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WHAT'S NEW THIS TUESDAY: CHOLERA AND CHOLERA VACCINATION

Sunday, 26th of August 2012

• CHOLERA AND CHOLERA VACCINATION

Readers of this webpage will remember animated exchanges, in Emerging Infectious Diseases, on the value of oral cholera vaccine, with special reference to Haiti. Now that the disease is claiming hundreds of victims in west Africa, cholera has once more come to the fore, with the British government pledging £2 million for cholera treatment, water and sanitation to Sierra Leone.

Harris and colleagues from Boston and Dhaka have written an extensive review article on cholera, reproduced below, including the following discussion on vaccine. The extract which follows, and the whole article, are best viewed, with tables, at
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60436-X/fulltext

EXCERPT ON ORAL CHOLERA VACCINES

"Although safe and effective cholera vaccines exist, cholera vaccination is not yet part of cholera control programmes outside of Vietnam; discussions are in progress regarding potential use in Haiti and elsewhere. The reasons for this are logistical, financial, and historical. Cholera vaccines are given orally, have an excellent safety profile, and target induction of mucosal immunity. Two oral killed vaccines, prequalified for use by WHO, are licensed and commercially available. Dukoral (WC-rBS, Crucell, Sweden) contains several biotypes and serotypes of V cholerae O1 supplemented with 1 mg per dose of recombinant cholera toxin B subunit. Shanchol (Shantha Biotechnics-Sanofi Pasteur, India) contains several biotypes and serotypes of V cholerae O1 and V cholerae O139 without supplemental cholera toxin B subunit. Shanchol is the bivalent vaccine that is internationally available; mORCVAX (VaBiotech, Vietnam) is the locally produced Vietnamese version of this vaccine.5

"Oral killed cholera vaccines have been administered to millions of recipients and are safe and immunogenic. The vaccines are administered as two or three doses depending on age and vaccine (table 4117—131). Overall, the vaccines provide 60—85% protective efficacy for 2—3 years, although protection among young children is of shorter duration.117—127 Dukoral has been safely administered to individuals with HIV infection.123

"Reanalysis of original studies of oral cholera vaccine in Bangladesh in the 1980s disclosed a measurable herd effect,132 and modelling suggests that vaccination of 50% of a population could result in a greater than 90% reduction in cholera incidence in that population overall.133 A cost-effectiveness model suggested that oral cholera vaccine could be cost effective in areas endemic for cholera.134

"Several live attenuated oral cholera vaccines have also been developed, including CVD 103-HgR (PaxVax, USA), Peru-15 (Haikou VTI Biological Insitute, China) and others.135 These genetically modified vaccine strains have in common the inability to express cholera toxin. These vaccines have been shown to be safe and immunogenic in volunteer studies;136—140 however, CVD 103-HgR failed to show protective efficacy when assessed in an initial field study.141 Peru-15 has been shown to be safe and immunogenic in different age groups in Bangladesh,142 but has not yet been investigated in field studies. Several other cholera vaccines are in various stages of development, including subunit vaccines, other live attenuated vaccines, and conjugate vaccines.143, 144

"WHO has endorsed the inclusion of oral vaccine in cholera control programmes in endemic areas in conjunction with other preventive and control strategies.5 WHO also recommends that oral vaccine be considered as part of an integrated control programme in areas at risk for outbreaks.5 The use of vaccine in reactive situations (ie, after an outbreak has occurred) is less certain. A case-control study in Vietnam suggested that such use could be of benefit,145 and modelling further supports such potential use.55,56,146—148 At present, WHO suggests that oral cholera vaccine be considered as part of an integrated programme in reactive situations in both epidemic and endemic settings in conjunction with provision of safe water, adequate sanitation, case detection, and rehydration strategies, but that collection of additional data to support vaccination in such settings is warranted.5 Creation of an international cholera vaccine stockpile is being discussed."

The Lancet

The Lancet, Volume 379, Issue 9835, Pages 2466 - 2476, 30 June 2012

Cholera

Original Text

Jason B Harris MD a b †, Regina C LaRocque MD a c †, Firdausi Qadri PhD e †, Prof Edward T Ryan MD a c f †, Prof Stephen B Calderwood MD a c d †

Summary

Cholera is an acute, secretory diarrhoea caused by infection with Vibrio cholerae of the O1 or O139 serogroup. It is endemic in more than 50 countries and also causes large epidemics. Since 1817, seven cholera pandemics have spread from Asia to much of the world. The seventh pandemic began in 1961 and affects 3—5 million people each year, killing 120 000. Although mild cholera can be indistinguishable from other diarrhoeal illnesses, the presentation of severe cholera is distinct, with pronounced diarrhoeal purging. Management of patients with cholera involves aggressive fluid replacement; effective therapy can decrease mortality from more than 50% to less than 0·2%. Antibiotic treatment decreases volume and duration of diarrhoea by 50% and is recommended for patients with moderate to severe dehydration. Prevention of cholera depends on access to safe water and sanitation. Two oral cholera vaccines are available and the most effective use of these in integrated prevention programmes is being actively assessed.

Introduction and history

Cholera is an acute secretory diarrhoea caused by the Gram-negative bacterium Vibrio cholerae.1—4 Cholera epidemics have been increasing in intensity, duration, and frequency, showing the need for more effective approaches to prevention and control.

Descriptions of a disease thought to be cholera are found in Sanskrit back to the 5th century BC, and the disease has existed on the Indian subcontinent for centuries. In 1817, cholera spread beyond the Indian subcontinent, and six worldwide cholera pandemics occurred between 1817 and 1923. Between 1849 and 1854, London physician John Snow proposed that cholera was a communicable disease and that stool contained infectious material. He suggested that this infectious material could contaminate drinking water supplies, resulting in transmission of cholera. Filippo Pacini, working independently in Italy in 1854, first observed comma-shaped forms under a microscope in cholera stools. In 1884, Robert Koch first isolated V cholerae in pure culture in work that began in Egypt and continued in Calcutta (Kolkata), India.

The continuing seventh cholera pandemic began in Indonesia in 1961 and spread through Asia to Africa, Europe, and Latin America. This pandemic is caused by a new biotype of V cholerae first isolated in 1905 in El Tor, Egypt.3 Although cholera is vastly under-reported, WHO estimates that 3—5 million cases occur per year,5 predominantly in Asia and Africa, with periodic major epidemics including that in Haiti in 2010.6 Diarrhoeal diseases including cholera are the second leading cause of mortality worldwide among children younger than 5 years, and are one of the main causes of morbidity.7 Cholera is also a major cause of severe dehydrating diarrhoea in adults.

Causative agent

V cholerae is a member of the Vibrionaceae family of curved, Gram-negative rods that are found in coastal waters and estuaries.1, 3 These organisms grow best in the presence of salt, although V cholerae can grow in water of low salinity when it is warm and contains sufficient organic nutrients.8V cholerae is often associated with zooplankton and shellfish in water,8 and it can use chitin as a carbon and nitrogen source.9 Chitin induces natural competence in V cholerae, suggesting that lateral gene transfer occurs in water, especially during zooplankton blooms.10 In water, V cholerae enter a viable but non-culturable form,11 also called active but non-culturable or conditionally viable environmental cells.4, 12

V cholerae is classified into more than 200 serogroups based on the O antigen of the lipopolysaccharide;1 of these, only O1 and O139 serogroups cause epidemic cholera. V cholerae O1 is further classified into two biotypes, classical and El Tor.3 Two major serotypes exist, Ogawa and Inaba, which vary in prevalence with time.13 In 1992, V cholerae O139 was first recognised in south Asia as a cause of epidemic cholera.14, 15 This organism is derived from V cholerae O1 El Tor by lateral transfer of a genomic island substituting the O139 for the O1 antigen, but is otherwise almost identical to V cholerae O1 El Tor.16, 17 Although classical V cholerae O1 caused the fifth and sixth pandemics (and presumably the earlier pandemics), the seventh pandemic is attributed to the El Tor biotype, which has now replaced the classical biotype.

