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Vaccines
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Recent Scientific Advances in Vaccines for Shigella
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Recent Scientific Advances in Vaccines for Shigella

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 2788

Special Issue Editors

Dr. Akamol Suvarnapunya

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Guest Editor
Center for Infectious Disease Research, Bacterial Diseases Branch, Department of Diarrheal Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Interests: shigella; salmonella; diarrhea; enteric disease; enteric vaccines; global health
Dr. Kristen A Clarkson

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Guest Editor
Center for Infectious Disease Research, Bacterial Diseases Branch, Department of Diarrheal Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Interests: vaccines; immunology; enterics; B cells; global health; correlates of protection
Dr. Renee Laird

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Guest Editor
Center for Infectious Disease Research, Bacterial Diseases Branch, Department of Diarrheal Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Interests: enteric; vaccines; immunology; antibodies; T cells; B cells
Dr. August Louis Bourgeois

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Guest Editor
Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
Interests: global health; enteric disease epidemiology; enteric vaccines; mucosal immunity; vaccine adjuvants; vaccine delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diarrheal disease is a major global health problem, especially for children in low- to middle-income countries. Shigella is the leading etiology of diarrhea-associated mortality in children under 5 years of age and the second-leading etiology of diarrhea-associated mortality across all age groups. Shigella is also an important cause of Traveler’s diarrhea and has been associated with several post-infectious sequelae such as reactive arthritis and irritable bowel syndrome (IBS).

Antibiotic treatment is commonly prescribed for shigellosis, but the global spread of antimicrobial-resistant (AMR) Shigella strains threatens this treatment option. Accordingly, the World Health Organization (WHO) has designated Shigella spp. as Priority Pathogens for the development of new therapeutics or preventive measures. The development of an effective vaccine against Shigella represents the ideal solution to the intertwined global health issues of shigellosis and the rise in AMR Shigella.

A variety of Shigella vaccine candidates are in clinical testing, including conjugate vaccines, outer membrane vesicles, recombinant subunit vaccines, and live attenuated vaccines. In addition, the preclinical pipeline contains several more vaccine candidates, including killed whole-cell vaccines and multi-pathogen (combination) vaccines. This Special Issue will feature the latest advances in the Shigella vaccine field. We invite contributions regarding preclinical vaccine development and clinical findings, as well as assay development for the evaluation of vaccine immunogenicity and potential correlates of protection.

Dr. Akamol E. Suvarnapunya
Dr. Kristen A Clarkson
Dr. Renee M. Laird
Dr. August Louis Bourgeois
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Shigella
  • vaccines
  • global health

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Published Papers (4 papers)

