Coverage and costs of mass immunization of an oral cholera vaccine in Vietnam

The objective of this study was to describe a mass-immunization campaign of a locally-produced oral, killed whole-cell cholera vaccine in Hue city, Vietnam. Mass immunization with a 2-dose regimen of the vaccine was conducted in 13 communes in early 1998. The total, age- and sex-specific vaccine coverage was calculated using data from the vaccination records and the government census. The number of vaccine doses procured, administered, wasted, and left over, and the human and other resources required to prepare and conduct the vaccination campaign were systematically recorded. Government expenditure for planning, procurement, and delivery of the vaccine were documented. In total, 118,555 (79%) of the 49,557 targeted population were fully vaccinated during the mass-vaccination campaign. The total expenditure for the project was US dollar 105,447, resulting in a cost per fully-vaccinated person of US dollar 0.89. Mass immunization with this locally-produced oral, killed cholera vaccine was found to be feasible and affordable with attainment of high vaccination coverage.     

Safety and immunogenicity of a reformulated Vietnamese bivalent killed, whole-cell, oral cholera vaccine in adults

Vietnam currently produces an orally administered, bivalent (O1 and O139) killed whole-cell vaccine and is the only country in the world with endemic cholera to use an oral cholera vaccine in public health practice. In order to allow international use, the vaccine had to be reformulated to meet World Health Organization (WHO) requirements. We performed a randomized, placebo controlled, safety and immunogenicity studies of this reformulated vaccine among Vietnamese adults. One hundred and forty-four subjects received the two-dose regimen and 143 had two blood samples obtained for analysis. We found that this reformulated oral killed whole-cell cholera vaccine was safe, well tolerated and highly immunogenic.     

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.     

Mass vaccination with a two-dose oral cholera vaccine in a refugee camp

In refugee settings, the use of cholera vaccines is controversial since a mass vaccination campaign might disrupt other priority interventions. We therefore conducted a study to assess the feasibility of such a campaign using a two-dose oral cholera vaccine in a refugee camp. The campaign, using killed whole-cell/recombinant B-subunit cholera vaccine, was carried out in October 1997 among 44,000 south Sudanese refugees in Uganda. Outcome variables included the number of doses administered, the drop-out rate between the two rounds, the proportion of vaccine wasted, the speed of administration, the cost of the campaign, and the vaccine coverage. Overall, 63,220 doses of vaccine were administered. At best, 200 vaccine doses were administered per vaccination site and per hour. The direct cost of the campaign amounted to US$ 14,655, not including the vaccine itself. Vaccine coverage, based on vaccination cards, was 83.0% and 75.9% for the first and second rounds, respectively. Mass vaccination of a large refugee population with an oral cholera vaccine therefore proved to be feasible. A pre-emptive vaccination strategy could be considered in stable refugee settings and in urban slums in high-risk areas. However, the potential cost of the vaccine and the absence of quickly accessible stockpiles are major drawbacks for its large-scale use.     

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.     

Construction of a Vibrio cholerae prototype vaccine strain O395-N1-E1 which accumulates cell-associated cholera toxin B subunit

Because of its production and use in Vietnam, the most widely used oral cholera vaccine consists of heat- or formalin-killed Vibrio cholerae whole cells (WC). An earlier version of this type of vaccine called whole cell-recombinant B subunit vaccine (BS-WC) produced in Sweden also contained the B subunit of cholera toxin (CTB). Both WC and BS-WC vaccines produced moderate levels of protection in field trials designed to evaluate their cholera efficacy. V. cholerae cells in these vaccines induce antibacterial immunity, and CTB contributes to the vaccine's efficacy presumably by stimulating production of anti-toxin neutralizing antibody. Although more effective than the WC vaccine, the BS-WC vaccine has not been adopted for manufacture by developing world countries primarily because the CTB component is difficult to manufacture and include in the vaccine in the doses needed to induce significant immune responses. We reasoned this was a technical problem that might be solved by engineering strains of V. cholerae that express cell-associated CTB that would co-purify with the bacterial cell fraction during the manufacture of WC vaccine. Here we report that construction of a V. cholerae O1 classical strain, O395-N1-E1, that has been engineered to accumulate CTB in the periplasmic fraction by disrupting the epsE gene of type II secretion pathway. O395-N1-E1 induces anti-CTB IgG and vibriocidal antibodies in mice immunized with two doses of formalin killed whole cells. Intraperitoneal immunization of mice with O395-N1-E1 induced a significantly higher anti-CTB antibody response compared to that of the parental strain, O395-N1. Our results suggest that this prototype cholera vaccine candidate strain may assist in preparing improved and inexpensive oral BS-WC cholera vaccine without the need to purify CTB separately.     

