Abstract: Context.—There is significant controversy about how best to control cholera epidemics in refugee settings. Specifically, there is marked disagreement about whether to use oral cholera vaccines in these settings, despite the improved safety and effectiveness profiles of these vaccines.Objective.—To determine the cost-effectiveness of alternative intervention strategies, including vaccination, to control cholera outbreaks in sub-Saharan refugee camps.Design.—A cost-effectiveness analysis based on probabilities of cholera outcomes derived from epidemiologic data compiled for refugee settings in Malawi from 1987 through 1993; data for costs were obtained from a large relief agency that provides medical care in such settings.Setting and Participants.—A hypothetical refugee camp with 50000 persons in sub-Saharan Africa evaluated for a 2-year period.Interventions.—We compared the costs and outcomes of alternative strategies in which appropriate rehydration therapy for cholera is introduced preemptively (at the establishment of a camp) or reactively (once an epidemic is recognized) and in which mass immunization with oral B subunit killed whole-cell (BS-WC) cholera vaccine is added to a rehydration program either preemptively or reactively.Main Outcome Measures.—Cost per cholera case prevented and cost per cholera death averted.Results.—In a situation with no available rehydration therapy suitable for the management of severe cholera, a strategy of preemptive therapy ($320 per death averted) costs less and is more effective than a strategy of reactive therapy ($586 per death averted). Adding vaccination to preemptive therapy is expensive: $1745 per additional death averted for preemptive vaccination and $3833 per additional death averted for reactive vaccination. However, if the cost of vaccine falls below $0.22 per dose, strategies combining vaccination and preemptive therapy become more cost-effective than therapy alone.Conclusions.—Provision for managing cholera outbreaks at the inception of a refugee camp (preemptive therapy) is the most cost-effective strategy for controlling cholera outbreaks in sub-Saharan refugee settings. Should the price of BS-WC cholera vaccine fall below $0.22 per dose, however, supplementation of preemptive therapy with mass vaccination will become a cost-effective option.

Abstract: Despite considerable experience with single-dose, live, oral cholera vaccine CVD 103-HgR in Asia, Europe, and the Americas, the vaccine had not been evaluated in sub-Saharan Africa or on individuals infected with human immunodeficiency virus (HIV). We therefore conducted a randomized, placebo-controlled, double-blind, cross-over clinical trial in 38 HIV-seropositive (without clinical acquired immunodeficiency syndrome (AIDS)) and 387 HIV-seronegative adults in Mali to assess its safety and immunogenicity. Adverse reactions (fever, diarrhoea and vomiting) were observed with similar frequency among vaccine and placebo recipients. The vaccine strain was not isolated from the coprocultures of any subject. The baseline geometric mean titre (GMT) of serum vibriocidal antibody was significantly lower in HIV-seropositives (1:23) than in HIV-seronegatives (1:65) (P = 0.002). Significant rises in vibriocidal antibody were observed in 71% of HIV-seronegatives and 58% of HIV-seropositives, and in 40% of HIV-seropositives with CD4+ counts below 500 per microliter. Following immunization, the peak vibriocidal GMT in HIV-seronegatives was 1:584 versus 1:124 in HIV-seropositives (P = 0.0006); in HIV-seropositives with CD4+ counts < 500 per microliter, the peak vibriocidal GMT was 1:40 (P = 0.03 versus other HIV-seropositives). CVD 103-HgR was safe in HIV-infected Malian adults, although serological responses were significantly attenuated among HIV-seropositives (particularly in those with CD4+ counts < 500 per microliter) relative to HIV-seronegatives. These results encourage further evaluations of this single-dose, oral cholera vaccine in high-risk populations such as refugees in sub-Saharan Africa.

Abstract: The authors present a nonparametric method for estimating vaccine efficacy as a smooth function of time from vaccine trials. Use of the method requires a minimum of assumptions. Estimation is based on the smoothed case hazard rate ratio comparing the vaccinated with the unvaccinated. The estimation procedure allows investigators to assess time-varying changes in vaccine-induced protection, such as those produced by waning and boosting. The authors use the method to reanalyze data from a vaccine trial of two cholera vaccines in rural Bangladesh. This analysis reveals the differential protection and waning effects for the vaccines as a function of biotype and age.

