DUKORAL Oral suspension / Granules Ref.[27525] Active ingredients: Cholera, inactivated, whole cell

Pharmacotherapeutic group: Bacterial vaccines
ATC-code: J07AE01

Mechanism of action

The vaccine contains killed whole V. cholerae O1 bacteria and the recombinant non-toxic B-subunit of the cholera toxin (CTB). Bacterial strains of both Inaba and Ogawa serotypes and of El Tor and Classical biotypes are included in the vaccine. Dukoral is taken orally with bicarbonate buffer, which protects the antigens from the gastric acid. The vaccine acts by inducing antibodies against both the bacterial components and CTB. The antibacterial intestinal antibodies prevent the bacteria from attaching to the intestinal wall thereby impeding colonisation of V. cholerae O1. The anti-toxin intestinal antibodies prevent the cholera toxin from binding to the intestinal mucosal surface thereby preventing the toxin-mediated diarrhoeal symptoms.

The heat-labile toxin (LT) of enterotoxigenic E. coli (ETEC) is structurally, functionally and immunologically similar to CTB. The two toxins cross-react immunologically.

Efficacy against cholera

Efficacy against cholera was assessed in three randomised double-blind placebo-controlled clinical trials conducted in Bangladesh (endemic region) and in Peru (non-endemic region). The number of patients enrolled, dosage regimens and follow-up periods are shown in the following table.

In the Bangladesh field trial, protective efficacy of Dukoral in the overall population was 85% (95%CI: 56, 95, per-protocol analysis) for the initial 6 months of follow-up. Duration of vaccine protection differed by age, lasting for 6 months in children and for 2 years in adults (see table below). An exploratory analysis suggested that 2 vaccine doses seemed as effective as 3 doses in adults.

Table. Protective efficacy against cholera in the Bangladesh study (per-protocol analysis):

In the second trial, conducted in Peru and enrolling military recruits, the short-term protective efficacy against cholera after 2 vaccine doses was 85% (95%CI: 36, 97, per-protocol analysis). The third study, a field trial conducted in Peru, failed to show any protective efficacy against cholera during the first year. Following a booster dose 10-12 months after primary immunisation, the protective efficacy during the second year was 60.5% (95%CI: 28,79).

Protective effectiveness against cholera was evaluated during two mass-vaccination campaigns conducted in Mozambique (December 2003 – January 2004) and Zanzibar (February 2009 – May 2010).

In the case-control study conducted during the mass vaccination campaign in Mozambique, protective effectiveness of 2 doses of Dukoral was 84% (95% CI: 43, 95, per-protocol analysis; p=0.005) for the initial 5 months of follow-up.

In the longitudinal cohort-analysis conducted during the mass-vaccination campaign in Zanzibar, protective effectiveness after 2 doses of Dukoral was 79% (95% CI, 47, 92) for a follow-up period of 15 months. In addition to the direct protection, it was shown that Dukoral provides significant indirect (herd) protection in the studied setting.

Protective efficacy of Dukoral against cholera has not been studied following repeated booster vaccination.

Immunogenicity

No established immunological correlates of protection against cholera after oral vaccination have been identified. There is a poor correlation between serum antibody responses, including vibriocidal antibody response, and protection. Locally produced secretory IgA antibodies in the intestine probably mediate protective immunity.

The vaccine induced intestinal antitoxin IgA responses in 70-100% of vaccinated subjects. Serum vibriocidal antibodies against the bacterial components were seen in 35-55% of vaccinated subjects and antitoxic antibodies in 78-87% of vaccinated subjects. A booster dose elicited an anamnestic response indicative of an immune memory. The duration of the immunological memory was estimated to last for at least 2 years in adults.