Although early isolates of V cholerae O1 were susceptible to most antibiotics, V cholerae O139, and some isolates of V cholerae O1 El Tor, have acquired an SXT element that mediates resistance to co-trimoxazole and streptomycin;18 this element is found in almost all strains isolated during the past decade.19 In the past few years, strains of V cholerae O1 resistant to tetracycline, erythromycin, or ciprofloxacin, or combinations thereof, have been recovered in Asia;19, 20 some of these strains have acquired additional resistance genes in the SXT element. These multiresistant strains have not yet been recognised in other locations.

Pathogenesis and pathophysiology

After ingestion of V cholerae, most of the bacteria are killed by gastric acid. Surviving organisms colonise the small intestine and elaborate cholera toxin, the major virulence factor for pathogenic strains.3 Cholera toxin is a protein exotoxin that consists of one A subunit associated with five B subunits.21 The B subunit pentamer binds to the ganglioside GM1 on eukaryotic cells, and the A subunit is translocated intracellularly, where it acts enzymatically to activate adenylate cyclase and raise intracellular cyclic AMP; this leads to chloride secretion through the apical chloride channel and secretory diarrhoea.22—24 The second major virulence factor of pathogenic strains of V cholerae is the toxin-coregulated pilus, a colonisation factor whose expression is regulated in parallel to cholera toxin.25, 26

The genes for cholera toxin are encoded within the genome of a filamentous bacteriophage, CTXϕ.27 Classical and El Tor strains have different versions of this bacteriophage, which can insert at one or two attachment sites in the genome depending on the biotype. The bacterial cell surface receptor for CTXϕ is the toxin-coregulated pilus,27 which is itself encoded within a genomic island—vibrio pathogenicity island (VPI-1).28, 29 Evolution of virulence in V cholerae involves sequential acquisition of VPI-1 followed by CTXϕ.

All seventh pandemic strains of V cholerae O1 El Tor contain VPI-1, and a second vibrio pathogenicity island VPI-2. Two genomic islands are specific to the seventh pandemic strains, vibrio seventh pandemic islands 1 and 2.30 Recent seventh pandemic strains have been described that have the classical CTXϕ instead of the El Tor CTXϕ, or a variant of the El Tor CTXϕ encoding the B subunit of cholera toxin that occurs in classical V cholerae O1 strains.31 These variant El Tor strains have largely replaced the earlier El Tor strains and might be associated with more severe diarrhoea.

Epidemiology

Cholera occurs in both endemic and epidemic patterns. It is endemic in many areas of Asia and Africa. In Asia, cholera occurs seasonally before and after the monsoon rains,3 the incidence is highest in children, and the disease can occur in neonates.32, 33 Cholera epidemics arise in a long cycle superimposed on existing endemic disease. This pattern relates to declining levels of population-level immunity from a previous outbreak, overlaid on cycles of climate variability.34 In the past decade, devastating epidemics of cholera have occurred in Angola, Ethiopia, Zimbabwe, Pakistan, Somalia, Sudan, Vietnam, and Haiti.35 Among immunologically naive populations, cholera affects all age groups, and epidemics can be associated with high case-fatality rates.35 This pattern was recorded in Haiti, where cholera had been notably absent before 2010. Population density, poor sanitation and health infrastructure, and logistical obstacles to appropriate case management also contribute to a high case-fatality rate in epidemic settings.

Environmental factors are important in the epidemiology of cholera. Changes in surface water temperature and terrestrial nutrient discharge lead to a proliferation of phytoplankton and zooplankton and a consequent increase in V cholerae.8, 36, 37 Cholera rates also increase substantially during floods compared with non-flood periods.38 Natural disasters that disrupt public health facilities, such as cyclones and earthquakes, also contribute to cholera epidemics.

The infectious dose of V cholerae O1 has been estimated to be 105—108 in experimental human infection, but could be as low as 103 in the presence of achlorhydria.39 The incubation period ranges between 12 h and 5 days.1, 40

Molecular epidemiology

The genome of a V cholerae O1 El Tor strain was sequenced in 2000;41 as with all vibrios, this organism has a large circular chromosome and a small circular chromosome.42 All Vibrionaceae have a super-integron in the small chromosome that acts as a gene capture system.43, 44 A comparison of genomic sequences of patient and environmental strains isolated for nearly 100 years showed 12 distinct lineages of V cholerae O1; the classical and El Tor O1 biotypes were one lineage in this phylogeny.31 All strains of V cholerae O1 El Tor shared a highly conserved core genome, with variations attributable mainly to laterally transferred genetic elements and single nucleotide variation.

An analysis suggested that the seventh pandemic strains originated from a single source in the Bay of Bengal that has spread to distant locations in three independent but overlapping waves.45 The first wave, which spread from Asia into Africa and South America, lacked the SXT element. The second wave acquired the SXT element and replaced the isolate in the first wave; the third wave also contains the SXT element. Isolates in the Haiti outbreak are closely related to south Asian strains in the third pandemic wave.46

Transmission

Patients infected with V cholerae O1 or O139 who have no symptoms generally shed the organism for only a few days; however, patients who are symptomatic shed the organism for between 2 days and 2 weeks, and rarely longer.4, 40 Transmission of cholera within households has been documented.40V cholerae are present in human stool both as individual planktonic cells and in biofilm-like aggregates.47, 48 In environmental water, organisms convert to conditionally viable environmental cells12 within 24 h.49 These organisms are infectious on reintroduction into people, although the infectious dose in this form is not known. Filtration of water through sari cloth reduces cholera transmission by nearly 50%, consistent with removal of organisms attached to zooplankton.50

The peak of a cholera epidemic is often preceded by increasing prevalence of the pathogenic strain in the environment.12 Bacteriophages that are lytic for V cholerae O1 or O139 are also found in the stools of patients and in environmental water.12, 51 Bacteriophage density increases as an outbreak proceeds, and these bacteriophages could modulate the severity and duration of an outbreak.12, 51, 52

As V cholerae O1 leave a person, the organisms have a phenotype referred to as hyperinfectivity—that is, the infectious dose is 10—100 times lower than for non-human-shed organisms.53 Hyperinfectivity of recently shed organisms persists in water for 5—24 h, suggesting that organisms transmitted from person to person might be more infectious than those that have acclimatised to the environment. When hyperinfectivity is incorporated into a mathematical model of a cholera outbreak, the characteristically explosive nature of such an outbreak is better reproduced than if hyperinfectivity is not included.54 Other key components of cholera transmission models4, 52, 55, 56 include the concentration of V cholerae O1 or O139 in stool, the difference of infectivity between planktonic cells and stool aggregates, the rapidity of spread of the organism from person to person, the presence of lytic bacteriophage in stool and water, and the concentration in water of the conditionally viable environmental cells for environment-to-person transmission.

Host susceptibility

Concomitant infection with enteropathogenic bacteria or parasites exerts an immunomodulatory effect on V cholerae-specific immunity,57, 58 and several host factors contribute to susceptibility to cholera. In particular, retinol deficiency is associated with an increased risk of V cholerae infection and with a raised risk of symptomatic disease.59, 60 Blood group O has been associated with severe cholera in different populations.61—63 The prevalence of blood group O is lower in south Asia than in other regions, perhaps related to evolutionary pressure from cholera.64 Results of a family-based study from Bangladesh59 showed that first-degree relatives of a patient with cholera had greater odds of being infected than did less closely related contacts in the same household independent of blood group, suggesting that additional genetic factors have a role in susceptibility. A variant in the promoter region of BPIFB1 (also known as LPLUNC1), a component of the innate immune system, was associated with cholera in a candidate gene study.65, 66 Additional studies of host genetic factors related to cholera could provide further insights into the interaction between V cholerae and the host.

