Shigella Vaccine for Shigellosis

(S4V03 Trial)

Recruiting at 1 trial location

Overseen By Bettina Wunderlich, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: LimmaTech Biologics AG

Must not be taking: Systemic steroids, Antibiotics

Disqualifiers: Pregnancy, HIV, Hepatitis, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

120 Participants Needed

Trial Summary

What is the purpose of this trial?

In this challenge study, the bioconjugate candidate vaccine Shigella4V2 will be tested for its ability to induce an immune response that protects healthy adult volunteers from infection with a wild-type Shigella sonnei strain compared to participants receiving placebo.

Will I have to stop taking my current medications?

The trial requires that you stop using any medication known to affect immune function, like systemic steroids, within 30 days before the study and during the study. You also need to avoid using systemic antibiotics in the 7 days before the injection.

What data supports the effectiveness of the treatment Shigella4V2 for shigellosis?

Research on similar vaccines, like the GMMA-based vaccine, shows promising results in producing strong immune responses and protection against various Shigella strains in preclinical studies, suggesting potential effectiveness for Shigella4V2. ^{1 2 3 4 5}

Is the Shigella vaccine safe for humans?

The Shigella vaccine candidates, including Shigella sonnei strains WRSs2 and WRSs3, have been tested in humans and animals, showing they are generally safe but can cause mild fever and diarrhea in some people. These newer versions are designed to reduce these side effects while still being effective. ^{1 6 7 8 9}

How is the Shigella4V2 treatment different from other treatments for shigellosis?

Shigella4V2 is unique because it uses a novel GMMA (Generalized Modules for Membrane Antigens) platform to deliver O-antigens from multiple Shigella serotypes, aiming to provide broad protection against the most common strains. Unlike other treatments, it is designed to be a low-cost vaccine option, addressing the challenge of antibiotic resistance in Shigella infections. ^{4 6 10 11 12}

Research Team

Robert W Frenck, Jr., MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Kawsar Talaat, MD

Principal Investigator

Johns Hopkins Bloomberg School of Public Health

Paulina A Rebolledo, MD

Principal Investigator

Emory University

Eligibility Criteria

Healthy adults aged 18-50 can join this trial if they're not pregnant, agree to use effective contraception, and are in stable health as confirmed by medical history, lab results, and physical exams. They must understand the risks of Shigella infection and commit to all study visits.

Inclusion Criteria

I am in good health and have stable medical conditions.

I can attend all study visits and answer follow-up calls.

I have taken a pregnancy test and it was negative.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Selection

Participants receive either a high or low dose of Shigella4V2 or placebo to determine the optimal dose for the next step

4 weeks

1 visit (in-person)

Challenge and Inpatient Monitoring

Participants are challenged with the Shigella sonnei strain and monitored for infection and safety

1 week

Inpatient stay from Day 29 to Day 37

Follow-up

Participants are monitored for safety and effectiveness after the challenge

4 weeks

Treatment Details

Interventions

• Shigella4V2

Trial Overview The trial is testing a new vaccine called Shigella4V2 against a placebo. The goal is to see if the vaccine can prevent infection with Shigella sonnei by comparing immune responses in vaccinated participants versus those given a placebo.

Participant Groups

Group I: Shigella4V2 Low dose Experimental Treatment 1 Intervention

2 injections of low dose of Shigella4V2 will be injected intramuscularly in the deltoid muscle

Group II: Shigella4V2 High dose Experimental Treatment 1 Intervention

1 injection of high dose Shigella4V2 and 1 injection of low dose Shigella4V2 will be injected intramuscularly in the deltoid muscle

Group III: Placebo Placebo Group 1 Intervention

2 injections of PBS will be injected intramuscularly in the deltoid muscle

Who Is Running the Clinical Trial?

