Cholera

Cholera is an acute infectious diarrheal disease caused by Bacteria of the species <i>Vibrio cholerae</i>. The pathogen enters the body through water or food contaminated with feces and produces toxins in the small intestine, causing the intestine to secrete large amounts of chloride ions and water. Patients can pass large volumes of watery, rice-water stools over a short period and rapidly become dehydrated. Without prompt fluid replacement, patients with severe disease may die within hours; however, timely replacement of fluids and electrolytes can reduce the case fatality rate to very low levels. Cholera is closely associated with drinking-water safety, sanitation, and social conditions. It was also one of the first infectious diseases to be studied systematically in the history of public health.

Cholera has caused multiple global pandemics since the nineteenth century and remains endemic in many countries. In recent years, cholera cases and deaths have risen again worldwide, with many of the worst-affected areas experiencing conflict, flooding, or inadequate sanitation infrastructure. Preventing cholera requires a comprehensive approach that includes safe drinking water, wastewater treatment, surveillance, and early warning systems. Oral cholera vaccines have also been used for emergency and preventive vaccination, but limited production capacity has led to prolonged supply shortages.

This article will cover, in sequence, the microbiological characteristics of <i>Vibrio cholerae</i>, the mechanisms by which its toxins cause disease, clinical features and diagnosis, treatment methods, global epidemiology and disease burden, prevention and vaccines, historical pandemics and scientific discoveries, pathogen evolution and antimicrobial resistance, and social and environmental factors. It will conclude with a discussion of current research and unresolved questions.

Pathogen and Microbiological Characteristics

Vibrio cholerae is a Gram-negative, curved or comma-shaped bacterium whose single polar flagellum enables it to swim rapidly through liquids. It is a facultative anaerobe and tests positive for oxidase. These morphological and biochemical characteristics form the basis of laboratory identification, but its epidemiological significance is ultimately determined by the antigenic structure of its cell surface.

The bacterium can be divided into more than 200 serogroups according to its somatic antigen, or O antigen. The O antigen occupies the outermost layer of Lipopolysaccharide and is the heat-stable polysaccharide component at the outer edge of the cell surface, allowing strains to be distinguished by serological methods. More than 200 serogroups of V. cholerae have been confirmed through O-antigen typing, of which only O1 and O139 have been reported to be toxigenic. Nearly all large-scale cholera epidemics throughout history have been caused by serogroup O1. Serogroup O139 emerged on the South Asian subcontinent around 1992 and caused severe epidemics. Early genetic and biochemical studies showed that it was closely related to the seventh-pandemic El Tor lineage of serogroup O1, and subsequent whole-genome sequencing confirmed that it forms a distinct branch within that lineage.

Classical and El Tor Biotypes

Serogroup O1 is further divided into two biotypes: classical and El Tor. They are distinguished primarily by phenotypic tests, such as their ability to lyse sheep red blood cells, susceptibility to polymyxin B, susceptibility to bacteriophages, and production of acetoin. These differences do not constitute a taxonomic distinction between species, but they are epidemiologically significant. The classical biotype was the principal pathogen responsible for the first six pandemics, while the El Tor biotype emerged in Indonesia in 1961 and replaced the classical biotype within about a decade, becoming the leading cause of epidemic cholera. Classical strains caused most cholera pandemics between approximately 1817 and 1961; they were generally highly virulent and caused devastating outbreaks.

Genomic differences between the two biotypes have also been identified. Compared with seventh-pandemic El Tor strains, the classical biotype lacks at least 22 genes, and under conditions that induce virulence expression, the two biotypes differ in the expression of 524 genes. The El Tor biotype appears better able to survive in the environment, whereas the classical biotype expresses relatively more virulence factors. In recent years, atypical El Tor variants carrying classical toxin genes have also emerged. Prototype El Tor strains, which produce biotype-specific cholera toxin, are being replaced by atypical El Tor variants carrying classical cholera toxin.

Natural Ecology and Environmental Survival

V. cholerae is a resident bacterium of aquatic environments, found mainly in brackish waters, estuaries, and coastal waters. It often attaches to the chitinous exoskeletons of plankton, such as copepods. This attachment allows it to persist in water over long periods, potentially remaining in the environment even when no human waste is being introduced.

Bacteria in the environment can also enter a “viable but non-culturable” state. Studies show that classical strains lose culturability when co-cultured with El Tor strains, but their membrane potential and the preservation of their genomic DNA indicate that they remain viable. Co-culture with the El Tor biotype protects classical strains from lysis, allowing the cells to survive even though they can no longer be cultured. This finding suggests that conventional culture methods may underestimate the actual abundance of V. cholerae in the environment.

Non-O1/O139 Strains and Environmental Strains

Not all V. cholerae strains can cause cholera. In the laboratory, strains that react negatively with both polyvalent O1 antiserum and O139 antiserum are designated non-O1/non-O139 strains. These strains are widespread in the environment and generally do not cause cholera epidemics, instead causing sporadic diarrhea or extraintestinal infections. Clinically distinguishing these infections from “diarrhea not caused by V. cholerae” requires a combination of serological testing and PCR detection of serogroup-specific genes, such as rfb, and virulence genes.

Pathogenicity also depends on whether a strain carries toxin genes. These genes are located on the bacteriophage-derived CTX element, so the distinction between environmental and pathogenic strains is not always clear-cut. Some O139 strains belong to that serogroup serologically but lack the CTX bacteriophage and cannot produce cholera toxin. Thus, serogroup alone cannot fully determine whether a strain has epidemic potential; toxin-gene testing and molecular typing are also required.

