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[The current status of research on a cholera vaccine].

Cholera remains today a major health problem in most developing countries. The long-term control of cholera depends on the improvement of hygiene but this is a distant goal for many countries. The availability of an effective cholera vaccine is thus important for the prevention of cholera in such countries. More than a century after the first attempt to vaccinate against cholera by Ferran in Spain, there is still no truly effective cholera vaccine. A bacterial fraction vaccine, referred to as CH1 +2 was prepared by Professor A. Dodin. A field trial of this vaccine was carried out in Zaire in 1983. Significant protection was observed but this vaccine was not evaluated in additional trials. Two other oral cholera vaccines, developed in Sweden and in the USA, were widely experimented on human beings: a combination of cholera toxin B-subunit and inactivated bacterial cells, and a live attenuated vaccine containing the genetically manipulated Vibrio cholerae O1 strain CVD 103-HgR. Despite their efficiency as evaluated in field trials (inactivated vaccine) or on volunteers (live vaccine), these vaccines have drawbacks that may limit their usefulness as practical vaccines. Protection induced by the inactivated vaccine was transient in young children, lasting only approximately for six months. One of the safety concerns associated with live vaccines is a possible reversion to virulence. Efforts should be continued to find a better cholera vaccine. A new vaccine development program based upon the hypothesis that immunoglobulin G directed to the O-specific polysaccharide of Vibrio cholerae O1 could confer protective immunity to cholera. This program may lead to the development of a cholera conjugate vaccine to elicit protection in infants.

Adjuvants, Immunologic↗

Recent progress in cholera vaccination.

Cholera disease remains an important cause of morbidity and mortality in the third world. The parenteral cholera vaccine actually used offers only a 50% protection during 6 months. As Vibrio cholerae and its toxin don't cross the gut wall, the aim of new vaccines is to prevent the colonization and growth of the vibrio in the jejuno-ileum and to inhibit the fixation of cholera toxin (CT) on its enterocyte membrane receptor. This can be afforded by stimulation of the gut local immune system mainly represented by secretory IgA antibodies (Abs). New vaccines should comprise both bacterial and CT antigens and must be given by the oral route to induce the production of specific secretory IgA Abs in the gut. Four different ways are actually under study to produce an oral cholera vaccine. 1. Combination of CT-B subunit and killed vibrios. 2. Live recombinant Vibrio cholerae in which the CT coding gene has been deleted. 3. Synthetic peptides reproducing some immunodominant CT-epitopes. 4. Manipulation of the idiotypic network to induce the production of Abs mimicking CT-epitopes. This paper reviews the actual developments and advantages of these four approaches.

Antibodies, Anti-Idiotypic↗

Cholera vaccines.

Cholera causes significant morbidity and mortality worldwide. For travelers, the risk of developing cholera per month of stay in a developing country is approximately 0.001%-0.01%, and cholera may present as traveler's diarrhea. In the United States, only a poorly tolerated, marginally effective, parenterally administered, phenol-inactivated vaccine is available. Outside the United States, 2 additional vaccines are commercially available: an oral killed whole cell-cholera toxin recombinant B subunit vaccine (WC-rBS) and an oral live attenuated Vibrio cholerae vaccine (CVD 103-HgR). These oral vaccines are well tolerated. In field trials, WC-rBS provides 80%-85% protection from cholera caused by V. cholerae serogroup O1 for at least 6 months. In volunteer studies, CVD 103-HgR provides 62%-100% protection against cholera caused by V. cholerae for at least 6 months. No commercially available cholera vaccine protects against disease caused by V. cholerae serogroup O139. New cholera vaccines are being developed.

Cholera↗

Vaccines for preventing cholera.