Diagnosis

According to WHO,67 a case of cholera should be suspected when a patient aged 5 years or older develops severe dehydration or dies from acute watery diarrhoea, even in an area where cholera is not known to be present, or when a patient aged 2 years or more develops acute watery diarrhoea in an area known to have cholera. Where microbiology facilities are available, V cholerae infection can be confirmed by isolation of the organism from stool on selective media, followed by biochemical tests, and serogrouping and serotyping with specific antibodies.68 Enrichment of stool in alkaline peptone water can increase the sensitivity of culture.69 Cholera can be rapidly diagnosed by examining fresh human stool under ×400 darkfield microscopy for vibrio-shaped cells with darting motility that is abrogated with specific antibody;70 about half of culture-positive stools are positive on darkfield microscopy.47

Immunoassays that detect cholera toxin71, 72 or V cholerae O1 and O139 lipopolysaccharide73—75 directly in stool have also been developed. Such assays can be used in settings with limited laboratory capacity and enable early detection of cases during an outbreak. One such commercially available dipstick for both O1 and O139-associated cholera has a 97% sensitivity and 71—76% specificity compared with PCR under field conditions.76 Dipstick assays seem to be more sensitive for detection of V cholerae in patients previously treated with antibiotics than is culture.

Clinical signs and symptoms

Few diseases have a clinical presentation as striking as that of cholera. Massive watery diarrhoea, up to 1 L per hour, can lead to hypotensive shock and death within hours of the first symptom (so-called cholera gravis). Death rates in untreated patients with severe cholera can exceed 70%.77 Although the stools of patients with cholera can contain faecal matter or bile in the early phases, the characteristic rice-water stool of cholera develops with continued purging (figure78); this term refers to the similarity of the stool to water in which rice has been washed. Vomiting is a common feature, particularly early in illness. The diarrhoea of cholera is typically painless and not accompanied by tenesmus; some patients have abdominal discomfort or cramping due to fluid distension of the bowel. Fever is rare and should raise suspicion for secondary infection.

 

Figure Full-size image (263K) Download to PowerPoint

Presentation and management of cholera

(A) Rice water stool in a patient with cholera. (B) Cholera cot used in management of patients with cholera to monitor continuing volume losses in stool. (C) Patient with cholera before rehydration. (D) Patient with cholera 8 h after starting rehydration therapy. (A, C, and D) reproduced from Chowdhury and colleagues,78 by permission of PLoS.

Dehydration and electrolyte abnormalities are the most important complications of cholera. Patients can be lethargic, and might have sunken eyes (figure), dry mouth, cold clammy skin, decreased skin turgor, or wrinkled hands and feet. Kussmaul breathing can occur because of acidosis from stool bicarbonate losses and lactic acidosis associated with poor perfusion.79 The peripheral pulse is rapid and thready, and can become difficult to palpate as blood pressure drops; urine output decreases with time.80, 81 Muscle cramping and weakness due to electrolyte losses and ion shifts (particularly potassium and calcium) are common. In children, depletion of glycogen stores and inadequate gluconeogenesis can lead to severe hypoglycaemia, shown by altered consciousness, seizures, or even coma.82, 83 Cholera sicca is an unusual form of the disease in which fluid accumulates in the intestinal lumen, and circulatory collapse and even death can occur before the passage of the first loose stool.84

The presentation of cholera differs between endemic and epidemic settings. In endemic settings, rates of asymptomatic V cholerae infection range from 40% to 80%,4 and cholera can present as mild diarrhoea indistinguishable from infection with other enteropathogens. The most severe cases of cholera in endemic settings are concentrated among young children and previously unexposed individuals. In the epidemic setting, severe disease occurs in adults as frequently as in children and is associated with high case-fatality rates.85 Laboratory tests are not required to care for most patients with cholera although they can be useful in patients with ileus, confusion, coma, or seizures, or in those with no urine output in response to fluid replacement. Laboratory abnormalities include changes in serum electrolytes (hypokalaemia, hyponatraemia, hypocalcaemia), renal dysfunction, the effects of haemoconcentration, and in a few children, hypoglycaemia. The clinical features of cholera due to V cholerae O1 and O139 are much the same.86, 87 Complications from severe hypotension can include stroke (especially in elderly patients) and renal compromise, and vomiting can lead to aspiration pneumonia,88 but cholera itself is an acute infection with no chronic symptoms.

Management

Rehydration is the cornerstone of management of patients with cholera. Early attempts at oral rehydration met with little success because the physiological requirements for sodium-glucose cotransport were not recognised. The introduction of oral rehydration solution in the late 1960s, with equimolar concentrations of sodium and glucose to maximise sodium uptake in the small intestine, and careful replacement of preceding and continuing fluid losses, ushered in present cholera treatment.84, 89

With the present standard of care, the mortality of severe cholera can be reduced to less than 0·2%, even in resource-limited settings.3 However, obstacles exist to administration of best possible rehydration, and mortality rates can still exceed 10% early in cholera epidemics before appropriate resources are available.90, 91 In the epidemic in Haiti, the median time between onset of symptoms and death within the community was 12 h.92 Decentralised treatment centres (such as oral rehydration points) improve access to therapy, reduce time to initial rehydration, and are crucial in management of outbreaks.

The approach to rehydration during severe cholera differs substantially from the approach to patients with gastroenteritis in developed countries because: patients with severe cholera present with a greater degree of initial dehydration, these patients have more rapid continuing losses once they come to medical attention, and they have proportionally greater electrolyte losses than in non-cholera gastroenteritis (table 193—98).

Table 1Table image  

Comparison of the composition of cholera stools and acceptable therapeutic fluids for cholera67, 94

For these reasons, the most common error in caring for patients with cholera is to underestimate the speed and volume of fluids required. Patients with severe cholera typically require an average of 200 mL/kg of isotonic oral or intravenous fluids in the first 24 h of therapy, and might require more than 350 mL/kg.67, 99 Estimation and replacement of ongoing losses, even during correction for the initial fluid deficit, is crucial. The rate of continuing fluid loss might exceed 20 mL/kg per h; cholera cots are inexpensive and useful for estimation of continuing volume losses (figure). In the absence of cholera cots, continuing losses can be estimated as 10—20 mL/kg of bodyweight for each diarrhoeal stool or episode of vomiting.

In severe cholera, the initial fluid deficit should be replaced within 3—4 h of presentation. The route of administration of fluids depends on the severity of dehydration (table 267). Patients with severe (≥10%) dehydration are in hypovolaemic shock and require immediate intravenous rehydration administered as rapidly as possible until circulation is restored. Oral rehydration should begin as soon as patients are capable of drinking (typically 3—4 h), because more potassium, bicarbonate, and glucose are available in oral rehydration solution than in standard intravenous fluids. In patients with some dehydration, the initial deficit should be replaced rapidly, with oral rehydration solution whenever possible, and patients should be monitored until signs of dehydration have resolved. Patients with some dehydration but with profound vomiting or continuing stool losses can rapidly progress to severe dehydration if only oral rehydration solution is provided, and should receive concomitant intravenous and oral rehydration. In patients without dehydration, management consists of oral fluids to replace continuing losses. WHO oral rehydration solution has glucose as the carbohydrate source. Rice-based oral rehydration solution formulations, if available, have been recorded in randomised trials to reduce the duration of diarrhoea and stool losses in severe cholera.93 Homemade oral rehydration solution can be used in an emergency situation (table 1). In patients with symptomatic hypoglycaemia, 0·25—0·50 g/kg of intravenous glucose can be administered and correction of the hypoglycaemia monitored until fluid repletion and the ability to take oral rehydration solution has occurred.83

Table 2Table image  

Approach to rehydration in a patient with suspected cholera67

Antibiotics are adjunctive therapy in patients with moderate to severe dehydration from cholera.39 As in other infections, use of antibiotics in cholera might contribute to increasing antimicrobial resistance. However, effective antibiotics shorten the duration of diarrhoea and reduce the volume of stool losses by up to 50%; they also reduce the duration of shedding of viable organisms in stool from several days to 1—2 days.77, 100 Antibiotics can be administered once the initial fluid deficit is corrected and vomiting has resolved, ideally within 4 h of initiation of therapy. Antibiotic therapy should be based on prevailing local resistance patterns (table 3101—106).