致病机制

Toxin architecture and receptor binding

The main virulence factor is an AB-type toxin made of two kinds of subunit, A and B cholera toxin consists of two subunits: the A subunit (CTA) and the B subunit (CTB). Inside the A subunit, a disulfide-linked loop is cleaved to yield A1 and A2 fragments [9-4]. A1 is the catalytic part, while A2 functions as a linker [11-3].

The B subunits form a ring that surrounds the A subunit. Five identical B subunits, each composed of 103 amino acids, form a pentameric ring, and the single A-unit is a disulfide-linked dimer... aligned through the central pore of that ring. Each B subunit contacts one GM1 pentasaccharide, but that sugar also reaches a neighbouring B subunit [3-6]. Because of this shared contact, the pentamer can engage several GM1 molecules at once, which raises binding strength [3-8]. The GM1 receptor is concentrated in lipid rafts on the enterocyte surface [6-9].

Entry and ADP-ribosylation of Gsα

After binding, the toxin is taken into the cell in endosomes. These move backward through the Golgi to the endoplasmic reticulum [10-6, 10-7]. There, the A1 chain is separated from A2 by protein disulfide isomerase and enters the cytosol through the Sec61 translocon [11-4].

In the cytosol, A1 transfers ADP-ribose from NAD onto an arginine residue (Arg-201) in the α subunit of the stimulatory G protein Gs [10-2], [12-2]. This modification blocks the protein's intrinsic GTP hydrolysis, so Gs stays in its active state [11-10]. The continuously active Gs keeps adenylate cyclase producing cAMP without pause [11-11]. Some reports describe the resulting cAMP increase as roughly 100-fold [10-11]. The reaction depends on the host cofactor ARF6 [12-1].

cAMP and fluid secretion

Elevated cAMP activates protein kinase A (PKA), which phosphorylates the regulatory domain of CFTR and opens the chloride channel [10-15]. CFTR then drives chloride efflux, and sodium follows partly through the paracellular route [12-6]. The net NaCl secretion creates an osmotic gradient into the lumen, and water moves out to balance it [12-7]. Sodium absorption is suppressed at the same time [3-1, 3-2], so the intestine loses fluid in large volumes.

Colonization, gene regulation and the phage link

Colonization of the small intestine is a separate prerequisite. The bacterium uses its flagellum to penetrate the mucus layer and reach the brush border of enterocytes [26-4]. The toxin-coregulated pilus (TCP), a type IV pilus, is essential for colonization [25-4]. TCP promotes bacterial aggregation and microcolony formation in the gut [25-5], although it is probably not the direct adhesin to the epithelium [25-6]. ToxT is the transcriptional activator of TCP genes [21-4].

The genes for cholera toxin sit on CTXφ, a filamentous phage that integrates into the bacterial chromosome as a prophage [24-3]. TCP acts as the receptor for this phage [27-3]. Phage entry also requires the TolQRA proteins: mutations in tolQ, tolR or tolA reduced CTXφ uptake by about four orders of magnitude [27-6], and infection needs both the pilus and TolQRA [27-9]. The TCP genes lie on the Vibrio pathogenicity island (VPI) [22-3], which is itself another phage genome [22-4]. The mechanism by which the VPI was acquired remains unclear [28-10], and the phage-borne toxin genes are horizontally transferred [28-9].

临床表现与诊断

Infection with Vibrio cholerae produces a wide range of outcomes. Symptoms are absent in about 75% of infected people, and among those who do become ill, roughly 80% have mild or moderate disease. Symptomless carriers still matter for transmission: most people with infection are asymptomatic but still carry bacteria in their stool for about one to two weeks. The typical incubation period is one to two days, but it can range from several hours to three to five days, and host susceptibility and the size of the infecting dose both affect it. Some references give a narrower window; the MSD Manual, for example, cites 1 to 3 days.

Symptomatic disease typically begins abruptly. Painless watery diarrhea and vomiting are usually the first symptoms. Vomiting may come before or after the diarrhea, and patients often have cramping rather than the sharp pain of dysentery (vomiting may begin before or after the onset of diarrhea; patients may have abdominal cramping but usually do not have frank abdominal pain). Early stools can contain fecal matter and bile, while the evacuation phase brings abrupt, profuse watery diarrhea, often with mucus flecks that give the "rice-water" appearance. Stool loss can be extreme: adults may lose more than 1 L per hour, though losses are usually much smaller, and the total output over an illness can reach as much as sixty litres. Fever is uncommon, and its presence should prompt a search for a concurrent infection. The most fulminant form, often called cholera gravis, can cause hypotensive shock and death within hours of the first symptom. In some patients, fluid accumulates in the intestinal lumen, causing circulatory collapse before the first loose stool is passed.

Dehydration drives most of the morbidity. Its signs include sunken eyes, dry mouth, cold clammy skin, decreased skin turgor, and wrinkled hands and feet, while acidosis from bicarbonate loss and muscle cramps from low potassium and calcium are later features. Shock is recognized by tachycardia, peripheral cyanosis and hypotension, together with decreased urine output. Clinicians usually stage dehydration by the proportion of body fluid lost. In one severe case report, a patient was classed as severely dehydrated, with more than 10% of total body volume depleted. The older three-tier scheme uses roughly under 5% for mild, 5–10% for moderate, and above 10% for severe dehydration. Management follows the stage: oral rehydration solution for mild to moderate dehydration and intravenous fluids for severe dehydration. Deaths from cholera are due to dehydration or complications of hypovolemic shock. Children are especially vulnerable. Severe illness can cause altered consciousness, seizures or coma in children, due to hypoglycaemia. Malnutrition and HIV infection also raise the risk of severe outcomes (individuals with weakened immune systems, such as malnourished children or people living with HIV, face higher risk). Older adults and people with chronic illness have less physiological reserve to tolerate large fluid losses, though the sources consulted did not analyse this group in detail. Reduced gastric acid also lowers the number of bacteria needed to cause infection (people with achlorhydria or low gastric acidity may need fewer organisms to become infected).

