Special Issue "Frontiers in Shigella Vaccine Development"

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Infectious Diseases".

Deadline for manuscript submissions: closed (1 January 2022) | Viewed by 9662

Special Issue Editors

Dr. Duncan Steele
E-Mail Website
Guest Editor
Enteric and Diarrheal Disease, Bill & Melinda Gates Foundation, Seattle, WA 98102, USA
Interests: vaccines; diarrhea; enteric; rotavirus; typhoid; cholera; virus; global health
Prof. Calman A. MacLennan
E-Mail Website
Guest Editor
Bill and Melinda Gates Foundation, Seattle, WA 98109, USA
Interests: vaccines; diarrhea; enteric; salmonella; shigella; bacteria; global health

Special Issue Information

Dear Colleagues, 

Shigella is the main cause of diarrheal deaths in children over one year of age and the most common cause of diarrheal deaths globally that currently lacks a vaccine. Children in low- and middle-income countries are disproportionately affected, making shigellosis a disease of poverty. Shigellosis has well-recognised sequelae manifested as linear growth stunting and cognitive impairment which result in further suffering and adverse economic impact. Levels of antimicrobial resistance are increasing globally among Shigella isolates making shigellosis increasingly difficult to treat. An effective vaccine against Shigella will save lives, increase economic growth and help curb global spread of antimicrobial resistance.

Although a Shigella glycoconjugate vaccine was shown to be efficacious in Israeli adults 24 years ago, the vaccine was never commercialised due to lack of commercial incentive, and was subsequently found to not be able to protect children under three years of age. The vaccine consisted of Shigella sonnei O-antigen conjugated to rEPA as carrier protein. Two vaccine two efficacy studies indicated that serum IgG to O-antigen is associated with protection against shigellosis.

In recent years, there has been a resurgence of interest in the development of vaccines against Shigella driven by the growing awareness of the impact of this pathogen on global health. This supplement provides an up-to-date landscape of Shigella vaccines currently in clinical development with individual papers contributed by vaccine developers themselves. Most of these vaccines are predicated on Shigella O-antigen and induce serum and mucosal antibodies to this molecule. A combination of platform technologies are being utilised to engineer these vaccines including bioconjugation, synthetic chemistry, outer membrane vesicles and whole cell/live attenuated bacteria.

Together with the reports on individual vaccines, we include background papers on the different approaches to these vaccines, the history of Shigella vaccines and justification for their development.

Dr. Duncan Steele
Prof. Calman A. MacLennan
Guest Editors

Manuscript Submission Information

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Keywords

  • Shigella
  • vaccines
  • O-antigen
  • global health

Published Papers (10 papers)

