Abstract: Protection against cholera has been correlated with the level of serum vibriocidal antibodies. The specificity of these vibriocidal antibodies was mostly to the lipopolysaccharide (LPS). We synthesized conjugates of detoxified LPS with cholera toxin (CT) and other proteins in order to elicit serum LPS antibodies with vibriocidal activity. Treatment with hydrazine (deacylated LPS) reduced the endotoxic properties of the LPS to clinically acceptable levels and resulted in a molecule larger and more antigenic than the saccharide produced by acid hydrolysis. More immunogenic conjugates resulted from multipoint compared with single-point attachment of the deacylated LPS to the protein. The conjugates containing CT had low levels of pyrogen and no toxic activity upon Chinese hamster ovary cells and elicited booster responses of vibriocidal and CT antibodies when injected subcutaneously as saline solutions into mice; the vibriocidal titers were similar to those elicited by comparable doses of cellular vaccines. We suggest how serum vibriocidal antibodies might prevent cholera.

Abstract: Cholera returned to the Americas after a 100 year hiatus in Peru in January 1991. Fecal contamination of water caused this epidemic. Even though health authorities informed the public about cholera early in the epidemic holdups to providing safe water permitted its spread. By the end of 1991 there were 391000 cases and 4000 deaths in 15 countries. The use of oral rehydration therapy kept the case fatality rate much lower (1%) than it had been in the past (>20%). This epidemic is a continuation of the 7th cholera pandemic begun in Asia in 1961 with the new Vibrio cholerae 01 El Tor biotype. In Chile the vehicle for transmission of cholera was uncooked vegetables irrigated with raw sewage. Public health authorities forbade the sale of such vegetables and informed the public to cook all vegetables. A decline in the incidence of cholera and typhoid followed these measures. In Ecuador contaminated shellfish spread cholera. US cholera cases were infected in either affected Latin American countries on the airplane returning to the US or from contaminated seafood they brought to the US. Cholera control measures are often difficult to implement. For example the Americas need to invest >US $200 billion over 12 years to provide safe drinking water and adequate sewage disposal. Until funding arrives however governments can repair existing water distribution systems and chlorinate water supplies. In areas not provided with such services authorities can promote use of small mouthed water containers and/or boiling or chlorinated household water. Further health educators can encourage people to wash their hands to cook contaminated foods and to avoid food/beverages prepared by street vendors. Research is accelerating in developing an effective cholera vaccine such as the promising killed whole cell vaccine (subunit B). The epidemic in the Americas is expected to spread to the Caribbean the Amazon Basin and the Atlantic Coast.

Abstract: Both specific polyclonal antiserum and monoclonal antibodies against mannose-binding hemagglutinin fimbriae of Vibrio cholerae (mannose-sensitive hemagglutinin [MSHA]) were shown to protect against experimental cholera caused by vibrios of the El Tor biotype in the infant mouse and in the rabbit intestinal loop models. MSHA-specific Fab immunoglobulin fragments were also protective. No protective effect was observed against challenge with V. cholerae O1 of the classical biotype. These results suggest that MSHA pili play an important role in the pathogenesis of cholera caused by the El Tor biotype of V. cholerae and that induction of intestinal anti-MSHA immunity may be a worthwhile additional objective in the development of oral cholera vaccines.

Abstract: In a randomized, placebo-controlled field trial of B subunit-killed whole cell (BS-WC) and killed whole cell only (WC) inactivated oral cholera vaccines in rural Bangladesh, active surveillance of selected neighborhoods during the first year after vaccination identified 127 Vibrio cholerae O1 infections among 3285 three-dose recipients. For each vaccine, protective efficacy was greater against symptomatic (57%, P 5 years were protected against asymptomatic infections. These results suggest that the inactivated oral vaccines acted both to protect against intestinal colonization by V. cholerae O1 and to interrupt the pathogenic sequence of established infections.

Abstract: Adult volunteers received a booster dose (4 x 10(8) CFU) of attenuated Vibrio cholerae CVD 103-HgR oral vaccine 15 or 24 months after primary immunization. The immune response was modest, presumably due to rapid clearance of the vaccine strain by a primed immune system.

Abstract: OBJECTIVE: To examine the clinical impact and financial cost of a vaccination program for the prevention of cholera in North Americans travelling to endemic and epidemic regions by means of the principles of decision analysis and a decision tree as well as to illustrate the effect of case attack rates on the cost per case prevented by vaccination. DESIGN: Review of the scientific literature to establish the probabilities of each significant outcome as well as a decision analysis and partial economic evaluation. OUTCOME MEASURES: Clinical impact (attack rates for cholera among vaccinated and nonvaccinated travellers), rates of death associated with cholera and vaccine-associated adverse events (VAAEs), and the number of VAAEs and the vaccine cost per case prevented. MAIN RESULTS: On the basis of our assumptions (including a rate of one case of cholera per 500,000 journeys to endemic regions), to prevent one case of cholera a vaccination program would cost $28.67 million and be associated with 105 VAAEs. CONCLUSION: Routine vaccination of travellers to endemic areas cannot be recommended; however, for people travelling to regions with a high transmission rate vaccination should be considered.

