Field trials of monovalent Ogawa and Inaba cholera vaccines in rural Bangladesh--three years of observation

A controlled cholera vaccine field trial was carried out to test the efficacy of monovalent whole-cell Inaba and Ogawa cholera vaccines and a purified Inaba antigen. This study was designed particularly to study the level of protection produced by these vaccines against homologous and heterologous serotypes and to correlate the results with mouse protection tests and human serological response to the vaccines. A cohort of 45 000 children, aged 0-14 years, was divided into a control group and three vaccine groups. Inoculations were given annually for 2 years just before the start of the cholera season, and follow-up was continued for one additional year. Essentially, all cholera cases were due to the Inaba serotype, so that protection could be studied only against that serotype. Two annual injections of the whole-cell Inaba vaccine gave the highest level of protection, averaging 84% over the 3 years of follow-up; a single injection of the purified Inaba vaccine gave less protection (51%). Two annual injections of the whole-cell Ogawa vaccine failed to protect children under the age of 5 but did produce 48% protection for children aged 5-14 against Inaba cholera. Serological surveys correlated poorly with protection; specifically, the Ogawa vaccine produced high anti-Inaba titres in young children but no protection. The cross-protection against Inaba cholera produced by Ogawa vaccine in the older children is assumed to be due to boosting of naturally acquired immunity in this population. Monovalent vaccine cannot be recommended for general public health use because of the serotype specificity of protection that this study has demonstrated.     

Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam

We assessed the long-term protection afforded by a killed whole-cell oral cholera vaccine produced in Vietnam. A mass immunization of children and adults with the killed whole-cell oral cholera vaccine was undertaken in half of the communes of Hue, Vietnam, in 1998; the remaining communes were immunized in 2000. No cholera was observed in Hue until 2003, when an outbreak of El Tor cholera made it possible to conduct a case-control study. The overall vaccine effectiveness 3-5 years after vaccination was 50% (9-63%). This low-cost, easily administered vaccine should be considered as a tool for the control of cholera.     

Report of the 1966-67 cholera vaccine field trial in rural East Pakistan. I. Study design and results of the first year of observation

A controlled cholera vaccine field trial was carried out in rural East Pakistan during the 1966-67 cholera season. A commercial cholera vaccine of average potency was tested in 40 000 children aged 3 months to 14 years in 1- and 2-dose schedules. In the cholera season extending for 8 months following immunization, a single dose produced an over-all protection of 46%; 2 doses at an interval of 1 month provided 64% protection. The single dose was virtually ineffective in children under 5 years, but provided significant protection in older children. The enhanced effect of the 2-dose schedule was primarily due to the boosting of protection in children under the age of 5 years. The duration of significant protection, even with the 2-dose schedule, did not appear to extend beyond the first 3 months of the 8-month cholera season.     

Investigations into the safety and immunogenicity of a killed oral cholera vaccine developed in Viet Nam

OBJECTIVE: To evaluate a killed oral cholera vaccine produced in Viet Nam, and to compare the Vietnamese vaccine with one that is licensed internationally. METHOD: Two-dose regimens of a locally produced, bivalent, anti-O1, anti-O139 killed oral whole-cell cholera vaccine (biv-WC) and of a commercially available, monovalent (anti-O1) oral recombinant B subunit-killed whole-cell cholera vaccine (rBS-WC) were compared in two trials in Viet Nam. In the first trial, 144 adults were randomized to biv-WC with or without buffer, rBS-WC with buffer, or placebo without buffer. In the second, 103 children aged 1-12 years were randomized to biv-WC without buffer, rBS-WC with buffer, or placebo without buffer. FINDINGS: No regimen was associated with significant side-effects. In adults, ca 60% of recipients of either vaccine exhibited at least fourfold serum anti-O1 vibriocidal antibody responses and ca 40% of recipients of biv-WC demonstrated anti-O139 vibriocidal responses. Both anti-O1 (ca 90% in each vaccine groupand anti-O139 (68% in the biv-WC group) vibriocidal responses occurred more frequently in children. The responses to biv-WC were unaffected by the receipt of buffer. CONCLUSION: It was concluded that biv-WC was safe and immunogenic, that it could be administered without buffer, and that it could elicit robust immune responses even in children, for whom the risk of endemic cholera is highest.     