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.     

Oral cholera vaccines containing B-subunit-killed whole cells and killed whole cells only. II. Field evaluation of cross-protection against other members of the Vibrionaceae family

Because of demonstrable cross-reactivity of cellular antigens contained in B subunit-killed whole-cell (BS-WC) and killed whole-cell-only (WC) oral cholera vaccines with antigens of various non-cholera species of the family Vibrionaceae (NCV), the protection conferred by the vaccines against diarrhoea associated with NCV was evaluated during a randomized, double-blind field trial in Bangladesh. Children aged 2-15 years and women aged greater than 15 years (62,285 in number) received three doses of BS-WC vaccine, WC-only vaccine, or a placebo consisting of Escherichia coli K12 strain (K12). During 1 year of follow-up, the incidence of treated episodes of diarrhoea associated with non-cholera vibrios known to be enteric pathogens (non-01 Vibrio cholerae, V. fluvialis, V. parahaemolyticus, V. mimicus) in the placebo group was low (1.9 cases per 10,000 recipients) and identical to that for the two vaccine groups combined. The incidence (per 10,000 recipients) of treated diarrhoeal episodes associated with Aeromonas species was considerably higher, but nearly identical in the three groups (26.1 cases for BS-WC, 26.0 cases for WC; 25.9 cases for K12). Pleisiomonas shigelloides was not isolated from any participant. It is concluded that NCV other than Aeromonas were rarely isolated from diarrhoeal patients in our study population and that killed oral vaccines which were effective against cholera exhibited no detectable cross-protection against diarrhoea associated with NCV organisms.     

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.     

Analysis of efficacy of CVD 103-HgR live oral cholera vaccine against all-cause travellers' diarrhoea in a randomised, double-blind, placebo-controlled study

Enterotoxigenic Escherichia coli (ETEC), which produces heat labile toxin (LT) and/or heat stable toxin (ST), is considered to be the most common known cause of travellers' diarrhoea (TD). Owing to the antigenic similarity between cholera toxin and LT, immunization with inactivated oral B-subunit/whole-cell cholera vaccine (BS-WC) offers short term (3 months) but significant (>67%) protection against TD caused by LT-related ETEC. Since it expresses the cholera toxin B (CTB) subunit, the live attenuated oral cholera vaccine strain CVD 103-HgR, may induce similar protection. A trial was performed to determine if CVD 103-HgR live oral cholera vaccine would provide a protective efficacy of at least 50% against TD. In addition, the protective efficacy of the vaccine against TD specifically due to LT-ETEC and LT/ST-ETEC was determined. Volunteers (n=134) travelling to Indonesia, India, Thailand or West-Africa were randomised to receive either a placebo (n=65) or the vaccine (n=69). In the placebo group, 46% reported an episode of diarrhoea, compared to 52% in the vaccine group. No significant group differences were found with regard to incidence, duration or severity of all caused TD or ETEC-associated TD. However, ETEC-associated TD occurred earlier in the placebo group (median 5 days), compared to the vaccine group (median 15 days). In conclusion, CVD 103-HgR live oral cholera vaccine failed to provide a 50% protection against TD. This study does not exclude that the vaccine may offer a short-lived protection against ETEC-associated TD. However, the power of the study was limited by the unexpected low incidence of LT-ETEC-associated diarrhoea (9% of all TD) compared to ST-associated TD (24% of all TD).     

New cholera vaccines

Development of improved cholera vaccines has progressed rapidly in recent years. An oral killed vaccine, designed to evoke antibacterial as well as antitoxic intestinal immunity, has proved to be completely safe and to protect against cholera for at least 3 years. This vaccine also confers substantial though more short-lasting immunity against diarrhoea caused by enterotoxigenic Escherichia coli. Significant progress has also been made towards developing a live attenuated cholera vaccine using recombinant DNA techniques. The advent of effective oral cholera vaccines gives hope for improved control of cholera in the Third World.     

Experimental evaluation of antitoxic protective effect of new cholera vaccines in mice.

Intraperitoneal immunization of mice and subsequent challenge with purified cholera toxin (CT) were employed to evaluate the anti-cholera toxin protective effect of two new oral cholera vaccines, live CVD 103-HgR and killed B subunit-whole cell (BS-WC). CVD 103-HgR vaccine demonstrated 100% protection of mice against 2.25 LD50 and 70% against 3 LD50 of CT. Mice immunized with BS-WC vaccine were protected against 2.25 and 3 LD50 of CT in 88 and 62% of cases, respectively. All three killed parenteral vaccines failed to protect against CT. We suggest this mouse system for preliminary evaluation of the antitoxic protective activity of cholera vaccines.     

