Vaccine 38 (2020) A31–A40

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Epidemiology of cholera
Jacqueline Deen a,b,⇑, Martin A Mengel c, John D Clemens d,e
a
Institute of Child Health and Human Development, National Institutes of Health, University of the Philippines, Pedro Gil Street, Ermita, Manila 1000, Philippines
b
Delivering Oral Vaccine Effectively (DOVE), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
c
Global-Health Consulting, Calle Isabel de Villena 99, 46011 Valencia, Spain
d
iccdr,b, GPO Box 128, Dhaka 1000, Bangladesh
e
UCLA Fielding School of Public Health, 650 Charles E Young Drive South, Los Angeles, CA 90095-1772, USA

a r t i c l e i n f o a b s t r a c t

Article history: Cholera is an ancient disease that remains a public health problem in many impoverished locations
Available online 5 August 2019 around the world. Seven pandemics of cholera have been recorded since the first pandemic in 1817,
the last of which is on going. Overcrowding, poverty, insufficient water and sanitation facilities increase
Keywords: the risk for cholera outbreaks. The epidemiology of cholera in the areas in Asia, Africa and the Americas
Cholera where the disease occurs continues to evolve.
Vibrio cholerae Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
Pandemics
creativecommons.org/licenses/by/4.0/).
Transmission
Epidemiology

1. Introduction
Cholera, caused by the bacterium Vibrio cholerae, is an acute
watery diarrheal syndrome. Descriptions of clinical illness consis-
tent with cholera date back to antiquity [1,2]. During the 19th
and 20th centuries, the disease spread globally beyond Asia seven
times, referred to as cholera pandemics. The first started in 1817
and subsequent pandemics began in 1829, 1852, 1863, 1881,
1889 and 1961, the last persisting until the present. The patterns
of global spread have taken various forms, although most of Asia,
Africa, Europe, and the Americas have been affected at one time
or another [1,3,4].
Following microscopic identification of cholera vibrios by Pacini
in 1854, Robert Koch isolated the causative organism in pure cul-
ture from patients in Egypt in 1883. Two V. cholerae serogroups
are known to include lineages that cause pandemic cholera, O1
and O139. On the basis of phenotypic and genotypic characteris-
tics, V. cholerae O1 is subdivided into two biotypes, classical and
El Tor [3]. V. cholerae O1, classical biotype, was the documented
or presumed etiologic agent of the first six pandemics, while the
El Tor lineage is the dominant strain in the current seventh pan-
demic (7P). The 7P emerged in the Sulawesi Archipelago and
spread to much of Asia in the 1960s; in the 1970s it affected Africa,
parts of the former USSR, the Middle East and southern Europe; in
the early 1990s there were multi-country outbreaks in South and
⇑ Corresponding author at: University of the Philippines, Manila, Philippines.
E-mail address: deen.jacqueline@gmail.com (J. Deen).
Central America [5–12]. The more recent outbreaks in Haiti and
Yemen are included in the ongoing pandemic.
The major hub linking the spread of cholera around the globe
during the 19th and early 20th centuries is the Bay of Bengal
[13]. Analysis of the core genome sequence of selected isolates
from 7P found that the pandemic originated from a single clone
that spread in at least three distinct, but overlapping waves from
the Bay of Bengal, with a common ancestor in the 1950s [14].
The current knowledge on cholera transmission, human suscepti-
bility and epidemiologic patterns in Asia, Africa and the Americas
are discussed below.
2. Transmission
V. cholerae, including members of the O1 and O139 serogroups
that cause cholera, is a natural inhabitant of the aquatic environ-
ment, particularly brackish riverine, estuarine, and coastal waters
[15]. Differentiation between globally spreading pandemic V. cho-
lerae clones and local bacterial populations is important. There
are locally circulating strains that cause syndromic cholera but
not pandemic cholera [16].
Cholera is spread through the fecal-oral route, either directly
from person-to-person or indirectly through contaminated fluids
from an environmental reservoir of varying duration, food and
potentially flies and fomites [17]. Endemic cholera has been found
to be associated with tidal seawater intrusions and seasonal cli-
matic patterns, whereas epidemic cholera often occurs near water-
ways when weather conditions are favorable for the growth of the

https://doi.org/10.1016/j.vaccine.2019.07.078
0264-410X/Ó 2019 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A32 J. Deen et al. / Vaccine 38 (2020) A31–A40
bacteria [18], such that an interaction between the aquatic envi-
ronment and fecal-oral spread of cholera has long been held [19].