A single-dose antihelminthic treatment does not influence immunogenicity of a meningococcal and a cholera vaccine in Gabonese school children

BackgroundWe recently described the effect of a single-dose antihelminthic treatment on vaccine immunogenicity to a seasonal influenza vaccine. Here we report the effect of antihelminthics on the immunogenicity of a meningococcal vaccine and a cholera vaccine in primary school children living in Lambaréné, Gabon. Since infection with helminths remains a major public health problem and the influence on cognitive and physical development as well as the immunomodulatory effects are well established, we investigated if a single-dose antihelminthic treatment prior to immunization positively influences antibody titers and vaccine-specific memory B-cells.MethodsIn this placebo-controlled, double-blind trial the effect of a single-dose antihelminthic treatment prior to immunization with a meningococcal as well as with a cholera vaccine was investigated. Anti-meningococcal antibodies were assessed by serum bactericidal assay, cholera vaccine-specific antibody titers by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Day 0; vaccination), four weeks (Day 28) and 12 weeks (Day 84) following vaccination. Meningococcal and cholera vaccine-specific memory B-cells were measured at Day 0 and 84 by vaccine-specific Enzyme-linked Immunospot (ELISpot) assay. The helminth burden of the participants was assessed four weeks before vaccination (Day −28) and at Day 84 by the Merthiolate-Iodine-Formaldehyde technique.ResultsOut of 280 screened school children, 96 received a meningococcal vaccine and 89 a cholera vaccine following allocation to either the single-dose antihelminthic treatment group or the placebo group. Bactericidal antibody titers increased following immunization with the meningococcal vaccine at Day 28 and Day 84 in 68 participants for serogroup A, and in 80 participants for serogroup C. The cholera vaccine titers increased in all participants with a peak at Day 28. The number of memory B-cells increased following vaccination compared to baseline. There was no statistically significant difference in antibody and B-cell response between children receiving albendazole compared to those receiving placebo.ConclusionA single-dose treatment with albendazole prior to immunization had no effect on meningococcal or cholera vaccine immunogenicity in our study population.     

Interventions for the control of diarrhoeal diseases among young children: rotavirus and cholera immunization

The potential effects of rotavirus and cholera immunization (with an improved vaccine) on diarrhea morbidity and mortality among young children are reviewed using data from field studies and theoretical calculations. In developing countries, rotavirus may be responsible for about 6% of all diarrhea episodes and 20% of all diarrhea deaths in children under age 5. In industrial countries, these proportions may be higher. Rotavirus immunization may reduce overall diarrhea morbidity rates by 2-3% and diarrhea mortality rates by 6-10% among children under 5 in developing countries, depending on vaccine efficacy and program coverage. The impact of improved cholera vaccines depends on the prominence of cholera as a cause of diarrhea, and this varies greatly from country to country. Taking the extreme example of Bangladesh, where cholera is endemic and may account for about 0.4% of all diarrhea episodes and 8% of all diarrhea deaths in children under 5 years of age, cholera immunization might reduce overall diarrhea morbidity rates by 0.06-0.13% and diarrhea mortality rates by 1-2% among these children. The similar incidence rates in industrial and developing countries suggest that rotavirus diarrhea may not be controlled by improvements in water supply, sanitation, or hygiene. Control may depend on the widespread use of an effective vaccine. (author's)     

Cost-Effectiveness of New-Generation Oral Cholera Vaccines: A Multisite Analysis

Objectives:  We evaluated the cost-effectiveness of a low-cost cholera vaccine licensed and used in Vietnam, using recently collected data from four developing countries where cholera is endemic. Our analysis incorporated new findings on vaccine herd protective effects.
Methods:  Using data from Matlab, Bangladesh, Kolkata, India, North Jakarta, Indonesia, and Beira, Mozambique, we calculated the net public cost per disability-adjusted life year avoided for three immunization strategies: 1) school-based vaccination of children 5 to 14 years of age; 2) school-based vaccination of school children plus use of the schools to vaccinate children aged 1 to 4 years; and 3) community-based vaccination of persons aged 1 year and older.
Results:  We determined cost-effectiveness when vaccine herd protection was or was not considered, and compared this with commonly accepted cutoffs of gross domestic product (GDP) per person to classify interventions as cost-effective or very-cost effective. Without including herd protective effects, deployment of this vaccine would be cost-effective only in school-based programs in Kolkata and Beira. In contrast, after considering vaccine herd protection, all three programs were judged very cost-effective in Kolkata and Beira. Because these cost-effectiveness calculations include herd protection, the results are dependent on assumed vaccination coverage rates.
Conclusions:  Ignoring the indirect effects of cholera vaccination has led to underestimation of the cost-effectiveness of vaccination programs with oral cholera vaccines. Once these effects are included, use of the oral killed whole cell vaccine in programs to control endemic cholera meets the per capita GDP criterion in several developing country settings.     

