Abstract: 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$ 105,447, resulting in a cost per fully-vaccinated person of US$ 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. Key words : Cholera; Cholera vaccine; Immunization; Immunization programmes; Costs and cost analysis; Vietnam

Abstract: The paper by Vu Dinh Thiem et al. in this issue of the Journal provides valuable documentation of the costs for providing killed oral cholera vaccine during a mass-vaccination programme in Vietnam (1). Vietnam is the only country where cholera vaccine is now being given to endemic populations, although many other countries in Asia and Africa have regular seasonal outbreaks of cholera. This raises the question of defining the circumstances for using cholera vaccine in endemic areas. The World Health Organization (WHO) has recommended use of killed oral cholera vaccine in refugee populations of Africa (2), but it has not yet formulated a policy for use of either the live or killed oral vaccines in areas endemic for cholera (Chaignat CL. Personal communication, 2003). There are several reasons why it has been difficult for WHO to formulate such a policy. The true burden of disease from cholera is not well-understood since many nations with cholera do not report it because of fears of restriction on trade and travel, and when they do, the numbers likely do not reflect the true rates of infection. Outbreaks or epidemics are more likely to be reported than cases occurring in endemic situations, and many endemic areas do not have the laboratory or epidemiological surveillance resources to document accurate rates. Since countries are not reporting cholera, it becomes difficult for WHO to recommend a vaccine for an infection that is not recognized to occur (3). However, many geographic areas continue to have a large burden of disease from cholera, often exceeding one hospital case per thousand annually. In these areas, cholera is well-known to the local population, they greatly fear it and would likely welcome a vaccine providing protection. Since the recommendations differ between refugee situations and endemic areas, it would be useful to review some differences in these two situations (Table). In endemic areas, people have some degree of acquired immunity, and this pre-existing immunity modulates the effectiveness of any vaccine. It is also possible to establish surveillance for cholera and, thus, to determine a true burden of disease. When patients develop symptoms of cholera, they use the routine primary healthcare facilities available for any other diarrhoeal disease, including government hospitals or traditional providers. In either case, the decision for implementing a cholera vaccine programme would logically depend on an analysis of its cost-effectiveness from a national perspective. Because the patients are using routine facilities, there is likely to be less public awareness of the problem, and it would be handled as a national problem, with little opportunity for urgent international funding. Thus, the funds to deal with the problem will need to come from a regular budgetary provision. By contrast, the situation of cholera outbreaks in refugees is quite different. Refugees often have little or no immunity since they may have migrated into a cholera area from one that was not cholera-endemic. By definition, there has been no background information on expected disease incidence since there has been no surveillance. Based on other similar situations, however, rates might be expected to be high (4). In contrast to the endemic area, medical care is often provided by special facilities for refugees, and these facilities are often provided by international agencies. These agencies are often well-connected to journalists who may publicize the cholera epidemics, and this publicity may generate substantial emergency funds from international donors. Cost-effectiveness considerations may then take a secondary role to the emergency humanitarian need from the epidemic. The experience of ICDDR,B in Bangladesh might be cited to illustrate the situation in a cholera-endemic area. In its rural Matlab field area with a population of over 200,000, the annual incidence has generally been from 1 to 5 case(s) of cholera per 1,000 as detected by hospital surveillance (5-7). …

Abstract: PURPOSE OF REVIEW International travelers may be at risk from a variety of potentially severe and life-threatening infections. Some of these diseases are preventable, and vaccination remains a cornerstone of travel medicine. Vaccines that are important for international travel are reviewed, in a succinct update based on the most recent literature. RECENT FINDINGS Discussed are vaccines for enteric infections (polio, cholera, hepatitis A, and typhoid), as well as those for hepatitis B, Japanese encephalitis, yellow fever, and meningococcal vaccines. The controversial end to the polio eradication campaign and the recognition of vaccine-derived polioviruses are discussed. New monovalent cholera vaccines, including the live attenuated Peru-15 and CVD 103-HgR and the oral killed whole cell B subunit vaccine are reviewed, as well as a new oral bivalent vaccine that may offer protection against Vibrio cholerae 0139. Advances in typhoid vaccination include promising preclinical and clinical trial results of recombinant ZH9 and CVD 908-htrA vaccines, which, in addition to providing protection against typhoid fever, may be useful vectors for heterologous antigens. A growing recognition of rare adverse reactions to the 17D yellow fever vaccine, especially postvaccinal encephalitis, has led to a reassessment of its risks and benefits. Development of a novel chimeric vaccine may improve the safety and efficacy of the current Japanese encephalitis vaccine. Vaccination for meningococcal disease is characterized by the need for polyvalent, conjugate vaccines as well as a product that affords protection against serotype B. SUMMARY This travel vaccination review highlights progress in new travel-related vaccine development and updates the reader on issues surrounding licensed products. It will be useful for generalists, infectious disease physicians, and travel medicine specialists.