Enhanced immunogenicity of an oral inactivated cholera vaccine in infants in Bangladesh obtained by zinc supplementation and by temporary withholding breast-feeding

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.     

Comparative study of reactions and serological response to cholera vaccines in a controlled field trial conducted in the USSR

This article presents the results of a comparative study of the reactogenicity and the serological response induced by a number of cholera vaccines. Conducted in the USSR on 998 adults aged 18 years and over, the study covered whole-cell heat-killed and formalin-inactivated cholera vaccines, whole-cell heat-killed El Tor vaccine, and a new partially purified toxoid preparation proposed for the immunoprophylaxis of cholera—all administered by hypodermic syringe or jet injector. The most marked reactions were found to occur with the formalin-inactivated cholera vaccine and the least marked with the partially purified toxoid. It was also established that the toxoid was no less effective than the whole-cell vaccine in inducing the intense production of antibodies to the Inaba serotype and, in somewhat lesser degree, to the Ogawa serotype of the El Tor vibrio. It was the only preparation to give rise to intense production of specific antitoxins in 95-98% of cases. The reactions to and immunogenic properties of the cholera vaccines did not show any statistically significant difference whether administered by hypodermic syringe or by jet injector.     

Antibody response in the intestinal secretions of volunteers immunized with various cholera vaccines

The efficacy of various cholera vaccines in eliciting an intestinal antibody response was assessed in human volunteers who received oral live, oral killed, or parenteral cholera vaccines, or placebo. The intestinal immune response in terms of antibacterial and antitoxin antibodies was determined 2 and 4 weeks after immunization. By means of the mouse peritoneum opsonization assay and the infant mouse protection test, antibacterial activity could be detected in the intestinal secretions of volunteers who had been immunized either orally or by the parenteral route. Significant protective activity and duration of immunity were observed with the oral killed vaccine. The bacteriological data indicated the absence of significant intestinal colonization of the live attenuated strain after oral administration, and probably explains the observed lack of effectiveness of the oral vaccine compared with that of the killed vaccine. The predominant immunoglobulin class of intestinal antibody was found to be IgA. None of the vaccines used in the study elicited significant antitoxin activity in the intestinal secretions, as determined by the skin permeability neutralization test.     

Crossed immunoelectrophoretic analysis of antigenic composition of B-subunit/whole-cell and whole-cell only killed oral cholera vaccines.

Crossed immunoelectrophoresis was used to identify antigens preserved in the whole-cell component of oral cholera vaccines tested in the field trial in Bangladesh. The composition and immunogenicity of the vaccine antigens were compared with those of antigens obtained from live cells of Vibrio cholerae 01 of both biovars and serovars. The whole-cell component of the vaccine contained ten antigens in comparison with the live Vibrio cells which revealed the presence of 30 antigens. The whole-cell component contained lipopolysaccharide, flagellar antigen, one cell-bound haemagglutinin and at least six outer membrane protein antigens.     

A non-inferiority trial comparing two killed,whole cell,oral cholera vaccines (Cholvax vs. Shanchol) in Dhaka,Bangladesh

Bangladesh remains cholera endemic with biannual seasonal peaks causing epidemics. At least 300,000 severe cases and over 4,500 deaths occur each year. The available oral cholera vaccines have not yet been adopted for cholera control in Bangladesh due to insufficient number of doses available for endemic control. With a public private partnership, icddr,b initiated a collaboration between vaccine manufacturers in Bangladesh and abroad. A locally manufactured Oral Cholera Vaccine (OCV) named Cholvax became available for testing in Bangladesh. We evaluated the safety and immunogenicity of this locally produced Cholvax (Incepta Vaccine Ltd) inexpensive OCV comparatively to Shanchol (Shantha Biotechnics-Sanofi Pasteur) which is licensed in several countries. We conducted a randomized non-inferiority clinical trial of bivalent, killed oral whole-cell cholera vaccine Cholvax vs. Shanchol in the cholera-endemic area of Mirpur, Dhaka, among three different age cohorts (1–5, 6–17 and 18–45 years) between April 2016 and April 2017. Two vaccine doses were given at 14 days apart to 2,052 healthy participants. No vaccine-related serious adverse events were reported. There were no significant differences in the frequency of solicited (7.31% vs. 6.73%) and unsolicited (1.46% vs. 1.07%) adverse events reported between the Cholvax and Shanchol groups. Vibriocidal antibody responses among the overall population for O1 Ogawa (81% vs. 77%) and O1 Inaba (83% vs. 84%) serotypes showed that Cholvax was non-inferior to Shanchol, with the non-inferiority margin of ?10%. For O1 Inaba, GMT was 462.60 (Test group), 450.84 (Comparator group) with GMR 1.02(95% CI: 0.92, 1.13). For O1 Ogawa, GMT was 419.64 (Test group), 387.22 (Comparator group) with GMR 1.12 (95% CI: 1.02, 1.23). Cholvax was safe and non-inferior to Shanchol in terms of immunogenicity in the different age groups. These results support public use of Cholvax to contribute for reduction of the cholera burden in Bangladesh. ClinicalTrials.gov number: NCT027425581.     