Suppressive effect of zinc on antibody response to cholera toxin in children given the killed, B subunit-whole cell, oral cholera vaccine

In a previous study, children aged 2-5 years old in Bangladesh were supplemented orally with a single dose of Vitamin A (200,000 IU) and a placebo for zinc (zinc equivalent to 20 mg of elemental zinc) everyday for 42 days (group A), zinc and a placebo for Vitamin A (group Z), zinc and Vitamin A (group AZ) or both placebos (group P). All children were orally immunised with two doses of the killed cholera vaccine containing whole cells and a recombinant B subunit of cholera toxin (CT). The number of children who responded with > or = 4-fold vibriocidal antibody (a proxy indicator of protection against cholera) was significantly greater among the zinc-supplemented groups than among the non-zinc-supplemented groups, while Vitamin A supplementation did not appear to have any effect. The sera from these children were assayed for antibody to CT. Antibody to CT is known to exert a synergistic protective effect against cholera in animal studies, and offer significantly higher short-term protection against cholera and significant short-term protection against enterotoxigenic Escherichia coli diarrhoea in humans on oral immunisation with the cholera vaccine. Children who received zinc had significantly reduced levels of serum antibodies to CT than children who received placebos only. Factorial analysis showed a trend for zinc showing a reduction in the number of children responding with CT-antibody, while Vitamin A did not appear to have any effect. Thus, zinc enhanced vibriocidal antibody response, but suppressed CT-antibody response, suggesting that zinc supplementation has different modulating effects on vibriocidal antibody response and CT-antibody response.     

Breast feeding and the risk of severe cholera in rural Bangladeshi children

The association between breast feeding and the risk of severe cholera was examined in a case-control study of rural Bangladeshi children under 36 months of age who were studied in 1985-1986 during a field trial of killed oral cholera vaccines. A total of 116 cases who were treated for severe cholera were compared with 464 age-matched community controls without severe cholera. Overall, the odds ratio relating breast feeding to severe cholera (0.30, p less than 0.0001) reflected a 70% reduction in the risk of severe cholera among breast-fed children. The estimated reduction of risk declined with age, but was clearly evident in children up to 30 months of age. Although the association between breast feeding and a reduced risk of severe cholera was not significantly greater in children of mothers who had received cholera vaccine than in children whose mothers had received placebo during the trial, maternal vaccination per se was suggestively associated with a reduced risk of severe cholera in their nonvaccinated children (odds ratio = 0.53, p = 0.05). These results indicate that breast feeding was associated with a substantial reduction of the risk of severe cholera and raise the possibility that vaccination of mothers may provide protection to their young children in endemic settings.     

Report of the 1966-67 cholera vaccine trial in rural East Pakistan

A controlled cholera vaccine field trial was carried out in rural East Pakistan to determine the efficacy of a cholera vaccine of average antigenic potency when used in a continuing programme with annual reimmunizations. A cohort of 40 000 children aged 0-14 years was equally divided into a control group and 3 vaccine groups. Inoculations of vaccine were given annually for 3 years just before the start of the cholera season, and follow-up continued for 2 additional years. The results indicate that there was increasing protection with reimmunization, reaching a maximum with 3 doses. One dose produced 43% protection, 2 doses 64%, 3 doses 81%, and 4 doses 76%. Protection was more sustained after reimmunization; being 50% and 39%, 1 and 2 years after the fourth injection, respectively. Serological surveys suggested a general parallel in the antibody response to vaccine and the level of protection achieved; however, the levels of vibriocidal antibody titres could not be related directly to levels of protection. The overall protection achieved with the 3-year programme of annual reimmunizations was 55% for the group receiving one inoculation annually, and 65% for the group receiving 2 inoculations in the first year followed by annual reimmunizations. When the costs and effectiveness of annual vaccine programmes are compared with those for cholera treatment centres, it becomes clear that the cholera vaccines now available are not appropriate alternatives to treatment in routine cholera control programmes.     

