Cholera

What

Cholera is usually caused by ingesting infected food or water. Cholera is characterised by the sudden onset of diarrhoea and can result in severe dehydration. Only 2 serogroups of the bacterium Vibrio cholerae produce the enterotoxin that causes disease: O1 and O139.

Who

Cholera vaccine is recommended for children (≥2 years of age) and adult travellers who:

• have a high risk of acquiring diarrhoeal disease
• are travelling to areas where there is a high likelihood of exposure to cholera

How

Cholera vaccination is only available in Australia as an oral vaccine against serogroup O1.

Children aged 2–6 years are recommended to receive 3 doses of inactivated oral cholera vaccine with an interval of 1–6 weeks between each dose, or 1 dose of live attenuated oral cholera vaccine.

Adults and children aged >6 years are recommended to receive 2 doses of cholera vaccine with an interval of 1–6 weeks between each dose, or 1 dose of live attenuated oral cholera vaccine.

Why

Cholera causes a large burden of disease in developing countries. It can be brought back to Australia by children and adults travelling to cholera-endemic areas.

Cholera vaccines available in Australia

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route

The cholera vaccines are oral vaccines.

Avoid food and drink for 1 hour before and 1 hour after receiving a cholera vaccine, because the vaccines are acid-labile.

Oral inactivated cholera vaccine

The oral inactivated cholera vaccine is supplied in a pack with aliquid vaccine dose vial and a buffer sachet. The dose and preparation of the vaccine is different for children aged 2-6 years and adults and children aged >6 years.

Children aged 2–6 years

Children aged 2–6 years are recommended to receive 3 doses of inactivated cholera vaccine. They need 75 mL inactivated cholera vaccine for each dose.

The interval between each dose is 1–6 weeks. If the previous dose was more than 6 weeks ago, restart the primary course.

To give the vaccine to children aged 2–6 years:

• dissolve the buffer granules in 150 mL water
• pour away half the solution (note, this cannot be kept for later use)
• mix the entire contents of the vaccine vial in the remaining 75 mL
• administer to the child

Reconstituted vaccine should be used within 2 hours.

If there is an ongoing risk of cholera, a single booster dose is recommended 6 months after finishing the primary course. If the interval between primary immunisation and the booster dose is more than 6 months, repeat the primary course.

Adults and children aged >6 years

Adults and children aged >6 years are recommended to receive 2 doses of inactivated cholera vaccine. They need 150 mL cholera vaccine for each dose.

The interval between doses is 1–6 weeks. If the 2nd dose is more than 6 weeks after the 1st dose, restart the primary course.

To give the vaccine to adults and children aged >6 years:

• dissolve the buffer granules in 150 mL water
• mix the entire contents of the vaccine vial in the buffer
• administer to the person

Reconstituted vaccine should be used within 2 hours.

Oral live attenuated cholera vaccine

The oral live attenuated cholera vaccine is supplied in a pack with a powder vaccine sachet and a buffer sachet. The dose is the same for both adults and children. The preparation of the vaccine is different for children aged 2-5 years and adults and children aged ≥6 years.  

Children aged 2–5 years  

Children aged 2-5 years are recommended to receive 1 dose of live attenuated cholera vaccine at least 10 days before travel. They need 50 mL of vaccine.  

To give the vaccine to children aged 2-5 years: 

• dissolve the buffer granules in 100 mL of cold or room temperature (≤25oC) bottled non-carbonated or carbonated drinking water (using non-bottled water, such as tap water, may render the vaccine ineffective) 
• pour away half the solution  
• mix the entire contents of the vaccine sachet in the remaining 50 mL and stir for at least 30 seconds. If desired, no more than 4 g (1 teaspoon) of sucrose (table sugar) or no more than 1 g (1/4 teaspoon) of stevia sweetener may be added and stirred into the suspension 
• administer to the child 

Reconstituted vaccine should be used within 15 minutes.    

Adults and children aged ≥6 years  

Adults and children aged ≥6 years are recommended to receive 1 dose of live attenuated cholera vaccine at least 10 days before travel. They need 100 mL of vaccine.  

To give the vaccine to adults and children aged ≥6 years: 

• dissolve the buffer granules in 100 mL of cold or room temperature (≤25oC) bottled non-carbonated or carbonated drinking water (using non-bottled water, such as tap water, may render the vaccine ineffective) 
• mix the entire contents of the vaccine sachet in the buffer solution and stir for at least 30 seconds. If desired, no more than 4g (1 teaspoon) of sucrose (table sugar) or no more than 1g (1/4 teaspoon) of stevia sweetener may be added and stirred into the suspension 
• administer to the person  

Reconstituted vaccine should be used within 15 minutes.  