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13 pages, 1186 KiB  
Article
Potential for a Combined Oral Inactivated Whole-Cell Vaccine Against ETEC and Shigella: Preclinical Studies Supporting Feasibility
by Manuela Terrinoni, Jan Holmgren, Kevin Ross Turbyfill, Lillian Van De Verg, Nicole Maier and Richard Walker
Vaccines 2025, 13(5), 513; https://doi.org/10.3390/vaccines13050513 - 13 May 2025
Viewed by 255
Abstract
Background: Enteric disease caused by Shigella, Campylobacter, and enterotoxigenic Escherichia coli (ETEC) represents a significant global health burden, particularly among children in low-resource settings. However, no licensed vaccines are currently available for these bacterial pathogens. Given the wide range of enteric [...] Read more.
Background: Enteric disease caused by Shigella, Campylobacter, and enterotoxigenic Escherichia coli (ETEC) represents a significant global health burden, particularly among children in low-resource settings. However, no licensed vaccines are currently available for these bacterial pathogens. Given the wide range of enteric pathogens and the constraints posed by an increasingly crowded infant immunization schedule, the development of combination vaccines or combined administration of individual oral vaccines may offer a practical approach to address this unmet need. Objectives: In this study, we evaluated the combined administration of two multicomponent oral vaccine candidates: ETVAX, targeting ETEC, and a trivalent whole-cell vaccine targeting Shigella. Methods: The vaccine candidates were administered orally in mice, both individually and in combination, with and without the inclusion of the double-mutant heat-labile toxin (dmLT) adjuvant. Results: The results demonstrated systemic and intestinal-mucosal immune responses to the key protective antigens following both individual and combined vaccine administration. Importantly, the combination of the two vaccines did not compromise the elicitation of specific antibody responses. The inclusion of dmLT as an adjuvant significantly enhanced immune responses to several antigens, highlighting its potential to improve vaccine efficacy. Conclusions: These findings underscore the feasibility of combining ETEC and Shigella vaccine candidates into a single formulation without compromising immunogenicity. This combined approach has the potential to provide broad protective coverage, thereby mitigating the global impact of enteric diseases and streamlining vaccine delivery within existing childhood immunization programs. Our results support further development of this combination vaccine strategy as a promising tool in combating enteric infections and improving health outcomes, particularly among young children in endemic regions who are vulnerable to enteric disease. Full article
(This article belongs to the Special Issue Recent Scientific Advances in Vaccines for Shigella)
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17 pages, 2925 KiB  
Article
Shigella Mutant with Truncated O-Antigen as an Enteric Multi-Pathogen Vaccine Platform
by Jae-Ouk Kim, Harald Nothaft, Younghye Moon, Seonghun Jeong, Anthony R. Vortherms, Manki Song, Christine M. Szymanski, Jessica White and Richard Walker
Vaccines 2025, 13(5), 506; https://doi.org/10.3390/vaccines13050506 - 10 May 2025
Viewed by 334
Abstract
Background/Objectives: Rising antibiotic resistance underscores the urgent need for effective vaccines against shigellosis. Our previous research identified the Shigella flexneri 2a truncated mutant (STM), a wzy gene knock-out strain cultivated in shake-flasks, as a promising broadly protective Shigella vaccine candidate. Expanding on [...] Read more.
Background/Objectives: Rising antibiotic resistance underscores the urgent need for effective vaccines against shigellosis. Our previous research identified the Shigella flexneri 2a truncated mutant (STM), a wzy gene knock-out strain cultivated in shake-flasks, as a promising broadly protective Shigella vaccine candidate. Expanding on this finding, our current study explores the feasibility of transitioning to a fermentor-grown STM as a vaccine candidate for further clinical development. Methods: The STM and STM-Cj, engineered to express the conserved Campylobacter jejuni N-glycan antigen, were grown in animal-free media, inactivated with formalin, and evaluated for key antigen retention and immunogenicity in mice. Results: The fermentor-grown STM exhibited significantly increased production yields and retained key antigens after inactivation. Immunization with the STM, particularly along with the double-mutant labile toxin (dmLT) adjuvant, induced robust immune responses to the conserved proteins IpaB, IpaC, and PSSP-1. Additionally, it provided protection against homologous and heterologous Shigella challenges in a mouse pulmonary model. The STM-Cj vaccine elicited antibody responses specific to the N-glycan while maintaining protective immune responses against Shigella. These findings underscore the potential of the fermentor-grown STM as a safe and immunogenic vaccine platform for combating shigellosis and possibly other gastrointestinal bacterial infections. Conclusions: Further process development to optimize growth and key antigen expression as well as expanded testing in additional animal models for the assessment of protection against Shigella and Campylobacter are needed to build on these encouraging initial results. Ultimately, clinical trials are essential to evaluate the efficacy and safety of STM-based vaccines in humans. Full article
(This article belongs to the Special Issue Recent Scientific Advances in Vaccines for Shigella)
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13 pages, 227 KiB  
Article
A Candidate Ac3-S-LPS Vaccine Against S. flexneri 1b, 2a, 3a, 6, and Y Activates Long-Lived Systemic and Mucosal Immune Responses in Healthy Volunteers: Results of an Open-Label, Randomized Phase 2 Clinical Trial
by Vladimir A. Ledov, Victor V. Romanenko, Marina E. Golovina, Biana I. Alkhazova, Alexander L. Kovalchuk and Petr G. Aparin
Vaccines 2025, 13(3), 209; https://doi.org/10.3390/vaccines13030209 - 20 Feb 2025
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Abstract
Objectives: Determination of reactogenicity and immunogenicity of a pentavalent candidate vaccine against S. flexneri 1b, 2a, 3a, 6, and Y (PLVF). Methods: The study involved 80 healthy adult volunteers aged 18–55 years. Groups were subcutaneously immunized twice at a 30-day interval with 62.5 [...] Read more.
Objectives: Determination of reactogenicity and immunogenicity of a pentavalent candidate vaccine against S. flexneri 1b, 2a, 3a, 6, and Y (PLVF). Methods: The study involved 80 healthy adult volunteers aged 18–55 years. Groups were subcutaneously immunized twice at a 30-day interval with 62.5 μg/0.5 mL or 125 μg/0.5 mL of the vaccine. Results: During the entire 8-month period of post-vaccination observation, the vaccine was well tolerated, with no local or systemic reactions detected objectively. The results of laboratory studies demonstrated no effect on the main indicators of hemogram, biochemical blood test, or urinalysis. IgA, IgG, and IgM levels against LPS S. flexneri 1b, 2a, 3a, 6, and Y were examined before vaccination, a month after each vaccination, and 6 months after booster vaccination. One month after vaccination, IgA and IgG seroconversions were observed in 67.5–82.5% (depending on serotype) and 60–77.5% of volunteers, respectively. Booster immunization did not have a significant effect on vaccine immunogenicity. In two separate groups of 15 and 9 volunteers for mucosal sIgA, IgA, and IgG titer determination after immunization with a 125 μg vaccine dose, paired stool, and saliva samples were taken before and one month after vaccination. In 26.7–40% of volunteers, there was a 2-fold and higher increase in sIgA titer for the studied serotypes in the feces and in 66.7–88.9% in saliva. IgA and IgG 2-fold conversion rates were 26.7–53.3% and 33.3–46.7% in the feces, 33.3–77.9%, and 66.7–77.8% in saliva, respectively. Conclusions: the tolerability of PLVF and the pronounced humoral immune response allow us to proceed to the phase 3 clinical trial stage. Full article
(This article belongs to the Special Issue Recent Scientific Advances in Vaccines for Shigella)

