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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 -
Travel Medicine and Infectious Disease 2023Southeast Asia is attractive for tourism. Unfortunately, travelers to this region are at risk of becoming infected with Shigella. We conducted a meta-analysis to provide... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Southeast Asia is attractive for tourism. Unfortunately, travelers to this region are at risk of becoming infected with Shigella. We conducted a meta-analysis to provide updates on Shigella prevalence in Southeast Asia, along with their serogroups and serotypes.
METHODS
We conducted a systematic search using PubMed, EMBASE, and Web of Science for peer-reviewed studies from 2000 to November 2022. We selected studies that detected Shigella in stools by culture or polymerase chain reaction (PCR). Two reviewers extracted the data using a standardized form and performed quality assessments using the Joanna Briggs Institute checklist. The random effects model was used to estimate the pooled prevalence of Shigella.
RESULTS
During our search, we identified 4376 studies. 29 studies (from six Southeast Asian countries) were included in the systematic review, 21 each in the meta-analysis of the prevalence of Shigella (Sample size: 109545) and the prevalence of Shigella serogroups. The pooled prevalence of Shigella was 4% (95% CI: 4-5%) among diarrhea cases. Shigella sonnei was the most abundant serogroup in Thailand (74%) and Vietnam (57%), whereas Shigella flexneri was dominant in Indonesia (72%) and Cambodia (71%). Shigella dysenteriae and Shigella boydii were uncommon (pooled prevalence of 1% each). The pooled prevalence of Shigella was 5% (95% CI: 4-6%) in children aged <5 years. The pooled prevalence showed a decreasing trend comparing data collected between 2000-2013 (5%; 95% CI: 4-6%) and between 2014-2022 (3%; 95% CI: 2-4%). Shigella prevalence was 6% in studies that included participants with mixed pathogens versus 3% in those without. Shigella flexneri serotype 2a was the most frequently isolated (33%), followed by 3a (21%), 1b (10%), 2b (3%), and 6 (3%).
CONCLUSIONS
This study provides compelling evidence for the development of effective Shigella vaccines for residents of endemic regions and travellers to these areas.
Topics: Child; Humans; Dysentery, Bacillary; Shigella; Shigella dysenteriae; Shigella flexneri; Indonesia
PubMed: 36792021
DOI: 10.1016/j.tmaid.2023.102554 -
Vaccine Aug 2019Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing... (Review)
Review
Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing vaccines against enterotoxigenic E. coli (ETEC) and Shigella, two of the leading diarrhea pathogens. As vaccine developers start to consider field efficacy trials of these vaccines, they should be aware of the importance of evaluating not only vaccine direct effects on the immunized, but also the herd effects that vaccination can afford to the unimmunized in a community. In a workshop held at the conference titled "Vaccines against Shigella and ETEC (VASE)", we described to participants what herd effects are and we presented on methods used in cholera and rotavirus studies that could be useful for future ETEC and Shigella vaccine trials conducted in low and middle-income nations. We also presented evidence on the effects of vaccine herd effects for estimates of vaccine cost-effectiveness.
Topics: Cholera; Cholera Vaccines; Clinical Trials as Topic; Cost-Benefit Analysis; Diarrhea; Dysentery, Bacillary; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Geographic Information Systems; Humans; Immunity, Herd; Immunization; Rotavirus Infections; Rotavirus Vaccines; Shigella; Shigella Vaccines
PubMed: 31358237
DOI: 10.1016/j.vaccine.2019.02.061 -
Vaccine Dec 2017PATH hosted the inaugural Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC in June 2016, bringing together experts from...
PATH hosted the inaugural Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC in June 2016, bringing together experts from around the world for a highly collaborative forum to discuss progress in the development of new enteric vaccines. Diarrheal disease and long-term sequelae caused by infections with the bacterial pathogens Shigella and enterotoxigenic E. coli (ETEC) pose a significant public health burden in low-income communities. There are currently no licensed vaccines against these pathogens, and the global health community has recently prioritized their development. The 2016 VASE Conference aimed to accelerate communication and progress among those working in the enteric vaccine field to make Shigella and ETEC vaccines a reality as quickly as possible. Research presented in oral and poster presentations at the VASE Conference covered a range of topics, including: the global burden of disease and public health case for Shigella and ETEC vaccines; current vaccine candidates in development; immunology and host responses to the pathogens; and the rationale for and status of combined Shigella-ETEC vaccine candidates. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2016 conference. Planning for the 2018 VASE Conference is underway and will likely provide an important platform for sharing the latest updates on Shigella and ETEC vaccine research efforts and maintaining the momentum for accelerating this work. It is also expected that the VASE Conference will continue to provide a unique opportunity for those in the enteric vaccine field to share ideas, make connections, and create workable plans to make Shigella and ETEC vaccines a reality. (Updates available at: www.vaseconference.org.).
