Abstract: CVD 103-HgR is a live oral cholera vaccine strain constructed by deleting 94% of the gene for the enzymatically active A subunit of cholera toxin from classical Inaba Vibrio cholerae O1 569B; the strain also contains a mercury resistance gene as an identifying marker. This vaccine was well tolerated and immunogenic in double-blind, controlled studies and was protective in open-label studies of volunteers challenged with V. cholerae O1. A randomized, double-blind, placebo-controlled, multicenter study of vaccine efficacy was designed to test longer-term protection of CVD 103-HgR against moderate and severe El Tor cholera in U.S. volunteers. A total of 85 volunteers (50 at the University of Maryland and 35 at Children's Hospital Medical Center/University of Cincinnati) were recruited for vaccination and challenge with wild-type V. cholerae El Tor Inaba. Volunteers were randomized in a double-blind manner to receive, with buffer, a single oral dose of either CVD 103-HgR (2 x 10(8) to 8 x 10(8) CFU) or placebo (killed E. coli K-12). About 3 months after immunization, 51 of these volunteers were orally challenged with 10(5) CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Ninety-one percent of the vaccinees had a >/=4-fold rise in serum vibriocidal antibodies after vaccination. After challenge, 9 (39%) of the 23 placebo recipients and 1 (4%) of the 28 vaccinees had moderate or severe diarrhea (>/=3-liter diarrheal stool) (P < 0.01; protective efficacy, 91%). A total of 21 (91%) of 23 placebo recipients and 5 (18%) of 28 vaccinees had any diarrhea (P < 0.001; protective efficacy, 80%). Peak stool V. cholerae excretion among placebo recipients was 1.1 x 10(7) CFU/g and among vaccinees was 4.9 x 10(2) CFU/g (P < 0.001). This vaccine could therefore be a safe and effective tool to prevent cholera in travelers.

Abstract: Vibrio cholerae 638 (El Tor, Ogawa), a new CTXPhi-negative hemagglutinin/protease-defective strain that is a cholera vaccine candidate, was examined for safety and immunogenicity in healthy adult volunteers. In a double-blind placebo-controlled study, no significant adverse reactions were observed in volunteers ingesting strain 638. Four volunteers of 42 who ingested strain 638 and 1 of 14 who received placebo experienced loose stools. The strain strongly colonized the human small bowel, as evidenced by its isolation from the stools of 37 of 42 volunteers. V. cholerae 638, at doses ranging from 4 x 10(7) to 2 x 10(9) vibrios, elicited significant serum vibriocidal antibody and anti-Ogawa immunoglobulin A antibody secreting cell responses.

Abstract: Nasal vaccine delivery is superior to oral delivery in inducing specific immunoglobulin A (IgA) and IgG antibody responses in the upper respiratory tract. Although an antibody response in the nasal passages is important in protecting against primary colonization with lung pathogens, antibodies in the lungs are usually required as well. We immunized 15 male volunteers twice nasally or orally with cholera toxin B subunit (CTB) and determined the specific antibody levels in serum, bronchoalveolar lavage (BAL) fluid, and urine before and 2 weeks after immunization. Nasal immunization induced fivefold increases in the levels of specific IgA antibodies in BAL fluid of most volunteers, whereas there were no significant specific IgA responses after oral immunization. The specific IgG antibody level increased eightfold in BAL fluid in the nasally vaccinated subjects, and the major part of IgG had most probably been transferred from serum. Since the specific IgG response in serum was lower in the individuals vaccinated orally, the IgG response in BAL fluid in this group was also lower and not significant. In conclusion, nasal immunization is also preferable to the oral route when vaccinating against lower respiratory tract infections, and a systemic immune response is considerably more important in the lower than in the upper respiratory tract. Moreover, both nasal and oral immunizations were able to stimulate 6- to 10-fold specific IgA and IgG responses in urine in about half of the individuals, which indicates that distant mucosal vaccination might be used to prevent adhesion of pathogens to the urogenital tract.

Abstract: 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.

