Cholera was confined to the Indian subcontinent until 1817, when the first cholera pandemic began, spreading to Asia, the Middle East and part of Africa. Other pandemics followed, all beginning in Asia but reaching every continent and progressing increasingly quickly with improvements to transport. We are currently in the seventh cholera pandemic, which originated in Indonesia in 1961, spreading to other countries in Asia (1962), then to the Middle East and some of Europe (1965), before hitting the African continent in 1970 and Latin America in 1991. Other countries in Africa have been affected more recently, such as Madagascar in 1999 and South Africa in 2000. Conflicts and mass movements of refugees facilitate the spread of outbreaks, as illustrated in July 1994 in Rwandan refugee camps in Goma, DR Congo, where estimates suggest that cholera claimed 23,800 lives in just a few weeks (a case fatality rate of nearly 30%). Cholera is rife across the world and still represents a very real threat for public health. It may occur in periodic waves in endemic areas, such as Sub-Saharan Africa and Asia, or as large-scale outbreaks, such as those in Haiti in late October 2010 and Yemen in 2017.
Between 2000 and 2016, the average annual figures reported to the World Health Organization (WHO) were 200,691 cases and 3,858 deaths. But under-reporting of cases, shortcomings in surveillance systems and the absence of standardized terminology to describe cholera cases mean that these figures are far lower than the actual cholera burden. In Bangladesh alone, the estimated number of cholera cases each year is thought to be between 100,000 and 600,000, despite the fact that no cases are officially reported. Some countries still report a case fatality rate (CFR) well above the acceptable level of 1%, especially in Africa, where several countries report CFRs of around 6% every year.
Vibrio cholerae O1 was the only known cholera agent until 1992, when a strain belonging to a new serogroup, O139, emerged in India and Bangladesh, raising fears of a new cholera pandemic. But this serogroup remained confined to Asia, and its incidence has since decreased. V. cholerae O1 strains have been divided into two biotypes: the classical biotype, which caused the fifth and sixth pandemics, and the El Tor biotype, responsible for the current seventh pandemic. New variants of V. cholerae O1 that are hybrids of these two biotypes have recently emerged in Bangladesh and spread across the world, to Asia, Africa and recently Haiti, where they have completely replaced the initially described El Tor strains. Field observations have shown these strains to be more virulent, leading to a higher case fatality rate. Careful epidemiological surveillance of the strains in circulation worldwide is therefore recommended.
Vibrio cholerae is a highly motile bacterium with modest nutritional requirements whose natural reservoir is mainly humans, but also in some cases the environment. Cholera is caused by ingesting contaminated water or food. Once the bacteria reach the intestines, they secrete cholera toxin, which leads to the severe dehydration characteristic of cholera infection – loss of water and electrolytes can reach up to 15 liters per day. Humans serve as both a culture medium and a means of transport for V. cholerae. The vast quantities of liquid stools released are responsible for spreading the bacteria in the environment and for fecal-oral transmission. The incubation period and asymptomatic carriage also enable V. cholerae to be transported over varying distances.
The main factors that encourage cholera transmission are low socio-economic status and poor living conditions. Crowded populations in areas with inadequate hygiene facilitate the emergence and development of cholera outbreaks.
Symptoms and treatment
Fewer than 25% of infected people develop symptoms, and 10 to 20% of those experience severe disease. The incubation period, which can range from a few hours to a few days, is followed by severe diarrhea and vomiting, but no fever. In the absence of treatment, in its most severe forms, cholera is one of the most rapidly fatal infectious diseases: patients die within 1 to 3 days as a result of cardiovascular collapse. The death rate is higher among children, elderly people and those with weak immune systems.
Treatment primarily involves replacing lost water and electrolytes. Depending on the level of dehydration, patients are rehydrated orally or by intravenous administration. Improvements can be observed after just a few hours and patients recover fully, with no lasting effects, within a few days.
Antibiotic therapy is useful in severe cases, but given the emergence of multiple-antibiotic-resistant strains of V. cholerae, antibiotic sensitivity first needs to be tested on a representative sample of isolated strains.
Improved access to drinking water and general hygiene measures are vital in tackling cholera. In the event of an outbreak, a comprehensive public health response is essential, and health education needs to be developed in countries with regular cholera outbreaks. But sufficient improvements to hygiene levels are unlikely to occur for several decades in the countries affected by cholera.