CD4+ T-cell responses to an oral inactivated cholera vaccine in young children in a cholera endemic country and the enhancing effect of zinc supplementation

Immunization of young children with the oral inactivated whole cell cholera vaccine Dukoral^® containing recombinant cholera toxin B subunit (CTB) induces antibody responses which can be further enhanced by zinc supplementation. We have investigated if immunization with the cholera vaccine induces specific T-cell responses in young children and also whether zinc supplementation influences these responses. Bangladeshi children (10–18 months old) received vaccine alone, vaccine together with zinc supplementation or only zinc. T-cell blast formation indicating a proliferative response was analyzed by the flow cytometric assay of cell-mediated immune response in activated whole blood (FASCIA) and cytokines were measured by ELISA. Stronger T-cell responses were detected if a modified CTB molecule (mCTB) with reduced binding to GM1 ganglioside was used for cell stimulation compared to normal CTB. After vaccination, CD4+ T cells responded to mCTB with significantly increased blast formation (P < 0.01) and IFN-γ production (P < 0.05) compared to before vaccination. No responses to mCTB were detected in children receiving zinc alone (P > 0.05). The IFN-γ production was significantly higher (P < 0.01) but the blast formation comparable (P > 0.05) in children receiving zinc plus vaccine compared to in children receiving vaccine alone. The vibriocidal antibody responses induced by the vaccine were also significantly higher in children receiving zinc supplementation (P < 0.001). Our results thus show that oral cholera vaccination induces a Th1 T-cell response in young children, and that the IFN-γ as well as the vibriocidal antibody responses can be enhanced by zinc supplementation.     

Report of the 1966-67 cholera vaccine field trial in rural East Pakistan. 2. Results of the serological surveys in the study population--the relationship of case rate to antibody titre and an estimate of the inapparent infection rate with Vibrio cholerae

The 1966-67 cholera vaccine field trials in East Pakistan tested 1- and 2-dose schedules of a commercial cholera vaccine in 40 000 children aged 3 months to 14 years. Randomsample serological surveys, made prior to the inoculations and 3 months and 6 months after the inoculations, demonstrated that there was a rise in the vibriocidal titres of the vaccinated children during the first 3 months after inoculation and a subsequent fall by the end of the second 3 months. The antibody response to 2 doses of cholera vaccine was better than the response to a single dose in children under 5 years of age. In children aged 5-14 years, the antibody response was similar for both inoculation schedules. Since the majority of the older children had vibriocidal antibodies before inoculation, the data suggest that the single dose acted as a booster, and this effect was not enhanced by a second inoculation.     

Scalable production and immunogenicity of a cholera conjugate vaccine

There is a need to develop cholera vaccines that are protective in young children under 5 years of age, which induce long-term immunity, and which can be incorporated into the Expanded Programme of Immunization (EPI) in cholera-endemic countries. The degree of protection afforded by currently available oral cholera vaccines (OCV) to young children is significantly lower than that induced by vaccination of older vaccine recipients. Immune responses that protect against cholera target the O-specific polysaccharide (OSP) of Vibrio cholerae, and young children have poor immunological responses to bacterial polysaccharides, which are T cell independent antigens. To overcome this, we have developed a cholera conjugate vaccine (CCV) containing the OSP of V. cholerae O1, the main cause of endemic and epidemic cholera. Here, we describe production of CCV through a scalable manufacturing process and preclinical evaluation of immunogenicity in the presence and absence of aluminum phosphate (alum) as an adjuvant. The vaccine displays V. cholerae O1 Inaba OSP in sun-burst display via single point attachment of core oligosaccharide to a recombinant tetanus toxoid heavy chain fragment (rTTHc). Two different pilot-scale production batches of non-GMP CCV were manufactured and characterized in terms of physico-chemical properties and immunogenicity. In preclinical testing, the vaccine induced OSP- and lipopolysaccharide (LPS)-specific IgG and IgM responses, vibriocidal responses, memory B cell responses, and protection in a V. cholerae O1 challenge model. The addition of alum to the administered vaccine increased OSP-specific immune responses. These results support evaluation of CCV in humans.     

A controlled field trial of an aluminium phosphate-adsorbed cholera vaccine in Calcutta

A controlled field trial to determine the efficacy of a single dose of an aluminium phosphate-adsorbed cholera vaccine was conducted in Calcutta during 1975-77. An aluminium phosphate-adsorbed tetanus toxoid was used as the placebo. Follow-up of the immunized volunteers for a period of two years showed that the adsorbed cholera vaccine provided 100% protection to children under five years of age for 6 months, 88.9% for 12 months, and 91.7% for 18 months (P<0.05). The overall protection for all age groups was 58.5% for 18 months. There were no serious side effects following the anti-cholera inoculations.     