However recent genome sequence analysis of clinical isolates have
indicated that only a subset of specific V. cholerae clones are
responsible for current epidemics, which circulate in the popula-
tion and which are largely unassociated with the diverse spectrum
of V. cholerae strains in the aquatic environment [13].
Persons with cholera infection excrete V. cholerae in their stool.
The period of excretion may be as short as one day in asymp-
tomatic infected contacts, whereas the stool of symptomatic
patients may contain the bacteria prior to the illness and for up
to 1–2 weeks [20]. More prolonged bacterial shedding has been
reported [21–24]. The median time from infection to onset of dis-
ease (incubation period) is 1.4 days, with 5% of cholera cases devel-
oping symptoms by 12 h and 95% by 4.4 days after infection [25].
The cholera organisms in stool are a mixture of free-swimming
cells of V. cholerae and biofilm-like aggregates [26]. The bacteria
alternate between these motile and biofilm forms to efficiently col-
onize the small intestine. The V. cholerae biofilms are more resis-
tant to stressful conditions in the host, exhibit a lower infective
dose and may enhance dissemination of the disease [27]. Rapid
spread of cholera through the fecal–oral route may also be facili-
tated by a transient hyperinfective state of V. cholerae present in
fresh stool [27,28]. Stool-derived, hyperinfective V. cholerae main-
tains its hyperinfectivity for a few hours after dissemination, which
may have implications for transmission, especially in areas with
high population density [20,29].
Cholera cases tend to cluster and this may be due to direct
person-to-person transmission, a common source of infection or
spread from the local environment contaminated by a case
[30,31]. Direct exposure within households contributes signifi-
cantly to transmission of cholera [32]. Those living close to a cho-
lera patient have a high risk for developing the disease. In studies
in Bangladesh, more than 70% of rectal swab-positive contacts
reported diarrhea during 21 days of observation following the pre-
sentation of an index case [21] and about a quarter of 294 house-
hold contacts of cholera cases had V. cholerae infection and
bacterial shedding [24]. Aside from interpersonal contact that
drives the clustering of secondary transmitted cases, close associa-
tion of risk factors (lack of access to safe water, poor sanitation,
poor hygiene and food handling behaviors) within population
groups may also explain the clustering of cholera cases [33]. The
clonal nature of cholera spread by interhuman transmission [13]
highlights the importance of improved sanitation for the control
of the disease.
Mass gatherings, particularly those involving large congrega-
tions of people with insufficient safe water supply and sanitation,
enhance the spread of cholera and may be followed by further dis-
semination when attendees return home. For example, 42 cholera
cases were identified among multinational attendees of a large
wedding reception in the Dominican Republic, associated with
the consumption of shrimp on ice and ice cubes in beverages
[34]. In another example, an analysis of population movement
using mobile phone data showed how a cholera outbreak flared-
up during a pilgrimage in 2005 in Duoba, Senegal and spread
throughout vast parts of the country [35]. Some traditional funeral
rites that include the washing of the deceased and preparation of a
large meal, which combined with mourners travelling home, may
magnify the spread of the disease [36]. Overcrowding, especially
in situations of poor sanitation and limited water supplies, such
as in prisons and camps for internally-displaced people also
increase the risk for transmission and spread of cholera [36].
Little is known about the possible role of flies and fomites in the
transmission of the disease. V. cholerae O1 has been isolated from
houseflies, Musca domestica, collected from a low socioeconomic
area in Delhi, India, during a cholera outbreak [37]. Houseflies
may help disseminate cholera by acting as mechanical vectors of
the bacteria. The survival and viable quantification of V. cholerae
O1 following inoculation on a range of household fomites was
investigated at 30 min intervals for up to 6 h [38]. The bacteria lost
culturability within one hour after inoculation on glass and alu-
minum surfaces but remained culturable on cloth and wood for
up to four hours, presumably because these surfaces are porous
and allow the bacteria to retain moisture for longer periods. The
prolonged survival of Vibrio cholerae O1 on these fomite surfaces
may contribute to the transmission of cholera.
3. Human susceptibility
A variety of host factors influence human susceptibility to cho-
lera. Gastric hypoacidity has been associated with the risk of cho-
lera, an observation not unexpected in view of the well-known acid
sensitivity of V. cholerae [39]. Less well understood from a mecha-
nistic point of view is the observation that the risk of severe cho-
lera is influenced by ABO blood group. Studies have shown that
individuals with group O are at highest risk, those with group AB
are at intermediate risk, and those with groups A or B are at lowest
risk. Recently, in vitro studies have demonstrated a more potent
effect of cholera toxin in inducing cAMP in enteric cells of humans
with blood group O than in those of humans with blood group A
[40]. Interestingly, these relationships apply to the risk of El Tor
biotype cholera but not classical biotype cholera [41,42]. Based
on these observations, and the additional observation that the pop-
ulation prevalence of blood group O in the Ganges delta is among
the lowest in the world, it has been proposed that cholera has
acted to influence natural selection in human evolution in this
region [41].