Repeating doses 

Drinking less than a half dose of the live attenuated cholera vaccine may result in decreased protection.  

If less than half the dose of the live attenuated vaccine is consumed, a repeat full dose of the live attenuated vaccine can be given within 72 hours. 

If half or more of the live attenuated vaccine is consumed, it is still considered valid — do not repeat the dose.

The degree of protection added by a repeat dose of live attenuated cholera vaccine is unknown. 

Co-administration with other vaccines

Oral inactivated cholera vaccine

Travellers can receive the inactivated oral cholera vaccine before, with, or after other parenteral travel vaccines.

People receiving inactivated oral cholera vaccine and oral live attenuated typhoid vaccine should have the vaccines at least 8 hours apart. The buffer in the cholera vaccine may affect how the capsules of oral typhoid vaccine move through the gastrointestinal tract. See Contraindications and precautions.

Oral live attenuated cholera vaccine

No interaction studies have been performed on co-administration of current formulation oral live attenuated cholera vaccines with other vaccines. Interaction studies on co-administration of older formulations of the oral live attenuated cholera vaccine with live oral typhoid vaccine, oral polio vaccine, and yellow fever vaccine found that the immune response was not affected for either vaccine.^1-4 Travellers can receive the live attenuated oral cholera vaccine at the same time as any other parenteral travel vaccines.  

If the person is also receiving the oral live attenuated typhoid vaccine, give the 2 vaccines at least 2 hours apart. See Contraindications and precautions.

Contraindications

Cholera vaccines are contraindicated in people who have had:

• anaphylaxis after a previous dose of any cholera vaccine
• anaphylaxis after any component of a cholera vaccine

Oral live attenuated vaccine

These groups should not receive the oral live attenuated cholera vaccine and should use the oral inactivated vaccine instead: 

• people who are immunocompromised, including people with HIV, or people receiving immunosuppressive drugs or treatments 
• people who are taking antibiotics 
• pregnant women 

Precautions

Use of antibiotic and antimalarial medications

Some antibiotics and antimalarial agents can inactivate the oral live attenuated cholera vaccine.  

Time the vaccination so the person receives the oral live attenuated cholera vaccine at least 14 days after receiving oral or parenteral antibiotics. Oral or parenteral antibiotics given within 10 days of receipt of the oral live attenuated cholera vaccine may impair the effectiveness of the vaccine. Consider using the inactivated cholera vaccine if the person has had antibiotics within the previous 14 days, or needs antibiotics within 10 days of their cholera vaccination.    

Children and adults should receive the oral live attenuated cholera vaccine at least 10 days before beginning antimalarial prophylaxis with chloroquine. Studies of a previous live attenuated cholera vaccine found that the immune response may be affected when administered with chloroquine. A study of a previous live attenuated cholera vaccine found that the immune response may be affected when administered with mefloquine, other studies did not find this effect.^1,3 There was no effect of atovaquone/proguanil on the previous live attenuated cholera vaccine.⁵ 

Acute gastroenteritis

People should not receive cholera vaccine if they have acute gastrointestinal illness with persistent diarrhoea or vomiting.

Wait until they have recovered.

People who are immunocompromised

People who are immunocompromised can receive the inactivated cholera vaccine, including people with HIV. However, there are limited data on the effectiveness of the inactivated vaccine in people with HIV.⁶

People who are immunocompromised should not receive the live attenuated cholera vaccine (See Contraindications).

See Table. Types of medical conditions and immunosuppressive therapy and associated levels of immunocompromise in Vaccination for people who are immunocompromised.

People living in households with people who are immunocompromised

People living in households with people who are immunocompromised can receive the inactivated cholera vaccine.  

Use caution when considering whether to prescribe live attenuated cholera vaccine to people living in households with people who are immunocompromised. The live attenuated cholera vaccine may be shed in the stool of any recipient for at least 7 days.⁷ There is a potential for transmission of the vaccine strain to unvaccinated close contacts (e.g., household contacts), including those who are immunocompromised.  

See Close contacts of people who are immunocompromised.

Women who are pregnant or breastfeeding

Women who are pregnant or breastfeeding can receive the inactivated cholera vaccine. Evidence of the safety and effectiveness of the inactivated cholera vaccine is limited, but suggests the benefits outweigh the minimal risks.^8,9 

Women who are pregnant or breastfeeding should not receive the live attenuated cholera vaccine. See Contraindications.

