Cholera: the return of a forgotten pandemic?

The resurgence of cholera in Haiti is a reminder of how quickly the diseases spread, said PAHO director Carissa F. Etienne

Researchers revealed in a study published in the scientific journal Nature, how the O139 Vibrio cholerae, instead of triggering the eighth pandemic as predicted, has disappeared after suddenly becoming susceptible to antibiotics. In the study entitled “Vibrio cholerae O139 genomes provide a clue to why it may have failed to usher in the eighth cholera pandemic”, researchers examined 330 samples taken between 1992 and 2015 and observed that over time there were significant changes in their genome and these changes caused the “unexpected decline” of the variant.

Dr. Ankur Mutreja, one of the authors of the study, explains that O139 Cholera spread in three overlapping waves and that antimicrobial resistance (AMR) was crucial for the early success and subsequent failure of the O139 cholera lineage. Also according to the researcher, there is always the possibility of a new variant of the O-antigen to emerge, which could lead to the eighth pandemic. However, as the seventh pandemic is still active and successfully circulating globally, a completely new and distinct variant of the seventh lineage should not appear in the short term. To avoid the eighth pandemic, we need to implement constant surveillance efforts to monitor the evolutionary changes of the population of V. cholerae worldwide, especially in endemic areas,” he says.

Cholera bacteria are not monitored regularly because cholera is generally easy to treat and to avoid when adequate WASH (Water, Sanitation and Hygiene) systems are adequate. In this sense, Dr. Mutreja calls attention to the importance of conducting studies on the circulation and survival of V. cholerae. With this analysis it is possible to monitor changes in its genome and plan changes in vaccines and public health responses accordingly. In addition, more recent strains may need an adaptation of diagnostics as well, he adds. That is, continuous surveillance of circulating variants is our best chance of preventing mass outbreaks. Continuous monitoring of this potentially pathogenic organism is necessary at each level, including its genetic diversity and disease presentation in the human population.

World records “most fatal outbreaks” of cholera

According to the World Health Organization (WHO), cholera cases increased in 2022 especially in regions suffering from poverty. After years of decreasing numbers, since 2021 the world has recorded “most fatal outbreaks” of the disease in 27 countries, recorded since January. According to WHO Director-General Tedros Ghebreyesus, the average mortality rate this year is almost three times higher than in the last five years. The reasons for the advance, according to the WHO leader, are related to climatic factors, such as floods, cyclones and droughts, as well as conflicts and forced displacements, which, by limiting access to drinking water in refugee camps, create the ideal environment for the spread of the disease.

Haiti is on the verge of a health catastrophe. Since the notification of the first two confirmed cases of the disease in the Port-au-Prince region on October 2 the Ministry of Public Health and Population (MSPP) reported more than 9 thousand suspected cases in eight areas of the country, until November 13. The population faces a deplorable health and humanitarian situation on a daily basis. Access to adequate drinking water and health care is hampered by the explosion of violence and fuel shortages. The lack of drinking water and precarious sanitary conditions lead to a rapid increase in the number of cases. With no record of cholera cases for over three years, the country was about to be declared disease-free. The director of the Pan American Health Organization (PAHO), Carissa F. Etienne, pointed out that the resurgence of cholera in Haiti is a reminder of how quickly the diseases spread.

Syria has recorded since September the first major outbreak of the disease in 15 years. Initially linked to contaminated water near the Euphrates River and severe water scarcity in the northern region, the outbreak has spread throughout the country, and more than 13 thousand suspected cases have been reported, including 60 deaths. This is the first time the disease has been confirmed in the northeast region since 2007, After 11 years of war, the country has the largest number of internally displaced people in the world, with 6.9 million people in this situation, most of whom are women and children.

Lebanon also confirmed an outbreak. The first record was in Akkar Province, in the north of the country. Most cases are among Syrian refugees in the country. About 2 million Syrians have taken refuge in Lebanon and many live in precarious conditions. Cholera was detected in Lebanon in early October and there are currently more than 2 thousand suspected cases, at a time when the country is experiencing an unprecedented economic crisis and struggles with old and precarious infrastructure. This is the biggest local outbreak in over three decades.

Nigeria has experienced a severe cholera outbreak since January, which has affected more than 18 thousand people in 31 states. Almost 500 people died as a result of the disease in the country, which now faces one of the worst floods in a decade. More than 3.2 million people were affected. Until November 3, the Northeast of the country recorded 14 thousand cases of cholera and 443 deaths. Borno has 81% of reported cases, followed by Yobe and Adamawa. Contamination of water sources has increased the risk of spreading cholera and other diseases such as malaria and typhoid.