Host diet and nutritional status also appear to influence suscep-
tibility. Being non-breastfed places infants at considerably higher
risk of cholera in endemic settings [43,44]. Retinol deficiency has
been suggested as a possible risk factor as well [44]. Among micro-
bial factors studied, HIV infection was noted in Mozambique to be
associated with a higher occurrence of cholera [45], and features of
the gut microbiome have been linked with the rate of recovery
from cholera, though the risk of cholera imparted by the gut micro-
biome remains to be elucidated [46].
Both innate and adaptive host immunity influence the suscepti-
bility of cholera. Duodenal biopsies of Bangladeshi patients with
cholera revealed an upregulation of several genes that encode 15
antibacterial proteins established or postulated to have a role in
the innate defense against cholera; two of these proteins were
demonstrated to have been induced by direct interaction of cholera
toxin with intestinal epithelia, and the most strongly upregulated
gene coded for the LPLUNC1 antibacterial protein [47]. Concordant
with this gene expression study was an additional study of human
genetic susceptibility that found that the LPLUNC1 polymorphism
was associated with the risk of cholera [48]. Further work in the
same Bangladeshi population found that genes involved in NF-kB
signaling in the innate immune system, together with potassium
channel genes involved in cAMP-mediated active chloride secre-
tion, were associated with risk of cholera, with the former genes
appearing to be under natural selection [49].
That adaptive immunity plays an important role in protection
against cholera was suggested by work in North American volun-
teers, in whom an initial experimental challenge with cholera vib-
rios conferred protection against a subsequent challenge [50].
Studies in cholera endemic populations demonstrated that an epi-
sode of clinical cholera appeared to protect against recurrent epi-
sodes for at least three years after the initial episode [51].
Correspondingly, substantial, long-lasting protection has been seen
with new generation oral cholera vaccines [52].
 J. Deen et al. / Vaccine 38 (2020) A31–A40
Studies dating back to the 1960s in Bangladesh have found that
a person’s serum vibriocidal titer correlates inversely with the sub-
sequent risk of cholera, suggesting a role for antibacterial immu-
nity [53–55]. It is now known that these serum antibodies do not
directly mediate anti-cholera immunity. Rather, protective immu-
nity against cholera results from stimulation of intestinal mucosal
immune responses, mainly anti-bacterial (anti-O1 LPS for O1 ser-
ogroup cholera and anti-O139 LPS for O139 serogroup cholera)
though with some role for anti-toxin responses, and that these
responses consist primarily of IgA secretory antibodies [56,57].
4. Epidemiologic patterns
In 2017, 1.2 million cholera cases and 5654 fatalities worldwide
were reported to the WHO, with Yemen accounting for 84% and
41% of cholera-attributed cases and deaths, respectively [58].
These numbers provide an incomplete assessment of the global
burden of the disease since many countries do not report cholera
cases and deaths. Underreporting is mainly due to weak or absent
surveillance systems but some countries may suppress reports
because of perceived risks to tourism and export industries [59].
Prior to the Yemen outbreak, a comprehensive burden of disease
study used a spatial regression model and published cholera inci-
dence data to calculate the annual number of cases in endemic
countries [60]. Between 2008 and 2012, the annual cholera burden
was estimated at 2.86 million cases (uncertainty range: 1.3–4 mil-
lion) and 95,000 deaths (uncertainty range: 21,000–143,000).
Cholera has long been endemic in large parts of Asia, but it has
become more recently established throughout Africa and in Haiti.
Based on the WHO definition of having culture-confirmed cases
for at least three of the past five years, cholera is now considered
endemic in many areas of Africa, for example, the Rift Valley region
of Central Africa [61]. No cholera outbreak had been reported in
Haiti for more than a century but after its re-emergence in 2010,
the disease is now endemic in the country [62].
Fig. 1 shows the annual number of cholera cases reported to the
WHO from 1989 to 2017, by continent [58]. The location and size
of cholera outbreaks have varied over the decades, with a particu-
larly large number of cholera cases reported in 2017. From 2017 to
2018, major cholera outbreaks were reported in Yemen, various
Fig. 1. Number of cholera cases reported to WHO by year and by continent, 1989–2017.