Abstract: Most human pathogens are acquired through mucosal portals of entry, and replicate in the mucosal tissues. Subsequently, the infecting agent may invade the blood stream and produce disease at distant systemic sites. However, a large number of pathogenic organisms are limited to development of disease only at the site of initial mucosal replication. Studies carried out with naturally acquired infections and mucosally delivered vaccines have provided strong evidence for the existence of a common mucosal immune system in the organized lymphoid follicles in respiratory and intestinal epithelium, and in the mucosa of genital tract, mammary glands, conjunctiva, upper airways, and the middle ear cavity. Mucosal application of live attenuated oral poliovaccine (OPV), rubella virus vaccine (RA 27/3), adenoviruses, influenza A virus, rotavirus, salmonella, and cholera vaccines have demonstrated consistent development of secretory IgA, serum antibody, and cellular immune responses. Mucosal immunization appears to result in preferential expression of several integrins and cell adhesion molecules associated with homing of lymphocytes to mucosal sites of immunization. Induction of mucosal immune responses often result in specific protection against reinfection challenge and against illness. Replicating agents introduced via the parenteral route also result in the development of mucosal responses and protection against systemic illness. Parenteral immunization with non-replicating agents often fails to induce specific mucosal responses. Such immunization, however, is quite effective in mounting high levels of serum antibody with development of protection against systemic illness. Parenteral vaccines, such as enhanced potency inactivated polio vaccine (eIPV), Haemophilus influenzae type B (HIB), hepatitis B virus (HBV), and other non-mucosal vaccines, have been highly effective in preventing systemic disease during subsequent exposure to natural infection. Recent evidence has shown that parenteral immunization can also be quite effective in inducing varying degrees of functional mucosal antibody responses as detected by ELISA and less frequently by neutralization. Systemic illnesses such as poliomyelitis and Haemophilus influenzae meningitis and community circulation of these agents has been eliminated or significantly limited in many parts of the world with the exclusive use of inactivated vaccines. Based on these observations, it is suggested that development of serum immunological responses are effective in the prevention of systemic disease regardless of the types of vaccines or route of their administration. However, induction of pathogen-specific antibody or cellular immunity at the mucosal sites is best elicited by mucosal application of the antigen.

Abstract: Constant antigenic stimulation of the large immune cell population contained within gut-associated lymphoid tissue during HIV infection may contribute to patients total viral load. The aim of this investigation was to evaluate the effect of a mucosal antigenic challenge on HIV replication. Design: Prospective clinical study. Twelve HIV-1-infected men (mean age 42.3 years) from the Casa de Apoio Santo Antonio Rio de Janeiro Brazil were immunized with combined whole cell--toxin B subunit oral cholera vaccine. Blood was collected on days 0 2 4 6 10 and 15 after immunization and plasma was tested for cholera toxin-specific antibody response (IgG and IgA) b2-microglobulin and plasma viral load. CD4 lymphocyte counts were performed within 1 week before immunization. Five HIV-infected nonimmunized individuals were studied as controls. There were no adverse effects following immunization and no deterioration in clinical outcome during 3 months of follow-up. A transient increase in viral load that ranged from twofold to 60-fold was observed in all cases and was statistically significant on days 2 6 and 10 (P = 0.017 P = 0.025 P = 0.021 respectively). There was no correlation with CD4 cell counts. None of the non-immunized subjects demonstrated the pattern of viraemia observed after immunization (P > 0.10 on all days). Our data indicate that mucosal immunization with oral cholera vaccine induces a transient increase in HIV viraemia regardless of clinical stage of infection and CD4 cell counts. These findings suggest that mucosal stimulation of HIV-infected patients enhances HIV replication. (authors)

Abstract: OBJECTIVES: Although maternal tetanus immunization has been shown to be highly effective in the prevention of neonatal tetanus, unresolved questions remain concerning the required minimum number of doses and the resulting duration of effective immunity. This study examined the duration of effective immunity against neonatal tetanus provided by maternal tetanus immunization. METHODS: A randomized, double-blind cholera vaccine trial of 41,571 children and nonpregnant adult women carried out in 1974 in the Matlab comparison area of rural Bangladesh provided a unique opportunity to address dose and immunity issues. RESULTS: Children of women who received either 1 or 2 injections of tetanus toxoid experienced 4- to 14-day mortality levels consistently lower than those of children of unimmunized mothers. Analysis of neonatal-tetanus-related mortality showed that 2 injections of tetanus toxoid provided significant protection for subsequent durations of up to 12 or 13 years. CONCLUSIONS: The data demonstrate that...