Laboratory confirmation is less common than clinical diagnosis. Laboratory diagnosis of cholera is extremely uncommon, and in most cases cholera is diagnosed presumptively, since no sign or symptom reliably separates it from other infectious causes. The reference method is stool culture on selective medium, and the laboratory must be told that cholera is suspected so that the appropriate medium is used (stool cultures on TCBS medium). Culture has limitations: its false-negative rate can reach 15–30%, worsened by poor sample handling, delayed transport and prior antibiotic use. PCR is more sensitive, but it is rarely available even at national reference laboratories, and no widely agreed PCR protocol exists. The US CDC recommends stool culture or PCR to confirm a case. Rapid diagnostic tests (rapid diagnostic tests) use lateral-flow strips on stool; a meta-analysis found a sensitivity of 91% and a specificity of 80% compared with culture or PCR when used directly on stool, and enriching samples in a selective medium for several hours raised specificity to about 98% with little loss of sensitivity. Darkfield microscopy is highly specific but lacks sufficient sensitivity for routine diagnosis. Routine blood chemistry is nonspecific and typically shows low sodium, low potassium, low glucose and raised haematocrit from water depletion. Surveillance adds another layer. In outbreaks, any person with acute watery diarrhoea is counted as a suspected case, and often more than half of these cases are caused by other enteric pathogens. The "cholera" incidence reported is usually the incidence of suspected cholera, which is why acute watery diarrhea counts and confirmed infections must be read separately.

Differential diagnosis rests on the age of the patient, the pattern of illness, and local pathogens. In resource-limited settings, rotavirus and cryptosporidium are common causes in infants and young children, while enterotoxigenic E. coli predominates among older children and adults. Enterotoxigenic E. coli is the most common cause of watery diarrhea, and norovirus is distinguished by prominent vomiting. Clinically, mild cholera can be indistinguishable from other diarrhoeal illnesses, but severe cholera has a distinctive pattern of profuse purging. A Bangladeshi study of children under five found that the mean purging rate and mean stool sodium concentration were highest in cholera, followed by ETEC, then rotavirus, while stool bicarbonate was markedly lower in rotavirus infection. Mixed infections complicate matters: about 13% of hospitalized diarrhoeal patients in one Bangladeshi series were infected with both V. cholerae O1 and ETEC, and co-infected patients had significantly higher odds of severe outcomes, including watery stools, vomiting and intravenous rehydration.

治疗与临床管理

Most people with cholera recover through fluid replacement alone, so treatment centres on correcting the water and electrolyte losses caused by secretory diarrhoea. Diagnosis of cholera is not required to initiate hydration therapy. Laboratory confirmation can therefore follow rehydration rather than precede it.

Oral rehydration as the first-line treatment

Oral rehydration solution (ORS) works because glucose drives sodium and water absorption in the small intestine even while the toxin keeps secretion running. A sugar such as glucose facilitates the absorption of sodium and water in the small intestine. The WHO formula, composed of Na+ 90 mEq/L, Cl– 80 mEq/L, K+ 20 mEq/L, citrate– 30 mEq/L, and glucose 111 mmol/L, is designed to match the losses. Replacement is calculated from the stool itself: because adult cholera stool contains roughly 135 mEq/L of sodium, one-and-a-half volumes of oral rehydration solution containing 90 mEq/L must be given for every volume of rice water diarrheal stool passed.

For mild cases, the usual approach is frequent small sips and a set volume after each stool. For children under two, the guidance is 50-100 ml of oral rehydration solution (ORS), after each evacuation, and for children aged 1 to 14 years the volume is larger, 100-200 ml.

The formula has been debated. Packets designed for all acute watery diarrhoea use lower sodium, and analysis found that use of the low-sodium ORS to treat cholera patients leads to negative sodium balance, leading to hyponatremia. For that reason, two separate ORS packet formulations be used, one for cholera therapy and the other for non-cholera pediatric AWD.

The historical evidence is strong. Oral therapy was formulated for treating cholera in the 1960s. During a 1971 refugee crisis in what is now Bangladesh, ORT alone decreased deaths from about 40% to 3% and was administered by friends and families of the cholera victims without any prior training.

Intravenous fluids in severe dehydration

Severe dehydration with shock is a medical emergency. Set the rate of intravenous infusion in severely dehydrated patients at 50-100 mL/kg/hr. Lactated Ringer solution is preferred over isotonic sodium chloride solution because saline does not correct metabolic acidosis. If the patient can drink, ORS can begin while the drip is being set up, because ORS can provide the potassium, bicarbonate, and glucose that saline solution lacks. The aim is to restore normal hydration within no more than 4 hours. Intravenous fluid is reserved for patients with severe dehydration or those who eliminate more than 10-20 mL/kg/h, and for those who cannot tolerate the oral route.