A33
African countries and Haiti [63]. The historical and current spread
of cholera in Asia, Africa and the Americas, as well as its burden,
phylogenetic pattern, and risk factors are discussed below.
4.1. Cholera in Asia
During the on-going seventh cholera pandemic that began in
1961, the El Tor biotype spread quickly and gradually replaced
the classical strain [64]. In the early 19600 s, El Tor cholera out-
breaks occurred throughout Indonesia then in the Philippines,
Malaysia and Taiwan followed by Cambodia, Thailand, Singapore
and India. In mid-19600 s, outbreaks were documented in Pakistan,
Nepal, Brunei, Afghanistan, Iran, Hong Kong, Laos and Myanmar
[65]. During the subsequent decades, El Tor cholera continued to
occur in many countries in Asia.
In late 1992, large outbreaks of cholera were reported in India
and Bangladesh that were due to a previously unrecognized ser-
ogroup of V. cholerae, designated as O139 Bengal [66]. V. cholerae
O139 was later isolated in other parts of Asia, including Pakistan,
Nepal, and China. Cholera caused by the O1 and O139 strains were
indistinguishable in clinical features and response to treatment
[65]. After causing explosive outbreaks from 1992 to 1993, V. cho-
lerae O139 became less frequently found [65]. Currently V. cholerae
O1 El Tor causes virtually all cholera cases and the O139 strain is
seldom isolated.
Starting in the mid-1990s, hybrid strains of V. cholerae that
were El Tor in phenotype but encoding classical cholera toxin were
isolated in Bangladesh [67]. Since 2002 these hybrid strains have
displaced the typical El Tor biotype in Bangladesh and several
other sites [68]. Certain of these El Tor variants were observed to
cause a higher proportion of severe dehydration than the typical
El Tor strains, perhaps due to an increased elaboration of cholera
toxin [69]. Pathogenic V. cholerae strains in Asia continue to evolve
genetically and phenotypically [64]. Analysis of data from Bangla-
desh suggest that cholera’s serotype-cycling arises from
population-level incomplete cross-immunity creating conditions
for strain-switching [70].
The estimated annual number of cholera cases and deaths in
Asian countries from the comprehensive burden of disease study
is shown in Table 1 [60]. From 2008 to 2012, India and Bangladesh
A34 J. Deen et al. / Vaccine 38 (2020) A31–A40

Table 1
A comparison of the number of estimated and reported cholera cases and deaths in Asian countries [58,60].

Country Estimated annual number Estimated annual number Reported number Reported number
of cases (2008–2012) of deaths (2008–2012) of cases in 2017 of deaths in 2017
Afghanistan 29,341 939 33 1
Bangladesh 109,052 3,272 – –
Bhutan 658 20 – –
Cambodia 991 10 – –
China 9,084 91 14 0
Indonesia 2,298 23 – –
India 675,188 20,256 385 3
Iran – – 634 (625 imported) 4
Japan – – 7 (5 imported) 0
Kiribati 7 0 – –
Lao People’s Democratic Republic 333 3 – –
Marshall Islands 1 0 – –
Malaysia – – 2 0
Micronesia (Fed. States of) 8 0 – –
Nauru 1 0 – –
Nepal 30,379 911 7 0
Palau 1 0 – –
Papua New Guinea 377 4 – –
Philippines 2,430 24 134 2
Qatar – – 5 (5 imported) 0
Republic of Korea – – 5 (5 imported) 0
Saudi Arabia – – 5 (5 imported) 0
Singapore – – 3 (3 imported) 0
Solomon Islands 36 0 – –
Thailand – – 8 0
Timor-Leste 938 28 – –
United Arab Emirates – – 12 (12 imported) 0
Vanuatu 10 0 – –
Yemen 17,546 561 1,032,481 2,261

had the highest estimated annual number of cholera cases and
deaths. Of India’s 35 states or union territories, 21 reported cholera
cases during at least one year between 1997 and 2006, with the
states of Orissa, West Bengal, Andaman and Nicobar Islands, Assam
and Chhattisgarh accounting for 91% of all cholera cases [71]. A
more recent review of 2010 to 2015 district level data on cholera
from India’s Integrated Disease Surveillance Program identified
27,615 reported cholera cases from 24 of 36 Indian states, of which
13 were classified as endemic [72]. A systematic surveillance of
acute watery diarrhea in 10 hospitals in Bangladesh from 2014 to
2018 detected cholera in all geographical regions of the country
and identified V. cholerae O1 from 6% of stool samples and [73].
