What is Shigellosis ?

Shigellosis is an infection by bacteria of the genus Shigella that causes severe abdominal symptoms, including diarrhea, dysentery, abdominal cramps, fever, and rectal pain. Shigellosis can result in death. The disease is more dangerous than other gut pathogens because it can penetrate the lining of the intestine and cause severe inflammation of the intestine and systemic complications.

Global Burden

Shigellosis

Diarrheal disease is the second leading cause of death in children under 5 years old (after lower respiratory tract infections). It is estimated that shigellosis accounts for 5-10% of all diarrheal episodes and 75% of all diarrheal deaths.1 Worldwide there are approximately 165 million cases of shigellosis per year (99% of cases occurring in the developing world), causing over 1.1 million deaths.2 Nearly 70% of all episodes and approximately 60% of all deaths occur in children under 5 years old.1

Causative Agent

bacteria

Shigella are Gram-negative bacteria transmitted in food or water contaminated with feces from an infected person. Consumption of as little as 10 bacteria can cause disease.

There are four species of Shigella that encompass more than 20 serotypes. These species vary in their geographic distribution.

Shigella species Geographic location
S. sonnei U.S. and other industrialized countries
S. flexneri Developing world
S. boydii Limited foci in India
S. dysentariae type 1 Epidemic outbreaks

Pathogenesis

Shigella bacteria multiply within the epithelial cells of the colon, cause cell death, and spread laterally to infect and kill adjacent epithelial cells, resulting in mucosal ulceration, inflammation, and bleeding. S. dysenteriae type 1 produces severe disease and may be associated with life-threatening complications.

In some children, shigellosis causes seizures. In adults, Reiter’s Syndrome can develop, leading to inflammation of the eye and joints as well as reactive arthritis.

Current Control Strategy

The primary control strategy for shigellosis is prevention of oral-fecal transmission through education and building sanitation infrastructure. Secondary to prevention, management of the disease using oral rehydration therapy is used to reduce morbidity and mortality associated with the disease.

Existing Products

Drugs

Although antibiotics can be used to shorten the length of infection, oral, or IV rehydration therapy is the standard of care of the treatment of shigellosis.

Vaccines

No vaccine for shigellosis is widely available. In China, a recombinant, live, oral, bivalent vaccine, produced by the Lanzhou Institute of Vaccines and Biological Products, is available for adults. The vaccine has approximately 60% efficacy for both S. flexinari and S. sonnei.3 The vaccine has never been evaluated or approved for use outside of China.

Diagnostics

Bacterial culture from stool is the only method of diagnosis in widespread use for shigellosis.

References

  1.  Kotloff KL. (1999) “Global burden of Shigella infections: implications for vaccine development and implementation of control strategies.” Bulletin of the World Health Organization 77: 651-666.
  2.  Kweon, M. (2008) “Shigellosis: the current status of vaccine development.” Current Opinion in Infectious Diseases 21: 313-318.

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Drugs

Analysis

Although drug resistance to common antibiotics is a concern, numerous antibiotics are available for the treatment of shigellosis. Vaccines are the primary focus of new product development for shigellosis, however at least one new antibacterial discovery program is specifically targeting treatment.

Vaccines

Analysis

Vaccines for the prevention of shigellosis are a key focus of research and development efforts for this disease. The only existing vaccine is a live attenuated vaccine that is administered orally. Live attenuated bacteria delivered by the natural route in infection have a high likelihood of producing an effective immune response, but the balance between attenuation to prevent disease and retaining immunity is difficult to achieve.

Additional clinical stage vaccines include polysaccharide protein conjugate vaccinesand combinations of polysaccharide protein conjugates with killed whole bacteria. The polysaccharides on the surface of bacteria are highly immunogenic but also highly variable. Because the exact composition of polysaccharides can vary widely across bacterial serotypes, this strategy does not always provide enough breadth of protection. Combination of these conjugates with inactivated whole cells may compliment the narrow range of protection provided by polysaccharide protein conjugates alone.

 StrengthsWeaknessesOpportunitiesRisks
Combination: Polysaccharide protein conjugate and inactivated whole cell
Most advanced program:  Invaplex 50 (intranasal), Phase IICombination of technologies provides improved chance for protection against multiple serogroups and serotypes with one vaccineComplex vaccine with multiple conjugates and inactivated whole cells which may be difficult to produce in consistent batchesPotential demonstration of intranasal vaccination as viable route of delivery for diarrheal disease vaccination Intranasal administration is not the natural route of infection, so may not be as effective as oral vaccines
Polysaccharide protein conjugate
Most advanced program:  GVXN AD133 and Shigella Sonnei O-SPC/rBRU, and Shigella Sonnei OSPC-rDT, Phase IImmune response to polysaccharides from bacterial surface is well characterized and known to be protectiveProtection will most likely be limited to single serotype (over 20 serotypes of Shigella spp. exist)Combination with other vaccine technologies Combination with vaccines that cause other diarrheal diseases Expand to other serotypesIf serotype coverage is too narrow, may not be widely useful
Live attenuated
Most advanced program:  WRSs1 and WRSs2, Phase ISame approach as used for vaccines for other bacteria that cause diarrhea (i.e., cholera and ETEC)Difficult to achieve balance between immunogenicity and attenuation of virulenceCombination with vaccines that cause other diarrheal diseases'May cause symptoms
Inactivated
Most advanced program:  SSWc and Sf2aWC, Phase I Most likely cheaper to produce and easier to store/deliver than more complex or live vaccines Less likely than live vaccine to produce robust immune response Potential for combination with other vaccines In other diseases, inactivated vaccines have sometimes been found to be too reactogenic

Diagnostics

Analysis

There are currently both nucleic acid amplification and rapid diagnostic tests (for use at the point of care) in development for shigellosis.

As the treatment for all forms of diarrhea focuses on supportive therapy, including rehydration, diagnostics are not necessarily essential for diarrheal management. The key needs for diarrheal disease diagnosis are point of care tests that can determine the origin of the illness (i.e., viral, bacterial, or protozoan) thus directing patient treatment with antibacterial or anti-parasitic medications in conjunction with rehydration.

References

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for shigellosis. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for shigellosis are generally well developed.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: S. flexnari 2a sequenced 

Key databases: GenBank AE014073 

In vitro culture: Yes

Gene knock-outs: Yes

Conditional gene knock-outs: Yes 

Transposon mutagenesis: Yes 

RNAi: Host cell only

Other antisense technology: Host cell only 

Viability assays: Yes

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures: Yes

Whole-cell screening assays: Yes 

Enzymatic screening assays: Yes

Animal models: Yes, mouse and guinea pig

Monitoring treatment efficacy: Yes

Availability of endpoints: Yes, clearance of bacteremia 

Availability of surrogate endpoints: End of symptoms

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes, guinea pig inoculated intra-rectally 

Detection of endogenous antigen specific response in clinical samples: Yes 

Natural immunity well characterized: Yes 

Surrogate markers of protection: No

Challenge studies possible: Yes

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes, but most biomarkers are species or serotype specific 

Access to clinical samples: Yes 

Possible sample types: Stool

Access to clinical trial patients/sites: Yes

Treatment available if diagnosed: Yes

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.