Antibiotics

Antibiotics are adjuncts, not replacements for fluids. Complementary therapies (antibiotics and zinc sulphate) are useful in reducing the duration and severity of diarrhea but do not replace fluid therapy rehydration. In a meta-analysis, antibiotic treatment shortened the duration of diarrhoea by about one and a half days (the normal duration is between three and four days), and reduced the total amount of diarrhoea fluid by half. Consequently, the need for rehydration fluids was also reduced by almost half. These effects reduce both the period of shedding and the fluid volume that must be replaced.

Single-dose azithromycin is now the preferred option. The usual regimen is 20 mg/kg (max. 1 g) single dose for children and 1 g single dose for adults. In a randomised trial of adult men with severe cholera, the diarrhoea lasted a median of 30 vs. 78 hours with azithromycin versus ciprofloxacin. The authors attributed ciprofloxacin's poor performance to diminished activity against V. cholerae O1 strains currently circulating in Bangladesh. In children, azithromycin shortened diarrhoea compared with erythromycin, and is associated with less vomiting.

Resistance has shaped drug choice. Older agents have lost activity: V. Cholerae showing significant resistance towards furazolidone and co-trimoxazole has been reported in India, and tetracycline resistance has also emerged. Doxycycline is therefore a second-line option. The broader mechanisms of resistance are covered in antibiotic resistance.

Zinc and nutritional support

WHO and UNICEF have recommended routine zinc for diarrhoea since 2005. 10 mg daily for infants below 6 months of age; 20 mg daily for children older than 6 months for 10–14 days. Cholera-specific evidence is more limited. In a Bangladeshi randomised trial, Zinc supplemented patients had 12% shorter duration of diarrhoea than control patients (64.1 v 72.8 h, P=0.028) and 11% less stool output. That trial used a daily dose of 30 mg, which differs from the WHO schedule. For diarrhoea in general, the evidence for reducing death or hospitalisation is not enough evidence from well conducted randomized controlled trials.

Feeding should resume early. Oral feeding can start as soon as the patient can tolerate feeds. Continue breast-feeding infants and young children. Patients receiving intravenous fluids need monitoring of serum electrolytes (Sodium, Potassium, Chloride, Bicarbonate), BUN, and creatinine. This monitoring is how clinicians detect the hypokalaemia and acute kidney injury that can complicate severe cases, which are treated by correcting electrolytes and adjusting fluid volumes.

Organisation of care and outcomes

Without treatment, the outcome can be grim: up to half of people with serious bouts of cholera could die. With treatment, deaths drop to less than 1%. Guidelines describe treatment is rehydration and, if applied appropriately, should keep the casefatality rate below 1%. The guidelines emphasise that timely detection of cholera cases and prompt initiation of treatment is key in reducing morbidity, mortality and containing disease transmission. During outbreaks, care is delivered through a tiered network that includes Cholera Treatment Center (CTC), Cholera Treatment Unit (CTU) and Oral Rehydration Points (ORPs), with severe cases directed to the higher-level facilities and mild cases managed at the lower-level points.

全球流行与疾病负担

Seven pandemics and their routes

Cholera has produced seven recorded pandemics since 1817. The first six are usually linked to the Ganges Delta. A particularly lethal outbreak in Jessore, India, in 1817 spread through most of India, Burma and Ceylon. By 1820 epidemics had been reported in Siam, in Java, where more than 100,000 people died, and as far away as the Philippines. The disease then moved along trade routes. At Basra, as many as 18,000 people died in a three-week period in 1821. The second pandemic reached the Americas. The first major U.S. wave, in 1832–1834, was tied to the second pandemic, and cholera reached Canada and then New York by 1833, spreading inland along rivers and steamboat routes. The fourth pandemic followed pilgrimage traffic. It spread via routes to Mecca and then across the Middle East, Europe, Africa and North America, and the Hajj became a major transmission hub that prompted quarantine measures at Mediterranean ports. The worst single year of the nineteenth century was 1854, when 23,000 died in Great Britain alone.

The seventh pandemic began differently. It started in 1961 on the island of Celebes in Indonesia, rather than in the Ganges Delta. The strain involved was the El Tor biotype, which had caused an outbreak in Makassar in 1960 before spreading overseas in 1961. It spread throughout Asia during the 1960s, then moved westward to the Middle East and reached Africa in the following decade, where cholera had been absent for about 70 years. Genomic work indicates the pandemic spread across the world in three waves in the decades that followed. By 1990, more than 90 percent of cholera cases reported to WHO came from Africa.

Current distribution and recent burden

WHO's 2024 global summary reported that 60 countries reported more than 560 000 cases and over 6000 deaths, compared with more than 535 000 cases and 4000 deaths in 2023. Africa carried the heaviest share of mortality, with 46% of cases and nearly 83% of deaths. Other regional summaries are not identical. One compilation of WHO data places the Eastern Mediterranean Region first in 2024, with 597,026 cases and 2,403 deaths across eight countries, followed by the African Region. The leading countries also vary by source: one listing puts Yemen, Afghanistan, Pakistan, Sudan and the Democratic Republic of the Congo at the top, while another lists Sudan, the Democratic Republic of the Congo, Ethiopia, Nigeria, Zambia, Somalia, Zimbabwe and South Sudan among the most affected African countries.