Table 3Table image  

Antibiotics for cholera

Nutritional interventions include the resumption of a high energy diet immediately after the initial fluid deficit is corrected to prevent malnutrition and immediate complications including hypokalaemia and hypoglycaemia. For infants, breastfeeding should be encouraged in concert with oral rehydration solution. In a randomised trial, zinc supplementation reduced the duration of diarrhoea and volume of stool in children with cholera.107 Zinc supplementation after childhood diarrhoea also reduced the incidence of subsequent episodes of diarrhoea for several months;108, 109 WHO recommends zinc for children younger than 5 years of age with diarrhoea (10 mg/day for children younger than 6 months and 20 mg/day for 10 days for children aged 6 months to 5 years67). Children with diarrhoea in developing countries also benefit from supplementation with vitamin A.110 Antimotility agents and antiemetics have no established benefit for treatment of cholera, and might prolong infection or have sedating effects that interfere with effective oral rehydration.67, 111

In an outbreak, clinicians and public health officials often need to manage many patients at the same time. Crucial response features include creation of cholera treatment centres; training of staff in case recognition and management; and provision of safe water and sanitation. Dependent on the local situation, radio advertisements, mobile phone messaging, messages on billboards, community volunteers, and other methods can be important ways to educate the public about seeking medical care, oral rehydration use, sanitation, and other ways to prevent or minimise transmission. Other important components of the public health response include disinfectants, proper disposal of waste and the bodies of those who die, and coordination of the response with community, regional, national, and international health authorities. The Cholera Outbreak Training and Shigellosis Program is an online resource that can assist with management of such features. Some countries are reluctant to declare a cholera epidemic because of concern about creating panic and the implications for tourism and exports; however, rapid reporting and a coordinated public health response should be encouraged to minimise the extent of the outbreak and prevent further spread.

Prevention

The response to the cholera pandemics of the 19th century led to the development of systems to provide safe water and adequate sanitation, but 1 billion people still do not have access to safe water and remain at risk of cholera.112 Continued progress in provision of safe water and adequate sanitation is a Millennium Development Goal but could take decades to achieve.113 During a cholera outbreak, the major response should focus on case detection, rehydration-based treatment, and provision of safe water, in conjunction with adequate sanitation, hand-washing, and safe food preparation.114 These goals have been used for decades in areas that remain at risk for cholera, without reducing the continuing effect of this disease, suggesting that consideration of additional control strategies, such as vaccination, is warranted.113, 115, 116

Although safe and effective cholera vaccines exist, cholera vaccination is not yet part of cholera control programmes outside of Vietnam; discussions are in progress regarding potential use in Haiti and elsewhere. The reasons for this are logistical, financial, and historical. Cholera vaccines are given orally, have an excellent safety profile, and target induction of mucosal immunity. Two oral killed vaccines, prequalified for use by WHO, are licensed and commercially available. Dukoral (WC-rBS, Crucell, Sweden) contains several biotypes and serotypes of V cholerae O1 supplemented with 1 mg per dose of recombinant cholera toxin B subunit. Shanchol (Shantha Biotechnics-Sanofi Pasteur, India) contains several biotypes and serotypes of V cholerae O1 and V cholerae O139 without supplemental cholera toxin B subunit. Shanchol is the bivalent vaccine that is internationally available; mORCVAX (VaBiotech, Vietnam) is the locally produced Vietnamese version of this vaccine.5

Oral killed cholera vaccines have been administered to millions of recipients and are safe and immunogenic. The vaccines are administered as two or three doses depending on age and vaccine (table 4117—131). Overall, the vaccines provide 60—85% protective efficacy for 2—3 years, although protection among young children is of shorter duration.117—127 Dukoral has been safely administered to individuals with HIV infection.123

Table 4Table image  

Internationally available killed-cell cholera vaccines for oral administration

Reanalysis of original studies of oral cholera vaccine in Bangladesh in the 1980s disclosed a measurable herd effect,132 and modelling suggests that vaccination of 50% of a population could result in a greater than 90% reduction in cholera incidence in that population overall.133 A cost-effectiveness model suggested that oral cholera vaccine could be cost effective in areas endemic for cholera.134

Several live attenuated oral cholera vaccines have also been developed, including CVD 103-HgR (PaxVax, USA), Peru-15 (Haikou VTI Biological Insitute, China) and others.135 These genetically modified vaccine strains have in common the inability to express cholera toxin. These vaccines have been shown to be safe and immunogenic in volunteer studies;136—140 however, CVD 103-HgR failed to show protective efficacy when assessed in an initial field study.141 Peru-15 has been shown to be safe and immunogenic in different age groups in Bangladesh,142 but has not yet been investigated in field studies. Several other cholera vaccines are in various stages of development, including subunit vaccines, other live attenuated vaccines, and conjugate vaccines.143, 144

WHO has endorsed the inclusion of oral vaccine in cholera control programmes in endemic areas in conjunction with other preventive and control strategies.5 WHO also recommends that oral vaccine be considered as part of an integrated control programme in areas at risk for outbreaks.5 The use of vaccine in reactive situations (ie, after an outbreak has occurred) is less certain. A case-control study in Vietnam suggested that such use could be of benefit,145 and modelling further supports such potential use.55,56,146—148 At present, WHO suggests that oral cholera vaccine be considered as part of an integrated programme in reactive situations in both epidemic and endemic settings in conjunction with provision of safe water, adequate sanitation, case detection, and rehydration strategies, but that collection of additional data to support vaccination in such settings is warranted.5 Creation of an international cholera vaccine stockpile is being discussed.

Unanswered questions

Cholera has had an immense effect on human history. Unfortunately, present control strategies have not proven highly effective in areas of the world bearing the global burden of cholera.113 Many questions remain. Will a new serogroup of V cholerae arise, as O139 did? Why are altered variants of V cholerae O1 El Tor developing? Will severe weather events such as regional flooding associated with global warming result in increased cholera? What role would surveillance, screening, vaccination, or empirical treatment have in limiting the spread of cholera into immunologically naive populations? Would short course targeted chemotherapy with highly active antimicrobials for close community contacts of patients with cholera limit transmission, or only lead to drug resistance? How can safe water and improved sanitation be attained in the many parts of the world without them? What are the obstacles to incorporation of cholera vaccines into immunisation programmes in countries where cholera is endemic, and how can these be overcome? Who will support and pay for the manufacture, distribution, and use of cholera vaccines? Will a vaccine stockpile be developed? And, if so, who will maintain, monitor, and activate its use? Will the development of more effective or longer acting cholera vaccines than are currently available simplify some these decisions?

We do not yet know the answers to these important questions, but the way forward will require scientific, medical, public health, environmental, financial, and political cooperation and action. As it has in the past, cholera remains largely a disease of impoverishment, social unrest and displacement, and continues to be a disease of major public health concern.

Search strategy and selection criteria

We searched Medline and Cochrane Library databases with the terms “cholera” or “Vibrio cholerae”, and “randomised controlled trials” from Jan 1, 1966 to Sept 30, 2011, in all languages.

Contributors

All authors contributed equally to this Seminar.

Conflicts of interest

SBC, ETR, RCL, FQ, and JBH receive support from grants from the National Institutes of Health for research into immunity to cholera. FQ receives grants from the Bill & Melinda Gates Foundation and the Swedish International Development Agency (Sida) for research into vaccines and immunology in cholera. JBH receives a grant from the Charles H Hood Foundation for research into cholera immunology, and RCL receives a grant from the Howard Hughes Medical Institute for research into human genetic susceptibility to cholera. SBC, ETR, and FQ are co-inventors on institutional patents related to cholera vaccine development. SBC and ETR are editors for the infectious diseases sections of UpToDate, a medical education programme that includes topics related to cholera, and receive editorial payments from the publisher.