Malawi has also been battling a devastating outbreak that has already affected all 28 districts of the country, which is already facing an ever-increasing hunger crisis. Government reports released in November indicate that there was a 33.5% increase in cholera cases reported in October, compared to September. With the rainy season about to begin, there are fears that there may be an increase in cases. Malawi remains one of the poorest nations in the world. Around 5.4 million people are fighting against hunger in the country. The combination of cholera and hunger creates a dangerous cycle that poses a great risk to the nation.

Cholera spread causes vaccine rationing

Unlike other diseases that threaten public health, cholera can be tackled with simple interventions, which include prevention with vaccines. Although avoidable, Dr. Mutreja emphasizes that the current situation is mainly due to the deficit in the supply of vaccines. “Inventories are limited in quantity and manufacturers do not see this as a sustainable business,” says the professor at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases. Unfortunately, the advance of the disease led entities to ration the immunizer. The decision was taken by the International Coordination Group (ICG), which manages emergency supplies of vaccines. With the temporary suspension of the standard two-dose regimen, each person will receive a single dose. Although vaccinated people are likely to be protected for less time, the alternative of rationing doses is preferable to having to choose which countries to send the vaccines to and which not. Members of the ICG include Médecins Sans Frontières (MSF), the WHO and the International Committees of the Red Cross and Red Crescent.

Oral cholera vaccines have recently become available for use. There are four variants of oral vaccines in use. A single dose live attenuated monovalent vaccine of lyophilized V. cholerae CVD 103-HgR is available in the United States for adults aged between 19 and 64 years-old travelling to cholera-infected areas. It protects against diseases caused by V. cholerae O1. In addition to this, there are three oral dead whole cell vaccines available for use in children and adults worldwide, except in the United States. They are: monovalent vaccine – against diarrhea and cholera of travelers (Dukoral®). It contains only the bacteria O1 and El Tor V. cholera plus a small amount of non-toxic cholera toxin from subunit b. Dukoral, in Brazil, is produced by Sanofi Pasteur®. The other two bivalent vaccines (ShanChol® and Euvichol®) contain serogroups O1 and O139 of V. cholerae. The three vaccines provide 60% to 85% protection for up to 5 years and require two doses. Booster doses are recommended after two years for people at permanent risk of cholera.

Although rarely used, injectable vaccines are effective for people living in places where cholera is common. They offer some degree of protection for up to two years after a single dose and for three years with annual booster. They reduce the risk of cholera death by 50% in the first year after vaccination.

Even with vaccines, the disease poses a great threat to humanity

The disease is caused by the toxigenic V. cholerae, a Gram-negative group O1 or O139 bacillus, mobile by polar flagellation and belonging to the family Vibrionaceae. Only toxigenic strains from both groups cause epidemics of proportions and are reported to the WHO as “cholera”. The V. cholerae O1 has two biotypes, the Classic and the El Tor, both are biochemically indistinguishable and depending on the antigenic constitution can be divided into three serotypes: Inaba, Ogawa and HI Kojima.

Cholera caused six pandemics between 1817 and 1923, all by the classical serotype O1. The current one, the seventh, caused by the El Tor biotype, began in Indonesia in 1961, spread to other countries in Asia, the Middle East, Africa (where it had 70% of all notifications), Europe and, in 1991, South America, via coastal cities in Peru, reaching Brazil, through the Alto Solimões region, in the Amazon. In 1992, a new enterotoxin serogroup, O139, emerged in India and quickly reached Pakistan, Bangladesh and China. In 2010, an epidemic of the El Tor biotype invaded Haiti after an earthquake that virtually destroyed much of the country.

Cholera, the spread of which is facilitated by the absence of basic sanitation and drinking water, is easily treatable. Among the adaptive measures for treatment, listed by the WHO, is the oral rehydration of patients and the distribution of antibiotics for more severe cases. However, if the patient does not have access to treatment, the disease can be lethal in a few hours.

Dr. Mutreja recalls that any country may be at risk of cholera by introduction with carriers, including Brazil. He cites the example of Haiti, where cholera was absent for years and is now out of control once again after the country has almost become cholera-free. When hygiene and sanitation systems are compromised, these carriers can spread cholera in the environment, sometimes contaminating the water supply, leading to outbreaks of the disease. Asked about what we learned from the previous experiences of cholera outbreaks, for example, in Haiti, countries on the African West Coast, the Indian Subcontinent, among others, Dr. Mutreja says that consistent surveillance and preventive vaccination of populations at risk are critical, and that WASH efforts should continue in parallel as a long-term solution. Every year there are between 1.4 and 4.3 million cases and from 28 thousand to 142 thousand deaths worldwide. Brazil was once the world leader in cholera cases, registering in 1993 the highest number of cases.