The 2025 picture is defined mainly by deaths. From 1 January to 26 October 2025, a cumulative total of 565 404 cholera cases and 7074 deaths were reported from 32 countries. For the comparable 2024 period, WHO had reported 486 760 cholera and acute watery diarrhoea cases and 4018 deaths from 33 countries. Deaths therefore rose by roughly three-quarters while cases rose by a smaller margin. Early 2026 data show lower totals: from 1 January to 29 March 2026, 58 740 cholera and AWD cases and 732 deaths were reported from 22 countries. Activity then shifted, and in May 2026 29 610 new cases were reported from 16 countries, showing a 43% increase from the previous month. The same period saw 271 cholera-related deaths globally. WHO continues to rate the global risk as very high, with an estimated population at risk of 1 billion.

Limits of case statistics

Reported figures understate the true burden. WHO researchers have noted that these figures likely underestimate cholera's true burden due to surveillance and reporting challenges. Mild and asymptomatic infections are seldom captured, and the monthly WHO reports count cholera and acute watery diarrhoea (AWD) cases together, so headline totals mix confirmed cholera with suspected cases of AWD that have not been laboratory-confirmed.

Cumulative totals are also revised as reports arrive. In late 2024, WHO reported 439 724 cases and 3432 deaths from 1 January to 29 September 2024. The final 2024 figures later cited by WHO were 560 823 cases, and deaths reached 6028 in 2024. Different compilations can also diverge sharply for the same year. One summary of WHO data gives 804,721 cases and 5,805 deaths from 33 countries for 2024, a case total well above the WHO global summary. Such differences reflect changing data cut-offs, the inclusion or exclusion of AWD, and country-level reporting delays. Users comparing years should therefore check which WHO product and data date each figure comes from.

预防、疫苗与应急供应

Cholera spreads mainly through faecal contamination of drinking water and food, so the first line of prevention is water, sanitation and hygiene (WASH). Chlorination of water supplies, provision of safe drinking water, and safe management of human faeces cut the routes by which the bacterium reaches people. Handwashing and food hygiene matter as well, but water and sanitation infrastructure has the largest effect at population level. The Global Roadmap models this approach in an illustrative urban hotspot. There, a multi-sectoral plan that raises WASH coverage to 80% of the population and includes two OCV campaigns could make the city cholera-free within seven years. The modelled cost was about $21 per person per year on average. Gaps in piped water and sanitation in informal urban settlements are therefore a central obstacle, not a side issue.

Oral cholera vaccines

Three oral cholera vaccines (OCVs) were prequalified by the World Health Organization: Dukoral, made by Valneva, Shanchol, made by Shantha Biotechnics, and Euvichol-Plus, made by EuBiologics. In 2022, Shantha Biotechnics, which produced about 15% of the world's supply, announced that it would end production and distribution of Shanchol by 2023. The standard regimen is two oral doses. The second dose matters for duration: one source notes that the second dose, administered within six months of the first, provides immunity for three years. Protection still wanes over time, so protection declines over time, necessitating revaccination strategies. Young children are a particular concern, since children under five exhibit lower and less durable immune responses.

Single-dose schedules have been used in emergencies. Protection after one dose was judged adequate to help control outbreaks, but the exact duration was uncertain. Next-generation candidates are being tested. A single-dose live-attenuated vaccine, PanChol, completed a phase 1 trial with 57 participants and was reported to produce strong immune responses against Vibrio cholerae antigens in those vaccinated; a further trial in Zambia was planned for 2026.

Global stockpile and the ICG

The International Coordinating Group (ICG) on Vaccine Provision, a body that also manages emergency stockpiles for other diseases, was established in 1997, following major outbreaks of meningitis in Africa. The global OCV stockpile was set up in 2013 and has been supported by Gavi since 2014. It has two parts: an emergency component, managed by the ICG, and a non-emergency reserve used for preventive vaccination in hotspots. Requests from countries for doses from the revolving stockpile are reviewed and decided by the ICG. Demand has consistently exceeded supply. One estimate placed annual demand at more than 75 million doses per year.

The shortage became acute in 2022. Of the total 36 million doses forecast to be produced in 2022, 24 million had already been shipped for preventive (17%) and reactive (83%) campaigns. Manufacturers were working at maximum capacity, so there was no quick fix. The ICG therefore suspended the two-dose schedule in outbreak response, allowing the remaining doses to reach more countries. Structural dependence on a single manufacturer compounded the problem: WHO has described EuBiologics as currently the only manufacturer producing cholera vaccines at the scale needed for mass vaccination campaigns. Production figures differ among sources. UNICEF and Gavi report that global supply of oral cholera vaccines (OCV) has doubled from 35 million doses in 2022 to nearly 70 million in 2025, whereas WHO's fact sheet gives a figure of approximately 80 million in 2025.

Resumption of preventive vaccination

On 4 February 2026, Gavi, UNICEF and WHO announced that supply had recovered enough to restart preventive campaigns, the first in over three years. A first allocation of 20 million doses was being deployed for preventive campaigns. Of these, 3.6 million doses went to Mozambique, 6.1 million to the Democratic Republic of the Congo, and 10.3 million were planned for Bangladesh. Allocation followed criteria set by the Global Task Force for Cholera Control (GTFCC). Reactive vaccination nonetheless reached its highest level on record in 2025, which means preventive and emergency needs are still competing for the same doses.

Roadmap targets

The GTFCC's strategy, Ending Cholera: A Global Roadmap to 2030, sets two quantitative goals: reduce global cholera deaths by 90% and eliminate the disease in at least 20 countries by 2030. The Roadmap is built on three axes: early detection and response to contain outbreaks, a multisectoral approach to prevent and control cholera in hotspots, and an effective coordination mechanism at local and global levels. Whether these targets are attainable at the current pace is contested. One analysis of Nigeria concluded that whether these targets can be achieved given the current pace of development and progress is highly uncertain.

历史上的大流行与科学发现

Cholera was already endemic in the Ganges delta of Bengal by the early nineteenth century, and the first pandemic, which ran from 1817 to 1824, began there. The disease dispersed from India to Southeast Asia, the Middle East, Europe, and Eastern Africa through trade routes. The second pandemic, which Wikipedia dates to 1826–1837, was the one that struck Europe and the Americas hardest. Its arrival was rapid: within 18 days of its arrival, the French reported at least 7,000 deaths. By 1832, cholera had spread to Canada and the United States, where 5,000 people died in New Orleans alone. Later pandemics were no less destructive in the aggregate. Estimates suggest that the first three pandemics of the nineteenth century in the Indian subcontinent, between 1817 and 1860, exceeded 15 million deaths, and another 23 million died between 1865 and 1917, during the next three pandemics. These outbreaks forced European and American cities to build the first formal public health machinery. In New York, for example, a health board was created and port quarantines were enforced, and the federal government later created a Public Health Service.

The most famous case of the period is John Snow's investigation of the Soho outbreak in London. Most authorities of the time attributed disease to miasma, or poisoned air. Snow instead used a simple map, interviews and basic arithmetic to link the great majority of the deaths to a single source: a water pump on Broad Street. He conducted interviews with local residents, gathering detailed information on their water sources and daily routines. A key piece of evidence came from comparison groups: workers at the nearby Lion Brewery and the inmates of a workhouse, both of which had their own private water supplies, had significantly lower rates of cholera compared to those using the public pump. Snow's argument was not conclusive by the standards of his own laboratory work, since his chemical and microscope examination of a sample of the water from this Broad Street pump did not conclusively prove its danger. Local authorities nonetheless disabled the pump by removing its handle. The outbreak was already waning, partly because residents had fled, so the timing of the handle removal has been debated since. Snow's theory was contested at the time, but with the passage of time his argument prevailed. A later inspection found that the pump's well was only a few feet away from an old cesspit that began leaking into its water supply. Snow's reasoning thus linked cholera to sewage-contaminated water decades before the causative organism was identified, and his work is often cited as a founding example of epidemiology and spatial mapping of disease. Its influence also fed into the sanitation projects of the period; for instance, Joseph Bazalgette's design of London's sewer system in the 1860s followed the same logic of separating drinking water from waste.

The bacterial cause was identified in stages. In 1854, the Italian anatomist Filippo Pacini isolated the cholera bacterium Vibrio cholerae in Florence, but his work was not widely accepted, and the discovery is often credited instead to Robert Koch. In August 1883, Koch, with a team of German physicians, went to Alexandria, Egypt, to investigate the cholera epidemic there. Koch found that the intestinal mucosa of people who died of cholera always had the bacterium, yet he could not confirm if it was the causative agent. He then moved to Calcutta, where he isolated the bacterium in a pure culture on 7 January 1884. A methodological advance underpinned this work: one of his most important innovations was the use of solid medium instead of liquid to prepare pure cultures of bacteria, which kept colonies from mixing. Koch's criteria for linking a microbe to a disease, known as Koch's postulates, were articulated in the 1880s in collaboration with Friedrich Loeffler. They require that the organism be found in diseased hosts but not in healthy ones, be isolated and grown in pure culture, cause disease when introduced into a healthy host, and be re-isolated from that host. Cholera, however, challenged the criteria: the postulates began to show problems, particularly with cholera, which clearly violated some of Koch's requirements, because the organism was also found in healthy people. This gap between the postulates and asymptomatic carriage later became an important point in the study of the disease.

Early attempts at a vaccine followed the new bacteriology. In 1892, the Russian-French bacteriologist Waldemar Haffkine developed a cholera vaccine. Vaccination, however, could not replace the conventional measures of the nineteenth century, which centered on water supply, sewage, and quarantine. The historical record shows that the scientific advances of this era, from Snow's maps to Koch's cultures, did not work in isolation but were linked to the institutional response: the same epidemics that prompted the creation of health boards and quarantine regimes also made clear that cholera's control depended on infrastructure and on the separation of drinking water from human waste.

病原体演化、基因组学与耐药性

Seventh-pandemic El Tor lineage

Researchers trace the ongoing pandemic to one clonal lineage, 7PET, that first appeared in Indonesia in 1961 2-6. Although it carries the same O1 antigen as classical strains, it did not descend from them. Instead, a non-epidemic El Tor ancestor acquired the CTXφ phage and two pathogenicity islands, VSP-I and VSP-II, and became epidemic 6-3. Phylogenetic reconstruction divides the lineage into three genomic waves and many named sublineages, with the African ones numbered AFR1 and AFR3 to AFR15 5-10. Historical records fit this picture. Sequencing matched two El Tor strains that reached Africa in 1970, a West African Ogawa strain and an East African Inaba strain 9-5.

The origin and routes of spread remain contested. Investigators still argue over whether repeated epidemics in Africa and the Americas come from new intercontinental imports or from local clones that persisted 3-6. One widely cited genome study places the origin in Bay of Bengal villages, with spread in three waves 7-5. National datasets can also test these models. In Iran, 74 isolates from 1965 to 2023 were sequenced, and the bacterium appeared not to settle into a lasting local reservoir; it was instead repeatedly reintroduced from endemic neighbours to the east 4-5, 4-6:4-7.