Topics: Congresses as Topic; Diarrhea; Dysentery, Bacillary; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Humans; Shigella; Shigella Vaccines; Vaccines, Combined
PubMed: 28987444
DOI: 10.1016/j.vaccine.2017.09.045 -
Pathogens (Basel, Switzerland) Nov 2019The type III secretion system (T3SS) is a conserved virulence factor used by many Gram-negative pathogenic bacteria and has become an important target for anti-virulence... (Review)
Review
The type III secretion system (T3SS) is a conserved virulence factor used by many Gram-negative pathogenic bacteria and has become an important target for anti-virulence drugs. Most T3SS inhibitors to date have been discovered using in vitro screening assays. Pharmacokinetics and other important characteristics of pharmaceuticals cannot be determined with in vitro assays alone. In vivo assays are required to study pathogens in their natural environment and are an important step in the development of new drugs and vaccines. Animal models are also required to understand whether T3SS inhibition will enable the host to clear the infection. This review covers selected animal models (mouse, rat, guinea pig, rabbit, cat, dog, pig, cattle, primates, chicken, zebrafish, nematode, wax moth, flea, fly, and amoeba), where T3SS activity and infectivity have been studied in relation to specific pathogens (, spp., spp., spp., spp., spp., spp., and spp.). These assays may be appropriate for those researching T3SS inhibition.
PubMed: 31766664
DOI: 10.3390/pathogens8040257 -
Pediatrics Jan 2022To inform next steps in pediatric diarrhea burden reduction by understanding the shifting enteropathogen landscape after rotavirus vaccine implementation.
OBJECTIVES
To inform next steps in pediatric diarrhea burden reduction by understanding the shifting enteropathogen landscape after rotavirus vaccine implementation.
METHODS
We conducted a case-control study of 1788 medically attended children younger than 5 years, with and without gastroenteritis, after universal rotavirus vaccine implementation in Peru. We tested case and control stools for 5 viruses, 19 bacteria, and parasites; calculated coinfection-adjusted attributable fractions (AFs) to determine pathogen-specific burdens; and evaluated pathogen-specific gastroenteritis severity using Clark and Vesikari scales.
RESULTS
Six pathogens were independently positively associated with gastroenteritis: norovirus genogroup II (GII) (AF 29.1, 95% confidence interval [CI]: 28.0-32.3), rotavirus (AF 8.9, 95% CI: 6.8-9.7), sapovirus (AF 6.3, 95% CI: 4.3-7.4), astrovirus (AF 2.8, 95% CI: 0.0-4.0); enterotoxigenic Escherichia coli heat stable and/or heat labile and heat stable (AF 2.4, 95% CI: 0.6-3.1), and Shigella spp. (AF 2.0, 95% CI: 0.4-2.2). Among typeable rotavirus cases, we most frequently identified partially heterotypic strain G12P[8] (54 of 81, 67%). Mean severity was significantly higher for norovirus GII-positive cases relative to norovirus GII-negative cases (Vesikari [12.7 vs 11.8; P < .001] and Clark [11.7 vs 11.4; P = .016]), and cases in the 6- to 12-month age range relative to cases in other age groups (Vesikari [12.7 vs 12.0; P = .0002] and Clark [12.0 vs 11.4; P = .0016]).
CONCLUSIONS
Norovirus is well recognized as the leading cause of pediatric gastroenteritis in settings with universal rotavirus vaccination. However, sapovirus is often overlooked. Both norovirus and sapovirus contribute significantly to the severe pediatric disease burden in this setting. Decision-makers should consider multivalent vaccine acquisition strategies to target multiple caliciviruses in similar countries after successful rotavirus vaccine implementation.