Abstract: An oral cholera vaccine made up of three Vibrio cholerae antigens, i.e. lipopolysaccharide (LPS), recombinant toxin co-regulated pili (rTcpA) and heat-treated cholera toxin (H-CT) has been developed in six different formulations. Eight-week-old Wistar rats were divided into nine groups and immunized as follows: the first group received the oral vaccine 1 consisting of the three antigens (LPS, rTcpA and H-CT) associated with a liposome (L) and bacterial CpG-DNA (ODN#1826). The rats of groups 2 and 3 received oral vaccines 2 and 3 consisting of the liposome-associated three antigens with and without non-bacterial CpG-DNA (ODN#1982), respectively. Rats of groups 4 received oral vaccine 4 consisting of the three antigens mixed with the ODN#1826, similar to vaccine 1, but without liposome. Rats of groups 5 and 6 received oral vaccines 5 and 6 consisting of the three antigens with and without ODN#1982, respectively, similar to vaccines 2 and 3, but without liposome. Rats of groups 7, 8 and 9 received oral placebos, namely liposomes (L), ODN#1826 (CpG), and vaccine diluent, i.e. 5% NaHCO3 solution, respectively. All vaccines were given in three doses at 14-day intervals. It was found that the combination of liposome and ODN#1826 in vaccine 1 evoked the highest immune response to V. cholerae antigen compared to other vaccine formulations and placebos, as measured by the appearance of antigen-specific antibody-producing cells in the intestinal lamina propria. The immunogenicity according to the magnitude of the immune response was: V1>V2=V3>V4>V5=V6>V7=V8=V9. The results of this study indicate that CpG-DNA and liposome are effective mucosal adjuvants for an oral cholera vaccine prepared from refined V. cholerae antigens and their combination seems to be synergistic. The potential role of liposome as a vaccine delivery vehicle has been confirmed.

Abstract: A process for preparing the antigen protein used for hog cholera vaccine includes extracting hog cholera virus RNA, reverse transcription to obtain the immune gene E2 of hog cholera virus, using E2 as template for PCR while inserting them to expression carrier of Bichia yeast, introducing the recombinant expression carrier to Bichia yeast, screening the recombinant Bichia yeast, discriminating its expression product testing its immunoactivity, determining the chosen recombinant yeast, testing and analyzing its culture condition, choosing the optimal culture condition, culturing the recombinant yeast and preparing the antigen protein of said vaccine.

Abstract: Cholera, the acute diarrheal disease caused by Vibrio cholerae serogroups O1 and Ol39, continues to cause endemic disease and epidemic outbreaks in many parts of the world The highest incidence of disease is found in poor countries with inadequate waste disposal and contaminated water supplies Over nearly two centuries, it has caused seven pandemics, the last of which began in 1961 and continues today The impact that cholera has had on the health of the worlds population, even in the last decade, remains substantial In 1991, cholera returned to Latin America causing hundreds of thousands of cases;1 in 1994, epidemic cholera rapidly swept through the Rwandan refugee camps in Zaire leading to an estimated 70,000 cases and 12,000 deaths2 In the year 2000, it was reported in 56 countries and in every region of the world In 2000 and 2001, large numbers of cases were reported in many countries including the Niger, Guinea, Burkina Faso, Ivory Coast, Mali, Chad, and Afghanistan India suffered tens of thousands of cases after severe flooding, and over 86,000 cases were reported in Kwazulu-Natal in South Africa Cholera has also found its way to the islands of Micronesia, the Marshalls, and Madagascar3 The worldwide case-fatality rate, as reported by the World Health Organization, was 36% in 2000 Although much progress has been made, it is clear that current efforts to curb the devastation of cholera remain inadequate