Abstract: Chapter 1, on the history of the disease, concluded that the quirks of cholera are likely to continue to cause concern and despair as this pestiferous disease continues to menace much of the developing world, where at least 65% of the world’s population lives. Since 1991 Latin America has been affected and North America may be at risk. The word “cholera” still provokes considerable fear because, although measures exist for its prevention, control, and treatment, they are not available where they are most needed. Platitude or not, cholera continues to harass the developing world because of the underlying social and economic predicaments.

Abstract: The pathogenesis of cholera has been well characterized during the past 25 years in several animal models and cholera patients. From these studies has come an understanding of this disease which is perhaps the most complete of any infectious disease. Clearly, there are still gaps in our knowledge about many of the details of the host-parasite relationship, but the major events (inoculum size, colonization, and enterotoxin production and its physiologic effects) are known, and from this knowledge specific interventions have been devised to interfere with the establishment of the infection, aid in treating it, or hasten its termination.

Abstract: Parenteral cholera vaccines consisting of whole killed cells have been used for nearly 100 years, but their efficiency, especially in young children, the most susceptible group, is not high, offering only partial protection for less than 6 months 11.21. The B subunit of cholera toxin (MW=I 1 Kd) is the non-toxic part of the molecule that binds to the GMI monosialoganglioside receptor on the brush border membrane of the intestine, so that the adenylate cyclaseactivating A subunit can be introduced into the cell 131. The CTB is also the main immunogenic component of the toxin since the neutralising antibodies are mainly directed against it, in order to prevent the binding of toxin to the mucosal receptors. Therefore, it seems to be an almost ideal immunogen for an oral cholera vaccine

Abstract: Publisher Summary This chapter discusses immunology of cholera and cholera vaccine development using older technologies and novel technological approaches. Cholera was one of the large groups of infectious diseases, such as anthrax, tuberculosis, typhoid fever, diphtheria, and tetanus, for which etiologic agents were discovered in the late 19th century. In the more than 100 years since that time, the study of cholera and of its etiologic agent, Vibrio cholera serotype O1, has progressed with advances in microbiology. Recently, cholera research has exploited the technology of molecular biology. Building on the knowledge that primary infection offers significant protection against reinfection and that mucosal immunity mediates this protection, several oral cholera vaccines have been developed. These vaccine candidates or future candidates derived using the techniques of molecular biology will contribute to the control of cholera.

Abstract: Clinico-immunological studies on men were conducted using associated immunization by pair combinations of 8 commercial national vaccines (typhoid, plague, typhus, smallpox, tick-borne encephalitis, yellow-fever, cholera and sextaanatoxine). As for reactogenicity and immunological efficiency (serological studies), these pair associations can be subdivided into three main groups. The first group consists of pair combinations of vaccines that cannot exert any influence on immunogenicity of cause the development of frequent post-vaccination reaction or temporary disability (typhus, smallpox, tick-borne encephalitis, yellow-fever vaccines). These preparations are completely compatible in every combination. The second group includes plague and cholera vaccines that reduce its immunogenicity under the influence of more active antigens or increase its reactogenicity being associated with typhoid vaccine or sextaanatoxine. The third group is composed of typhoid vaccine and sextaanatoxine that have high reactogenicity and stable serological shifts. Associations of the first group are the most favourable for anti-epidemiological practice.

Abstract: 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.

Abstract: It is now over 30 years since the cholera enterotoxin was discovered in India and more than 20 years since it was first purified to homogeneity. Early expectations that, as with diphtheria and tetanus, a toxoid vaccine would solve the cholera problem have not been fulfilled. We are examining the reasons why cholera toxin (CT) vaccines have failed to provide effective immunity.

Abstract: 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.

Abstract: Haemophilus b conjugate vaccines recent advances in development of pertussis vaccines cholera vaccines malaria helminths influenza vaccines approaches to immunization against respiratory synctial virus hepatitis B vaccines blueprints for vaccines of the future poliovirus vaccines herpes simplex vaccines rotavirus vaccines flavivirus human immunodeficiency virus recent advances in antitumour vaccines vaccinia virus vectors adenovirus based on expression vectors and recombinant vaccines active immunication strategies using anti-idiotypic antibodies passive immunoprophyiaxis with human monoclonal antibodies immunological adjuvants and their mode of action synthetic peptides.

Abstract: We conducted a double-blind, placebo-controlled, randomized crossover study to evaluate the safety and immunogenicity of a single 5 x 10(8)-CFU dose of live oral recombinant cholera vaccine CVD 103-HgR in 94 North American adults. The vaccine was well tolerated without associated adverse reactions. Despite minimal fecal excretion of vaccine, 97% of subjects exhibited serum vibriocidal antibody and 72% had antitoxin responses.