Dukoral

Pharmacotherapeutic group: Bacterial vaccines, ATC code: J07AE01 Mechanism of action The vaccine contains whole killed V. cholerae O1 bacteria together with a recombinant non-toxic B subunit of cholera toxin (CTB). The bacterial strains included represent the Inaba and Ogawa serotypes and the El Tor and classical biotypes. Dukoral is administered orally with a bicarbonate buffer that protects the antigens from gastric acid. The vaccine acts by inducing antibodies against both the bacterial components and CTB. Antibacterial intestinal antibodies block adherence of the bacteria to the intestinal wall, thereby preventing colonisation by V. cholerae O1. Antitoxin intestinal antibodies prevent the cholera toxin from binding to the intestinal mucosal surface, thereby averting 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 show immunological cross-reactivity. Efficacy against cholera Efficacy against cholera was assessed in three randomised, double-blind, placebo-controlled clinical trials conducted in Bangladesh (endemic area) and Peru (non-endemic area). The number of subjects enrolled, the dosing regimens, and the follow-up periods are shown in the table below. Study site Year Dosing regimen Number (age group) Follow-up Cholera Bangladesh 1985–88 3 doses at 6-week intervals 89,152 (2–65 years) 6 months – 5 years Peru, military cohort 1994 2 doses at intervals of 7–11 days 1,563 (18–65 years) 5 months Peru, Pampas 1993–95 2 doses at a two-week interval and a single booster dose one year later 21,924 (2–65 years) 2 years In the field trial in Bangladesh, the overall protection afforded by Dukoral across the whole population was 85% (95% confidence interval – CI: 56, 95; per-protocol analysis) during the first six months of follow-up. The duration of vaccine-induced protection varied with age, lasting 6 months in children and 2 years in adults (see table below). Exploratory analysis suggests that 2 doses of vaccine are as effective as 3 doses in adults. Table: Protection against cholera in the Bangladesh trial (per-protocol analysis) Protection, % (95% CI) Adults and children > 6 years Children aged 2–6 years 6 months 76 (30, 92) 100 Year 1 76 (60, 85) 44 (10, 65) Year 2 60 (36, 76) 33 (–23, 64) In the second trial, conducted in Peru in military recruits, short-term protection against cholera after two doses of vaccine was 85% (95% CI: 36, 97; per-protocol analysis). In the third trial, conducted in the field in Peru, no protection against cholera was demonstrated during the first year. Following a booster dose administered 10–12 months after primary immunisation, protection during the second year was 60.5% (95% CI: 28, 79). Protective efficacy against cholera was also assessed during two mass vaccination campaigns conducted in Mozambique (December 2003 – January 2004) and Zanzibar (February 2009 – May 2010). In a case-control study performed during the mass vaccination campaign in Mozambique, the protective efficacy of 2 doses of Dukoral was 84% (95% CI: 43, 95; per-protocol analysis; p = 0.005) over the initial 5 months of follow-up. In a longitudinal cohort analysis performed during the mass vaccination campaign in Zanzibar, the protective efficacy after 2 doses of Dukoral was 79% (95% CI: 47, 92) over a 15-month follow-up period. In addition to direct protection, Dukoral was shown to confer significant indirect (herd) protection within the population assessed. Protection against cholera afforded by Dukoral has not been studied following repeated booster doses. Immunogenicity No immunological correlates of protection against cholera following oral vaccination have been established. There is a weak correlation between serum antibody responses, including vibriocidal antibody responses, and protection. Protective immunity is likely mediated by locally secreted intestinal IgA antibodies. The vaccine elicited an intestinal antitoxin IgA response in 70–100% of vaccinated subjects. Serum vibriocidal antibodies against the bacterial components were detected in 35–55% of vaccinated subjects and antitoxin antibodies in 78–87% of vaccinated subjects. A booster dose elicited an anamnestic response indicative of immunological memory. The duration of immunological memory in adults is estimated to be at least two years.