Acknowledgments

This work was supported by the International Centre for Diarrhoeal Research, Dhaka, and grants from the National Institutes of Health, AI058935 (SBC, ETR, FQ), U01 AI077883 (ETR, FQ) and an International Research Scientist Development Award, K01 TW07409 (JBH), a Physician-Scientist Early Career Award from the Howard Hughes Medical Institute (RCL), and a Charles H Hood Foundation Child Health Research Award (JBH).

References

1 Morris JG. Cholera and other types of vibriosis: a story of human pandemics and oysters on the half shell. Clin Infect Dis 2003; 37: 272-280. CrossRef | PubMed

2 Greenough WB. The human, societal, and scientific legacy of cholera. J Clin Invest 2004; 113: 334-339. CrossRef | PubMed

3 Sack DA, Sack RB, Nair GB, Siddique AK. Cholera. Lancet 2004; 363: 223-233. Summary | Full Text | PDF(990KB) | CrossRef | PubMed

4 Nelson EJ, Harris JB, Morris JG, Calderwood SB, Camilli A. Cholera transmission: the host, pathogen and bacteriophage dynamic. Nat Rev Microbiol 2009; 7: 693-702. CrossRef | PubMed

5 Cholera vaccines: WHO position paper. Wkly Epidemiol Rec 2010; 85: 117-128. PubMed

6 Enserink M. Infectious diseases. Haiti's outbreak is latest in cholera's new global assault. Science 2010; 330: 738-739. CrossRef | PubMed

7 Bryce J, Boschi-Pinto C, Shibuya K, Black REfor the WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet 2005; 365: 1147-1152. Summary | Full Text | PDF(611KB) | CrossRef | PubMed

8 Colwell RR. Global climate and infectious disease: the cholera paradigm. Science 1996; 274: 2025-2031. CrossRef | PubMed

9 Kirn TJ, Jude BA, Taylor RK. A colonization factor links Vibrio cholerae environmental survival and human infection. Nature 2005; 438: 863-866. CrossRef | PubMed

10 Meibom KL, Blokesch M, Dolganov NA, Wu CY, Schoolnik GK. Chitin induces natural competence in Vibrio cholerae. Science 2005; 310: 1824-1827. CrossRef | PubMed

11 Roszak DB, Colwell RR. Survival strategies of bacteria in the natural environment. Microbiol Rev 1987; 51: 365-379. PubMed

12 Faruque SM, Islam MJ, Ahmad QS, et al. Self-limiting nature of seasonal cholera epidemics: role of host-mediated amplification of phage. Proc Natl Acad Sci USA 2005; 102: 6119-6124. PubMed

13 Longini IM, Yunus M, Zaman K, Siddique AK, Sack RB, Nizam A. Epidemic and endemic cholera trends over a 33-year period in Bangladesh. J Infect Dis 2002; 186: 246-251. CrossRef | PubMed

14 Ramamurthy T, Garg S, Sharma R, et al. Emergence of novel strain of Vibrio cholerae with epidemic potential in southern and eastern India. Lancet 1993; 341: 703-704. CrossRef | PubMed

15 Albert MJ, Siddique AK, Islam MS, et al. Large outbreak of clinical cholera due to Vibrio cholerae non-O1 in Bangladesh. Lancet 1993; 341: 704. CrossRef | PubMed

16 Comstock LE, Maneval D, Panigrahi P, et al. The capsule and O antigen in Vibrio cholerae O139 Bengal are associated with a genetic region not present in Vibrio cholerae O1. Infect Immun 1995; 63: 317-323. PubMed

17 Bik EM, Bunschoten AE, Gouw RD, Mooi FR. Genesis of the novel epidemic Vibrio cholerae O139 strain: evidence for horizontal transfer of genes involved in polysaccharide synthesis. EMBO J 1995; 14: 209-216. PubMed

18 Waldor MK, Tschape H, Mekalanos JJ. A new type of conjugative transposon encodes resistance to sulfamethoxazole, trimethoprim, and streptomycin in Vibrio cholerae O139. J Bacteriol 1996; 178: 4157-4165. PubMed

19 Faruque SM, Islam MJ, Ahmad QS, et al. An improved technique for isolation of environmental Vibrio cholerae with epidemic potential: monitoring the emergence of a multiple-antibiotic-resistant epidemic strain in Bangladesh. J Infect Dis 2006; 193: 1029-1036. CrossRef | PubMed

20 Kim HB, Wang M, Ahmed S, et al. Transferable quinolone resistance in Vibrio cholerae. Antimicrob Agents Chemother 2010; 54: 799-803. CrossRef | PubMed

21 Gill DM. The arrangement of subunits in cholera toxin. Biochemistry 1976; 15: 1242-1248. CrossRef | PubMed

22 Gill DM. Involvement of nicotinamide adenine dinucleotide in the action of cholera toxin in vitro. Proc Natl Acad Sci USA 1975; 72: 2064-2068. PubMed

23 Cassel D, Pfeuffer T. Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc Natl Acad Sci USA 1978; 75: 2669-2673. PubMed

24 Gill DM, Meren R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc Natl Acad Sci USA 1978; 75: 3050-3054. PubMed

25 Taylor RK, Miller VL, Furlong DB, Mekalanos JJ. Use of phoA gene fusions to identify a pilus colonization factor coordinately regulated with cholera toxin. Proc Natl Acad Sci USA 1987; 84: 2833-2837. PubMed

26 Matson JS, Withey JH, DiRita VJ. Regulatory networks controlling Vibrio cholerae virulence gene expression. Infect Immun 2007; 75: 5542-5549. CrossRef | PubMed

27 Waldor MK, Mekalanos JJ. Lysogenic conversion by a filamentous phage encoding cholera toxin. Science 1996; 272: 1910-1914. PubMed

28 Karaolis DK, Johnson JA, Bailey CC, Boedeker EC, Kaper JB, Reeves PR. A Vibrio cholerae pathogenicity island associated with epidemic and pandemic strains. Proc Natl Acad Sci USA 1998; 95: 3134-3139. PubMed

29 Karaolis DK, Somara S, Maneval DR, Johnson JA, Kaper JB. A bacteriophage encoding a pathogenicity island, a type-IV pilus and a phage receptor in cholera bacteria. Nature 1999; 399: 375-379. CrossRef | PubMed

30 Dziejman M, Balon E, Boyd D, Fraser CM, Heidelberg JF, Mekalanos JJ. Comparative genomic analysis of Vibrio cholerae: genes that correlate with cholera endemic and pandemic disease. Proc Natl Acad Sci USA 2002; 99: 1556-1561. PubMed

31 Chun J, Grim CJ, Hasan NA, et al. Comparative genomics reveals mechanism for short-term and long-term clonal transitions in pandemic Vibrio cholerae. Proc Natl Acad Sci USA 2009; 106: 15442-15447. PubMed

32 Deen JL, Von SL, Sur D, et al. The high burden of cholera in children: comparison of incidence from endemic areas in Asia and Africa. PLoS Negl Trop Dis 2008; 2: e173. PubMed

33 Khan AM, Hossain MS, Khan AI, et al. Bacterial enteropathogens of neonates admitted to an urban diarrhoeal hospital in Bangladesh. J Trop Pediatr 2009; 55: 122-124. CrossRef | PubMed

34 Koelle K, Rodo X, Pascual M, Yunus M, Mostafa G. Refractory periods and climate forcing in cholera dynamics. Nature 2005; 436: 696-700. CrossRef | PubMed

35 Harris JB, LaRocque RC, Charles RC, Mazumder RN, Khan AI, Bardhan PK. Cholera's western front. Lancet 2010; 376: 1961-1965. Full Text | PDF(911KB) | CrossRef | PubMed

36 Pascual M, Rodo X, Ellner SP, Colwell R, Bouma MJ. Cholera dynamics and El Nino-southern oscillation. Science 2000; 289: 1766-1769. CrossRef | PubMed

37 Jutla AS, Akanda AS, Griffiths JK, Colwell R, Islam S. Warming oceans, phytoplankton, and river discharge: implications for cholera outbreaks. Am J Trop Med Hyg 2011; 85: 303-308. CrossRef | PubMed