Abstract: Each year cholera epidemics occur in various places around the world. Though there is no effective vaccine against cholera, people who recover from an infection usually have prolonged immunity to the disease. Sera from convalescent patients contain antibodies to a number of outer membrane proteins (OMPs) of V. cholerae. We isolated several OMPs (43, 42, 30, and 22 kDa) from V. cholerae V86 El Tor Inaba, sequenced their amino-termini, and generated hyperimmune sera against them in rabbits. Antisera to the 43-, 42-, and 22-kDa OMPs, but not the preimmune sera, significantly reduced V. cholerae-induced fluid secretion seen in rabbit intestinal loops challenged with the homologous strain. In addition, a combination of antisera to the different OMPs reduced the fluid secretion induced by challenge with heterologous V. cholerae Ogawa and O139 strains. These results have significance in the development of vaccines to V. cholerae, as the hyperexpression of these OMP encoding genes in vaccine strains may improve the efficacy of cholera vaccines.

Abstract: 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.

Abstract: A mutant cholera toxin B subunit containing a G33E substitution was constructed and expressed in V. cholerae. The G33E amino acid substitution did not affect the amount of recombinant CTB secreted to the culture medium. The overexpression of the mutant B subunits in wild-type toxigenic cholera vibrios led to an 80% decrease in production of active cholera toxin in vitro and in vivo. Overexpression of BG33E subunits could be instrumental in the increase of the biosafety of live attenuated cholera candidate vaccine strains.

Abstract: The possibility that a mucolytic drug, i.e., acetylcysteine, given orally may enhance the gut mucosal or systemic immune response to an oral B-subunit–whole-cell (B-WC) cholera vaccine was evaluated for 40 adult Swedish volunteers, and the kinetics of the immune responses were monitored for responding volunteers. Two doses of vaccine induced similar frequencies of immunoglobulin A (IgA) and IgG antitoxin responses (80 to 90%) and vibriocidal titer increases (60 to 65%) in serum irrespective of whether the vaccine was given alone or together with 2 g of acetylcysteine. In feces the frequencies of IgA antitoxin (67%) and antibacterial (33 to 40%) antibody responses were also comparable in the two immunization groups. Six months after vaccination, IgA and IgG antitoxin as well as vibriocidal antibody titer increases in serum could still be detected in approximately 80% of initially responding vaccinees. Significantly elevated fecal antitoxin and antibacterial IgA antibody levels were found in, respectively, 50 and 43% of those volunteers who initially had responded to the vaccine. Determination of IgA antibodies in feces does not seem to offer any advantages compared to determination in serum for assessment of immune responses after immunization with inactivated cholera vaccine.

Abstract: The goal of the present study was to evaluate the tolerability and acceptability of an oral cholera vaccine (CVD103HgR) in individuals preparing for travel to countries endemic for cholera. 2545 Austrian travelers between 6 months and 81.5 years of age received a single dose of CVD103HgR and were asked to complete a questionnaire for documentation of adverse events during a 7 day period post immunization. Events were recorded regardless of whether they were caused by concomitant vaccinations or other factors and thus, a causative relationship was not necessarily present. Despite this drawback and the possibility of overreporting this study has proven a low frequency in side effects and the good tolerability of CVD103HgR. Occasional gastrointestinal side effects (15% diarrhea, 8.1% nausea, 1.1% vomiting) were seen and were of mild character and probably a consequence of associated intake of sodium bicarbonate buffer. Other events (7% skin eruptions, 2.7% fever) were mild and considered as harmless (or not vaccine related). The results show that the oral cholera vaccine CVD103HgR was well tolerated and accepted by travelers.

