BACKGROUND:

Cholera is a major public-health problem, with children most affected. However, effective single-dose antimicrobial regimens have been identified only for adults. Our aim was to compare the efficacy of azithromycin and erythromycin regimens in the treatment of children.

METHODS:

We did a double-blind, randomised study of 128 severely dehydrated children (age 1-15 years) with cholera, treated at one of two treatment centres in Bangladesh in 1999. Children were assigned single-dose azithromycin (20 mg/kg bodyweight, maximum individual dose 1 g; n=65) or 12.5 mg/kg erythromycin (maximum dose 500 mg; n=63) every 6 h for 3 days. Patients stayed in hospital for 5 days. We measured fluid balance every 6 h, and obtained a rectal swab or stool sample for culture daily. Our primary outcome measures were clinical success of treatment-ie, cessation of watery diarrhoea within 48 h-and bacteriological success-ie, absence of Vibrio cholerae O1 or O139 from cultures of stool or rectal swab samples after study day 2. Analysis was per protocol.

FINDINGS:

Two children in both groups withdrew from the study, and we excluded one child in the erythromycin group. Treatment was clinically successful in 48 (76%) patients who received azithromycin and 39 (65%) who received erythromycin (difference 11%, 95% CI -5 to 27, p=0.244); and bacteriologically successful in 45 (71%) and 49 (82%) patients, respectively (10%, -5 to 25, p=0.261). Patients treated with azithromycin had a shorter duration of diarrhoea (median 24 h vs 42 h; difference 12 h, 0-18 h, p=0.019) and fewer episodes of vomiting (1 vs 4; difference 1 episode, 0-3 episodes, p=0.023).

INTERPRETATION:

Single-dose azithromycin is as effective for treatment of cholera in children as standard erythromycin therapy, but is associated with less vomiting.

Attenuated Vibrio cholerae oral vaccine CVD 103-HgR was well tolerated by 324 Thai soldiers and civilians. Most received a single 5 x 10(8) cfu dose, while 40 each received one or two 5 x 10(9) cfu doses. Vibriocidal antibody (the best correlate of immunity) seroconversion was lower in soldiers than civilians (P less than .001). Increasing the vaccine dose to 5 x 10(9) cfu raised the geometric mean titer (P less than .001). A second 5 x 10(9) cfu dose one week later did not notably increase seroconversions. Likelihood of seroconversion was inversely correlated with baseline vibriocidal titer (P less than .001). CVD 103-HgR caused seroconversion in most subjects with baseline titers less than or equal to 1:40, including 100% of civilians after one 5 x 10(8) cfu dose, 79% of soldiers after one 5 x 10(9) cfu dose, and 45% of soldiers after one 5 x 10(8) cfu dose. In persons with elevated baseline titers, vibriocidal antibody seroconversion is not a sensitive measure of whether vaccine has boosted intestinal immunity; for such subjects, other measurements must be used. Study regimens in endemic areas should use a single 5 x 10(9) cfu dose.

To assess the safety, immunogenicity, and lot stability of the whole cell/recombinant B subunit cholera vaccine, 2 lots manufactured in June 1991 and February 1992 were tested in January 1995. Two oral doses of vaccine or placebo given 2 weeks apart were given with buffer to 216 Peruvian adults and children. Symptoms were elicited for 3 days after each dose. Serum and plasma specimens obtained from each volunteer before vaccination and 10-14 days after the second dose were tested for vibriocidal and anti-cholera toxin antibodies. The vaccine was well-tolerated. Nearly half of the 100 vaccinees had pre-vaccination vibriocidal titers > or = 1:40. Elevated titers were observed in 22% of 37 children 2-5 years of age compared with 66% of 63 vaccinees 6-65 years (P < 0.001). A > or =2-fold serum vibriocidal response was observed in 55% of 100 vaccinees and 6% of 32 placebo recipients. An elevated pre-vaccination titer (< or =1:40) did not change the proportion of vaccinees who responded with a > or =2-fold increase in vibriocidal titer (51% versus 59%, difference not significant), but did change the proportion responding with a > or =4-fold increase (41% versus 22%; P < 0.05). The vibriocidal seroconversion rate was lowest in children 2-5 years old despite low pre-vaccination titers. Two-fold or greater serum antitoxic responses in IgA and IgG were observed in >90% of the vaccinees; > or =4-fold responses were seen in 65-70% of the vaccinees with a 6-8-fold increase over baseline. Plasma specimens were as good as sera for determining anti-toxic antibodies by ELISA, but were less satisfactory for determining vibriocidal antibody titers.

Enterotoxigenic Escherichia coli (ETEC) is the leading cause of bacterial diarrhea in young children in developing countries. The safety and immunogenicity of a killed, oral ETEC vaccine consisting of whole cells plus recombinantly produced cholera toxin B subunit (rCTB) was evaluated in Egypt, which is endemic for ETEC diarrhea. Seventy-four healthy Egyptian adults (21-45 years old) were randomized and received two doses of the ETEC/rCTB vaccine (E003) or placebo 2 weeks apart. The frequency of adverse events after either dose did not differ by treatment group, and no severe adverse events were reported. After vaccination, peripheral blood IgA B cell responses to CTB (100%) and to vaccine colonization factor antigens CFA/I (94%), CS4 (100%), CS2 (81%), and CS1 (69%) were significantly higher than response rates for the placebo group. These favorable results in Egyptian adults indicate that the ETEC/rCTB vaccine is a promising candidate for evaluation in younger age groups in this setting.