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12 pages, 517 KiB  
Study Protocol
Safety, Tolerability, and Immunogenicity of the InvaplexAR-Detox Shigella Vaccine Co-Administered with the dmLT Adjuvant in Dutch and Zambian Adults: Study Protocol for a Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase Ia/b Clinical Trial
by Geert V. T. Roozen, Nsofwa Sukwa, Masuzyo Chirwa, Jessica A. White, Marcus Estrada, Nicole Maier, Kevin R. Turbyfill, Renee M. Laird, Akamol E. Suvarnapunya, Aicha Sayeh, Flavia D’Alessio, Candice Marion, Laura Pattacini, Marie-Astrid Hoogerwerf, Rajagopal Murugan, Manuela Terrinoni, Jan R. Holmgren, Sodiomon B. Sirima, Sophie Houard, Michelo Simuyandi and Meta Roestenbergadd Show full author list remove Hide full author list
Vaccines 2025, 13(1), 48; https://doi.org/10.3390/vaccines13010048 - 8 Jan 2025
Cited by 1 | Viewed by 1195
Abstract
Background: Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well as a major contributor to gut enteropathy and stunting. There are currently no licensed vaccines for shigellosis but it has been estimated [...] Read more.
Background: Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well as a major contributor to gut enteropathy and stunting. There are currently no licensed vaccines for shigellosis but it has been estimated that an effective vaccine could avert 590,000 deaths over a 20-year period. A challenge to effective Shigella vaccine development has been the low immunogenicity and protective efficacy of candidate Shigella vaccines in infants and young children. Additionally, a new vaccine might be less immunogenic in a highly endemic setting compared to a low endemic setting (“vaccine hyporesponsiveness”). The use of a potent adjuvant enhancing both mucosal and systemic immunity might overcome these problems. InvaplexAR-Detox is an injectable Shigella vaccine that uses a novel combination of conserved invasion plasmid antigen proteins and a serotype-specific bacterial lipopolysaccharide attenuated for safe intramuscular administration. The adjuvant dmLT has been shown to enhance Shigella immune responses in mice, has safely been administered intramuscularly, and was shown to enhance immune responses in healthy volunteers when given in combination with other antigens in phase I trials. This article describes the protocol of a study that will be the first to assess the safety, tolerability, and immunogenicity of InvaplexAR-Detox co-administered with dmLT in healthy adults in low-endemic and high-endemic settings. Methods: In a multi-center, randomized, double-blind, and placebo-controlled dose-escalation phase Ia/b trial, the safety, tolerability, and immunogenicity of three intramuscular vaccinations administered 4 weeks apart with 2.5 µg or 10 µg of InvaplexAR-Detox vaccine, alone or in combination with 0.1 µg of the dmLT adjuvant, will first be assessed in a total of 50 healthy Dutch adults (phase Ia) and subsequently in 35 healthy Zambian adults (phase Ib) aged 18–50 years. The primary outcome is safety, and secondary outcomes are humoral and cellular immune responses to the adjuvanted or non-adjuvanted vaccine. Discussion: This trial is part of the ShigaPlexIM project that aims to advance the early clinical development of an injectable Shigella vaccine and to make the vaccine available for late-stage clinical development. This trial addresses the issue of hyporesponsiveness in an early stage of clinical development by testing the vaccine and adjuvant in an endemic setting (Zambia) after the first-in-human administration and the dose-escalation has proven safe and tolerable in a low-endemic setting (Netherlands). Besides strengthening the vaccine pipeline against a major diarrheal disease, another goal of the ShigaPlexIM project is to stimulate capacity building and strengthen global North-South relations in clinical research. Trial registration: EU CT number: 2023-506394-35-02, ClinicalTrials.gov identifier: NCT05961059. Full article
(This article belongs to the Special Issue Recent Scientific Advances in Vaccines for Shigella)
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