Abstract: The mucosal and systemic immune responses after primary and booster immunizations with two attenuated live oral vaccine strains derived from a noninvasive (Vibrio cholerae) and an invasive (Salmonella typhi) enteric pathogen were comparatively evaluated. Vaccination with S. typhi Ty21a elicited antibody-secreting cell (ASC) responses specific for S. typhi O9, 12 lipopolysaccharide (LPS), as well as significant increases in levels of immunoglobulin G (IgG) and IgA antibodies to the same antigen in serum. A strong systemic CD4+ T-helper type 1 cell-mediated immune (CMI) response was also induced. In contrast to results with Ty21a, no evidence of a CMI response was obtained after primary immunization with V. cholerae CVD 103-HgR in spite of the good immunogenicity of the vaccine. Volunteers who received a single dose of CVD 103-HgR primarily developed an IgM ASC response against whole vaccine cells and purified V. cholerae Inaba LPS, and seroconversion of serum vibriocidal antibodies occurred in four of five subjects. Serum IgG anti-cholera toxin antibody titers were of lower magnitude. For both live vaccines, the volunteers still presented significant local immunity 14 months after primary immunization, as revealed by the elevated baseline antibody titers at the time of the booster immunization and the lower ASC, serum IgG, and vibriocidal antibody responses after the booster immunization. These results suggest that local immunity may interfere with colonization of the gut by both vaccine strains at least up to 14 months after basis immunization. Interestingly, despite a low secondary ASC response, Ty21a was able to boost both humoral (anti-LPS systemic IgG and IgA) and CMI responses. Evidence of a CMI response was also observed for one of three volunteers given a cholera vaccine booster dose. The direct comparison of results with two attenuated live oral vaccine strains in human volunteers clearly showed that the capacity of the vaccine strain to colonize specific body compartments conditions the pattern of vaccine-induced immune responses.

Abstract: The changing epidemiology of cholera in Ibadan, Nigeria, has become a public health challenge, and outbreaks of the disease have been occurring with increasing frequency since the first outbreak in modern times in 1970. In this outbreak, 1384 persons were seen, diagnosed and treated for the disease at the cholera unit, Ibadan from January to December 1996. The outbreak lasted for a whole year. No child under one year was seen. The age adjusted case fatality rate was 5.3%. Diarrhoea and vomiting were the most common combination of symptoms present in 97.3% of all cases, followed by diarrhoea, vomiting and dehydration (84.3%). The median number of days spent on admission was only 2 days. Cholera cases were clustered within the densely populated and poorly planned areas of the city. Though significantly more cases were seen during the rainy season than during the dry season (p < 0.01), the deaths were not seasonally related (p = 0.67). Contamination of otherwise potable sources of water, late presentation to the cholera treatment unit and low levels of knowledge about diseases need to be addressed in order to effectively control this disease in the community. Progress should also be made towards developing a suitable vaccine for the control of this internationally important public health disease so that the responsibility of its control is not left entirely to individuals and communities, particularly in developing countries.

Abstract: Background.Live oral cholera vaccine CVD 103-HgR is well-tolerated and immunogenic when administered to adults, school age children and preschool children in a single 5 × 109 colony-forming unit dose. Because elicitation of immune responses after administration of a single dose is exceptional for an

Abstract: Sir -- Further to the mass cholera vaccination campaign in refugee camps in Adjumani district, Northern Region, Uganda, reported in the last issue of the Bulletin (1), we describe below the situation when a cholera outbreak occurred in the district one year after the campaign. Adjumani district has offered asylum to Sudanese refugees since 1989. The refugee population, which represents about 55% of the total district population (125 000 people), is spread over 35 different settlement camps. At the request of WHO, a pilot vaccination campaign with the WC/rBS oral cholera vaccine was conducted in October 1997 in six of these camps. The objective was to assess the feasibility and acceptability of mass vaccination in a large refugee setting (2). Vaccine coverage was 87.0%, a total of 27 607 persons being fully vaccinated. A cholera epidemic caused by Vibrio cholerae El Tor serotype Ogawa reached the north of Uganda in April 1998. In Adjumani district the first cases of cholera were reported in August, and the epidemic peaked in October 1998. Between 17 August and 8 November, 358 cases of cholera were reported from 60 different locations covering the entire district. The overall attack rate was 0.3% and the case-fatality ratio was 4.2% (15 deaths). The epidemic affected the entire district, and all the refugees, including those living in the vaccinated camps, were exposed to the risk of cholera. A total of 28 cases out of 358 (7.8%) occurred among refugees, but none of them came from a settlement that participated in the vaccination campaign in 1997. Attack rates were higher in the Ugandan population than in the refugee population (0.59% v 0.04%, relative risk: 14.4 (95% confidence interval, 9.8-21.2)). Water supplies and sanitation facilities were similar in the vaccinated and non-vaccinated settlements, but were better in the settlements than in the Ugandan villages. This fact might partly explain the lower attack rate observed in the refugee population. Since no case of cholera was reported from the vaccinated population, it was not possible to measure vaccine effectiveness using classic epidemiological studies (3). Therefore, in order to assess whether the cholera vaccination had had a protective effect, we compared the global incidences of common (non-bloody) diarrhoea between vaccinated and non-vaccinated refugee settlements for the month of October 1998. We also compiled the evolution of common diarrhoea incidences in four vaccinated settlements over the period October 1997 (vaccination) to October 1998 (outbreak). The median incidences of common diarrhoea in October 1998 were lower in the vaccinated settlements (2.8/1000) compared with non-vaccinated settlements (10.0/1000) and the Ugandan population (4.3/1000) attending the same health units, but the differences were not statistically significant. The trends in the common diarrhoea incidences since October 1997 in four vaccinated camps did not show any marked increase during the cholera epidemic period (Fig. …