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Research

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Article
Pivotal Shigella Vaccine Efficacy Trials—Study Design Considerations from a Shigella Vaccine Trial Design Working Group
Vaccines 2022, 10(4), 489; https://doi.org/10.3390/vaccines10040489 - 22 Mar 2022
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Abstract
Vaccine candidates for Shigella are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time [...] Read more.
Vaccine candidates for Shigella are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time to licensure and implementation. We convened an ad hoc working group to identify the key aspects of trial design that would meet the regulatory requirements to achieve the desired indication of prevention of moderate or severe shigellosis due to strains included in the vaccine. The proposed primary endpoint of pivotal Shigella vaccine trials is the efficacy of the vaccine against the first episode of acute moderate or severe diarrhea caused by the Shigella strains contained within the vaccine. Moderate or severe shigellosis could be defined by a modified Vesikari score with dysentery and molecular detection of vaccine-preventable Shigella strains. This report summarizes the rationale and current data behind these considerations, which will evolve as new data become available and after further review and consultation by global regulators and policymakers. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
Article
Evaluation of the Safety, Tolerability and Immunogenicity of ShigETEC, an Oral Live Attenuated Shigella-ETEC Vaccine in Placebo-Controlled Randomized Phase 1 Trial
Vaccines 2022, 10(2), 340; https://doi.org/10.3390/vaccines10020340 - 21 Feb 2022
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Abstract
Background: Shigella spp. and enterotoxigenic Escherichia coli (ETEC) cause high morbidity and mortality worldwide, yet no licensed vaccines are available to prevent corresponding infections. A live attenuated non-invasive Shigella vaccine strain lacking LPS O-antigen and expressing the ETEC toxoids, named ShigETEC was characterized [...] Read more.
Background: Shigella spp. and enterotoxigenic Escherichia coli (ETEC) cause high morbidity and mortality worldwide, yet no licensed vaccines are available to prevent corresponding infections. A live attenuated non-invasive Shigella vaccine strain lacking LPS O-antigen and expressing the ETEC toxoids, named ShigETEC was characterized previously in non-clinical studies. Methods: ShigETEC was evaluated in a two-staged, randomized, double-blind and placebo-controlled Phase I clinical trial. A single dose of increasing amounts of the vaccine was given to determine the maximum tolerated dose and increasing number of immunizations were administered with an interval based on the duration of shedding observed. Results: Oral immunization with ShigETEC was well tolerated and safe up to 4-time dosing with 5 × 1010 colony forming units. ShigETEC induced robust systemic immune responses against the Shigella vaccine strain, with IgA serum antibody dominance, as well as mucosal antibody responses evidenced by specific IgA in stool samples and in ALS (Antibodies in Lymphocyte Supernatant). Anti- ETEC toxin responses were detected primarily in the 4-times immunized cohort and for the heat-labile toxin correlated with neutralizing capacity. Conclusion: ShigETEC is a promising vaccine candidate that is scheduled for further testing in controlled human challenge studies for efficacy as well as in children in endemic setting for safety and immunogenicity. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Article
Safety and Immunogenicity of a Shigella Bivalent Conjugate Vaccine (ZF0901) in 3-Month- to 5-Year-Old Children in China
Vaccines 2022, 10(1), 33; https://doi.org/10.3390/vaccines10010033 - 28 Dec 2021
Cited by 1 | Viewed by 1089
Abstract
No licensed Shigella vaccine is presently available globally. A double-blinded, randomized, placebo-controlled, age descending phase II clinical trial of a bivalent conjugate vaccine was studied in China. The vaccine ZF0901 consisted of O-specific polysaccharides purified and detoxified from lipopolysaccharide (LPS) of S. flexneri [...] Read more.
No licensed Shigella vaccine is presently available globally. A double-blinded, randomized, placebo-controlled, age descending phase II clinical trial of a bivalent conjugate vaccine was studied in China. The vaccine ZF0901 consisted of O-specific polysaccharides purified and detoxified from lipopolysaccharide (LPS) of S. flexneri 2a and S. sonnei and covalently bonded to tetanus toxoid. A total of 224, 310, and 434 children, consented by parents or guardians, aged 3 to 6 and 6 to 12 months and 1 to 5 years old, respectively, were injected with half or full doses, with or without adjuvant or control Hib vaccine. There were no serious adverse reactions in all recipients of ZF0901 vaccine independent of age, dosage, number of injections, or the adjuvant status. Thirty days after the last injection, ZF0901 induced robust immune responses with significantly higher levels of type-specific serum antibodies (geometric mean concentrations (GMCs) of IgG anti-LPS) against both serotypes in all age groups compared with the pre-immune or the Hib control (p < 0.0001). Here, we demonstrated that ZF0901 bivalent Shigella conjugate vaccine is safe and immunogenic in infants and young children and is likely suitable for routine immunization. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review