LimmaTech Biologics AG

Lead Sponsor

Trials

9

Recruited

1,500+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Children's Hospital Medical Center, Cincinnati

Collaborator

Trials

844

Recruited

6,566,000+

Johns Hopkins Bloomberg School of Public Health

Collaborator

Trials

441

Recruited

2,157,000+

Findings from Research

The live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S was shown to be safe and capable of inducing strong T cell-mediated immunity (T-CMI) responses in 14 volunteers, with 73% showing responses in CD8 T cells and 90% in CD4 T cells after three doses.

CVD 1208S not only triggered T-CMI responses but also demonstrated a diverse cytokine production profile, suggesting that it could effectively complement humoral immunity in protecting against shigellosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans. Toapanta, FR., Bernal, PJ., Kotloff, KL., et al.[2022]

Despite over 60 years of research and various vaccine strategies, a safe and effective vaccine for shigellosis has not yet been developed.

Recent advancements in understanding Shigella's virulence mechanisms and the immune response, along with progress in molecular technology, offer hope for creating a licensed vaccine to combat the significant health impacts of shigellosis globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on vaccines against Shigella. Ashkenazi, S., Cohen, D.[2021]

Researchers have developed live attenuated vaccine candidates for shigellosis by mutating virulence genes in Shigella flexneri, which showed promising protective effects in macaque monkeys.

Similar mutations are being introduced in Shigella dysenteriae 1, including one that disables the harmful Shiga toxin, with plans for upcoming human phase I trials to test these vaccine candidates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Construction and evaluation of live attenuated vaccine strains of Shigella flexneri and Shigella dysenteriae 1. Fontaine, A., Arondel, J., Sansonetti, PJ.[2019]

The newly developed 4-component vaccine (altSonflex1-2-3) against Shigella serotypes S. sonnei and S. flexneri showed high immunogenicity in preclinical studies, inducing bactericidal antibodies even against different Shigella strains.

Safety assessments indicated that the vaccine formulation had no significant reactogenicity compared to a previously tested mono-component vaccine, and it was well tolerated in a GLP toxicology study in rabbits, supporting its progression to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A next-generation GMMA-based vaccine candidate to fight shigellosis. Rossi, O., Citiulo, F., Giannelli, C., et al.[2023]

Current research indicates that live attenuated Shigella vaccines, which are taken orally, are more effective at providing protection against shigellosis compared to killed vaccines administered through injections.

Advancements in understanding Shigella's pathogenesis and the immune response to infection are guiding the development of new vaccine strategies, highlighting the importance of this knowledge in creating effective vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Live attenuated Shigella flexneri mutants as vaccine candidates against shigellosis and vectors for antigen delivery. Phalipon, A., Sansonetti, P.[2005]

In a pilot study involving 5 rhesus macaques, the new Shigella sonnei vaccines WRSs2 and WRSs3 showed improved safety profiles compared to the previously tested WRSS1 vaccine, which caused mild fever and diarrhea in some volunteers.

Both WRSs2 and WRSs3 maintained comparable immunogenicity to WRSS1, suggesting they could be effective candidates for further development as a safe vaccine against shigellosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and colonization of two novel VirG(IcsA)-based live Shigella sonnei vaccine strains in rhesus macaques (Macaca mulatta). Collins, TA., Barnoy, S., Baqar, S., et al.[2021]

Vaccine candidates for Shigella are nearing phase 3 clinical trials aimed at young children in low- and middle-income countries, focusing on preventing moderate to severe shigellosis.

The primary endpoint for these trials will be the vaccine's efficacy against the first episode of diarrhea caused by the specific Shigella strains included in the vaccine, using a modified Vesikari score for assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pivotal Shigella Vaccine Efficacy Trials-Study Design Considerations from a Shigella Vaccine Trial Design Working Group. Pavlinac, PB., Rogawski McQuade, ET., Platts-Mills, JA., et al.[2022]

New second-generation Shigella vaccine candidates, WRSs2 and WRSs3, are designed to be less reactogenic than the earlier candidate WRSS1, potentially reducing side effects like fever and diarrhea while maintaining strong immune responses.

