Cholera is an acute dehydrating diarrheal disease caused by the Gram-negative bacterium Vibrio cholerae
. Despite suboptimal surveillance and reporting, it is estimated that globally 2–3 million people have cholera each year, and more than 100,000 die from this infection annually [1
]. Cholera is a disease of poverty, made worse in endemic urban areas by the overcrowding of informal housing settlements or slums [3
]. The disease is endemic in over 50 countries; however, it also appears in epidemic form, both in endemic areas and in regions made susceptible by civil unrest and natural disasters, such as following the earthquake in Haiti in 2010 [4
]. Although epidemic cholera is seen in all age groups in endemic areas, young children have a higher burden of disease [5
The majority of cases of epidemic cholera are caused by infection with toxigenic strains of the O1 and O139 serogroups of V. cholerae. The O139 serogroup is differentiated from the O1 by the O antigen of the lipopolysaccharide (LPS). Although V. cholerae O139 has epidemic potential, for unknown reasons it has largely disappeared as a cause of cholera. The O1 serogroup is further divided into two biotypes: El Tor and classical. Although the classical biotype was the causative agent of earlier pandemics for which we have microbiologic data, the current seventh pandemic, which began in 1961, is now caused by the El Tor biotype.
In humans, ingestion of water or food contaminated with V. cholerae
results in colonization of the small intestine, an attachment facilitated by the toxin coregulated pilus, a fimbrial protein involved in the formation of microcolonies [8
]. Subsequent elaboration of cholera toxin (CT), and the action of the toxin on intestinal epithelial cells, causes the secretion of large amounts of chloride, sodium and water via activation of adenylate cyclase and increases in intracellular cyclic AMP [9
]. Important factors affecting immune responses in V. cholerae
infections are listed in BOX 1
. In both adults and children, severity of infection can vary from asymptomatic or mild-to-moderate infection to death within hours of onset of massive diarrhea. Vomiting combined with purging of large volumes of stools resembling rice water can result in rapid dehydration and death due to hypovolemic shock [10
]. In children, cholera can be complicated by severe hypoglycemia [11
] and concomitant pneumonia [12
]. The mainstay of treatment of patients with cholera is rapid fluid and electrolyte replacement, optimally in the form of oral rehydration solution containing salts, sugar and water, if the patient is able, including initiation of this at home upon onset of symptoms [10
]. If available, the use of rice-based oral rehydration solution for the management of diarrhea owing to cholera having been shown to decrease volume of stools and is indicated for those 6 months and older [13
]. Intravenous administration of isotonic fluids is often necessary for those who are severely dehydrated or unable to tolerate oral therapy. Antibiotic use is beneficial in severe cholera, shortening the duration of illness and thus lessening the amount of fluid replacement needed in both adults and children [14
]. With prompt and appropriate treatment, the mortality rate of cholera is <1%, although higher mortality rates are common in complex emergencies and during the initial phase of an epidemic [17
Box 1. Important microbial factors expressed by Vibrio cholerae.
- Lipopolysaccharide – T-cell-independent antigen, a serogrouping and serotyping determinant of Vibrio cholerae strains
- O-specific polysaccharide – T-cell-independent antigen, the determinant of serogroup and serotype
- Toxin coregulated pilus – T-cell-dependent group of antigens, involved in intestinal colonization
- Cholera toxin – T-cell-dependent antigen, causes intestinal secretion of electrolytes and water. A potent enterotoxin and immunoadjuvant. B subunit referred to as CTB or CtxB.
CTB: Cholera toxin B (CtxB).
In areas of the world endemic for cholera, although all age groups are susceptible, the largest burden of symptomatic cholera is often among children [5
]. In a study of household contacts of patients with V. cholerae
O1 infection in an urban area of Bangladesh, those who were ≤5 years of age had a significantly higher risk of acquiring infection than older family members in a 21-day observational period [18
]. Despite the susceptibility and high burden of disease among young children in endemic areas, currently available cholera vaccines have shown lower protective efficacy and a shorter duration of protection in children under 5 years of age compared with older individuals [19
]. Currently available cholera vaccines include two killed, whole-cell oral cholera vaccines (OCVs), both of which are WHO prequalified. One contains killed whole cells of a number of strains of classical and El Tor V. cholerae
O1, supplemented with 1 mg/dose of recombinant CT B subunit (WC-rBS; Dukoral, Crucell, Sweden); the other is bivalent, containing killed strains of classical and El Tor V. cholerae
O1 as well as O139, without CtxB supplementation (WC; Shanchol, Shantha Biotechnics, India). In children aged 2–5 years, the WC-rBS vaccine is administered as three doses orally at least 1 week apart. The WC-rBS vaccine is not recommended for children under 2 years of age. The WC vaccine is approved for children ≥1 year old, and given as two doses orally at least 14 days apart.
A recent review of studies of current OCVs and their predecessors demonstrated that vaccine efficacy in the first 2 years after vaccination was 66% in those >5 years old, but only 38% for children <5 years old [20
]. A recently published report of the 3-year follow-up to a large field study of Shanchol in Kolkata, India, showed that while the overall efficacy was 66%, efficacy in those <5 years old was only 43%, with no significant protection in the third year of follow-up for this age group [21
]. This is despite: the fact that after symptomatic infection, young children and older persons appear to achieve a similar reduction of at least 60–70% in disease lasting at least 3 years after an initial episode compared with controls [22
]; that in volunteer studies, previous cholera is associated with 90–100% protection against subsequent challenge for the 3 years of the evaluation period [23
]; that population-based field studies suggest that previous infection with classical cholera provides protection against subsequent disease lasting 6–10 years; and that previous infection with El Tor cholera provides protection against subsequent disease lasting 3–6 years [24
]. It is important to note that protection against cholera following wild-type symptomatic disease appears to be similar among older individuals and young children. The reasons behind the differences between protection from natural infection and vaccination, and differences in vaccine efficacy between age groups, have yet to be determined, and such information could significantly contribute to an improved cholera vaccine or immunization strategy optimally effective in young children.