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Review
Detoxified O-Specific Polysaccharide (O-SP)–Protein Conjugates: Emerging Approach in the Shigella Vaccine Development Scene
Vaccines 2022, 10(5), 675; https://doi.org/10.3390/vaccines10050675 - 24 Apr 2022
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Abstract
Shigella is the second most common cause of moderate to severe diarrhea among children worldwide and of diarrheal disease-associated mortality in young children in low-and middle-income countries. In spite of many years of attempts to develop Shigella vaccines, no licensed vaccines are yet [...] Read more.
Shigella is the second most common cause of moderate to severe diarrhea among children worldwide and of diarrheal disease-associated mortality in young children in low-and middle-income countries. In spite of many years of attempts to develop Shigella vaccines, no licensed vaccines are yet available. Injectable conjugate vaccines made of the detoxified lipopolysaccharide (LPS) of S. flexneri 2a, S. sonnei, and S. dysenteriae type 1 covalently bound to protein carriers were developed in the early 1990s by John B. Robbins and Rachel Schneerson at the US National Institutes of Health. This approach was novel for a disease of the gut mucosa, at a time when live, rationally attenuated oral vaccine strains that intended to mimic Shigella infection and induce a protective local immune response were extensively investigated. Of keystone support to Shigella glycoconjugates development were the findings of a strong association between pre-existent serum IgG antibodies to S. sonnei or S. flexneri 2a LPS and a lower risk of infection with the homologous Shigella serotypes among Israeli soldiers serving in field units. In view of these findings and of the successful development of the pioneering Haemophilus influenzae type b conjugate vaccines, it was hypothesized that protective immunity may be conferred by serum IgG antibodies to the O-Specific Polysaccharide (O-SP) following parenteral delivery of the conjugates. S. sonnei and S. flexneri 2a glycoconjugates induced high levels of serum IgG against the homologous LPS in phase I and II studies in healthy volunteers. The protective efficacy of a S. sonnei detoxified LPS-conjugate was further demonstrated in field trials in young adults (74%) and in children older than three years of age (71%), but not in younger ones. The evaluation of the Shigella conjugates confirmed that IgG antibodies to Shigella LPS are correlates of protection and provided solid basis for the development of a new generation of glycoconjugates and other injectable LPS-based vaccines that are currently in advanced stages of clinical evaluation. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review
From Kiyoshi Shiga to Present-Day Shigella Vaccines: A Historical Narrative Review
Vaccines 2022, 10(5), 645; https://doi.org/10.3390/vaccines10050645 - 20 Apr 2022
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Abstract
We are at an exciting moment in time with the advancement of many vaccines, including a shigella vaccine for the world. It is instructive to look at the long road that some vaccines have traveled to recognize the remarkable accomplishments of those who [...] Read more.
We are at an exciting moment in time with the advancement of many vaccines, including a shigella vaccine for the world. It is instructive to look at the long road that some vaccines have traveled to recognize the remarkable accomplishments of those who were pioneers, appreciate the evolution of scientific and applied technology, and inform the future history of a vaccine that would have great potential for global health. To achieve this valuable retrospective, a narrative historical literature review was undertaken utilizing PubMed and Embase databases with relevant search terms. Retrieved articles were reviewed and information was organized into historical themes, landmark discoveries, and important vaccine development parallels. The literature reviewed was synthesized into major eras of shigella vaccine development from pathogen discovery and first attempts to empirical approaches of killed whole-cell and live-attenuated approaches, and a modern era that applied recombinant DNA engineering and structural vaccinology. The history of shigella vaccine development has largely followed the evolutionary path of vaccine development over the last 120 years, but with important lessons learned that should be considered as we embark on the future chapters of bringing to the world a safe and effective vaccine for global health. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review
From Concept to Clinical Product: A Brief History of the Novel Shigella Invaplex Vaccine’s Refinement and Evolution
Vaccines 2022, 10(4), 548; https://doi.org/10.3390/vaccines10040548 - 01 Apr 2022
Cited by 1 | Viewed by 668
Abstract
The Shigella invasin complex or Invaplex vaccine is a unique subunit approach to generate a protective immune response. Invaplex is a large, macromolecular complex consisting of the major Shigella antigens: lipopolysaccharide (LPS) and the invasion plasmid antigen (Ipa) proteins B and C. Over [...] Read more.
The Shigella invasin complex or Invaplex vaccine is a unique subunit approach to generate a protective immune response. Invaplex is a large, macromolecular complex consisting of the major Shigella antigens: lipopolysaccharide (LPS) and the invasion plasmid antigen (Ipa) proteins B and C. Over the past several decades, the vaccine has progressed from initial observations through pre-clinical studies to cGMP manufacture and clinical evaluations. The Invaplex product maintains unique biological properties associated with the invasiveness of virulent shigellae and also presents both serotype-specific epitopes, as well as highly conserved invasin protein epitopes, to the immunized host. The vaccine product has evolved from a native product isolated from wild-type shigellae (native Invaplex) to a more defined vaccine produced from purified LPS and recombinant IpaB and IpaC (artificial Invaplex). Each successive “generation” of the vaccine is derived from earlier versions, resulting in improved immunogenicity, homogeneity and effectiveness. The current vaccine, detoxified artificial Invaplex (InvaplexAR-Detox), was developed for parenteral administration by incorporating LPS with under-acylated lipid A. InvaplexAR-Detox has demonstrated an excellent safety and immunogenicity profile in initial clinical studies and is advancing toward evaluations in the target populations of children and travelers to endemic countries. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review