Reduction of travellers’ diarrhoea by WC/rBS oral cholera vaccine in young,high-risk travellers

Aims

A bidirectional cohort study investigates whether pre-travel vaccination with whole cell/recombinant B subunit inactivated, killed oral cholera vaccine reduces the incidence of diarrhoea in young adult travellers to high-risk areas.

Scope

Risk of travellers’ diarrhoea was assessed according to destination and reason for travel in high-risk travellers of a travel clinic in Barcelona, Spain.Those at high-risk between January and December 2005 were advised on water/food safety and hygiene. High-risk travellers between January and December 2006 were additionally vaccinated with WC/rBS oral cholera vaccine. Data regarding diarrhoea were gathered by structured telephone interview or e-mailed questionnaire following the travellers’ return.The incidence of diarrhoea in the group vaccinated with WC/rBS oral cholera vaccine (n = 321) was 17.4%, compared with 39.7% in the non-vaccinated group (n = 337) (adjusted risk ratio 0.40). The first episode was significantly shorter in the vaccinated group (mean 2.3 days) than in the non-vaccinated group (mean 3.8 days) (p < 0.001).Conclusions: The protective effect of the WC/rBS oral cholera vaccine was 57% in the young, high-risk travellers. Vaccination with the WC/rBS oral cholera vaccine as well as food safety and hygiene advice could offer effective means of reducing the risk of diarrhoea while abroad.     

Construction of novel vaccine strains of Vibrio cholerae co-expressing the Inaba and Ogawa serotype antigens

The approach of inducing protective immunity against cholera by oral vaccination with killed whole Vibrio cholerae cells is effective, but the complexity of current cholera vaccines makes them difficult and relatively expensive to manufacture, especially if recombinant cholera toxin B subunit is included in the formulation. In an effort to simplify the composition of a new generation of oral cholera vaccines we have generated a novel non-toxigenic candidate vaccine strain of V. cholerae O1 that stably expresses both the Ogawa and Inaba serotype antigens on its surface. This was done by introducing a functional wbeT gene without a functional promoter into the chromosome of an O1 Inaba strain. The resulting low levels of expression of the wbeT gene product allowed for the desired partial serotype switching. This strain (MS1342) can potentially replace the three virulent strains used in currently manufactured cholera vaccines. Oral immunization of mice with formalin-killed MS1342 bacteria gave rise to Ogawa-specific, Inaba-specific and cross-reactive serum antibodies that were detectable both by lipopolysaccharide (LPS)-specific ELISAs and as vibriocidal antibodies that are considered to predict protective efficacy. These responses as well as intestinal mucosal IgA anti-LPS antibody responses were fully comparable with those obtained by immunization with the internationally licensed oral cholera vaccine Dukoral^®. We propose that such a strain may form the basis of a single strain killed whole cell cholera vaccine protecting against cholera caused by either the Inaba or Ogawa serotype of V. cholerae O1.     

Can oral cholera vaccination play a role in controlling a cholera outbreak?

Control measures to limit the spread of a cholera outbreak in Pohnpei Island (Micronesia), included mass vaccination with the single-dose live-attenuated oral cholera vaccine CVD 103-HgR as a potential adjunct measure. The outbreak provided a unique opportunity to evaluate the practicality of use and effectiveness of this vaccine. Under field conditions encountered in Pohnpei, crude vaccine efficacy was estimated at 79.2% (95% CI: 71.9-84.6%) in the target population. Retrospective analysis suggests that mass vaccination with oral cholera vaccines can be a useful adjunct tool for controlling outbreaks, particularly if implemented early in association with other standard control measures.