BACKGROUND: Oral cholera vaccines (either killed whole cell or live recombinant vaccines) are newer alternatives to the parenteral vaccines which have been thought to confer only moderate and short-term immunity. OBJECTIVES: The objective of this review was to assess the effect of cholera vaccines in preventing cases of cholera and preventing deaths. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, Medline, Embase and reference lists of articles. We handsearched the journal Vaccine, contacted researchers in the field and manufacturers. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing cholera vaccines (killed or live) with placebo, control vaccines or no intervention, or comparing types, doses or schedules of cholera vaccine. We included adults and children irrespective of immune status or special risk category. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of trial quality was done independently by two reviewers. MAIN RESULTS: Thirty-two trials were included. Seventeen efficacy trials of relatively good quality, testing parenteral and oral killed whole cell vaccines and involving over 2. 6 million adults, children and infants were included. Nineteen safety trials have been conducted for both types of killed whole cell vaccines and for live vaccines and have involved 11,459 people. For all types of vaccines compared to placebo, the relative risk of contracting cholera at 12 months was 0.49, 95% confidence interval 0. 41 to 0.59 (random effects model). This translates to an efficacy of 51%, 95% confidence interval 41% to 59%. Both parenteral and oral administration were relatively efficacious, but significant protection extended into the third year for oral killed whole cell vaccines. Children under 5 were only protected for up to a year, while older children or adults were protected for up to three years. Parenteral killed whole cell vaccines were associated with increased systemic and local adverse effects compared to placebo. Oral killed whole cell vaccines or oral live vaccines were not. REVIEWER'S CONCLUSIONS: Cholera killed whole cell vaccines appear to be relatively effective and safe. Live oral recombinant vaccines appear to be safe, but efficacy data are not available. Protection against cholera appears to persist for up to two years following a single dose of vaccine, and for three to four years with an annual booster.

Adult↗

Molecular design of cholera vaccines.

Cholera is still a serious public health problem in developing countries, particularly those in tropical regions. This has stimulated considerable research into the molecular analysis of pathogenesis resulting in the identification of a number of critical components required for both colonization of the gut mucosa and the disease symptoms. These components are the targets for rational molecular approaches to vaccine development.

Bacterial Proteins↗

Botulinum antitoxins and antibacterial IgM and IgG antibodies in sera of persons immunized with botulinum polytoxoid combined with cholera vaccine. II. Response to cholera vaccine.

The response of humans to cholera vaccine was very heterogeneous. The proportion of IgG vibriocidal antibodies was high in persons having previous natural or artificial contact with V. cholerae antigens. Predominance of IgM antibody response was seen in persons vaccinated for the first time. This type of response was sometimes evoked by unspecific stimuli such as botulinum polytoxoid without cholera vaccine. Antibodies passively protecting mice were found both in IgM and IgG globulins but the activity of these antibodies was higher in IgG than in IgM globulins.

Adult↗

IgG and IgA subclass distribution of antitoxin antibody responses after oral cholera vaccination or cholera disease.

The immunoglobulin subclass distribution of cholera antitoxin antibody responses in serum was studied in Swedish volunteers after different routes of immunization with a cholera B subunit-whole cell vaccine (B + WCV) and in Bangladeshi patients convalescing from cholera disease. Both oral and parenteral immunization induced antitoxin antibodies of all the different IgG subclasses (IgG1, IgG2, IgG3 and IgG4) whilst the IgA antibodies were restricted to the IgA1 subclass. A single oral dose of B + WCV induced proportionally higher levels of IgG4 antitoxin in previously cholera-immunized volunteers than in a matched group who had not been cholera-vaccinated before, suggesting that repeated immunization preferentially stimulate formation of IgG4 antibodies. The IgG and IgA subclass distribution of antitoxin antibodies in orally vaccinated Swedes closely resembled that in Bangladeshi cholera patients.

Antibodies, Bacterial↗

The current status of cholera vaccine development and experience with cholera vaccine trials in volunteers.