Mobile genetic elements and virulence

Virulence in this lineage depends heavily on horizontal gene transfer. The toxin operon sits inside the genome of a filamentous phage, CTXφ, a discovery dating to the late 1990s 22-5. After infecting a cell, the phage DNA inserts into the chromosome at a defined attB (dif) site, and this integration is what allows ctxAB to pass between strains 23-8. Genetic evidence points to the toxin-coregulated pilus as the phage's surface receptor 26-4. Epidemic isolates almost universally carry the phage, whereas non-O1/non-O139 strains seldom do 20-7. Identical sequences in two phage genes shared by V. mimicus and V. cholerae suggest a recent exchange between the species, and estuaries, where both coexist, are the likely venue 20-3, 20-12. Phage gene trees that disagree with chromosomal trees are a further signature of horizontal movement 21-9:21-10. In suckling mice, El Tor lysogens released infectious virions in the intestine 25-6. Free virions in contaminated water could in principle transfer toxin genes, although the receptor pilus may be rarely expressed outside the host 25-7:25-8.

Integrative conjugative elements and antibiotic resistance

SXT is a roughly 99.5 kb integrative conjugative element of the SXT/R391 family 11-2:11-3. A conserved core of 52 syntenic genes handles integration, excision, transfer and regulation, while variable segments carry resistance cassettes 11-3:11-4. Transfer is switched on by SetC and SetD, a pair of conserved genes encoding a transcriptional activator complex 16-3. Beyond V. cholerae, these elements can integrate into many other Gammaproteobacteria 16-2. Most clinical SXT variants confer resistance to sulfamethoxazole and trimethoprim, drugs that have been commonly used against cholera 18-2. Multidrug-resistance genes in seventh-pandemic strains appear to have spread mainly through circulation of these elements, while IncA/C conjugative plasmids turn up only sporadically 15-9, 15-10. Element variants differ markedly by region and keep changing 17-3. Some non-O1/non-O139 strains carry SXT without any resistance cassettes, which still warrants monitoring 14-2. A multidrug-resistant ST69 lineage recovered from Kerala's coastal water lacks the ctx prophage yet has gained mobile elements and resistance genes 8-4.

Resistance monitoring and genomic epidemiology

Resistance is tracked by combining phenotypic testing with molecular detection. In a study of 34 isolates from European sampling, full ampicillin resistance and partial cotrimoxazole resistance were found, while the strains remained susceptible to several other agents 5-11, 5-15. Kolkata surveillance from 2008 to 2015 paired susceptibility tests with screening for ICEs and sequencing of their conserved genes 17-5. Genomic epidemiology uses the same data to reconstruct where outbreaks came from. Of 49 European genomes, all belonged to Wave 3, and most grouped within the Pre-AFR15 sublineage 5-12:5-13, which suggests a clade still feeding the global resurgence 5-14. Overlaying phylogenies onto historical outbreak records strengthens such inferences 9-4, and reference panels now draw on well over a thousand 7PET genomes 2-8.

Social, Environmental, and Humanitarian Context

Cholera is a disease directly linked to water, so climate, conflict, and urban conditions influence its transmission by altering access to drinking water and sanitation. During floods, sewage and waste may spill into drinking-water sources and overwhelm drainage systems; during droughts, communities are forced to rely on unsafe water sources, while severe flooding can overwhelm sanitation systems and increase exposure to contaminated water. In Ethiopia’s Somali Region, an outbreak associated with prolonged drought resulted in approximately 772 confirmed cases and 23 deaths reported within two weeks, with children accounting for about 80% of cases. The quantitative relationship between climate and cholera remains uncertain: a study of 13 outbreaks in four African countries found that outbreaks were 3.07 times more likely under drought conditions (95% confidence interval: 0.95–9.88), but the confidence interval was wide. Another study cited data from Zanzibar suggesting that case numbers approximately doubled with every 1°C increase in temperature. In coastal and low-lying areas, sea-level rise has been identified as a risk factor because it exacerbates flooding and disrupts water supply systems.

Conflict and displacement are another major pathway. In Sudan, war has displaced millions of people, forcing them into crowded camps with inadequate sanitation. Conflict has also damaged water infrastructure. According to the United Nations Children’s Fund (UNICEF), damage to water treatment plants, boreholes, water storage tanks, and water mains has left approximately 9 million women and children without access to safe drinking water. Since the beginning of 2025, Sudan’s outbreak has affected 11 states, with more than 50,000 confirmed cases and approximately 1,350 deaths reported. In Syria, the 2022–2023 outbreak following the Aleppo earthquake was believed to have expanded because existing water treatment networks had been destroyed and imports of chlorine disinfectants were restricted. Conflict in the eastern Democratic Republic of the Congo has driven nearly 1 million people into crowded urban settlements, where inadequate sanitation and extremely high population density have significantly accelerated transmission. Displaced people may carry the pathogen even without symptoms and spread it to surrounding areas through their use of contaminated water sources. In 1994, a large outbreak among Rwandan refugees in the Lake Kivu region of the Democratic Republic of the Congo caused approximately 42,000 deaths. Standards for cholera prevention and control in refugee camps were substantially strengthened afterward.