Topics: Case-Control Studies; Child, Preschool; Diarrhea; Feces; Gastroenteritis; Genotype; Humans; Norovirus; Peru; Prospective Studies; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sapovirus; Severity of Illness Index
PubMed: 34918158
DOI: 10.1542/peds.2020-049884 -
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 -
Serum IgG antibodies to lipopolysaccharide antigens - a correlate of protection against shigellosis.Human Vaccines & Immunotherapeutics 2019is a leading cause of diarrhea among children globally and of diarrheal deaths among children under 5 years of age in low- and middle-income countries. To date, no... (Review)
Review
is a leading cause of diarrhea among children globally and of diarrheal deaths among children under 5 years of age in low- and middle-income countries. To date, no licensed vaccine exists. We review evidence that serum IgG antibodies to LPS represent a good correlate of protection against shigellosis; this could support the process of development and evaluation of vaccine candidates. Case-control and cohort studies conducted among Israeli soldiers serving under field conditions showed significant serotype-specific inverse associations between pre-exposure serum IgG antibodies to LPS and shigellosis incidence. The same serum IgG fraction showed a dose-response relationship with the protective efficacy attained by vaccine candidates tested in phase III trials of young adults and children aged 1-4 years and in Controlled Human Infection Model studies and exhibited mechanistic protective capabilities. Identifying a threshold level of these antibodies associated with protection can promote the development of an efficacious vaccine for infants and young children.
Topics: Antibodies, Bacterial; Clinical Trials as Topic; Diarrhea; Dysentery, Bacillary; Humans; Immunoglobulin G; Lipopolysaccharides; Shigella; Shigella Vaccines
PubMed: 31070988
DOI: 10.1080/21645515.2019.1606971 -
Vaccine Mar 2024The global nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, on November... (Review)
Review
The global nonprofit organization PATH hosted the third Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC, on November 29 to December 1, 2022. With a combination of plenary sessions and posters, keynote presentations, and breakout workshops, the 2022 VASE Conference featured key updates on research related to the development of vaccines against neglected diarrheal pathogens including Shigella, enterotoxigenic Escherichia coli (ETEC), Campylobacter, and Salmonella. The presentations and discussions highlighted the significant impact of these diarrheal pathogens, particularly on the health of infants and young children in low- and middle-income countries, reflecting the urgent need for the development and licensure of new enteric vaccines. Oral and poster presentations at the VASE Conference explored a range of topics, including: the global burden and clinical presentation of disease, epidemiology, and the impact of interventions; the assessment of the value of vaccines against enteric pathogens; preclinical evaluations of vaccine candidates and models of enteric diseases; vaccine candidates in clinical trials and human challenge models; host parameters and genomics that predict responses to infection and disease; the application of new omics technologies for characterization of emerging pathogens and host responses; novel adjuvants, vaccine delivery platforms, and immunization strategies; and strategies for combination/co-administered vaccines. The conference agenda also featured ten breakout workshop sessions on topics of importance to the enteric vaccine field, which are summarized separately. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2022 VASE Conference.
Topics: Humans; Diarrhea; Dysentery, Bacillary; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Oligopeptides; Shigella; Shigella Vaccines
PubMed: 38030421
DOI: 10.1016/j.vaccine.2023.11.031 -
Vaccine Nov 2019Enterotoxigenic E. coli (ETEC) and Shigella are enteropathogens causing significant global morbidity and mortality, particularly in low-income countries. No licensed... (Review)
Review
Enterotoxigenic E. coli (ETEC) and Shigella are enteropathogens causing significant global morbidity and mortality, particularly in low-income countries. No licensed vaccine exists for either pathogen, but candidates are in development, with the most advanced candidates potentially approaching pivotal efficacy testing within the next few years. A positive policy recommendation for introduction of any vaccine, following licensure, depends on evidence of vaccine cost-effectiveness and impact on morbidity and mortality. The mortality estimates for these two pathogens have fluctuated over recent years, which has led to uncertainty in the assessment of their relative public health importance for use in low and middle-income countries. This paper summarizes the various ETEC and Shigella disease burden estimates, based on a review of current literature and informal consultations with leading stakeholders in enteric disease modelling. We discuss the factors that underpin the variability, including differences in the modelling methodology; diagnostic tools used to ascertain diarrheal etiology; epidemiological setting; the data that are available to incorporate; and absolute changes in the total number of diarrheal deaths over time. We consider the further work that will strengthen the evidence needed to support future decision making with respect to recommendations on the relative utility of these vaccines.
Topics: Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Humans; Shigella
PubMed: 29031690
DOI: 10.1016/j.vaccine.2017.09.083