38 Schwartz BS, Harris JB, Khan AI, et al. Diarrheal epidemics in Dhaka, Bangladesh, during three consecutive floods: 1988, 1998, and 2004. Am J Trop Med Hyg 2006; 74: 1067-1073. PubMed

39 Nelson EJ, Nelson DS, Salam MA, Sack DA. Antibiotics for both moderate and severe cholera. N Engl J Med 2011; 364: 5-7. CrossRef | PubMed

40 Weil AA, Khan AI, Chowdhury F, et al. Clinical outcomes in household contacts of patients with cholera in Bangladesh. Clin Infect Dis 2009; 49: 1473-1479. CrossRef | PubMed

41 Heidelberg JF, Eisen JA, Nelson WC, et al. DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae. Nature 2000; 406: 477-483. CrossRef | PubMed

42 Trucksis M, Michalski J, Deng YK, Kaper JB. The Vibrio cholerae genome contains two unique circular chromosomes. Proc Natl Acad Sci USA 1998; 95: 14464-14469. PubMed

43 Rowe-Magnus DA, Guerout AM, Ploncard P, Dychinco B, Davies J, Mazel D. The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons. Proc Natl Acad Sci USA 2001; 98: 652-657. PubMed

44 Mazel D, Dychinco B, Webb VA, Davies J. A distinctive class of integron in the Vibrio cholerae genome. Science 1998; 280: 605-608. CrossRef | PubMed

45 Mutreja A, Kim DW, Thomson NR, et al. Evidence for several waves of global transmission in the seventh cholera pandemic. Nature 2011; 477: 462-465. CrossRef | PubMed

46 Chin CS, Sorenson J, Harris JB, et al. The origin of the Haitian cholera outbreak strain. N Engl J Med 2011; 364: 33-42. CrossRef | PubMed

47 Nelson EJ, Chowdhury A, Harris JB, et al. Complexity of rice-water stool from patients with Vibrio cholerae plays a role in the transmission of infectious diarrhea. Proc Natl Acad Sci USA 2007; 104: 19091-19096. PubMed

48 Faruque SM, Biswas K, Udden SM, et al. Transmissibility of cholera: in vivo-formed biofilms and their relationship to infectivity and persistence in the environment. Proc Natl Acad Sci USA 2006; 103: 6350-6355. PubMed

49 Nelson EJ, Chowdhury A, Flynn J, et al. Transmission of Vibrio cholerae is antagonized by lytic phage and entry into the aquatic environment. PLoS Pathog 2008; 4: e1000187. CrossRef | PubMed

50 Colwell RR, Huq A, Islam MS, et al. Reduction of cholera in Bangladeshi villages by simple filtration. Proc Natl Acad Sci USA 2003; 100: 1051-1055. PubMed

51 Faruque SM, Naser IB, Islam MJ, et al. Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages. Proc Natl Acad Sci USA 2005; 102: 1702-1707. PubMed

52 Jensen MA, Faruque SM, Mekalanos JJ, Levin BR. Modeling the role of bacteriophage in the control of cholera outbreaks. Proc Natl Acad Sci USA 2006; 103: 4652-4657. PubMed

53 Merrell DS, Butler SM, Qadri F, et al. Host-induced epidemic spread of the cholera bacterium. Nature 2002; 417: 642-645. CrossRef | PubMed

54 Hartley DM, Morris JG, Smith DL. Hyperinfectivity: a critical element in the ability of V. cholerae to cause epidemics?. PLoS Med 2006; 3: e7. CrossRef | PubMed

55 Andrews JR, Basu S. Transmission dynamics and control of cholera in Haiti: an epidemic model. Lancet 2011; 377: 1248-1255. Summary | Full Text | PDF(1665KB) | CrossRef | PubMed

56 Tuite AR, Tien J, Eisenberg M, Earn DJ, Ma J, Fisman DN. Cholera epidemic in Haiti, 2010: using a transmission model to explain spatial spread of disease and identify optimal control interventions. Ann Intern Med 2011; 154: 593-601. PubMed

57 Chowdhury F, Begum YA, Alam MM, et al. Concomitant enterotoxigenic Escherichia coli infection induces increased immune responses to Vibrio cholerae O1 antigens in patients with cholera in Bangladesh. Infect Immun 2010; 78: 2117-2124. CrossRef | PubMed

58 Harris JB, Podolsky MJ, Bhuiyan TR, et al. Immunologic responses to Vibrio cholerae in patients co-infected with intestinal parasites in Bangladesh. PLoS Negl Trop Dis 2009; 3: e403. PubMed

59 Harris JB, LaRocque RC, Chowdhury F, et al. Susceptibility to Vibrio cholerae infection in a cohort of household contacts of patients with cholera in Bangladesh. PLoS Negl Trop Dis 2008; 2: e221. PubMed

60 Chowdhury F, Khan AI, Harris JB, et al. A comparison of clinical and immunologic features in children and older patients hospitalized with severe cholera in Bangladesh. Pediatr Infect Dis J 2008; 27: 986-992. CrossRef | PubMed

61 Barua D, Paguio AS. ABO blood groups and cholera. Ann Hum Biol 1977; 4: 489-492. CrossRef | PubMed

62 Harris JB, Khan AI, Larocque RC, et al. Blood group, immunity, and risk of infection with Vibrio cholerae in an area of endemicity. Infect Immun 2005; 73: 7422-7427. CrossRef | PubMed

63 Chaudhuri A, DasAdhikary CR. Possible role of blood-group secretory substances in the aetiology of cholera. Trans R Soc Trop Med Hyg 1978; 72: 664-665. CrossRef | PubMed

64 Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol 1985; 121: 791-796. PubMed

65 LaRocque RC, Sabeti P, Duggal P, et al. A variant in long palate, lung and nasal epithelium clone 1 is associated with cholera in a Bangladeshi population. Genes Immun 2009; 10: 267-272. CrossRef | PubMed

66 Shin OS, Uddin T, Citorik R, et al. LPLUNC1 modulates innate immune responses to Vibrio cholerae. J Infect Dis 2011; 204: 1349-1357. CrossRef | PubMed

67 WHO. The treatment of diarrhoea, a manual for physicians and other senior health workers. 4th revision. http://whqlibdoc.who.int/publications/2005/9241593180.pdf. (accessed May 5, 2012).

68 Qadri F, Wenneras C, Albert MJ, et al. Comparison of immune responses in patients infected with Vibrio cholerae O139 and O1. Infect Immun 1997; 65: 3571-3576. PubMed

69 Lesmana M, Rockhill RC, Sutanti D, Sutomo A. An evaluation of alkaline peptone water for enrichment of Vibrio cholerae in feces. Southeast Asian J Trop Med Public Health 1985; 16: 265-267. PubMed

70 Benenson AS, Islam MR, Greenough WB. Rapid identification of Vibrio cholerae by darkfield microscopy. Bull World Health Organ 1964; 30: 827-831. PubMed

71 Yam WC, Lung ML, Ng MH. Evaluation and optimization of a latex agglutination assay for detection of cholera toxin and Escherichia coli heat-labile toxin. J Clin Microbiol 1992; 30: 2518-2520. PubMed

72 Almeida RJ, Hickman-Brenner FW, Sowers EG, Puhr ND, Farmer JJ, Wachsmuth IK. Comparison of a latex agglutination assay and an enzyme-linked immunosorbent assay for detecting cholera toxin. J Clin Microbiol 1990; 28: 128-130. PubMed

73 Colwell RR, Hasan JA, Huq A, et al. Development and evaluation of a rapid, simple, sensitive, monoclonal antibody-based co-agglutination test for direct detection of Vibrio cholerae 01. FEMS Microbiol Lett 1992; 76: 215-219. PubMed

74 Hasan JA, Huq A, Tamplin ML, Siebeling RJ, Colwell RR. A novel kit for rapid detection of Vibrio cholerae O1. J Clin Microbiol 1994; 32: 249-252. PubMed

