What is Cholera?

Global Burden

Cholera

There are approximately 3-5 million cases of cholera each year resulting in 100,000-120,000 deaths.1 The majority of disease is concentrated in Asia and Africa with an estimated 2.5 million cases and 1.3 million cases per year, respectively.2 However, outbreaks of cholera can occur in nearly every region of the world. From 2008-2010, notable cholera outbreaks occurred in Vietnam, Iraq, Democratic Republic of Congo, Zimbabwe, South Africa, Nigeria, and, most recently, Haiti. Cholera tends to be seasonal in endemic areas and associated with large outbreaks in displaced persons populations associated with natural disasters or other humanitarian crisis situations.

Causative Agent

Vibrio cholerae

Cholera is caused by the bacterium Vibrio cholerae. Although there are many strains of V. cholerae living in aquatic environments throughout the world, only two strains of the bacterium are known to cause disease in humans, serogroups O1 and O139. Serogroup O1 is the predominant form while serogroup O139 was not identified until 1992 when it caused several epidemics in Asia.

Cholera is transmitted primarily through consumption of contaminated water. The bacteria replicate on the chitinous surface of small marine shellfish called copepods. In endemic regions of Asia and Africa, seasonal blooms of phytoplankton, the main food source of copepods, cause massive increases in the numbers of copepods and subsequently increases the amount of cholera-causing bacteria in waterways. People become infected by consumption of contaminated water, especially when copepods colonized by the bacteria are inadvertently consumed. Poor sanitation allows this cycle to continue as sewage containing feces from cholera infected patients contaminates water sources, allowing cholera to continue to propagate.

Interestingly, V. cholerae does not infect humans very efficiently. Unlike other bacterial diseases, such as tuberculosis where a single bacterium can be sufficient for infection, a person must consume more than 500 bacteria to become infected. The surface of a copepod colonized by V. cholerae can contain upward of 10,000 bacteria, making copepod consumption a key source of transmission.

Pathogenesis

The pathogenic serogroups O1 and O139 secrete a toxin that attaches to the cells of the intestine and causes hypersecretion of fluids into the intestine. It is this hypersecretion of fluids that leads to the classic “rice water” appearance and high volume diarrhea associated with the disease.

Only 7-10% of people infected with cholera are symptomatic. Because not everyone who is infected displays symptoms, it can be very difficult to track the spread of disease.

Current Control Strategy

Control strategies for cholera focus on:

  1. Prevention
  2. Outbreak monitoring and response
  3. Appropriate treatment
  4. Vaccination

Prevention of V. cholerae infection is key for cholera control. Cholera generally occurs in areas with poor sanitation, especially where sewage contamination of water sources occurs. Improved water and sewer infrastructure and water safety can drastically reduce cholera transmission.

Taking advantage of the inefficient infection properties of V. cholera, studies carried out in Bangladesh have demonstrated that filtration of copepods from drinking water using a simple folded cotton sari can reduce cholera transmission by 48%.3 A similar method of filtration of copepods from drinking water has played a key role in the near eradication of Guinea worm, a parasitic disease that is also transmitted on the surface of copepods.

The specific treatments, vaccines, and diagnostics used in cholera monitoring and control strategies are discussed in more detail below.

Existing Products

Drugs

The recommended treatment for cholera infection is oral or IV rehydration. The World Health Organization (WHO) estimates that 80% of people can be effectively treated with immediate oral rehydration therapy.1 Antibiotics can also be used in patients with severe disease to reduce the duration of symptoms. As antibiotics work on the bacteria, but not the secreted toxin causing the diarrhea, symptoms do not stop immediately and the use of rehydration in conjunction with antibiotics remains key to preventing death.

Vaccines

Injection of inactivated whole bacteria for protection against cholera has been in use since the 1880s.4 However, this inoculation strategy provided only short term protection and painful immune responses at the injection site. Since that time, newer oral inactivated whole cell vaccines have been developed. There are currently two vaccines approved for the prevention of cholera, Dukoral and Shanchol (also called mORCVAC).

Dukoral (SBL Vaccin, Sweden) was produced and approved in Sweden in 1991, is pre-qualified by WHO, and is now licensed in over 60 countries. The vaccine uses a combination of formalin and heat-killed bacteria with recombinant cholera toxin B protein. This vaccine provides a high level of protection for a short duration, 85-90% protection for 4-6 months. Dukoral only protects against O1 serotype V. cholerae but has the added benefit of partial cross protection against diarrhea caused by enterotoxigenic E. coli (ETEC). The cross protection is attributed to the recombinant cholera toxin B included in the vaccine, which has high homology with a toxin from ETEC. Due to the short duration of protection, this vaccine is primarily used in travellers rather than people living in endemic countries.

Shanchol (Shantha Biotechnics, India) and mORCVAC (VaBiotech, Vietnam) are identical inactivated whole cell vaccines produced by different sources. Shanchol and mORCVAC were approved in India and Vietnam, respectively, in March 2009. Shanchol received WHO prequalification in November 2011. These vaccines have several advantages over Dukoral, including protection against both O1 and O139 serotypes, a longer duration of protection in children, and a cheaper cost of production. However, Shanchol and mORCVAC do not have ETEC cross protection.

There are several unmet needs for cholera vaccine development including 1) developing new vaccines that increase the duration of protection and can be given as single dose, and 2) more extensive testing to evaluate the value of using the current cholera vaccines to prevent or manage cholera outbreaks.