For comparison, the number of cholera cases and deaths officially
reported from Asian countries to the WHO in 2017 is also shown in
Table 1 [58]. In 2017, Yemen reported over a million cases. Several
Asian countries at risk for cholera outbreaks [60] did not report cases
in 2017 [58]. Many of these countries do not officially recognize cho-
lera despite significant seasonal transmission. The Asian region cur-
rently contributes the largest proportion of worldwide cholera cases
but the lack or incomplete reporting by many countries complicates
the assessment of the true burden of disease [58].
The cholera epidemic in Yemen has become the largest and
fastest-spreading outbreak of the disease in recent history. The
country is located in Western Asia at the southern end of the Arabian
Peninsula and has been devastated by more than two years of civil
conflict between Houthi rebels and the internationally recognized
Yemeni regime. Destruction of Yemeni infrastructure, health, water
and sanitation systems and facilities by Saudi-led coalition air
strikes led to the spread of cholera [74]. In addition, ongoing com-
mercial blockades have resulted in shortages of fuel and food, lead-
ing to famine. In 2019, torrential rains and widespread flooding
across Yemen has worsened the humanitarian disaster with more
than 364,000 suspected cases of cholera and 639 deaths reported
since the beginning of the year [75]. Isolates from the on-going
Yemen cholera epidemic have been shown to be from the 7P El Tor
(7PET) cholera lineage, which originated from South Asia and caused
outbreaks in East Africa before appearing in Yemen [76].
Aside from war and devastation, risk factors for cholera in the
region include poverty, lack of development, high population den-
sity and immune status [36]. In Eastern Kolkata, the socio-
demographic variables that increase the risk for cholera are pov-
erty, use of unsafe water and proximity to canals [30]. In Bangla-
desh, lack of education and having a family member with
diarrhea in the past seven days increased the risk for hospitalized
cholera; in children under five, the risk factors were older age,
lower socioeconomic status and lack of breastfeeding [77,78]. Also
in Bangladesh, water temperature and depth, rainfall, and copepod
counts, was shown to correlate with the occurrence of cholera
toxin-producing bacteria [79,80].
In many parts of Southeast Asia, endemic cholera appears regu-
larly, often yearly and is linked to seasonal conditions. Areas with
inadequate water and sanitation infrastructure are susceptible to
cholera epidemics associated with extreme environmental factors,
such as frequent and widespread flooding, that can contaminate
water sources and dislocate populations, or droughts that affect
water supplies. On the other hand, many countries in the Asian
region have made impressive strides in the prevention and control
of cholera [81]. China suffered appalling cholera epidemics in the
past, but has made tremendous progress [82]. Vietnam has
reported no cases of cholera since 2012 [81]. These successes are
correlated with the overall economic advancement in these coun-
tries, similar to the historical evolution of cholera in South America
(discussed below) [83].
4.2. Cholera in Africa
The seventh cholera pandemic reached Africa in 1970 and
spread rapidly (Fig. 2) [84]. During the nearly five decades until
2017, African countries reported over 4 million cholera cases to
the WHO [58,85,86]. In 2017, there were explosive outbreaks in
 J. Deen et al. / Vaccine 38 (2020) A31–A40
the Democratic Republic of the Congo (DRC), Ethiopia, Nigeria,
Somalia, South Sudan, Sudan, and Zambia [59] The total number
of cholera cases and deaths officially reported to the WHO from
Africa in 2017 was 179,835 and 3,220, respectively, with reported
case fatality rates ranging from 0 in many countries to 3.2% in Zam-
bia, 5.2% in Angola and 6.8% in Chad (Table 2) [58]. These high case
fatality rates reflect significant limitations in access to adequate
case management in large parts of the African continent.
The number of African countries reporting indigenous cholera
cases to the WHO rose from 16 in 1970 to 45 in 2006 and fell to
14 in 2017. With underreporting and inadequate surveillance sys-
tems, the number of cholera cases in Africa is probably much
higher than what is officially reported. A large number of outbreaks
occur in a context of societal vulnerability and often become
humanitarian emergencies leading to the collapse of health struc-
tures, including surveillance systems [87]. In contrast to the low
number of officially reported cases and deaths, the comprehensive
burden of disease study covering the period from 2008 to 2012,
estimated 1,341,080 to 1,411,453 cholera cases and 53,632 to
160,930 cholera deaths per year (Table 2) [60].
Fig. 2. Inferred propagation routes of seventh pandemic V.cholerae O1 El Tor populations to, from, and within Africa.
