The implications of this new genomic view of cholera were profound. They showed that natural environmental populations of V. cholerae and epidemic V. cholerae are very different beasts. Environmental V. cholerae causes sporadic outbreaks, with a limited number of cases that spread no further. By contrast, cholera epidemics are caused by individual lineages of V. cholerae that appear to have adapted for human-to-human transmission, and that have spread worldwide on the back of human movement, one lineage for each of the seven pandemics.
“The data were disruptive at every level. We have spent the subsequent decade focused on convincing the public health community that seventh pandemic and perennial environmental V. cholerae strains move very differently. Our message is that you cannot control V. cholerae, which is in waterways everywhere, but you can control the epidemic cholera lineage responsible for the seventh pandemic by focusing on disrupting human-to-human transmission chains.”
Professor François-Xavier Weill,
Discussions were already ongoing about using genomics as the gold standard for defining bacterial strains, and the WHO, which had established the Global Task Force for Cholera Control, were on board with integrating genomic definitions into cholera control efforts. Accordingly, the role of the specific V. cholerae lineage in causing the current pandemic has been recognised and the need for genomic definitions is now being included in local and regional cholera control plans. They are also being included in processes designed to confirm the end of an epidemic and declare cholera-free status, with WHO asking countries to use both molecular and genomic definitions when recording potential outbreaks. Ultimately this will put the onus on countries to collect and sequence samples from every outbreak, although at the moment there is an opt-out given that many cholera endemic countries do not have the necessary infrastructure and genomic capabilities.
Cholera outbreaks have serious economic implications, with people less willing to travel to a cholera endemic country for trade or tourism, meaning that there are strong incentives for countries to declare that they are free of cholera. Furthermore, like all other infectious diseases, cholera cares nothing for national borders. As such, the real goal should be using genomics to enable entire regions to cooperate in tackling pandemic cholera with the aim of being able to declare that their region is free from epidemic cholera caused by the genomically defined seventh pandemic El Tor lineage, or 7PET for short.
Unfortunately, there is currently no unified way of collecting cholera samples from every outbreak to be sequenced, either locally or through a centralised body. This represents a missed opportunity. As has been shown for outbreaks in Bangladesh6 and Pakistan in 2022, sequencing even a handful of samples is enough to determine whether an epidemic strain within the 7PET lineage or an environmental strain is responsible. Establishing a system for sampling of all outbreaks, as well as isolates from sporadic cases between outbreaks would enable researchers to better define the risk of having a large-scale outbreak and importantly delineate the routes by which epidemic cholera spreads.
Having a genomic definition of the V. cholerae strain behind the early cases in an outbreak could also help to ensure that appropriate control measures are directed to where they are most needed to reduce morbidity and mortality. Oral cholera vaccine stockpiles are managed through Gavi, the vaccine alliance, who on request from the government of an affected country can begin distribution of vaccines to at risk populations almost immediately, in concert with humanitarian responses. In 2017 and 2018, nearly 2.2 million doses of inactivated oral cholera vaccine were deployed among Rohingya refugees and the wider population in Bangladesh, with 750,000 people receiving the vaccine within a two week period at one point7. In this case, swift action saw the vaccines rolled out before the strain responsible for the early cases had been characterised, which is fortuitous given that subsequent analysis revealed it to be a high risk 7PET epidemic strain. However, if an environmental strain had been responsible, a vaccination programme may have diverted vaccine stocks and resources away from other outbreaks of epidemic cholera that would not have been naturally self-limiting. This is particularly important given that cholera vaccine production is limited and there are significant challenges ahead in even maintaining current global stockpiles of cholera vaccine8, with the manufacturer of one of the two cholera vaccines used in humanitarian emergencies halting production by the end of 20239.
Professor Munirul Alam, from the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) outlines the insights genomic surveillance could reveal: “The Ganges Delta of Bay of Bengal, Bangladesh, is the historic hotspot for global cholera. We used genome sequencing to investigate the 2022 cholera outbreak in Dhaka, Bangladesh, finding evidence for a new subclade of the 7PET lineage designated BD-1.2. Strains within the BD-1.2 subclade caused a massive cholera outbreak, displacing other 7PET strains that were locally dominant at the time providing evidence that cholera is not only transmitted from but also imported to Bangladesh.”
“The genomes of BD-1.2 strains revealed unique mutations in genes that promote growth, resistance to bile salt, cell wall organization, and toxigenicity. The speed with which BD-1.2 came to dominate existing strains in Dhaka is particularly concerning and suggests that this new subclade may cause even more devastating epidemics. Without genomic surveillance, we would be entirely in the dark about the changing nature of the bacterium responsible for such cholera outbreaks.”
Professor Munirul Alam,
International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh