type display of OSP from carrier protein rTTHc, a 52 kDa recombinant protein fragment of the heavy chain of tetanus toxoid. We confirmed structure and demonstrated that these conjugates were recognized by serotype-specific monoclonal antibodies and convalescent sera of humans recovering from shigellosis in Bangladesh, suggesting correct immunological display of OSP. We vaccinated mice and found induction of serotype-specific OSP and LPS IgG responses, as well as rTTHc-specific IgG responses. Vaccination induced serotype-specific bactericidal antibody responses against S. flexneri, and vaccinated animals were protected against keratoconjunctivitis (Sereny test) and intraperitoneal challenge with virulent S. flexneri 2a and 3a, respectively. Our results support further development of this platform conjugation technology in the development of shigella conjugate vaccines for use in resource-limited settings.
Topics: Humans; Child; Animals; Mice; Child, Preschool; Shigella Vaccines; Shigella flexneri; Vaccines, Conjugate; Dysentery, Bacillary; Shigella; Lipopolysaccharides; O Antigens; Antibodies, Bacterial; Immunoglobulin G
PubMed: 37400283
DOI: 10.1016/j.vaccine.2023.06.052 -
MSphere Aug 2023The artificial invasin complex (Invaplex) vaccine is a subunit approach that effectively induces robust immunogenicity directed to serotype-specific lipopolysaccharide...
The artificial invasin complex (Invaplex) vaccine is a subunit approach that effectively induces robust immunogenicity directed to serotype-specific lipopolysaccharide and the broadly conserved IpaB and IpaC proteins. One advantage of the vaccine approach is the ability to adjust the constituents to address suboptimal immunogenicity and to change the serotype targeted by the vaccine. As the vaccine moves through the product development pipeline, substantial modifications have been made to address manufacturing feasibility, acceptability to regulatory authorities, and developing immunogenic and effective products for an expanded list of serotypes. Modifications of the recombinant clones used to express affinity tag-free proteins using well-established purification methods, changes to detergents utilized in the assembly process, and and evaluation of different Invaplex formulations have led to the establishment of a scalable, reproducible manufacturing process and enhanced immunogenicity of Invaplex products designed to protect against four of the most predominant serotypes responsible for global morbidity and mortality. These adjustments and improvements provide the pathway for the manufacture and clinical testing of a multivalent Invaplex vaccine. IMPORTANCE species are a major global health concern that cause severe diarrhea and dysentery in children and travelers to endemic areas of the world. Despite significant advancements in access to clean water, the increases in antimicrobial resistance and the risk of post-infection sequelae, including cognitive and physical stunting in children, highlight the urgent need for an efficacious vaccine. One promising vaccine approach, artificial Invaplex, delivers key antigens recognized by the immune system during infection, which results in increased resistance to re-infection. The work presented here describes novel modifications to a previously described vaccine approach resulting in improved methods for manufacturing and regulatory approvals, expansion of the breadth of coverage to all major serotypes, and an increase in the potency of artificial Invaplex.
Topics: Child; Humans; Shigella flexneri; Shigella Vaccines; Shigella; Lipopolysaccharides; Vaccines
PubMed: 37389412
DOI: 10.1128/msphere.00073-23 -
Frontiers in Cellular and Infection... 2023is a major global pathogen and the etiological agent of shigellosis, a diarrheal disease that primarily affects low- and middle-income countries. Shigellosis is... (Review)
Review
is a major global pathogen and the etiological agent of shigellosis, a diarrheal disease that primarily affects low- and middle-income countries. Shigellosis is characterized by a complex, multistep pathogenesis during which bacteria use multiple invasion proteins to manipulate and invade the intestinal epithelium. Antibodies, especially against the O-antigen and some invasion proteins, play a protective role as titres against specific antigens inversely correlate with disease severity; however, the context of antibody action during pathogenesis remains to be elucidated, especially with being mostly an intracellular pathogen. In the absence of a correlate of protection, functional assays rebuilding salient moments of pathogenesis can improve our understanding of the role of protective antibodies in blocking infection and disease. assays are important tools to build correlates of protection. Only recently animal models to recapitulate human pathogenesis, often not in full, have been established. This review aims to discuss assays to evaluate the functionality of anti- antibodies in polyclonal sera in light of the multistep and multifaced infection process. Indeed, measurement of antibody level alone may limit the evaluation of full vaccine potential. Serum bactericidal assay (SBA), and other functional assays such as opsonophagocytic killing assays (OPKA), and adhesion/invasion inhibition assays (AIA), are instead physiologically relevant and may provide important information regarding the role played by these effector mechanisms in protective immunity. Ultimately, the review aims at providing scientists in the field with new points of view regarding the significance of functional assays of choice which may be more representative of immune-mediated protection mechanisms.