Two types of oral vaccine are currently prequalified by WHO:
- A monovalent O1 vaccine, composed of killed whole cells of V. cholerae O1 in combination with a recombinant B-subunit of cholera toxin (WC/rBS, Dukoral®). It underwent large-scale clinical trials in Bangladesh (from 1985 to 1989) and Peru, and provides 85-90% protection for all age groups for six months. This figure falls rapidly in children under 5 but remains close to 60% after two years in older children and adults. The vaccine, which is not licensed for children under the age of 2, is administered to adults and children over the age of 6 in two doses at least 7 days but no more than 6 weeks apart, and provides protection one week after administration of the second dose. It has received marketing authorization in Europe It has received a European Marketing Authorization (MA) but, but the French public health authorities advised that it should not normally be given to travelers, for whom the primary means of cholera prevention should be good hygiene practices.
- Two bivalent O1 and O139 vaccines, prepared from killed whole cells and made by different manufacturers, which do not contain cholera toxin B-subunit. The ShancholTM vaccine was licensed in 2009 in India and the Euvichol® vaccine in 2015 in the Republic of Korea. They have the same formulation and are available for the international market. They provide longer-term protection than the monovalent oral vaccine in children under the age of 5: studies on the ShancholTM vaccine in India after two years of monitoring revealed overall protective efficacy of 67 to 69% among those having received two doses of vaccine for all age groups, including children aged 1 to 4. The cumulative protective efficacy of ShancholTM is 65% over five years. Clinical trials have demonstrated equivalent performances for ShancholTM and Euvichol® in immunological terms. The absence of B-subunit and the fact that they do not require a buffer to be administered makes them less costly to produce.
Other vaccines have been removed from the market:
- An injectable vaccine based on killed whole cells was withdrawn from the market in the early 1990s because of its limited efficacy (it offered protection for 50% of subjects for around six months) and its side effects.
- An oral vaccine based on live attenuated strains (in which some of the genes encoding the cholera toxin had been deleted), which could be administered in single doses, was proven to be effective in North American volunteers infected with a virulent strain in a challenge study, and it received WHO approval. But in a clinical trial carried out on more than 60,000 people in Indonesia, in a context of low cholera incidence, the vaccine offered no significant protection. There was also a risk of reversion to virulence of the vaccine strain by the horizontal exchange of genetic material with wild virulent strains, and the vaccine was withdrawn from the market in 2003. But the efficacy of a new formulation of the vaccine developed by the University of Maryland (MD, United States) is currently under study.
WHO considers oral cholera vaccines (OCVs) to be a potentially useful public health tool in addition to traditional preventive measures. A global stockpile of OCV was created in 2013. Vaccines are deployed either by WHO's Global Task Force on Cholera Control (GTFCC), during preventive vaccination campaigns, or by the International Coordinating Group (ICG), whose secretariat is also hosted by WHO, during emergency vaccination campaigns. It is important to emphasize, however, that there is currently no vaccine that provides long-term protection against cholera. Given the threat that cholera still represents and the difficulties in implementing hygiene and sanitation measures in several countries, continued research on cholera vaccination remains vital.
At the Institut Pasteur
The Vibrios and Cholera National Reference Center (CNR), hosted in the Institut Pasteur's Enteric Bacterial Pathogens Unit, has been tasked by the General Directorate of Health in the French Health Ministry with monitoring, confirming and reporting cases of cholera imported into France (there are around 4 or 5 each year). As in many countries, cholera is a notifiable disease in France. The CNR works with microbiologists in countries affected by cholera outbreaks and with non-governmental humanitarian organizations, and is therefore involved in monitoring the strains of V. cholerae in circulation worldwide and in reporting the emergence of new variants or multiple-antibiotic-resistant strains. A genome database recently developed by the unit that traces the history of the seventh cholera pandemic in Africa and Latin America is a valuable tool for improving our understanding of cholera epidemiology.
The Institut Pasteur is a member of WHO's Global Task Force on Cholera Control (GTFCC), a network of over 50 organizations that has adopted a comprehensive multi-sector approach, bringing together multiple partners working to tackle cholera. The Institut Pasteur also leads a Surveillance Working Group, which has published various technical notes. In October 2017, 35 GTFCC partners, including the Institut Pasteur, made an unprecedented commitment to fight cholera by implementing a Global Roadmap (Declaration on Ending Cholera) designed to reduce cholera deaths by 90% by 2030.
Surveillance and public health : The Vibrios and Cholera National Reference Center