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 × 109 CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24 h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers. © 2009.

The killed oral cholera vaccine Dukoral is recommended for adults and only children over 2 years of age, although cholera is seen frequently in younger children and there is an urgent need for a vaccine for them.

Every year since its introduction in 1991, there have been epidemics of cholera in Lima, Peru. Vaccination is one approach to the control of cholera. A pilot study was conducted to assess the safety and immunogenicity of a whole cell plus recombinant B subunit (WC/rBS) cholrea vaccine in Lima, Peru. Five hundred and forty-one volunteers aged 2-65 years received two doses two weeks apart of WC/rBS vaccine or Escherichia coli K12 placebo administered in bicarbonate buffered water. Symptoms were monitored on all subjects and blood was collected from 102 persons before the first dose and two weeks after the second dose. Mild post-vaccination gastrointestinal symptoms were reported with equal frequency for both the vaccine and placebo recipients. Among 51 vaccines, 49% had a twofold or greater increase in serum vibriocidal titers (GMT = 78; range < 1:10 to 1:5120); and 92% and 82% developed a twofold or greater serum anti-cholera toxin IgG and IgA response, respectively. Persons with elevated prevaccination vibriocidal titers had a decreased response to the WC/rBS. Age and blood group did not affect the immune response. The WC/rBS vaccine was safe and immunogenic in a group of native Peruvians.

BACKGROUND:

We conducted the first trial to assess the safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli plus cholera toxin B-subunit vaccine in children <2 years old.

METHODS:

Three doses of vaccine or killed E. coli K-12 control were given at 2-week intervals to 64 Egyptian infants, 6 to 18 months old, in a randomized, double blind manner. Adverse events were monitored for 3 days after each dose. Blood was collected before immunization and 7 to 10 days after each dose to assess vaccine-specific serologic responses.

RESULTS:

There was no statistically significant intergroup difference in the percentage of subjects reporting the primary safety endpoint (diarrhea or vomiting) after the first (31%, vaccine; 30%, control) or third (14%, vaccine; 18%, control) dose, whereas there was a trend toward greater reporting in the vaccine group after Dose 2 (36%, vaccine; 18%, control; P = 0.052). The percentage of children showing IgA seroconversion after any dose was higher in the vaccine than the control group for recombinant cholera toxin B-subunit (97% vs. 46%), colonization factor antigen I (61% vs. 18%) and coli surface antigen 4 (39% vs. 4%) (P < 0.001 for each comparison). IgG seroconversion rates in the vaccine and control groups were 97 and 21% to recombinant cholera toxin B-subunit (P < 0.001), 64 and 29% for colonization factor antigen I (P < 0.01), 53 and 21% for coli surface antigen 2 (P < 0.05) and 58 and 4% for coli surface antigen 4 (P < 0.001), respectively. The third vaccine dose was followed by augmented IgG antitoxin titers.

CONCLUSION:

The oral enterotoxigenic E. coli vaccine was safe and immunogenic in this setting in Egyptian infants.

Serum responses to oral cholera vaccines were assessed in three paediatric vaccine trials, two in León, Nicaragua and one in Stockholm, Sweden. A calibrated anti-cholera toxin B subunit (CTB) IgA ELISA was used together with an assay for vibriocidal antibodies. Swedish children had lower pre-vaccination levels of antibody, but serum responses were more pronounced in Swedish children than in Nicaraguan children. Post-vaccination levels of anti-toxin antibody were generally above those found after natural infections with enterotoxigenic Escherichia coli, that cross-reacts serologically with Vibrio cholerae. Adverse events seen after vaccination were generally mild and of little clinical significance.

Background: A prospective, randomized, double-blind, placebo-controlled trial of WC/rBS oral cholera vaccine was conducted in 502 U.S. college students attending summer educational programs in Mexico. Methods: Two doses of vaccine (or placebo) were administered 10 days apart immediately after arrival in Mexico. Results: The vaccine was free of significant adverse side effects. Anticholera toxin seroconversion was demonstrated in 86.7% of vaccinees compared to 8.2% of controls (p <.001). Postvaccination titers varied according to disease status (travelers' diarrhea) and enteropathogen isolated when disease developed. Protective efficacy (PE) against enterotoxigenic Escherichia coli (ETEC) diarrhea was 50% (95% CI, 14-71%), beginning 7 days after the second dose of WC/rBS. However, 74% of ETEC cases occurred within 7 days of the second dose, when no efficacy was demonstrated. Conclusions: Vaccines employed to prevent travelers' diarrhea will likely need to be administered before arrival in a developing country to be predictably beneficial. An unexpected finding was that infection with LT-ETEC after primary oral cholera immunization appears to augment the antitoxin response to WC/rBS vaccine. (J Travel Med 2:22-27, 1995)