Diagnostics

Outbreak monitoring is important both in endemic countries and in non-endemic countries after major natural or man-made disasters. Disasters can destroy sanitation infrastructure making disaster victims more susceptible to outbreaks. Monitoring for cholera outbreaks occurs through a combination of monitoring water sources, primarily for phytoplankton blooms or increased levels of V. cholera, and monitoring the population, primarily for symptomatic or asymptomatic carriers. Patient monitoring is primarily done through bacterial culture of stool samples although rapid diagnostic tests are also available to look for the presence of O1 or O139 strain lipopolysaccharides.

References

  1. WHO Cholera Fact Sheet.
  2. Sacks, D. “Global Cholera Estimates”.
  3. Huq, A et al. (2010) “Simple Sari Cloth Filtration of Water Is Sustainable and Continues To Protect Villagers from Cholera in Matlab, Bangladesh.”  MBio ASM 1:  e00034-10.
  4. Sack, DA et al. (2004) “Cholera.” The Lancet 363: 223-33.

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Drugs

As the primary focus of treatment for cholera is on preventing dehydration rather than targeting the causative bacteria, no antibiotics are specifically in development for the treatment of cholera. Novel general anti-diarrheal compounds are in development but beyond the scope of this analysis.

Vaccines

Analysis

There are several key challenges that need to be addressed in order to determine the appropriate role and value of cholera vaccines in disease prevention and outbreak control strategies:

  1. How can protection be extended, or what is the minimum length of protection that warrants widespread preventative use of a cholera vaccine in a non-outbreak scenario? Existing vaccines have only transient protection so are not likely to be valuable as routine vaccinations except in extremely high-risk regions.
  2. What role should cholera vaccines play in outbreak or epidemic scenarios? As the majority of infected patients are asymptomatic, by the time symptomatic cases are detected in an outbreak scenario, it may be too late to initiate a vaccination campaign to respond to an epidemic. However, more extensive studies with current and future cholera vaccines are needed for evaluation.
  3. What are the barriers to access for cholera vaccines? The supply of currently approved vaccines for cholera is limited. Unless there is increased commitment to produce and purchase vaccines for cholera, there is little incentive to advance research programs for new products. Understanding why current vaccines are not more widely used should help guide strategies for subsequent development.

There are currently multiple live attenuated vaccines in development for cholera. These vaccines protect against the O1 serotype and are based on the hypothesis that using a live strain will induce better immunity that the current killed or inactivated strains. Improving the duration of protection will be important for any new vaccine. In order for a cholera vaccine to gain traction in the global health community, more evidence for the usefulness of cholera vaccines in outbreak or suspected outbreak scenarios needs to be established.

 StrengthsWeaknessesOpportunitiesRisks
Live Attenuated
Serogroup targeted: O1 Most advanced program: PXVX-0200,Phase III (additional products in phase II)Potential for more robust immune response and increased duration of protectionOnly protects against O1, not O139, serogroup Practicality of live cholera vaccine for field use is untestedPotential business opportunities for travelers or military in addition to global health applicationsIf immune response strength and duration are not improved over on-market inactivated vaccines, may not be valuable
Combination: Live attenuated and recombinant protein
Serogroup targeted: O1 Most advanced program: Peru-15 pCTB,Phase I Inclusion of recombinant cholera toxin B provides cross protection against ETEC Combination formulation is potentially more expensive to produce  Only protects against O1, not O139, serogroup Potential business opportunities for travelers or military in addition to global health applications If immune response strength and duration are not improved over on-market inactivated vaccines, may not be valuable

Diagnostics

Analysis

Rapid diagnostic tests (RDTs) are available for the detection of the two most clinically relevant V. cholera serogroups, O1 and O139. The main limitations of these tests are (1) an inability of the test to type the serogroup of cholera strain, which is important for initial detection of an outbreak or for identification of non-classical pathogenic serogroups, and (2) the RDTs cannot evaluate antibiotic susceptibility of the bacteria. While these features are desirable, they are not essential as the majority of cholera treatment relies on the use of oral rehydration rather than antibiotic therapy. There are several early-stage diagnostics in development for cholera, including a novel PCR method that distinguishes between toxigenic and non-toxigenic strains of the bacteria. 

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 cholera. 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 cholera are generally well developed. However, as cholera is a human restricted pathogen, it has been difficult to develop animal models that recapitulate human disease and immune response.

Drugs Development Tools

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

Genome: sequenced 

Key databases: Vibrio cholerae Database 

In vitro culture: Yes

Gene knock-outs: Yes 

Conditional gene knock-outs: Yes 

Transposon mutagenesis: Yes 

RNAi: No, but can be used to study host factors 

Other antisense technology:  No 

Viability assays:  Yes 

Transcription microarrays: Yes 

Proteomics: Yes 

Crystal structures:  Not extensive

Whole-cell screening assays: Yes 

Enzymatic screening assays: Yes

Animal models: Yes, but difficult to recapitulate human disease Rabbit ileal loop model Removable intestinal tie adult rabbit diarrhea (RITARD) model Suckling mouse model Infant rabbit model

Monitoring treatment efficacy:Yes 

Availability of endpoints: Yes, end of diarrheal episode 

Availability of surrogate endpoints:  No 

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: No 

Detection of endogenous antigen specific response in clinical samples:Yes 

Natural immunity well characterized:No, natural immunity minimal, transient, and not well understood

Surrogate markers of protection: No 

Challenge studies possible: No

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes 

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.