Both WRSs2 and WRSs3 have shown similar safety and efficacy profiles in animal studies compared to WRSS1, indicating they could be promising alternatives for preventing shigellosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of WRSs2 and WRSs3, new second-generation virG(icsA)-based Shigella sonnei vaccine candidates with the potential for reduced reactogenicity. Barnoy, S., Jeong, KI., Helm, RF., et al.[2021]

The SC602 vaccine candidate, which has specific virulence gene deletions, was shown to induce protective immune responses against Shigella flexneri 2a in a human challenge study, with no severe symptoms in vaccinated individuals compared to a significant illness in control subjects.

While the vaccine demonstrated efficacy, with none of the vaccinated volunteers developing severe shigellosis after exposure, the safety window appears narrow, as some vaccinees experienced mild diarrhea, indicating careful dose management is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccination against shigellosis with attenuated Shigella flexneri 2a strain SC602. Coster, TS., Hoge, CW., VanDeVerg, LL., et al.[2022]

Shigellosis is a significant global health issue, causing over 200,000 deaths annually, particularly affecting children under 5 in low- and middle-income countries, and is complicated by the rise of antimicrobial-resistant strains.

Currently, there are no widely available vaccines for shigellosis, but several candidates are in various stages of development, focusing on understanding Shigella's epidemiology, pathogenesis, and potential antigens for effective vaccine formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toward a Shigella Vaccine: Opportunities and Challenges to Fight an Antimicrobial-Resistant Pathogen. Raso, MM., Arato, V., Gasperini, G., et al.[2023]

Shigellosis is a significant global health issue, especially in low- and middle-income countries, with rising concerns about antibiotic-resistant Shigella strains.

A promising low-cost four-component Shigella vaccine is being developed using GMMA technology, which targets the O-antigen of Shigella to stimulate a strong immune response against the most common serotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a Four-Component GMMA-Based Vaccine against Shigella. Micoli, F., Nakakana, UN., Berlanda Scorza, F.[2022]

Shigellosis, particularly caused by Shigella dysenteriae serotype 1, poses a significant public health threat in developing countries, with many strains showing resistance to current antibiotics, highlighting the urgent need for effective vaccines.

Research has led to the development of live oral vaccines using non-pathogenic Shigella strains and hybrid strains with carrier organisms, which aim to stimulate the immune system while minimizing the risk of disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis and genetic manipulation of Shigella virulence determinants for vaccine development. Mills, SD., Sekizaki, T., Gonzalez-Carrero, MI., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans. [2022]

2. England pubmed.ncbi.nlm.nih.gov

An update on vaccines against Shigella. [2021]

3. France pubmed.ncbi.nlm.nih.gov

Construction and evaluation of live attenuated vaccine strains of Shigella flexneri and Shigella dysenteriae 1. [2019]

4. England pubmed.ncbi.nlm.nih.gov

A next-generation GMMA-based vaccine candidate to fight shigellosis. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Live attenuated Shigella flexneri mutants as vaccine candidates against shigellosis and vectors for antigen delivery. [2005]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and colonization of two novel VirG(IcsA)-based live Shigella sonnei vaccine strains in rhesus macaques (Macaca mulatta). [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pivotal Shigella Vaccine Efficacy Trials-Study Design Considerations from a Shigella Vaccine Trial Design Working Group. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Characterization of WRSs2 and WRSs3, new second-generation virG(icsA)-based Shigella sonnei vaccine candidates with the potential for reduced reactogenicity. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Vaccination against shigellosis with attenuated Shigella flexneri 2a strain SC602. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Toward a Shigella Vaccine: Opportunities and Challenges to Fight an Antimicrobial-Resistant Pathogen. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Towards a Four-Component GMMA-Based Vaccine against Shigella. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Analysis and genetic manipulation of Shigella virulence determinants for vaccine development. [2019]