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NPJ Vaccines Mar 2023Shigella is a leading cause of moderate to severe diarrhea worldwide and of diarrhea-associated deaths in children under 5 years of age in low-and middle-income...
Shigella is a leading cause of moderate to severe diarrhea worldwide and of diarrhea-associated deaths in children under 5 years of age in low-and middle-income countries. A vaccine against shigellosis is in high demand. SF2a-TT15, a synthetic carbohydrate-based conjugate vaccine candidate against Shigella flexneri 2a (SF2a) was found safe and strongly immunogenic in adult volunteers. Here, SF2a-TT15 at 10 µg oligosaccharide (OS) vaccine dose is shown to induce a sustained immune response in magnitude and functionality in the majority of volunteers followed up 2 and 3 years post-vaccination. High levels of either one of the humoral parameters as well as the number of specific-IgG memory B-cells determined 3 months after vaccination were good predictors of the durability of the immune response. This study is the first to examine the long-term durability of antibody functionality and memory B-cell response induced by a Shigella vaccine candidate.
PubMed: 36894570
DOI: 10.1038/s41541-023-00624-y -
Vaccines Feb 2023A multivalent vaccine is much needed to achieve protection against predominant serotypes. Recently, we demonstrated the clinical applicability and immunogenic potential...
A multivalent vaccine is much needed to achieve protection against predominant serotypes. Recently, we demonstrated the clinical applicability and immunogenic potential of tri-acylated 2a lipopolysaccharide (Ac-S-LPS). Using a similar approach, we designed a pentavalent LPS candidate vaccine against 1b, 2a, 3a, 6, and Y (PLVF). In this study, we performed molecular and antigenic characterization of the vaccine candidate and its preclinical evaluation. There were no signs of acute toxicity after subcutaneous administration of PLVF in rabbits at a proposed human dose of 125 μg. No pyrogenic reactions and adverse effects associated with chronic toxicity after repeated administration of PLVF were revealed either. The immunization of mice with PLVF led to ≥16-fold increase in 1b-, 2a-, 3a-, 6-, and Y-specific antibodies. In a serum bactericidal antibody (SBA) assay, we registered 54%, 66%, 35%, 60%, and 60% killing of 1b, 2a, 3a, 6, and Y, respectively. In the guinea pig keratoconjunctivitis model, the efficacy was 50% to 75% against challenge with all five serotypes. These studies demonstrate that PLVF is safe, immunogenic over a wide range of doses, and provides protection against challenge with homologous strains, thus confirming the validity of pentavalent design of the combined vaccine.
PubMed: 36851223
DOI: 10.3390/vaccines11020345 -
The Lancet. Global Health Mar 2023Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be...
BACKGROUND
Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs).
METHODS
Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum.
FINDINGS
20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76-0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76-0·88]).
INTERPRETATION
The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges-Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns.
FUNDING
NASA, National Institutes of Health-The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation.
Topics: Child; Humans; Dysentery, Bacillary; Diarrhea; Africa South of the Sahara; Temperature; Family Characteristics; Global Health
PubMed: 36796984
DOI: 10.1016/S2214-109X(22)00549-6 -
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 Mar 2023Immunization is an essential component of national health plans. However, the growing number of new vaccine introductions, vaccination campaigns and increasing... (Review)
Review
Immunization is an essential component of national health plans. However, the growing number of new vaccine introductions, vaccination campaigns and increasing administrative costs create logistic and financial challenges, especially in resource-limited settings. Sub-national geographic targeting of vaccination programs is a potential strategy for governments to reduce the impact of infectious disease outbreaks while optimizing resource allocation and reducing costs, promoting sustainability of critically important national immunization plans. We conducted a systematic review of peer-reviewed literature to identify studies that investigated the cost-effectiveness of geographically targeted sub-national vaccination programs, either through routine immunization or supplementary immunization activities. A total of 16 studies were included in our review, covering nine diseases of interest: cholera, dengue, enterotoxigenic Escherichia coli (ETEC), hepatitis A, Japanese encephalitis, measles, rotavirus, Shigella and typhoid fever. All studies modelled cost-effectiveness of geographically targeted vaccination. Despite the variation in study design, disease focus and country context, studies generally found that in countries where a heterogenous burden of disease exists, sub-national geographic targeting of vaccination programs in areas of high disease burden was more cost-effective than a non-targeted strategy. Sensitivity analysis revealed that cost-effectiveness was most sensitive to variations in vaccine price, vaccine efficacy, mortality rate, administrative and operational costs, discount rate, and treatment costs. This systematic review identified several key characteristics related to geographic targeting of vaccination, including the vaccination strategy used, variations in modelling parameters and their impact on cost-effectiveness. Additional research and guidance is needed to support the appropriateness and feasibility of geographically targeted vaccination and to determine what country context would make this a viable complement to routine immunization programs.
Topics: Cost-Benefit Analysis; Vaccination; Immunization Programs; Immunization; Vaccines
PubMed: 36781333
DOI: 10.1016/j.vaccine.2023.02.006 -
Frontiers in Immunology 2022Correlates of protection are key for vaccine development against any pathogen. In this paper we summarize recent information about correlates for vaccines against...
Correlates of protection are key for vaccine development against any pathogen. In this paper we summarize recent information about correlates for vaccines against dengue, Ebola, influenza, pneumococcal, respiratory syncytial virus, rotavirus, shigella, tuberculosis and Zika virus.
Topics: Humans; Influenza Vaccines; Respiratory Syncytial Virus, Human; Influenza, Human; Zika Virus; Zika Virus Infection
PubMed: 36776392
DOI: 10.3389/fimmu.2022.1081107 -
International Journal of Molecular... Feb 2023Shigellosis is the leading cause of diarrheal disease, especially in children of low- and middle-income countries, and is often associated with anti-microbial...
Shigellosis is the leading cause of diarrheal disease, especially in children of low- and middle-income countries, and is often associated with anti-microbial resistance. Currently, there are no licensed vaccines widely available against , but several candidates based on the O-antigen (OAg) portion of lipopolysaccharides are in development. We have proposed Generalized Modules for Membrane Antigens (GMMA) as an innovative delivery system for OAg, and a quadrivalent vaccine candidate containing GMMA from and three prevalent serotypes (1b, 2a and 3a) is moving to a phase II clinical trial, with the aim to elicit broad protection against . GMMA are able to induce anti-OAg-specific functional IgG responses in animal models and healthy adults. We have previously demonstrated that antibodies against protein antigens are also generated upon immunization with GMMA. In this work, we show that a quadrivalent GMMA-based vaccine is able to promote a humoral response against OAg and proteins of all GMMA types contained in the investigational vaccine. Proteins contained in GMMA provide T cell help as GMMA elicit a stronger anti-OAg IgG response in wild type than in T cell-deficient mice. Additionally, we observed that only the trigger of Toll-like Receptor (TLR) 4 and not of TLR2 contributed to GMMA immunogenicity. In conclusion, when tested in mice, GMMA of a quadrivalent vaccine candidate combine both adjuvant and carrier activities which allow an increase in the low immunogenic properties of carbohydrate antigens.
Topics: Animals; Mice; Shigella; Methylmethacrylates; O Antigens; Vaccines; Dysentery, Bacillary; Immunoglobulin G; Antibodies, Bacterial
PubMed: 36769063
DOI: 10.3390/ijms24032742 -
Journal of Nanobiotechnology Jan 2023No commercial vaccines are available against drug-resistant Shigella due to serotype-specific/narrow-range of protection. Nanoparticle-based biomimetic vaccines...
BACKGROUND
No commercial vaccines are available against drug-resistant Shigella due to serotype-specific/narrow-range of protection. Nanoparticle-based biomimetic vaccines involving stable, conserved, immunogenic proteins fabricated using facile chemistries can help formulate a translatable cross-protective Shigella vaccine. Such systems can also negate cold-chain transportation/storage thus overcoming challenges prevalent in various settings.
METHODS
We explored facile development of biomimetic poly (lactide-co-glycolide)/PLGA 50:50 based nanovaccines (NVs), encapsulating conserved stabilized antigen(s)/immunostimulant of S. dysenteriae 1 origin surface-modified using simple chemistries. All encapsulants (IpaC/IpaB/LPS) and nanoparticles (NPs)-bare and modified (NV), were thoroughly characterized. Effect of IpaC on cellular uptake of NPs was assessed in-vitro. Immunogenicity of the NVs was assessed in-vivo in BALB/c mice by intranasal immunization. Cross-protective efficacy was assessed by intraperitoneally challenging the immunized groups with a high dose of heterologous S. flexneri 2a and observing for visible diarrhea, weight loss and survival. Passive-protective ability of the simplest NV was assessed in the 5-day old progeny of vaccinated mice.