Toward a Multivalent Synthetic Oligosaccharide-Based Conjugate Vaccine against Shigella: State-of-the-Art for a Monovalent Prototype and Challenges
Vaccines 2022, 10(3), 403; https://doi.org/10.3390/vaccines10030403 - 07 Mar 2022
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Abstract
This review focuses on the molecular glycovaccine concept, a promising option to develop a Shigella glycoconjugate vaccine. Subsequent to original developments involving, as main vaccine component, the detoxified Shigella lipopolysaccharide randomly conjugated at multiple sites to a carrier protein, novelty stems from the [...] Read more.
This review focuses on the molecular glycovaccine concept, a promising option to develop a Shigella glycoconjugate vaccine. Subsequent to original developments involving, as main vaccine component, the detoxified Shigella lipopolysaccharide randomly conjugated at multiple sites to a carrier protein, novelty stems from the use of rationally designed, well-defined chemically synthesized oligosaccharide haptens conceived as functional surrogates of the main surface antigen, linked via single-point attachment onto a carrier. The concept and design of such a fine-tuned Shigella glycovaccine are presented by way of SF2a-TT15, a neoglycoprotein featuring a synthetic 15-mer oligosaccharide, which constitutes an original vaccine prototype targeting Shigella flexneri 2a, one of the predominant circulating strains in endemic settings. The clinical testing of SF2a-TT15 is summarized with the first-in-human phase I trial in young healthy adults showing a good safety profile and tolerability, while inducing bactericidal antibodies towards S. flexneri 2a bacteria. The proof-of-concept of this novel approach being established, an ongoing phase IIa clinical study in the nine-month-old infant target population in endemic area was launched, which is also outlined. Lastly, some challenges to move forward this original approach toward a multivalent cost-effective Shigella synthetic glycan conjugate vaccine are introduced. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review
Towards a Four-Component GMMA-Based Vaccine against Shigella
Vaccines 2022, 10(2), 328; https://doi.org/10.3390/vaccines10020328 - 18 Feb 2022
Cited by 1 | Viewed by 725
Abstract
Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrhoeal disease in low- and middle-income countries, particularly in young children. The increasing reports of Shigella cases associated with anti-microbial resistance are an additional element [...] Read more.
Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrhoeal disease in low- and middle-income countries, particularly in young children. The increasing reports of Shigella cases associated with anti-microbial resistance are an additional element of concern. Currently, there are no licensed vaccines widely available against Shigella, but several vaccine candidates are in development. It has been demonstrated that the incidence of disease decreases following a prior Shigella infection and that serum and mucosal antibody responses are predominantly directed against the serotype-specific Shigella O-antigen portion of lipopolysaccharide membrane molecules. Many Shigella vaccine candidates are indeed O-antigen-based. Here we present the journey towards the development of a potential low-cost four-component Shigella vaccine, eliciting broad protection against the most prevalent Shigella serotypes, that makes use of the GMMA (Generalized Modules for Membrane Antigens) technology, a novel platform based on bacterial outer membranes for delivery of the O-antigen to the immune system. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Review
The Ongoing Journey of a Shigella Bioconjugate Vaccine
Vaccines 2022, 10(2), 212; https://doi.org/10.3390/vaccines10020212 - 29 Jan 2022
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Abstract
Shigellosis is a serious disease with a major impact, especially in low-income countries where mortality and morbidity are high. In addition, shigellosis among travelers and military personnel is a cause of significant morbidity and contributes to the increase in antimicrobial resistance. The World [...] Read more.
Shigellosis is a serious disease with a major impact, especially in low-income countries where mortality and morbidity are high. In addition, shigellosis among travelers and military personnel is a cause of significant morbidity and contributes to the increase in antimicrobial resistance. The World Health Organization (WHO) considers the development of a Shigella vaccine a priority for public health. Over the past 60 years, several efforts to develop a Shigella vaccine have been pursued, without success. The principle of preventing shigellosis with a conjugate vaccine was demonstrated in the 1990′s, but this vaccine was not further developed. Bioconjugation is an innovative technology that allows the production of conjugate vaccines in a biological environment to preserve native immunogenic structures. In this review, we describe the journey of the bioconjugate Shigella vaccine, one of the most advanced clinical programs for a Shigella vaccine. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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Commentary
What Drives the Value of a Shigella Vaccine?
Vaccines 2022, 10(2), 282; https://doi.org/10.3390/vaccines10020282 - 12 Feb 2022
Cited by 2 | Viewed by 685
Abstract
The development and licensure of a safe and highly efficacious Shigella vaccine has been a priority in international public health circles for decades and would represent a great scientific achievement. Nonetheless, in the context of increasingly crowded and costly childhood immunization programs, and [...] Read more.
The development and licensure of a safe and highly efficacious Shigella vaccine has been a priority in international public health circles for decades and would represent a great scientific achievement. Nonetheless, in the context of increasingly crowded and costly childhood immunization programs, and with a myriad of other new and improved vaccines currently or soon on the market, there is no guarantee that even a highly effective Shigella vaccine would become a priority for adoption and introduction by the low- and middle-income countries that could benefit from it the most. We discuss here some of the major determinants and questions regarding the introduction of Shigella vaccines and the importance of developing a succinct, compelling public health value proposition. Full article
(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)
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