Topics: Animals; Humans; Dysentery, Bacillary; Antibodies, Bacterial; Shigella; Immunoglobulins; Intestinal Mucosa; Shigella flexneri
PubMed: 37260708
DOI: 10.3389/fcimb.2023.1171213 -
BioRxiv : the Preprint Server For... May 2023Shigella is the second leading cause of diarrheal disease-related death in young children in low and middle income countries. The mechanism of protection against...
Shigella is the second leading cause of diarrheal disease-related death in young children in low and middle income countries. The mechanism of protection against shigella infection and disease in endemic areas is uncertain. While historically LPS-specific IgG titers have been associated with protection in endemic settings, emerging deeper immune approaches have recently elucidated a protective role for IpaB-specific antibody responses in a controlled human challenge model in North American volunteers. To deeply interrogate potential correlates of immunity in areas endemic for shigellosis, here we applied a systems approach to analyze the serological response to shigella across endemic and non-endemic populations. Additionally, we analyzed shigella-specific antibody responses over time in the context of endemic resistance or breakthrough infections in a high shigella burden location. Individuals with endemic exposure to shigella possessed broad and functional antibody responses across both glycolipid and protein antigens compared to individuals from non-endemic regions. In high shigella burden settings, elevated levels of OSP-specific FcαR binding antibodies were associated with resistance to shigellosis. OSP-specific FcαR binding IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation and reactive oxygen species production. Moreover, IgA depletion from resistant serum significantly reduced binding of OSP-specific antibodies to FcαR and antibody mediated activation of neutrophils and monocytes. Overall, our findings suggest that OSP-specific functional IgA responses contribute to protective immunity against shigella infection in high-burden settings. These findings will assist in the development and evaluation of shigella vaccines.
PubMed: 37205407
DOI: 10.1101/2023.05.04.539451 -
The Lancet. Global Health Jun 2023Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to...
BACKGROUND
Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to linear growth faltering (LGF). However, benefits from potential reductions in LGF are rarely included in economic analyses of enteric infections. We aimed to quantify the economic benefits of vaccination related to reduced Shigella-attributable disease and associated LGF compared with the net costs of a vaccine programme.
METHODS
In this benefit-cost analysis, we modelled productivity benefits in 102 low-income and middle-income countries that had recent stunting estimates available, at least one Shigella-attributable death annually, and available economic data, particularly on gross national income and growth rate projections. We modelled benefits strictly related to linear growth improvements and no other benefits associated with reducing diarrhoeal burden. The effect size in each country was calculated as shifts in height-for-age Z score (HAZ), representing population average changes for preventing Shigella-attributable less-severe diarrhoea and moderate-to-severe diarrhoea separately for children younger than 5 years. Benefits data were calculated per country and combined with estimated net costs of the vaccine programme in the form of benefit-cost ratios (BCRs); BCRs above parity, or $1 in benefits per $1 in costs (with a 10% margin representing borderline results: 1·10:1), were considered cost-beneficial. Countries were aggregated for analysis by WHO region, World Bank income category, and eligibility for support from Gavi, the Vaccine Alliance.
FINDINGS
In the base-case scenario, all regions exhibited cost-beneficial results, with the South-East Asia region and Gavi-eligible countries exhibiting the highest BCRs (21·67 for the South-East Asia region and 14·45 for Gavi-eligible countries), and the Eastern Mediterranean region yielding the lowest BCRs (2·90). All regions exhibited cost-beneficial results from vaccination, except in more conservative scenarios (eg, those assuming early retirement ages and higher discount rates). Our findings were sensitive to assumed returns for increased height, assumptions about vaccine efficacy against linear growth detriments, the anticipated shift in HAZ, and discount rate. Incorporating the productivity benefits of LGF reduction into existing cost-effectiveness estimates resulted in longer-term cost-savings in nearly all regions.
INTERPRETATION
LGF is a secondary outcome of Shigella infection and reduction in LGF is not often quantified as a health or economic benefit of vaccination. However, even under conservative assumptions, a Shigella vaccine only moderately effective against LGF could pay for itself from productivity gains alone in some regions. We recommend that LGF be considered in future models assessing the economic and health impacts of interventions preventing enteric infections. Further research is needed on vaccine efficacy against LGF to inform such models.
FUNDING
Bill & Melinda Gates Foundation, Wellcome Trust.
Topics: Child; Humans; Diarrhea; Vaccines; Growth Disorders; Child Development; Cost-Benefit Analysis; Shigella
PubMed: 37202024
DOI: 10.1016/S2214-109X(23)00050-5 -
The Lancet. Global Health Jun 2023Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with...
BACKGROUND
Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea.
METHODS
We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes.
FINDINGS
We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions.
INTERPRETATION
Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis.
FUNDING
Bill & Melinda Gates Foundation and Wellcome Trust.