A35
A genomic analysis of 1070 V. cholerae O1 isolates from 45 Afri-
can countries collected between 1966 and 2014 has been recently
carried out [84]. The investigators mapped the phylogenetic data
onto historical records of African cholera outbreaks. They showed
that the African epidemics have been due to a single expanded lin-
eage introduced at least 11 times since 1970, into West Africa and
East/Southern Africa, causing epidemics that lasted up to 28 years
[84]. The presence or introduction of a pandemic cholera strain in a
population living with inadequate water and sanitation infrastruc-
ture may be an overriding risk factor for cholera outbreaks [13]. A
recent study used data from Demographic and Health Surveys to
assess access to water and sanitation services over a 25-year time
period in 15 countries across sub-Saharan Africa [88]. Although
household access to improved water sources increased from 47%
in 1990–1995 to 74% in 2010 to 2015, access to improved sanita-
tion facilities declined from 69% in 1990–1995 to 53% in 2010–
2015.
Inadequate water and sanitation infrastructure combined with
social and environmental challenges are especially acute in many
African cities. A large part of the cholera and diarrheal disease bur-
A36 J. Deen et al. / Vaccine 38 (2020) A31–A40

Table 2
A comparison of the number of estimated and reported cholera cases and deaths in African countries [58,60].

Country Estimated annual number Estimated annual number Reported number Reported number
of cases (2008–2012) of deaths (2008–2012) of cases in 2017 of deaths in 2017
Angola 16,421 624 828 43
Benin 16,547 629 11 0
Burkina Faso 25,797 980 – –
Burundi 19,943 758 399 0
Cameroon 21,037 799 – –
Cape Verde 380 14 – –
Central African Republic 11,484 436 – –
Chad 20,394 775 1,266 86
Comoros 874 33 – –
Congo 13,486 512 – –
Côte d’Ivoire 57,689 2,192 – –
Democratic Republic of the Congo 189,061 7,184 56,190 1,190
Eritrea 21,816 829 – –
Ethiopia 275,221 10,458 – –
Gabon 2,085 79 – –
Gambia 1,076 41 – –
Ghana 41,732 1,586 – –
Guinea 17,837 678 – –
Guinea Bissau 2,539 96 – –
Kenya 111,273 4,228 4,288 82
Lesotho 5,946 226 – –
Liberia 6,491 247 – –
Madagascar 35,835 1,362 – –
Malawi 29,425 1,118 344 5
Mali 21,818 829 – –
Mauritania 5,342 203 – –
Mozambique 78,613 2,987 5,892 10
Namibia 5,927 225 – –
Niger 28,927 1,099 – –
Nigeria 220,397 8,375 12,174 288
Rwanda 19,506 741 – –
Sao Tome and Principe 264 10 – –
Senegal 12,433 472 – –
Sierra Leone 10,008 380 – –
Somalia 75,414 1,007
South Sudan 29,427 1,118 16,088 353
Swaziland 2,052 78 – –
Togo 10,972 417 – –
Uganda 89,726 3,410 252 0
United Republic of Tanzania 161,904 6,152 4,895 99
Zambia 27,491 1,045 1,794 57
Zimbabwe 31,385 1,193 – –

den occurs in urban settings [89]. Detailed surveillance and analy-
sis of the spatial distribution of this burden reveals that within
these cities certain neighborhoods drive the epidemics [31,89].
While the trend towards increasing urbanization in Africa may
increase cholera risk, it also offers growing opportunities for tar-
geted public-health interventions [90–92]. Other high population
density situations with insufficient water and sanitation such as
in refugee camps [93–95], during mass gatherings [96], and among
marginalized people in prisons [36] or mental institutions [97] also
have an increased risk for cholera outbreaks.
A study analyzed cholera data from 2010 to 2016 in sub-
Saharan Africa, excluding Djibouti and Eritrea, from various
sources (WHO, Médecins Sans Frontières, ProMED, ReliefWeb,
Ministries of health and the scientific literature) [98]. Cholera
was reported throughout sub-Saharan Africa. However, when the
region was mapped into 3751 grid cells 20 km  20 km in size,
the highest incidence was found to be concentrated in a small pro-
portion, 151 (4%) of these cells [98].
The temporal occurrence of cholera varies around Africa. In the
DRC, cases occur year-round with a rise in incidence during the
rainy season [99]. Elsewhere in Africa, cholera generally occurs in
explosive outbreaks [100], as in Zimbabwe, which reported
128,208 cases and 5634 deaths between August 2008 and mid-
January 2009 [101]. An assessment of 78 cholera outbreaks in
Mozambique from 2009 to 2011 showed an average duration of
7.2 weeks with 68% of cases and 89% of deaths occurring within
the first six weeks of an outbreak [102]. Guinea’s capital Conakry
had over 7000 cholera cases in only 12 weeks during 2012 [103].