Abstract: Broiler breeder pullets were vaccinated against fowl cholera at 10 and 20 wk of age using a live PM-1 Pasteurella multocida vaccine administered by wing web stick. Antibody production for P. multocida was measured at vaccination and at 1-4-wk intervals following vaccination by enzyme-linked immunosorbent assay. Groups of vaccinated birds were challenged at 23 and 32 wk of age. Two doses of a live PM-1 P. multocida vaccine protected broiler breeder hens against virulent challenge up to 32 wk of age when measured antibody levels had a range of 1951-4346 and a geometric titer of 3000.

Abstract: Cholera is a severe diarrheal illness caused by several strains of Vibrio cholerae that produce a powerful enterotoxin. Effective treatment for cholera is now well established and inexpensive. V. cholerae is a comma-shaped gram-negative halophilic rod that swims with rapid darting movements, propelled by a single polar flagellum. As a pathogen, toxigenic V. cholerae has remarkable host specificity. Studies of the molecular taxonomy of epidemic V. cholerae suggest that the sixth and seventh pandemics were caused by independently derived clones. In the current pandemic, several mechanisms have been documented by which V. cholerae can be introduced into new geographic areas. The first and perhaps the most important is via a person who travels while harboring an incubating infection. Food-borne transmission is an important component of many epidemics and has been the predominant mode of transmission in some. Moist grains eaten without reheating or acidification are a common vehicle as V. cholerae can grow rapidly on rice, lentils, or other cooked grains. Epidemic cholera can be controlled by reducing the risk of sustained transmission following introduction. In the developed world, this control was achieved by the engineered separation of the human fecal stream from water and food streams. The search for better cholera vaccines has yielded a substantially improved understanding of virulence mechanisms and of the nature of a protective immune response.

Abstract: Sera from an immunogenicity study of killed oral cholera vaccine was tested in high and low binding Elisa plates. High binding plates yielded 5 to 7-fold higher prevaccination IgG antitoxin titres and about 3-fold higher post-vaccine antitoxin titres, but lower cero-conversion rates (39% for high and 68% for low binding plates) when they were compared with low binding plates, because the pre-vaccine titres were relatively higher than the post-vaccine titres. The high titre serum, being used as a standard control serum in each ELISA plate, did not detect the problem. We suggest using lowbinding plates when carryng out ELlSA assays for cholera antitoxin antibodies.

Abstract: The capacity of an oral inactivated B-subunit–whole-cell cholera vaccine to induce immune responses in patients colectomized due to ulcerative colitis was studied. Two doses of vaccine induced significant mucosal immunoglobulin A (IgA) antibody responses in ileostomy fluid against cholera toxin in 14 of 15 (93%) patients and against whole vibrios in 9 of 15 (60%) cases. The serological responses were lower (but not significantly) than those observed in healthy Swedish volunteers. Increased IgA antitoxin levels were found in ileostomy fluid as late as 2 years after vaccination.

Abstract: Background: Several live attenuated vaccines against bacterial enteric pathogens have recently been licensed. These include the Salmonella typhi Ty21a typhoid vaccine (Vivotif Berna® Vaccine) and Vibrio cholerae CVD103-HgR cholera vaccine (Mutacol Berna® Vaccine). They comprise a unique class of biologics in which patient compliance is required for their optimal use. This is of particular importance in the case of the Ty21a vaccine strain of which multiple doses are required. Furthermore, exposure to heat, concomitant use with antibiotics or antimalarial drugs, and timing of vaccination with respect to food intake can affect vaccine potency and/or efficacy. This study was conducted to determine the level of compliance among adult North American travelers and to evaluate compliance errors with respect to potential vaccine efficacy. Methods: Questionnaires were provided to 1091 travelers at twelve travel clinics in the United States and Canada. The patients were requested to complete forms which asked questions relating to vaccine storage and usage, and to return them to the travel clinic. A total of 762 completed questionnaires were returned. Results: Few compliance errors were made regarding proper storage of the vaccine. The most common compliance errors involved not taking all four capsules on alternate days (10%) and not taking all four doses of vaccine prior to departure (6%). Conclusions: Pretravel counselling was effective in obtaining a high compliance rate among adult travelers in the use of Vivotif Berna® Vaccine. The majority of compliance errors reported would not be expected to negatively impact upon vaccine efficacy.