Urbanization and poverty are also critical. The expansion of informal settlements is considered one of the important mechanisms behind drought-related outbreaks in Africa. Low-income populations are often the first to be exposed to risk. Children living in poor, densely populated urban neighborhoods, as well as those in refugee camps and camps for internally displaced people, are particularly vulnerable; these settings often fail to meet minimum requirements for safe drinking water and sanitation. A study using WHO and World Bank data found that the burden of cases was significantly higher in low-income countries than in middle- and high-income countries. Malnutrition increases both the risk of infection and the case fatality rate: among severely wasted children, fatality rates from diarrheal diseases such as cholera are more than ten times higher. Diarrhea, in turn, worsens malnutrition, creating a vicious cycle. Differences in case fatality rates depend primarily on timely access to treatment. Untreated cases can have a case fatality rate of 30%–50%, whereas prompt and appropriate treatment should keep it below 1%. From January to August 2025, 6 of the 31 reporting countries had case fatality rates above 1%, indicating serious gaps in case management and delays in seeking care. During the 2010 outbreak in Haiti, only 23% of those who died in the community had taken oral rehydration salts at home, and 59% had not sought medical care.

The distribution of cholera also reflects inequality. WHO describes cholera as a global public health threat that reflects inequity and inadequate social and economic development. Official figures may therefore underestimate its burden, as some countries are reluctant to report cases because of concerns about trade and tourism. Prevention and control consequently depend on international cooperation and humanitarian assistance. In Sudan, the Ministry of Health, WHO, and UNICEF have jointly led the response. UNICEF and its partners have ensured water deliveries by tanker to camps for displaced people and maintained water-quality monitoring. However, funding shortages and restricted humanitarian access can interrupt these measures. Médecins Sans Frontières (MSF) has noted that funding gaps have forced water delivery services to stop. Damaged water and electricity systems, large-scale displacement, restricted humanitarian access, and an under-resourced response have together exacerbated the outbreak.

研究前沿与未解决的问题

Supply is the first frontier. Global output of oral cholera vaccine doubled from 35 million doses in 2022 to nearly 70 million doses in 2025, and in February 2026 WHO, Gavi, and UNICEF announced that supply was enough to restart preventive campaigns, beginning in Mozambique after the 2022 halt caused by a global surge in demand. The shortage was shaped by concentration as well as demand. For years, a single manufacturer, EuBiologics in Seoul, South Korea, whose production capacity is limited, was the main source of doses. Gavi has projected that its manufacturing capability could exceed 90 million doses by 2026 ("more than 90 million doses by 2026"), but that is a forecast, and the outcome is not yet known. Open questions include whether new oral cholera vaccine producers can enter at volume while maintaining quality, and whether demand stays ahead of supply once preventive campaigns scale up. Researchers have built system-dynamics models to simulate vaccine supply and demand out to 2035 [2-7], partly to test these scenarios.

The single-dose versus two-dose debate has moved from theory to measurement. A modelling study found that, at the start of an epidemic and with fixed supply, a single dose would need to reach roughly 35–56% of the efficacy of two doses to avert the same number of cases [11-4]. Field data show that single-dose protection is strong early but declines. In Bangladesh, a meta-analysis put single-dose protection at about 87% at two months, falling to about 33% at two years [15-4]. In Haiti, one-dose effectiveness was estimated at 79% at twelve months and then appeared to disappear before the second year, while two doses gave consistent protection over four years [17-2,17-8]. In Uvira, in the Democratic Republic of the Congo, adjusted single-dose effectiveness was 52% at 12–17 months and about 41% at 24–31 months [18-6]. Few published estimates had come from African endemic foci before this work [16-3], so the duration of single-dose protection in such settings is still poorly characterised. Which schedule is best depends on whether the goal is reactive outbreak control or preventive protection, and this trade-off is not yet settled.

Rapid diagnostics are the second frontier. Cholera tests detect O1 and O139 antigens within 15 to 30 minutes [19-3], and they can be run by minimally trained staff at the bedside without a cold chain or laboratory equipment [19-5]. Their accuracy varies. Compared with stool culture, the Crystal VC dipstick showed 72% sensitivity and 86.8% specificity when used directly, while the locally produced Cholkit reached 76% and 90.2% [22-9,22-11]. Culture is itself an imperfect reference, since its sensitivity is limited [21-2], which complicates validation. In Cameroon, decentralised testing by non-laboratory staff gave negative predictive values above 90%, with no significant difference between operator cadres [26-1,26-3]. Gavi's diagnostic procurement pilot in Nepal distributed tests to surveillance facilities in 2023 [20-2,20-3]. Molecular methods such as a rapid LAMP-based test have reported detection from stool and water in under an hour [25-5]. Because current rapid tests target only O1 and O139, non-O1 strains would be missed, and integrating these tools with environmental water sampling for early warning remains an open task.

Forecasting outbreaks combines epidemiological time series with climate and hydrological drivers. One example is a machine-learning model for Yemen that uses data such as rainfall, previous cholera cases, and civil war mortality, and its authors report that it accurately forecasts cholera incidence. Flooding is a key pathway: in Nepal's monsoon season, frequent flooding and landslides interfere with water and sanitation infrastructure. A basic limit is data quality, because inaccuracies and delays in cholera reporting prevent precise disease burden estimates, and models trained on such counts inherit those biases. Accuracy across regions with different water systems, conflict levels, and surveillance capacity has not been systematically benchmarked, so transferability is uncertain.

Several questions about protection itself remain unresolved. Waning after single doses is documented, but the durability of two-dose protection beyond four years has not been established by the existing cohorts. Whether a population-level threshold for indirect protection exists, and what value it takes, likely depends on transmission intensity and how immunity is distributed, and the answer is not settled. Finally, the two-dose vaccine developed by IVI is built from inactivated V. cholerae bacteria from several strains, so whether current formulations will remain well matched to future circulating lineages, including emerging O139 or El Tor variants, depends on continued genomic surveillance.

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