A serological survey for cholera antibodies in rural east Pakistan. 2. A comparison of antibody titres in the innunized and control populationd of a cholera-vaccine field-trial area and the relation of antibody titre to cholera case rate

Controlled field trials of a highly antigenic cholera vaccine were held in Matlab Bazar in rural East Pakistan in 1963 and again in 1964. In July—September 1965, a serological survey for cholera antibodies was carried out on a random sample of the field-trial population. This survey revealed that it was possible to demonstrate the effect of a single injection of the cholera vaccine per head on the proportion of the population with detectable vibriocidal and agglutinating antibody 10 and 22 months after injection. More significantly, the reduction in cholera case rate caused by the vaccine could be correlated with the rise in vibriocidal antibody after vaccination, suggesting that the serological response to vaccine in man may be a useful measure of vaccine potency. The survey also indicated that in this endemic cholera area, with a high level of immunity in adults, a single injection of cholera vaccine was in fact a booster dose for the majority of the population. Thus, the results of cholera vaccine field trials in endemic areas cannot be directly extrapolated to predict the effects of the same vaccine in non-endemic areas.     

A controlled field trial on the effectiveness of the intradermal and subcutaneous administration of cholera vaccine in the Philippines

In view of the encouraging laboratory findings on the efficacy of intradermal administration of cholera vaccination in small doses, a controlled field trial was undertaken in the Philippines to evaluate the efficacy of the two routes for cholera vaccination. The trial has shown that these routes are effective, both giving a significant degree of protection against cholera. However, the vaccine afforded longer-lasting protection when administered subcutaneously (6 months) than when given intradermally (4 months), and was significantly more effective in children in the 1-5-year age group in this endemic area.     

Evaluation of a probiotics, Bifidobacterium breve BBG-01, for enhancement of immunogenicity of an oral inactivated cholera vaccine and safety: a randomized, double-blind, placebo-controlled trial in Bangladeshi children under 5 years of age

To evaluate the probiotic, Bifidobacterium breve strain Yakult (BBG-01), for safety and enhancement of immunogenicity in an oral inactivated cholera vaccine, a randomized double-blind placebo-controlled study was performed. Bangladeshi children under 5-year-old received BBG-01 or placebo for 4 weeks with two doses of oral cholera vaccine. Serum/fecal antibodies and fecal bacterial flora in the study participants were monitored. All adverse events were mild and transient and had no significant difference between the two groups. Immunological responses were similar comparing the two groups. A negative correlation between Bifidobacterium and Enterobacteriaceae in the probiotic group suggests a possible involvement of BBG-01 in alteration of the enteric bacterial flora. In conclusion, BBG-01 is well tolerated by Bangladeshi children although the post vaccinal immunostimulatory effect of BBG-01 was not evident.     

A serological survey for cholera antibodies in rural East Pakistan: 1. The distribution of antibody in the control population of a cholera-vaccine field-trial area and the relation of antibody titre to the pattern of endemic cholera*

Controlled cholera vaccine field trials were held in Matlab Bazar in rural East Pakistan in 1963 and 1964. In July—September 1965, a serological survey for cholera antibodies was carried out on a random sample of the field-trial population. Results are given for the control group only, as representative of the pattern found in an endemic cholera area. Only 2% of the blood samples from children under 10 years of age were found to have detectable agglutinating antibody (titres of 1:20 or more), while the proportion in the age-group over 30 years was 27%-30%. Tests for vibriocidal antibody showed that none of the blood samples from children under 1 year of age contained detectable antibody, while 87%-90% of those from adults over 30 years did so. The rise in the geometric mean vibriocidal titre showed an almost linear correlation with a sharp fall in the cholera case rate with age. Since a similar survey in a non-endemic area (Czechoslovakia) did not reveal any rise in antibody titre with age, and since cholera epidemics in areas without recent experience of the disease are characterized by a higher incidence rate in adults than in children, it is suggested that the antibody titres give a measure of the level of immunity in a population.     

Cost-effectiveness of oral cholera vaccine in a stable refugee population at risk for epidemic cholera and in a population with endemic cholera.

Recent large epidemics of cholera with high incidence and associated mortality among refugees have raised the question of whether oral cholera vaccines should be considered as an additional preventive measure in high-risk populations. The potential impact of oral cholera vaccines on populations prone to seasonal endemic cholera has also been questioned. This article reviews the potential cost-effectiveness of B-subunit, killed whole-cell (BS-WC) oral cholera vaccine in a stable refugee population and in a population with endemic cholera. In the population at risk for endemic cholera, mass vaccination with BS-WC vaccine is the least cost-effective intervention compared with the provision of safe drinking-water and sanitation or with treatment of the disease. In a refugee population at risk for epidemic disease, the cost-effectiveness of vaccination is similar to that of providing safe drinking-water and sanitation alone, though less cost-effective than treatment alone or treatment combined with the provision of water and sanitation. The implications of these data for public health decision-makers and programme managers are discussed. There is a need for better information on the feasibility and costs of administering oral cholera vaccine in refugee populations and populations with endemic cholera.