In recent years notable advances have been made in the development of improved vaccines to prevent cholera. These new vaccines are administered orally to maximally stimulate intestinal secretory immunity. Killed vibrios, given in conjunction with purified B subunit or administered alone, in three spaced doses, caused no adverse reactions and have conferred significant protection in volunteer challenge studies and in field trials. Two attenuated mutants of V. cholerae, prepared by recombinant DNA techniques, CVD 103 and CVD 103-HgR are well-tolerated and elicit prominent immune responses and protective immunity after ingestion of a single oral dose. Other modern approaches being pursued include the development of auxotrophic strains and of modifying attenuated S. typhi strain Ty21a to express V. cholerae Inaba and Ogawa LPS antigens.

Administration, Oral↗

Postgenomic approaches to cholera vaccine development.

Cholera remains an important public health threat. A cholera vaccine that provides durable protection at the mucosal surface, especially among children in endemic settings, is urgently needed. The availability of the complete genome sequence of a clinical isolate of Vibrio cholerae O1 El Tor has allowed for comparative and functional genomic approaches in the study of cholera. This work holds promise for the identification of bacterial targets of protective human immune responses and may contribute to the development of a new generation of cholera vaccines.

Animals↗

Effect of storage temperatures on opacity and total nitrogen content of cholera vaccine.

Fluid cholera vaccine was examined for its stability at 4-8 degrees C, 20-25 degrees C and 37 degrees C with regard to the number of organisms present and the total nitrogen content. Ten batches of fluid cholera vaccine manufactured at the Central Research Institute, Kasauli, India were taken for the study. The number of organisms was determined at weekly intervals for the first month and at monthly intervals for the next 11 months. The percentage loss in the number of organisms after one year averaged 6.5 at 4-8 degrees C, 20.6 at 20-25 degrees C and 21.5 at 37 degrees C. The maximum loss in number of organisms took place during the first six months at these temperatures, in the following six months the number of organisms remained almost constant even at 37 degrees C. The total nitrogen content of the vaccine remained virtually unaltered during the same period. From this study it was concluded that the number of organisms and the total nitrogen content does not reflect the antigenicity nor potency of the vaccine.

Cholera Vaccines↗

Protective activity of cholera vaccines against E1 Tor cholera vibrios.

With the advent of epidemic El Tor cholera there has been concern about the value of cholera vaccine prepared from classical cholera strains.Using a recently developed mouse protection test, the authors have determined the protective activity of five commercial vaccines against strains of epidemic El Tor and classical cholera vibrios. Both Ogawa and Inaba types of each kind of vibrio were used. With each vaccine, protection against El Tor vibrios was as good as that against classical cholera vibrios. There was, however, a greater than tenfold difference in the potency of the vaccines.The findings support the use of cholera vaccine for immunization against El Tor cholera and show that there are wide variations in the mouse-measured potency of lots of vaccine. The significance of the findings must await results of controlled field trials.

Animals↗

Onset and duration of protective immunity in challenged volunteers after vaccination with live oral cholera vaccine CVD 103-HgR.

CVD 103-HgR is a live oral cholera vaccine that, in phase I and II studies to date, has been well tolerated and immunogenic. In challenge studies of US volunteers conducted 4-5 weeks after vaccination, CVD 103-HgR provided significant protection against experimental cholera due to classical and El Tor Vibrio cholerae O1. To determine the onset and duration of protection, two volunteer challenge studies were conducted: the first, 6 months after vaccination and the second, 8 days after vaccination. In both studies, CVD 103-HgR was 100% protective against diarrhea and significantly reduced the rate of shedding of vibrios after challenge with V. cholerae classical Inaba strain 569B, the virulent parent strain of CVD 103-HgR. Previously vaccinated subjects were less likely than naive controls to develop rises in titer of vibriocidal antibodies after challenge (P = .002), and the mean peak titer of vibriocidal antibodies was less than among controls. CVD 103-HgR can provide homologous protective immunity as soon as 8 days after vaccination and protection can persist for at least 6 months.

Administration, Oral↗