Vaccines

Editorial

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5 pages, 207 KiB

Open AccessEditorial

Frontiers in Shigella Vaccine Development

by Calman Alexander MacLennan and Andrew Duncan Steele

Vaccines 2022, 10(9), 1536; https://doi.org/10.3390/vaccines10091536 - 15 Sep 2022

Cited by 5 | Viewed by 2005

Abstract

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 [...] Full article

(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)

Research

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14 pages, 280 KiB

Open AccessArticle

Pivotal Shigella Vaccine Efficacy Trials—Study Design Considerations from a Shigella Vaccine Trial Design Working Group

by Patricia B. Pavlinac, Elizabeth T. Rogawski McQuade, James A. Platts-Mills, Karen L. Kotloff, Carolyn Deal, Birgitte K. Giersing, Richard A. Isbrucker, Gagandeep Kang, Lyou-Fu Ma, Calman A. MacLennan, Peter Patriarca, Duncan Steele and Kirsten S. Vannice

Vaccines 2022, 10(4), 489; https://doi.org/10.3390/vaccines10040489 - 22 Mar 2022

Cited by 10 | Viewed by 2240

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)

15 pages, 4328 KiB

Open AccessArticle

Evaluation of the Safety, Tolerability and Immunogenicity of ShigETEC, an Oral Live Attenuated Shigella-ETEC Vaccine in Placebo-Controlled Randomized Phase 1 Trial

by Petra Girardi, Shushan Harutyunyan, Irene Neuhauser, Katharina Glaninger, Orsolya Korda, Gábor Nagy, Eszter Nagy, Valéria Szijártó, Denes Pall, Krisztina Szarka, Gábor Kardos, Tamás Henics and Frank J. Malinoski

Vaccines 2022, 10(2), 340; https://doi.org/10.3390/vaccines10020340 - 21 Feb 2022

Cited by 13 | Viewed by 2966

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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14 pages, 1166 KiB

Open AccessArticle

Safety and Immunogenicity of a Shigella Bivalent Conjugate Vaccine (ZF0901) in 3-Month- to 5-Year-Old Children in China

by Yi Mo, Wenjian Fang, Hong Li, Junji Chen, Xiaohua Hu, Bin Wang, Zhengli Feng, Honghua Shi, Ying He, Dong Huang, Zhaojun Mo, Qiang Ye and Lin Du

Vaccines 2022, 10(1), 33; https://doi.org/10.3390/vaccines10010033 - 28 Dec 2021

Cited by 12 | Viewed by 3268

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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19 pages, 832 KiB

Open AccessReview

The Shigella Vaccines Pipeline

by Calman Alexander MacLennan, Stephanie Grow, Lyou-fu Ma and Andrew Duncan Steele

Vaccines 2022, 10(9), 1376; https://doi.org/10.3390/vaccines10091376 - 24 Aug 2022

Cited by 34 | Viewed by 3899

Abstract

Shigella is the leading cause of global diarrheal deaths that currently lacks a licensed vaccine. Shigellosis drives antimicrobial resistance and leads to economic impact through linear growth faltering. Today, there is a robust pipeline of vaccines in clinical development which are broadly divided [...] Read more.

Shigella is the leading cause of global diarrheal deaths that currently lacks a licensed vaccine. Shigellosis drives antimicrobial resistance and leads to economic impact through linear growth faltering. Today, there is a robust pipeline of vaccines in clinical development which are broadly divided into parenteral glycoconjugate vaccines, consisting of O-antigen conjugated to carrier proteins, and oral live attenuated vaccines, which incorporate targeted genetic mutations seeking to optimize the balance between reactogenicity, immunogenicity and ultimately protection. Proof of efficacy has previously been shown with both approaches but for various reasons no vaccine has been licensed to date. In this report, we outline the requirements for a Shigella vaccine and describe the current pipeline in the context of the many candidates that have previously failed or been abandoned. The report refers to papers from individual vaccine developers in this special supplement of Vaccines which is focused on Shigella vaccines. Once readouts of safety and immunogenicity from current trials of lead candidate vaccines among the target population of young children in low- and middle-income countries are available, the likely time to licensure of a first Shigella vaccine will become clearer. Full article

(This article belongs to the Special Issue Frontiers in Shigella Vaccine Development)

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17 pages, 1318 KiB

Open AccessReview

Detoxified O-Specific Polysaccharide (O-SP)–Protein Conjugates: Emerging Approach in the Shigella Vaccine Development Scene

by Dani Cohen, Shiri Meron-Sudai, Anya Bialik, Valeria Asato and Shai Ashkenazi

Vaccines 2022, 10(5), 675; https://doi.org/10.3390/vaccines10050675 - 24 Apr 2022

Cited by 10 | Viewed by 2172

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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14 pages, 713 KiB

Open AccessReview

From Kiyoshi Shiga to Present-Day Shigella Vaccines: A Historical Narrative Review

by Crystal M. Herrera, Jessicia S. Schmitt, Erum I. Chowdhry and Mark S. Riddle

Vaccines 2022, 10(5), 645; https://doi.org/10.3390/vaccines10050645 - 20 Apr 2022

Cited by 8 | Viewed by 2352

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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18 pages, 1472 KiB

Open AccessReview

From Concept to Clinical Product: A Brief History of the Novel Shigella Invaplex Vaccine’s Refinement and Evolution

by K. Ross Turbyfill, Kristen A. Clarkson, Edwin V. Oaks and Robert W. Kaminski

Vaccines 2022, 10(4), 548; https://doi.org/10.3390/vaccines10040548 - 01 Apr 2022

Cited by 16 | Viewed by 3277

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 (Invaplex_AR-Detox), was developed for parenteral administration by incorporating LPS with under-acylated lipid A. Invaplex_AR-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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10 pages, 658 KiB

Open AccessReview

Toward a Multivalent Synthetic Oligosaccharide-Based Conjugate Vaccine against Shigella: State-of-the-Art for a Monovalent Prototype and Challenges

by Armelle Phalipon and Laurence A. Mulard

Vaccines 2022, 10(3), 403; https://doi.org/10.3390/vaccines10030403 - 07 Mar 2022

Cited by 17 | Viewed by 2788

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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14 pages, 1195 KiB

Open AccessReview

Towards a Four-Component GMMA-Based Vaccine against Shigella

by Francesca Micoli, Usman N. Nakakana and Francesco Berlanda Scorza

Vaccines 2022, 10(2), 328; https://doi.org/10.3390/vaccines10020328 - 18 Feb 2022

Cited by 24 | Viewed by 3214

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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11 pages, 677 KiB

Open AccessReview

The Ongoing Journey of a Shigella Bioconjugate Vaccine

by Patricia Martin and Cristina Alaimo

Vaccines 2022, 10(2), 212; https://doi.org/10.3390/vaccines10020212 - 29 Jan 2022

Cited by 19 | Viewed by 3627

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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Other

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8 pages, 242 KiB

Open AccessCommentary

What Drives the Value of a Shigella Vaccine?

by William P. Hausdorff, Suzanne Scheele and Birgitte K. Giersing

Vaccines 2022, 10(2), 282; https://doi.org/10.3390/vaccines10020282 - 12 Feb 2022

Cited by 13 | Viewed by 2050

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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