See Table. Recommendations for vaccines that are not routinely recommended in pregnancy: inactivated bacterial vaccines and Table. Vaccines that are contraindicated in pregnancy: live attenuated vaccines in Vaccination for women who are planning pregnancy, pregnant or breastfeeding for more details.

Oral live attenuated typhoid vaccine

People receiving inactivated oral cholera vaccine and oral live attenuated typhoid vaccine should have the vaccines at least 8 hours apart.

People receiving live attenuated oral cholera vaccine and oral live attenuated typhoid vaccine should have the vaccines at least 2 hours apart.

The buffer in the cholera vaccine may affect how the capsules of oral typhoid vaccine move through the gastrointestinal tract.

People with metabolic diseases

The live attenuated cholera vaccine contains lactose as sugars and sucrose. People with metabolic diseases such as rare hereditary problems of galactose intolerance, congenital lactase deficiency, glucose-galactose malabsorption, fructose intolerance, or sucrose-isomaltase insufficiency, should receive inactivated oral cholera vaccine.

Oral inactivated vaccine

Mild abdominal pain, discomfort and diarrhoea were reported from post-marketing surveillance at a frequency of 0.1–1%.¹⁰ Similar rates of adverse events were reported among vaccine and placebo clinical trial participants.^8,11,12

Oral live attenuated vaccine

Similar rates of adverse events were reported among live attenuated vaccine and placebo clinical trial participants.^7,13-17 One large scale clinical trial found that diarrhoea was more frequently reported among vaccine participants (3.9%) than among placebo clinical trial participants (1.2%).¹⁴  

The rates of adverse events in vaccine recipients in the two largest clinical trials were:^13,14  

• 31.3 – 34.4% tiredness 
• 24.7 – 28.9% headache 
• 18.7 – 21.5% abdominal pain 
• 15.1 – 18.3% nausea or vomiting 
• 16.5 – 18.3% lack of appetite  
• 1.1 – 3.9% diarrhoea  
• 0.6 – 2.2% fever  

Pathogenesis and transmission

Cholera is caused by Vibrio cholerae, a motile, curved gram-negative bacterium. Transmission mainly occurs when people ingest faecally contaminated food or water. Seafood caught from contaminated water has also caused outbreaks.¹⁸

There are more than 150 serogroups of V. cholerae, distinguished by differences in the O antigens. Only 2 serogroups produce the enterotoxin that causes cholera disease: O1 and O139.

Persistence in the environment

Vibrio cholerae can persist in water, depending on the temperature, pH, salinity and nutrient availability.

It can survive under unfavourable conditions in a viable dormant state.¹⁸

Symptoms of cholera

Cholera is an acute bacterial infection that is characterised by the sudden onset of diarrhoea that is:

• painless
• profuse
• watery

Cases vary from mild to severe. Subclinical infection can also occur.¹⁸

When cases are severe, cholera is one of the most rapidly fatal diseases in humans.⁶ Cholera can be fatal within 6–12 hours of symptom onset. Case-fatality rates can range from 2% to 10% without appropriate medical care.¹⁹

The cholera toxin does not cause intestinal inflammation. It causes increased amounts of electrolytes to be secreted into the intestinal lumen. This results in mild to severe dehydration, and sometimes metabolic acidosis.

Cholera in Australia

About 2–6 cases of cholera occur in Australia each year.

Since the National Notifiable Diseases Surveillance System started in 1991, nearly all reported cholera cases have been acquired outside Australia. The exceptions include 1 case of laboratory-acquired cholera in 1996 and 3 cases in 2006 that were associated with eating raw imported whitebait.^20,21 These 3 people with food-acquired cholera had no history of recent travel to known cholera-endemic areas.²¹

In 1977, a locally acquired case led to the discovery of Vibrio cholerae in some rivers along the Queensland coast.²² Because of this, health workers should be aware that sporadic cases of cholera may occur after contact with estuarine waters. However, this is rare.

Cholera in other countries

Cholera is a large health burden in developing countries. It is endemic in:⁸

• Haiti
• South and Southeast Asia
• sub-Saharan Africa

Cholera epidemics are common in situations in which food and water supplies can be contaminated, such as after natural disasters and civil unrest.²³ The overall risk of cholera is low for travellers who have access to a safe water source and hygienic food preparation, even in endemic countries.

