M. R. Khan

Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up

The protective efficacy (PE) of B subunit killed whole-cell (BS-WC) and killed whole-cell-only (WC) oral cholera vaccines was assessed in a randomised double-blind field trial among children aged 2-15 years and women over 15 years in rural Bangladesh. Among the 62 285 subjects who received three doses of BS-WC, WC, or Escherichia coli K12 strain placebo, cumulative PE at 3 years of follow-up was 50% for BS-WC and 52% for WC. PE was similar against severe and non-severe cholera, but was significantly lower in children who were vaccinated at 2-5 years (26% for BS-WC; 23% for WC) than in older persons (63% for BS-WC; 68% for WC). Among persons vaccinated at 2-5 years, protection at 4-6 months of follow-up was similar to that for older persons, but rapidly waned thereafter and was not evident during the third year of follow-up. In contrast, persons vaccinated at older ages were protected even in the third year of follow-up (PE 40% for BS-WC; 62% for WC). PE was substantially higher against classical cholera (58% for BS-WC; 60% for WC) than against El Tor cholera (39% and 40%).

Protection against Cholera in Breast-Fed Children by Antibodies in Breast Milk

We performed a prospective study to examine whether the IgA antibodies against cholera that are present in breast milk protect breast-fed infants and children against colonization with Vibrio cholerae 01 and disease. Among families of patients with cholera, we collected breast milk from mothers who had not had diarrhea in the previous week and monitored them and their breast-fed children for cholera colonization and diarrhea for 10 days. Breast milk was assayed for IgA antibodies to cholera toxin and lipopolysaccharide. Ninety-three mother--child pairs were studied; 30 infants became colonized with V. cholerae 01 and disease developed in 19. There were no differences between the antibody levels in milk fed to children who became colonized and in milk fed to children who did not. However, among the children who became colonized, those who had diarrhea drank breast milk containing significantly lower levels of both kinds of cholera antibodies than were present in the milk consumed by children who had no symptoms. We conclude that breast-milk antibodies against cholera do not appear to protect children from colonization with V. cholerae 01 but do protect against disease in those who are colonized.

Field trial of oral cholera vaccines in Bangladesh.

The protective efficacy of oral B subunit killed whole-cell (BS-WC) and killed whole-cell (WC) cholera vaccines was assessed in 63 498 Bangladeshi children aged 2-15 years and women aged over 15 years. Each received three doses of BS-WC, WC, or placebo in a randomised, double-blinded fashion. Surveillance for cases seeking medical care up to six months after the third dose revealed 26 cases of confirmed cholera in the placebo group, 4 cases in the BS-WC group (protective efficacy 85%; p less than 0.0001), and 11 cases in the WC group (protective efficacy 58%; p less than 0.01). For each vaccine protective efficacy was consistent in different age-groups (2-10 years versus greater than 10 years) and for different severities of cholera.

Impact of B subunit killed whole-cell and killed whole-cell-only oral vaccines against cholera upon treated diarrhoeal illness and mortality in an area endemic for cholera.

The impact of B subunit killed whole-cell (BS-WC) and killed whole-cell-only (WC) oral cholera vaccines was assessed in a randomised double-blind trial in rural Bangladesh. 62,285 children aged 2-15 years and women aged over 15 ingested three doses of one of the vaccines or placebo. During the first year of follow-up there was a 26% reduction of all visits for treatment of diarrhoea in the BS-WC group and a 22% reduction in the WC group. The reduction of all admissions for fatal or severely dehydrating diarrhoea was 48% in the BS-WC group and 33% in the WC group. Overall mortality rates were 26% lower in the BS-WC group and 23% lower in the WC group during the first year, and reductions of mortality were observed only in women vaccinated at ages over 15 years. However, no differences in cumulative mortality were evident at the end of the second year of surveillance.

Biotype as determinant of natural immunising effect of cholera

To test the hypothesis that clinical Vibrio cholerae O1 infections protect against recurrent cholera, treated cholera episodes in a rural Bangladesh population of 188,153 people who were followed between 1985 and 1988 were analysed. Of the 2214 people with initial episodes of cholera, 7 had a second episode. The incidence of cholera was 61% lower in subjects who had had an earlier episode than in those without such an episode. Whereas initial episodes of classical cholera were associated with complete protection against subsequent cholera, initial episodes of El Tor cholera were associated with negligible protection.

Field trial of oral cholera vaccines in Bangladesh: evaluation of anti-bacterial and anti-toxic breast-milk immunity in response to ingestion of the vaccines

In a field trial conducted in Bangladesh, ingestion of either B subunit-killed whole cell (BS-WC) or killed whole cell (WC) oral cholera vaccines by mothers was associated with a 47% reduction of the risk of cholera in their non-vaccinated children aged under 36 months. Because vaccine-induced breast-milk immunity seemed a possible explanation for these findings, we evaluated anti-lipopolysaccharide (LPS) and anti-cholera toxin (CT) IgA antibody responses in breast milk collected during the trial from 53 lactating women who ingested three doses of BS-WC, WC, or an Escherichia coli K12 strain (K12). Despite induction of moderate vibriocidal (1.4 to 2.0-fold) and anti-CT (4.5-fold) serum antibody responses, the vaccines did not elicit significant rises of anti-LPS or anti-CT IgA breast-milk antibodies. The failure of the vaccines to elicit significant levels of breast-milk anti-cholera antibodies suggests an alternative explanation for protection of young children by maternal vaccination, such as interruption of maternal-child transmission of Vibrio cholerae 01.

Oral cholera vaccines containing B-subunit-killed whole cells and killed whole cells only. II: Field evaluation of cross-protection against other members of the Vibrionaceae family

Because of demonstrable cross-reactivity of cellular antigens contained in B subunit-killed whole-cell (BS-WC) and killed whole-cell-only (WC) oral cholera vaccines with antigens of various non-cholera species of the family Vibrionaceae (NCV), the protection conferred by the vaccines against diarrhoea associated with NCV was evaluated during a randomized, double-blind field trial in Bangladesh. Children aged 2-15 years and women aged greater than 15 years (62,285 in number) received three doses of BS-WC vaccine, WC-only vaccine, or a placebo consisting of Escherichia coli K12 strain (K12). During 1 year of follow-up, the incidence of treated episodes of diarrhoea associated with non-cholera vibrios known to be enteric pathogens (non-01 Vibrio cholerae, V. fluvialis, V. parahaemolyticus, V. mimicus) in the placebo group was low (1.9 cases per 10,000 recipients) and identical to that for the two vaccine groups combined. The incidence (per 10,000 recipients) of treated diarrhoeal episodes associated with Aeromonas species was considerably higher, but nearly identical in the three groups (26.1 cases for BS-WC, 26.0 cases for WC; 25.9 cases for K12). Pleisiomonas shigelloides was not isolated from any participant. It is concluded that NCV other than Aeromonas were rarely isolated from diarrhoeal patients in our study population and that killed oral vaccines which were effective against cholera exhibited no detectable cross-protection against diarrhoea associated with NCV organisms.