The frequency and size of cholera outbreaks in Africa increases
during the rainy season [104], as documented for Zanzibar [105],
eastern DRC [106], Angola [107] and regionally in West Africa
[108], as heavy rainfall [36,109–111] may cause the mixing of sew-
age and drinking water [112–115]. Conversely, drought and dry
seasons may favor the spread of epidemics in some places due to
scarcity of water sources [116]. High population density, poverty
and poor housing increase the frequency and size of cholera out-
breaks [117]. Attack rates may range from 1.2 cases per 1000 peo-
ple in low-density residential suburbs to 90.3 per 1000 in
overcrowded suburbs [118,119]. Several studies discuss possible
cholera transmission by migrant populations [120].
4.3. Cholera in the Americas
Central and South America were not affected by all seven cho-
lera pandemics but suffered five epidemics of the disease. The first
epidemic started in Peru and Chile in 1832, during the second pan-
demic and lasted until 1851, while the second epidemic occurred
from 1853 to 1859 and was part of the third pandemic [121].
 J. Deen et al. / Vaccine 38 (2020) A31–A40
The third epidemic, during the fourth pandemic, started in north-
east Brazil and lasted from 1863 to 1879 [122] and the fourth epi-
demic, during the fifth pandemic, lasted from 1881 to 1895 [2]. The
seventh cholera pandemic reached South America in 1991 as the
fifth epidemic. The fifth epidemic was originally suspected to have
come from Asia via contaminated ballast water discharged by
international trade ships into Peruvian ports but isolates from
the 1991 epidemic in Latin America have recently been found to
be closely related with 1970s isolates from Africa, suggesting a
possible African origin [123]. By 2001, a total of 1,298,947 cases
had been reported; of these, 985,942 (76%) occurred within the
first three years.
The rapid spread of cholera across large distances during the
fifth epidemic has spawned much discussion among the scientific
community. A study by the Pan American Health Association found
an inverse correlation between national cholera incidence rate and
per capita gross national product indicating the role of socioeco-
nomic factors on cholera outbreaks [124]. The decline of cholera
transmission in South America went along with general societal
and financial advances in the region. Between 1990 and 2002 there
was a significant boost in the economy of Latin American and Car-
ibbean countries. Parallel to this improvement, the percentage of
the population in the region with access to safe water rose from
85% to 90% and to sanitation from 67% to 76% [125].
The possible influence of the El Niño macroclimate variability
pattern on the spread and later decline of cholera also received
much attention. However, over the period of time when cholera
was eliminated, climate and environmental conditions did not
become more benign in the region, but there was general economic
progress and large improvements in municipal water and sanita-
tion systems. The elimination of pandemic cholera from almost
all of continental South America argues against a persistent pres-
ence in aquatic ecosystems or a significant role for climate in sus-
taining cholera in areas where economic growth occurs and where
markedly improved water and sanitation prevents transmission.
By 2002, cholera had almost vanished from South- and Central
America. Notifications remained at an average of 10 cases per year,
until it re-emerged in October 2010 in Haiti. Community based
studies later revealed that the index case had likely been a men-
tally ill man who often bathed and drank in the waters of the Meye
tributary waters to the Artibonite River [126]. He developed cho-
lera on October 12, 2010, and later died in his home. Between then
until 2017 there have been at least 27,000 cholera cases annually
[62] A retrospective survey at four sites in Haiti from 2010 to
2011 that included 70,903 participants found crude mortality rates
of 19–35 deaths/1000 person-years, several folds higher than the
expected baseline mortality rate for Haiti of 9 deaths/1000
person-years and suggesting a considerable cholera mortality rate
[127]. Haiti was in the middle of a public-health emergency, hav-
ing recently experienced a devastating earthquake that cost an
estimated 222,650 lives and that made over two million people
homeless.
Soon after the first cases, allegations arose that Nepalese sol-
diers of the UN Stabilization Mission in Haiti (MINUSTAH) had
caused the cholera outbreak. In response, the UN Secretary-
General convened the ‘‘Independent Panel of Experts on the Cho-
lera Outbreak in Haiti” with the mandate to ‘‘. . .determine the
source of the 2010 cholera outbreak in Haiti [128].” The panel con-
cluded that the ‘‘. . .evidence overwhelmingly supported the con-
clusion that the source of the Haiti cholera outbreak was due to
contamination of the Meye Tributary of the Artibonite River with
a pathogenic strain of current South Asian type V. cholerae as a
result of human activity [129].” Epidemiological investigations
and genetic characterization of isolates from the Haitian cholera
epidemic point to the United Nations peacekeeping troops from
Nepal as the source of cholera to Haiti [130]. The United Nations
A37
Secretary General apologized for the role and the conduct of the
United Nations during the surge and the spread of the epidemic
[131]. After hurricane Matthew struck the island of Hispaniola on
October 4, 2016, cholera surged again.