RESULTS
All the antigens and immunostimulant to be encapsulated were successfully purified and found to be stable both before and after encapsulation into NPs. The ~ 300 nm sized NPs with a zeta potential of ~ - 25 mV released ~ 60% antigen by 14th day suggesting an appropriate delivery kinetics. The NPs could be successfully surface-modified with IpaC and/or CpG DNA. In vitro experiments revealed that the presence of IpaC can significantly increase cellular uptake of NPs. All NVs were found to be cytocompatible and highly immunogenic. Antibodies in sera of NV-immunized mice could recognize heterologous Shigella. Immunized sera also showed high antibody and cytokine response. The immunized groups were protected from diarrhea and weight loss with ~ 70-80% survival upon heterologous Shigella challenge. The simplest NV showed ~ 88% survival in neonates.
CONCLUSIONS
Facile formulation of biomimetic NVs can result in significant cross-protection. Further, passive protection in neonates suggest that parental immunization could protect infants, the most vulnerable group in context of Shigella infection. Non-invasive route of vaccination can also lead to greater patient compliance making it amenable for mass-immunization. Overall, our work contributes towards a yet to be reported platform technology for facile development of cross-protective Shigella vaccines.
Topics: Animals; Mice; Pharmaceutical Preparations; Biomimetics; Shigella; Adjuvants, Immunologic; Shigella Vaccines; Nanoparticles; Antibodies, Bacterial; Mice, Inbred BALB C
PubMed: 36710326
DOI: 10.1186/s12951-023-01780-y -
Microbes and Infection Jun 2023In today's world and mostly in low and middle income countries, Shigella flexneri and Shigella sonnei remains the major causative agent of clinical bacillary dysentery....
In today's world and mostly in low and middle income countries, Shigella flexneri and Shigella sonnei remains the major causative agent of clinical bacillary dysentery. Based on contemporary epidemiology, a tetravalent Outer Membrane Vesicle (OMVs) based immunogen was formulated using the most commonly circulating Shigella strains, namely, S. flexneri 2a, S. flexneri 3a, S. flexneri 6 and S. sonnei I, in a 1:1:1:1 ratio. Adult BALB/c mice were orally immunized in a prime-boost-boost manner. Tetravalent Shigella OMVs immunogen induced significant and persistent serum and mucosal antibodies against OMVs, Outer Membrane Proteins (OMPs) and lipopolysaccharides (LPS). Tetravalent OMVs also primed cell mediated immune response effectively. Protective efficacy against six heterologous Shigella strains was checked in an intra-peritoneal mouse model. Immunized mice survived lethal infection better than the non-immunized mice cohort with fewer replicating bacteria isolated from their gut. This study establishes the possibilities of tetravalent OMVs immunogen to become a potent vaccine candidate against human shigellosis, overcoming the limitations of sero-specific cross-protection of Shigella species.
Topics: Animals; Adult; Humans; Mice; Shigella Vaccines; Serogroup; Shigella; Dysentery, Bacillary; Shigella flexneri; Vaccines; Antibodies, Bacterial
PubMed: 36696935
DOI: 10.1016/j.micinf.2023.105100 -
Vaccines Dec 2022Infections by Salmonella Typhi and Paratyphi A strain are still a major cause of morbidity and mortality in developing countries. Generation of antibodies against the Vi...
Infections by Salmonella Typhi and Paratyphi A strain are still a major cause of morbidity and mortality in developing countries. Generation of antibodies against the Vi capsular polysaccharide of . Typhi via either pure polysaccharide or protein-polysaccharide conjugate is a very effective way to protect against . Typhi. To date, there is no commercially available vaccine against . Paratyphi A. The O-specific polysaccharide (OSP) has been generally considered a good vaccine target for Paratyphi A. Here, a bivalent vaccine against Vi and OSP was generated using the Multiple Antigen Presenting System (MAPS). Three different protein constructs, including CRM197, rEPA of Pseudomonas, and a pneumococcal fusion protein SP1500-SP0785, were fused to Rhizavidin (Rhavi) and evaluated their impact on immunogenicity when incorporated as fusion proteins affinity-bound to the two polysaccharides. We compared the antibody responses, antibody avidity, and cidal activity of sera post-immunization with monovalent vs. combination vaccines. We also wished to evaluate the generation of Vi-specific memory B cells in mice. We found little interference when combination vaccine was compared to monovalent vaccines with respect to antibody concentration and cidal activity of sera. Significant affinity maturation was noted for both Vi and OSP antigens. Thus, our preclinical results with a combination Vi- and OSP-MAPS vaccine strongly support the feasibility of this approach and its application of this approach to other important salmonella and Shigella species.
PubMed: 36679935
DOI: 10.3390/vaccines11010091