75 Bhuiyan NA, Qadri F, Faruque AS, et al. Use of dipsticks for rapid diagnosis of cholera caused by Vibrio cholerae O1 and O139 from rectal swabs. J Clin Microbiol 2003; 41: 3939-3941. CrossRef | PubMed

76 Harris JR, Cavallaro EC, de Nobrega AA, et al. Field evaluation of crystal VC Rapid Dipstick test for cholera during a cholera outbreak in Guinea-Bissau. Trop Med Int Health 2009; 14: 1117-1121. CrossRef | PubMed

77 Lindenbaum J, Greenough WB, Islam MR. Antibiotic therapy of cholera in children. Bull World Health Organ 1967; 37: 529-538. PubMed

78 Chowdhury F, Khan AI, Faruque AS, Ryan ET. Severe, acute watery diarrhea in an adult. PLoS Negl Trop Dis 2010; 4: e898. PubMed

79 Wang F, Butler T, Rabbani GH, Jones PK. The acidosis of cholera. Contributions of hyperproteinemia, lactic acidemia, and hyperphosphatemia to an increased serum anion gap. N Engl J Med 1986; 315: 1591-1595. CrossRef | PubMed

80 Tariq M, Memon M, Jafferani A, et al. Massive fluid requirements and an unusual BUN/creatinine ratio for pre-renal failure in patients with cholera. PLoS One 2009; 4: e7552. CrossRef | PubMed

81 Benyajati C, Keoplug M, Beisel WR, Gangarosa EJ, Sprinz H, Sitprija V. Acute renal failure in Asiatic cholera: clinicopathologic correlations with acute tubular necrosis and hypokalemic nephropathy. Ann Intern Med 1960; 52: 960-975. PubMed

82 Lindenbaum J, Akbar R, Gordon RS, Greenough WB, Hirschorn N, Islam MR. Cholera in children. Lancet 1966; 1: 1066-1068. PubMed

83 Bennish ML, Azad AK, Rahman O, Phillips RE. Hypoglycemia during diarrhea in childhood. Prevalence, pathophysiology, and outcome. N Engl J Med 1990; 322: 1357-1363. CrossRef | PubMed

84 Guerrant RL, Carneiro-Filho BA, Dillingham RA. Cholera, diarrhea, and oral rehydration therapy: triumph and indictment. Clin Infect Dis 2003; 37: 398-405. CrossRef | PubMed

85 Goma Epidemiology Group. Public health impact of Rwandan refugee crisis: what happened in Goma, Zaire, in July, 1994?. Lancet 1995; 345: 339-344. Summary | CrossRef | PubMed

86 Dhar U, Bennish ML, Khan WA, et al. Clinical features, antimicrobial susceptibility and toxin production in Vibrio cholerae O139 infection: comparison with V. cholerae O1 infection. Trans R Soc Trop Med Hyg 1996; 90: 402-405. CrossRef | PubMed

87 Mahalanabis D, Faruque AS, Albert MJ, Salam MA, Hoque SS. An epidemic of cholera due to Vibrio cholerae O139 in Dhaka, Bangladesh: clinical and epidemiological features. Epidemiol Infect 1994; 112: 463-471. CrossRef | PubMed

88 Ryan ET, Dhar U, Khan WA, et al. Mortality, morbidity, and microbiology of endemic cholera among hospitalized patients in Dhaka, Bangladesh. Am J Trop Med Hyg 2000; 63: 12-20. PubMed

89 Nalin DR, Cash RA, Islam R, Molla M, Phillips RA. Oral maintenance therapy for cholera in adults. Lancet 1968; 2: 370-373. CrossRef | PubMed

90 Walton DA, Ivers LC. Responding to cholera in post-earthquake Haiti. N Engl J Med 2011; 364: 3-5. CrossRef | PubMed

91 Mintz ED, Guerrant RL. A lion in our village—the unconscionable tragedy of cholera in Africa. N Engl J Med 2009; 360: 1060-1063. CrossRef | PubMed

92 Centers for Disease Control and Prevention. Update: outbreak of cholera—Haiti, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 1586-1590. PubMed

93 Ramakrishna BS, Venkataraman S, Srinivasan P, Dash P, Young GP, Binder HJ. Amylase-resistant starch plus oral rehydration solution for cholera. N Engl J Med 2000; 342: 308-313. CrossRef | PubMed

94 Molla AM, Rahman M, Sarker SA, Sack DA, Molla A. Stool electrolyte content and purging rates in diarrhea caused by rotavirus, enterotoxigenic E. coli, and V. cholerae in children. J Pediatr 1981; 98: 835-838. CrossRef | PubMed

95 WHO. Global Task Force on Cholera Control. First steps for managing an outbreak of acute diarrhoea. http://www.who.int/cholera/publications/firststeps/en/. (accessed May 5, 2012).

96 Alam NH, Majumder RN, Fuchs GJfor the CHOICE study group. Efficacy and safety of oral rehydration solution with reduced osmolarity in adults with cholera: a randomised double-blind clinical trial. Lancet 1999; 354: 269-296. Full Text | PDF(40KB) | CrossRef | PubMed

97 Murphy C, Hahn S, Volmink J. Reduced osmolarity oral rehydration solution for treating cholera. Cochrane Database Syst Rev 2004; 4. CD003754.

98 Alam NH, Yunus M, Faruque AS, et al. Symptomatic hyponatremia during treatment of dehydrating diarrheal disease with reduced osmolarity oral rehydration solution. JAMA 2006; 296: 567-573. CrossRef | PubMed

99 Mahalanabis D, Wallace CK, Kallen RJ, Mondal A, Pierce NF. Water and electrolyte losses due to cholera in infants and small children: a recovery balance study. Pediatrics 1970; 45: 374-385. PubMed

100 Greenough WB, Rosenberg IS, Gordon RS, Davies BI, Benenson AS. Tetracycline in the treatment of cholera. Lancet 1964; 283: 355-357. CrossRef | PubMed

101 Yamamoto T, Nair GB, Albert MJ, Parodi CC, Takeda Y. Survey of in vitro susceptibilities of Vibrio cholerae O1 and O139 to antimicrobial agents. Antimicrob Agents Chemother 1995; 39: 241-244. CrossRef | PubMed

102 Saha D, Khan WA, Karim MM, Chowdhury HR, Salam MA, Bennish ML. Single-dose ciprofloxacin versus 12-dose erythromycin for childhood cholera: a randomised controlled trial. Lancet 2005; 366: 1085-1093. Summary | Full Text | PDF(136KB) | CrossRef | PubMed

103 Khan WA, Bennish ML, Seas C, et al. Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139. Lancet 1996; 348: 296-300. Summary | Full Text | PDF(45KB) | CrossRef | PubMed

104 Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish ML. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med 2006; 354: 2452-2462. CrossRef | PubMed

105 Islam MS, Midzi SM, Charimari L, Cravioto A, Endtz HP. Susceptibility to fluoroquinolones of Vibrio cholerae O1 isolated from diarrheal patients in Zimbabwe. JAMA 2009; 302: 2321-2322. CrossRef | PubMed

106 Kaushik JS, Gupta P, Faridi MM, Das S. Single dose azithromycin versus ciprofloxacin for cholera in children: a randomized controlled trial. Indian Pediatr 2010; 47: 309-315. CrossRef | PubMed

107 Roy SK, Hossain MJ, Khatun W, et al. Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial. BMJ 2008; 336: 266-268. CrossRef | PubMed

108 Bhandari N, Mazumder S, Taneja S, et al. Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial. Pediatrics 2008; 121: e1279-e1285. CrossRef | PubMed

109 Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics 2008; 121: 326-336. CrossRef | PubMed

110 Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. CrossRef | PubMed

111 Li ST, Grossman DC, Cummings P. Loperamide therapy for acute diarrhea in childre: systematic review and meta-analysis. PLoS Med 2007; 4: e98. CrossRef | PubMed

112 WHO. Water Sanitation and Health. Fact and figures on water quality and health. http://www.who.int/water_sanitation_health/facts_figures/en/index.html. (accessed May 15, 2011).