The explosive spread and continuing problem of cholera in Haiti
resulted from the introduction of pandemic cholera into a popula-
tion with an initial lack of immunity and living in conditions with
water, sanitation, hygiene and healthcare deficiencies worsened by
natural disasters [62]. Cholera will not be easy to eliminate from
Haiti, despite the ambitious plan that has been laid out. The Haiti
situation underscores the persisting vulnerability of many geo-
graphic locations to cholera when the conditions are favorable.
In the Americas as a whole, molecular studies of V. cholerae iso-
lates have been used to understand the epidemiology of the 1991
epidemic that started in Peru and the 2010 epidemic in Haiti
[16]. As in the Yemeni and African phylogenetic frameworks
described above [76,84], representative isolates from both the
1991 and 2010 epidemics clustered within the 7PET lineage, which
likely were the result of intercontinental introductions and were
not derived from indigenous local lineages. [16]. V. cholerae lin-
eages local to the Americas were associated with disease that dif-
fers epidemiologically from epidemic cholera.
5. Conclusion
There are many similarities in the spread, dynamics and risk
factors for cholera in areas around the world where the disease
occurs, but there are also important differences. In Asia, many
parts of India and Bangladesh are endemic for cholera and have
seasonal recurrence of the disease. The scale of Yemen’s cholera
outbreak is unprecedented and is continuing. Some countries of
sub-Saharan Africa have become endemic for cholera, while other
areas have seemingly unpredictable outbreaks. After an absence of
cholera in the Americas for several years, the disease has now
become endemic in Haiti.
The global cholera picture continues to evolve and will likely
change in the coming years. But it appears certain that in the times
to come, cholera will continue to affect impoverished populations
without proper access to adequate water and sanitation. A global
oral cholera vaccine stockpile was created in 2011 for a rapid
response to cholera outbreaks [132]. Through the stockpile mech-
anism, the killed oral cholera vaccine has been deployed in large
mass campaigns under diverse circumstances. From 2013 to
2017, over 25 million doses have been requested from the cholera
vaccine stockpile but of which only 51% were shipped to countries
for 46 deployments [133]. As the stockpile aims to expand the
availability and distribution of oral cholera vaccines to more
affected populations [134] and with increasing awareness of poli-
cymakers, demand will likely increasingly outstrip supply.
The killed oral cholera vaccine provides remarkable protection
against cholera [135]. Because of the finding that the current pan-
demic is caused by a single clone limited to humans [13], it is pos-
sible, but unproven, that this narrow genetic spectrum may
contribute to the field effectiveness of the killed oral cholera vac-
cine. In mass vaccination campaigns, vaccine effectiveness is
enhanced by the indirect protection conferred to the unvaccinated
in the community [136], likely due to the reduced shedding of V.
cholerae by the vaccinated into the surrounding water sources.
Epidemiological data are crucial for decision-making regarding
the implementation of vaccination and other interventions against
cholera, at the national and regional levels. As a specific example,
mapping of high-incidence areas could be used to prioritize coun-
tries for launching of cholera control programs aimed specifically
at these high-incidence areas [98]. In the recent past, the results
of six years of case-based multi-country surveillance data [61]
A38 J. Deen et al. / Vaccine 38 (2020) A31–A40
were used to develop adapted vaccination programs [137]. Essen-
tially, the current WHO cholera strategy is built on multiple
sources of surveillance and modelling data provided by its various
national and international partners [138]. Because of the ever-
changing characteristics and locations of cholera outbreaks, con-
stantly updated data is necessary.
The global public-health community should use all available
means of prevention, from advocating for increased stockpiled
doses of the killed oral cholera vaccine for deployment with
improved case management and promotion of hygiene to the
longer-term construction of water and sanitation infrastructure.
Global stakeholders have already called for targeted stockpiles of
oral cholera vaccine in the most at-risk places to contain outbreaks
at the earliest possible time.
Funding
JDC is supported by the Bill and Melinda Gates Foundation, the
Wellcome Trust, and Globvac, as well as by the governments of
Bangladesh, Canada, Sweden, and the United Kingdom, which pro-
vide core support to the icddr,b.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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