Topics: Humans; Child; Infant; Cost-Benefit Analysis; Developing Countries; Diarrhea; Shigella; Vaccination; Growth Disorders
PubMed: 37202023
DOI: 10.1016/S2214-109X(23)00192-4 -
Carbohydrate Polymers Aug 2023Outer membrane vesicles (OMV) represent an innovative platform for the design of polysaccharide based vaccines. Generalized Modules for Membrane Antigens (GMMA), OMV...
Outer membrane vesicles (OMV) represent an innovative platform for the design of polysaccharide based vaccines. Generalized Modules for Membrane Antigens (GMMA), OMV released from engineered Gram-negative bacteria, have been proposed for the delivery of the O-Antigen, key target for protective immunity against several pathogens including Shigella. altSonflex1-2-3 is a GMMA based vaccine, including S. sonnei and S. flexneri 1b, 2a and 3a O-Antigens, with the aim to elicit broad protection against the most prevalent Shigella serotypes, especially affecting children in low-middle income countries. Here we developed an In Vitro Relative Potency assay, based on recognition of O-Antigen by functional monoclonal antibodies selected to bind the key epitopes of the different O-Antigen active ingredients, directly applied to our Alhydrogel-formulated vaccine. Heat-stressed altSonflex1-2-3 formulations were generated and extensively characterized. The impact of detected biochemical changes in in vivo and in vitro potency assays was assessed. The overall results showed how the in vitro assay can replace the use of animals, overcoming the inherently high variability of in vivo potency studies. The entire panel of physico-chemical methods developed will contribute to detect suboptimal batches and will be valuable to perform stability studies. The work on Shigella vaccine candidate can be easily extended to other O-Antigen based vaccines.
Topics: Animals; O Antigens; Shigella sonnei; Shigella; Shigella Vaccines
PubMed: 37173008
DOI: 10.1016/j.carbpol.2023.120920 -
Vibrio cholerae in rural and urban Bangladesh, findings from hospital-based surveillance, 2000-2021.Scientific Reports Apr 2023With more than 100,000 cases estimated each year, Bangladesh is one of the countries with the highest number of people at risk for cholera. Moreover, Bangladesh is...
With more than 100,000 cases estimated each year, Bangladesh is one of the countries with the highest number of people at risk for cholera. Moreover, Bangladesh is formulating a countrywide cholera-control plan to satisfy the GTFCC (The Global Task Force on Cholera Control) Roadmap's goals. With a particular focus on cholera trends, variance in baseline and clinical characteristics of cholera cases, and trends in antibiotic susceptibility among clinical isolates of Vibrio cholerae, we used data from facility-based surveillance systems from icddr,b's Dhaka, and Matlab Hospitals from years 2000 to 2021. Female patients comprised 3,553 (43%) in urban and 1,099 (51.6%) in rural sites. Of the cases and most patients 5,236 (63.7%) in urban and 1,208 (56.7%) in the rural site were aged 15 years and more. More than 50% of the families belonged to the poor and lower-middle-class; in 2009 (24.4%) were in urban and in 1,791 (84.2%) were in rural sites. In the urban site, 2,446 (30%) of households used untreated drinking water, and 702 (9%) of families disposed of waste in their courtyard. In the multiple logistic regression analysis, the risk of cholera has significantly increased due to waste disposal in the courtyard and the boiling of water has a protective effect against cholera. Rotavirus (9.7%) was the most prevalent co-pathogen among the under-5 children in both sites. In urban sites, the percentage of V. cholerae along with co-existing ETEC and Campylobacter is changing in the last 20 years; Campylobacter (8.36%) and Enterotoxigenic Escherichia coli (ETEC) (7.15%) were the second and third most prevalent co-pathogens. Shigella (1.64%) was the second most common co-pathogen in the rural site. Azithromycin susceptibility increased slowly from 265 (8%) in 2006-2010 to 1485 (47.8%) in 2016-2021, and erythromycin susceptibility dropped substantially over 20 years period from 2,155 (98.4%) to 21 (0.9%). Tetracycline susceptibility decreased in the urban site from 2051 (45.9%) to 186 (4.2%) and ciprofloxacin susceptibility decreased from 2,581 (31.6%) to 1,360 (16.6%) until 2015, then increased 1,009 (22.6%) and 1,490 (18.2%) in 2016-2021, respectively. Since 2016, doxycycline showed 902 (100%) susceptibility. Clinicians need access to up-to-date information on antimicrobial susceptibility for treating hospitalized patients. To achieve the WHO-backed objective of eliminating cholera by 2030, the health systems need to be put under a proper surveillance system that may help to improve water and sanitation practices and deploy oral cholera vaccines strategically.
Topics: Child; Humans; Female; Vibrio cholerae; Cholera; Bangladesh; Hospitals; Enterotoxigenic Escherichia coli; Water
PubMed: 37076586
DOI: 10.1038/s41598-023-33576-3 -
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