113 Ryan ET. The cholera pandemic, still with us after half a century: time to rethink. PLoS Negl Trop Dis 2011; 5: e1003. PubMed

114 WHO. Global Task Force on Cholera Control. Prevention and control of cholera outbreaks: WHO policy and recommendations. http://www.who.int/cholera/technical/prevention/control/en/index.html. (accessed May 15, 2011).

115 Ivers LC, Farmer P, Almazor CP, Leandre F. Five complementary interventions to slow cholera: Haiti. Lancet 2010; 376: 2048-2051. Full Text | PDF(54KB) | CrossRef | PubMed

116 Farmer P, Almazor CP, Bahnsen ET, et al. Meeting cholera's challenge to Haiti and the world: a joint statement on cholera prevention and care. PLoS Negl Trop Dis 2011; 5: e1145. PubMed

117 Sur D, Lopez AL, Kanungo S, et al. Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1694-1702. Summary | Full Text | PDF(193KB) | CrossRef | PubMed

118 Van Loon FP, Clemens JD, Chakraborty J, et al. Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years of follow-up. Vaccine 1996; 14: 162-166. CrossRef | PubMed

119 Clemens JD, Harris JR, Khan MA, et al. Impact of B subunit killed whole-cell and killed whole-cell-only oral vaccines against cholera upon treated diarrhoeal illness and mortality in an area endemic for cholera. Lancet 1988; 331: 1375-1379. Summary | CrossRef | PubMed

120 Sanchez JL, Vasquez B, Begue RE, et al. Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits. Lancet 1994; 344: 1273-1276. Summary | CrossRef | PubMed

121 Clemens JD, Sack DA, Ivanoff B. Misleading negative findings in a field trial of killed, oral cholera vaccine in Peru. J Infect Dis 2001; 183: 1306-1309. CrossRef | PubMed

122 Taylor DN, Cardenas V, Sanchez JL, et al. Two-year study of the protective efficacy of the oral whole cell plus recombinant B subunit cholera vaccine in Peru. J Infect Dis 2000; 181: 1667-1673. CrossRef | PubMed

123 Lucas ME, Deen JL, Von SL, et al. Effectiveness of mass oral cholera vaccination in Beira, Mozambique. N Engl J Med 2005; 352: 757-767. CrossRef | PubMed

124 Anh DD, Canh dG, Lopez AL, et al. Safety and immunogenicity of a reformulated Vietnamese bivalent killed, whole-cell, oral cholera vaccine in adults. Vaccine 2007; 25: 1149-1155. CrossRef | PubMed

125 Mahalanabis D, Lopez AL, Sur D, et al. A randomized, placebo-controlled trial of the bivalent killed, whole-cell, oral cholera vaccine in adults and children in a cholera endemic area in Kolkata, India. PLoS One 2008; 3: e2323. CrossRef | PubMed

126 Trach DD, Clemens JD, Ke NT, et al. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam. Lancet 1997; 349: 231-235. Summary | Full Text | PDF(69KB) | CrossRef | PubMed

127 Thiem VD, Deen JL, Von SL, et al. Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam. Vaccine 2006; 24: 4297-4303. CrossRef | PubMed

128 Peltola H, Siitonen A, Kataja MJ, et al. Prevention of travellers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991; 338: 1285-1289. Summary | CrossRef | PubMed

129 Clemens JD, Sack DA, Harris JR, et al. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up. Lancet 1990; 335: 270-273. Summary | CrossRef | PubMed

130 Saha A, Chowdhury MI, Khanam F, et al. Safety and immunogenicity study of a killed bivalent (O1 and O139) whole-cell oral cholera vaccine Shanchol, in Bangladeshi adults and children as young as 1 year of age. Vaccine 2011; 29: 8285-8292. CrossRef | PubMed

131 Kanungo S, Paisley A, Lopez AL, et al. Immune responses following one and two doses of the reformulated, bivalent, killed, whole-cell, oral cholera vaccine among adults and children in Kolkata, India: a randomized, placebo-controlled trial. Vaccine 2009; 27: 6887-6893. CrossRef | PubMed

132 Ali M, Emch M, von Seidlein L, et al. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: a reanalysis. Lancet 2005; 366: 44-49. Summary | Full Text | PDF(350KB) | CrossRef | PubMed

133 Longini IM, Nizam A, Ali M, Yunus M, Shenvi N, Clemens JD. Controlling endemic cholera with oral vaccines. PLoS Med 2007; 4: e336. CrossRef | PubMed

134 Jeuland M, Cook J, Poulos C, Clemens J, Whittington D. Cost-effectiveness of new-generation oral cholera vaccines: a multisite analysis. Value Health 2009; 12: 899-908. CrossRef | PubMed

135 Ryan ET, Calderwood SB, Qadri F. Live attenuated oral cholera vaccines. Expert Rev Vaccines 2006; 5: 483-494. CrossRef | PubMed

136 Cohen MB, Giannella RA, Bean J, et al. Randomized, controlled human challenge study of the safety, immunogenicity, and protective efficacy of a single dose of Peru-15, a live attenuated oral cholera vaccine. Infect Immun 2002; 70: 1965-1970. CrossRef | PubMed

137 Levine MM, Kaper JB, Herrington D, et al. Safety, immunogenicity, and efficacy of recombinant live oral cholera vaccines, CVD 103 and CVD 103-HgR. Lancet 1988; 2: 467-470. PubMed

138 Kotloff KL, Wasserman SS, O’Donnell S, Losonsky GA, Cryz SJ, Levine MM. Safety and immunogenicity in North Americans of a single dose of live oral cholera vaccine CVD 103-HgR: results of a randomized, placebo-controlled, double-blind crossover trial. Infect Immun 1992; 60: 4430-4432. PubMed

139 Kenner JR, Coster TS, Taylor DN, et al. Peru-15, an improved live attenuated oral vaccine candidate for Vibrio cholerae O1. J Infect Dis 1995; 172: 1126-1129. CrossRef | PubMed

140 Sack DA, Sack RB, Shimko J, et al. Evaluation of Peru-15, a new live oral vaccine for cholera, in volunteers. J Infect Dis 1997; 176: 201-205. PubMed

141 Richie EE, Punjabi NH, Sidharta YY, et al. Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area. Vaccine 2000; 18: 2399-2410. CrossRef | PubMed

142 Qadri F, Chowdhury MI, Faruque SM, et al. Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants. Vaccine 2007; 25: 231-238. CrossRef | PubMed

143 Garcia L, Jidy MD, Garcia H, et al. The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers. Infect Immun 2005; 73: 3018-3024. CrossRef | PubMed

144 Liang W, Wang S, Yu F, Zhang L, Qi G, Liu Y, et al. Construction and evaluation of a safe, live, oral Vibrio cholerae vaccine candidate, IEM108. Infect Immun 2003; 71: 5498-5504. CrossRef | PubMed

145 Anh DD, Lopez AL, Thiem VD, et al. Use of oral cholera vaccines in an outbreak in Vietnam: a case control study. PLoS Negl Trop Dis 2011; 5: e1006. PubMed

146 Reyburn R, Deen JL, Grais RF, et al. The case for reactive mass oral cholera vaccinations. PLoS Negl Trop Dis 2011; 5: e952. PubMed

147 Miller Neilan RL, Schaefer E, Gaff H, Fister KR, Lenhart S. Modeling optimal intervention strategies for cholera. Bull Math Biol 2010; 72: 2004-2018. CrossRef | PubMed

148 Chao DL, Halloran ME, Longini IM. Vaccination strategies for epidemic cholera in Haiti with implications for the developing world. Proc Natl Acad Sci USA 2011; 108: 7081-7085. PubMed

a Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA

b Department of Pediatrics, Harvard Medical School, Boston, MA, USA

c Department of Medicine, Harvard Medical School, Boston, MA, USA

d Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA

e International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh

f Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA

Correspondence to: Prof Stephen B Calderwood, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 2114, USA

† All authors contributed equally