The risk of infection is estimated to be 0.2 cases per 100,000 travellers from western countries. The risk of severe disease is considerably lower.²⁴ However, cholera in travellers is likely to be underdetected and under-reported.^23-25

Vaccine efficacy

Oral inactivated cholera vaccine

Efficacy trials of the oral inactivated cholera vaccine have mainly been done in Bangladesh and Peru. These trials used vaccines containing inactivated whole-cell Vibrio cholerae serogroup O1 combined with recombinant cholera toxin B subunit (rCTB).^11,26-31

The large randomised controlled trial in Bangladesh found that age appeared to affect vaccine efficacy. Efficacy was lower and waned more rapidly in children aged 2–5 years.²⁹ In this age group, efficacy was 100% during the first 4–6 months after vaccination but decreased rapidly after that. Overall efficacy was 38% after 1 year and similar after 2 years. 

In contrast, for people aged >5 years, the efficacy estimates were 78% after 1 year and 63% after 2 years.^27-29 When the cholera cases in all age groups were aggregated, the protective efficacy was 62% after 1 year and 57% after 2 years.

Long-term follow-up to 5 years showed no significant protective efficacy beyond 2 years.^28,29

The protective efficacy of the inactivated vaccine over a 3-year follow-up period was not significantly different between those who received 2 doses and those who received 3 doses (including all ages).^27,28

The randomised controlled trial in Peru among military recruits 16–45 years of age found a vaccine efficacy of 86% against symptomatic cholera after 2 vaccine doses.³¹

Another Peruvian household study in people 2–65 years of age showed that a booster dose 10 months after a 2-dose inactivated primary series had an overall efficacy of 61%.¹¹

Oral live attenuated cholera vaccine

Efficacy trials of the live attenuated cholera vaccine have mainly been done in the United States. These trials used a new formulation of live CVD 103-HgR vaccine in adults aged 18 to 45 years against the O1 El Tor Inaba cholera strain. Efficacy against severe cholera diarrhoea was highest at 10 days after vaccination (93.3%) and decreased slightly at 3 months after vaccination. Efficacy was 85.7% against severe cholera diarrhoea at 3 months after vaccination, 79.5% against moderate or worse cholera diarrhoea, and 50.8% against mild or worse cholera diarrhoea.¹³ 

No efficacy trials of the current formulation live vaccine have been completed in cholera-endemic countries. There is no long-term efficacy data for this vaccine. A study looking at the immune response at 2 years after vaccination found that 64.5% vaccine recipients aged 12 to 17 years were seropositive and therefore likely protected against cholera.

Vaccine effectiveness

Oral inactivated cholera vaccine

A case–control study was done in Mozambique during a mass oral cholera vaccination program. People in the study were aged ≥2 years and lived in an endemic area. The inactivated oral cholera vaccine was 78% protective 1–6 months after the 1st dose and 84% protective 0.5–4.5 months after the 2nd dose.³²

Oral live attenuated cholera vaccine

The effectiveness of the live attenuated cholera vaccine has not been established in people living in cholera-affected areas or in people who may have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine.^33,34

Vaccine against serogroup O139

The cholera vaccines marketed in Australia do not protect against infection with Vibrio cholerae serogroup O139.

Transport according to National Vaccine Storage Guidelines: Strive for 5.³⁵ Store refrigerated at +2°C to +8°C. Do not freeze. Protect from light.

The person to be vaccinated is responsible for the vaccine after they buy it. Carefully explain:

• how to transport the vaccine from pharmacy to home
• how to store the vaccine at home in the refrigerator

Cholera is a notifiable disease in all states and territories in Australia. People with cholera must also be quarantined.

State and territory public health authorities can provide advice about the public health management of cholera, including management of cases and contacts.

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2. Cryz SJ, Jr., Que JU, Levine MM, Wiedermann G, Kollaritsch H. Safety and immunogenicity of a live oral bivalent typhoid fever (Salmonella typhi Ty21a)-cholera (Vibrio cholerae CVD 103-HgR) vaccine in healthy adults. Infection and Immunity 1995;63:1336-9. 
3. Foster RH, Noble S. Bivalent cholera and typhoid vaccine. Drugs 1999;58:91-6; discussion 7-8. 
4. Kollaritsch H, Cryz SJ, Jr., Lang AB, et al. Local and systemic immune responses to combined vibrio cholerae CVD103-HgR and salmonella typhi ty21a live oral vaccines after primary immunization and reimmunization. Vaccine 2000;18:3031-9. 
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