Abstract: Zinc plays a critical role in the normal functioning of the immune system. We investigated whether zinc sulfate administered orally to adult zinc-replete volunteers modulates systemic and intestinal immune responses to an oral killed cholera toxoid B subunit (CTB) whole-cell cholera vaccine. The 30 participants were immunized twice, with a 17-day interval. The vaccinees in the intervention group ingested 45 mg of elemental zinc thrice daily for 9 days starting 2 days before each vaccine dose. The median serum anti-CTB immunoglobulin A (IgA) and IgG responses from day 0 to day 30, i.e. after two vaccine doses, were 13-fold lower (P value for identical distribution, <0.005) in the zinc-supplemented compared to the nonsupplemented vaccinees. The median serum vibriocidal responses from baseline to after one (day 0 to day 17) and two (day 0 to day 30) vaccine doses were at least sixfold (P = 0.033) and fourfold (P = 0.091) higher, while the median fecal anti-CTB IgA response after two doses was estimated to be fourfold higher (P = 0.084) in the zinc-supplemented vaccinees. These observations show that zinc reduces the antitoxin and may enhance the antibacterial responses in serum. Zinc may also improve the intestinal antitoxin immune response. Oral zinc administration has the potential to modify critical immune responses to antigens applied to mucosal surfaces.

Abstract: IEM101, a Vibrio cholerae O1 El Tor Ogawa strain naturally deficient in CTXPhi, was previously selected as a live cholera vaccine candidate. To make a better and safer vaccine that can induce protective immunity against both the bacteria and cholera toxin (CT), a new vaccine candidate, IEM108, was constructed by introducing a ctxB gene and an El Tor-derived rstR gene into IEM101. The ctxB gene codes for the protective antigen CTB subunit, and the rstR gene mediates phage immunity. The stable expression of the two genes was managed by a chromosome-plasmid lethal balanced system based on the housekeeping gene thyA. Immunization studies indicate that IEM108 generates good immune responses against both the bacteria and CT. After a single-dose intraintestinal vaccination with 10(9) CFU of IEM108, both anti-CTB immunoglobulin G and vibriocidal antibodies were detected in the immunized-rabbit sera. However, only vibriocidal antibodies are detected in rabbits immunized with IEM101. In addition, IEM108 but not IEM101 conferred full protection against the challenges of four wild-type toxigenic strains of V. cholerae O1 and 4 micro g of CT protein in a rabbit model. By introducing the rstR gene, the frequency of conjugative transfer of a recombinant El Tor-derived RS2 suicidal plasmid to IEM108 was decreased 100-fold compared to that for IEM101. This indicated that the El Tor-derived rstR cloned in IEM108 was fully functional and could effectively inhibit the El Tor-derived CTXPhi from infecting IEM108. Our results demonstrate that IEM108 is an efficient and safe live oral cholera vaccine candidate that induces antibacterial and antitoxic immunity and CTXPhi phage immunity.

Abstract: To investigate whether micronutrient supplementation could improve the vibriocidal antibody response of children to a killed oral cholera vaccine, 2-5-year-old children were randomly assigned to receive vitamin A and zinc (AZ group), vitamin A and a placebo (A group), zinc and a placebo (Z group), or both placebos (P group). All children received 2 doses of the vaccine. The number of children who had a > or = 4-fold increase in vibriocidal antibody was significantly greater in the AZ group than in the P group (P = .025-.028). Factorial analysis suggested that the proportion of children with a > or = 4-fold increase in vibriocidal antibody titer was significantly greater in the zinc-supplemented groups than in the groups that did not receive zinc (P = .013-.048) and that vitamin A supplementation did not have a significant effect. Thus, supplementation with zinc improves seroconversion to vibriocidal antibody and, hence, has the potential to improve the efficacy of oral cholera vaccine in children.