Abstract: Earlier this year my colleagues and I carried out a Cochrane review of the effects of cholera vaccines. The review was large, but because of the data available we concentrated mainly on the older killed whole cell (KWC) variety of vaccines. At the beginning of the review we were aware that cholera KWC vaccines have been discouraged since the 1970s in either endemic or epidemic areas on the grounds that they had low efficacy and short duration (four to six months), required multiple doses, and were less effective in children under 5than in adults. Important adverse effects were said to occur in 30% of recipients of injected KWC vaccines. Our Cochrane review re-examined the evidence for these statements through a systematic review of randomised and quasirandomised controlled cholera vaccine trials of over 2.5m participants conducted world wide since 1963.The overall efficacy of vaccine compared with placebo was 57% (95% confidence …

Abstract: Vast changes are taking place in vaccinology consequent to the introduction of new technologies. Amongst the vaccines included in the Expanded Programme of Immunization (EPI), the pertussis vaccine has been replaced by acellular purified fractions devoid of side-effects. Non-pathogenic but immunogenic mutants of tetanus and diptheria toxins are likely to replace the toxoids. An effective vaccine against hepatitis B prepared by recombinant technology is in large-scale use. Conjugated vaccines against Haemophilus influenzae b, S. pneumococcus and meningococcus are now available, as also vaccines against mumps, rubella and measles. Combination vaccines have been devised to limit the number of injections. Vaccine delivery systems have been developed to deliver multiple doses of the vaccine at a single contact point. A genetically-engineered oral vaccine for typhoid imparts better and longer duration of immunity. Oral vaccines for cholera and other enteric infections are under clinical trials. The nose as a route for immunization is showing promise for mucosal immunity and for anti-inflammatory experimental vaccines against multiple sclerosis and insulin-dependent diabetes mellitus. The range of vaccines has expanded to include pathogens resident in the body such as Helicobacter pylori (duodenal ulcer), S. mutans (dental caries), and human papilloma virus (carcinoma of the cervix). An important progress is the recognition that DNA alone can constitute the vaccines, inducing both humoral and cell-mediated immune responses. A large number of DNA vaccines have been made and shown interesting results in experimental animals. Live recombinant vaccines against rabies and rinderpest have proven to be highly effective for controlling these infections in the field, and those for AIDS are under clinical trial. Potent adjuvants have added to the efficacy of the vaccines. New technologies have emerged to 'humanize' mouse monoclonals by genetic engineering and express these efficiently in plants. These recombinant antibodies are opening out an era of highly specific and safe therapeutic interventions. Human recombinant antibodies would be invaluable for treating patients with terminal tetanus and rabies. Antibodies are already in use for treatment of cancer, rheumatoid arthritis and allergies. An advantage of preformed antibodies directed at a defined target and given in adequate amounts is the certainty of efficacy in every recipient, in contrast to vaccines, where the quality and quantum of immune response varies from individual to individual.

Abstract: A process for the isolation of nontoxinogenic V. cholerae strain and a process for preparing a cholera vaccine from said V. cholerae strain, said process comprising (a) isolating V. cholerae from the stool of a patient suffering from cholera by spreading the stool on a selector medium specific for V. cholerae, (b) separating the non-toxinogenic V. cholerae strain from the population of the V. cholerae strains isolated in step (a), and (c) incorporating immunogenic cholera toxin (ctx) B subunit gene into the chromosome of the strain by conventional methods to produce the vaccine.

Abstract: Immunization is the most effective public health tool used to control infectious disease. Moreover, immunization is extremely cost effective given that disease treatment is far more expensive than prevention of disease. The cost of vaccines and their administration from birth to age 16 is estimated by the Centers for Disease Control (CDC) to be US $500. Each US $1 spent on vaccinations saves US $16 in avoiding costly drug therapies and hospitalizations (Fettner 1994) ultimately saving approximately US $7500 per vaccinated individual. Furthermore, phenomena such as herd immunity can provide protection to a community, even when only a minority of the total population has been vaccinated. Ideally, vaccination leads to the total eradication of an infectious agent that has no alternative hosts or environmental reservoirs, e.g., smallpox and, in the near future, polio.

Abstract: To assess the safety, immunogenicity, and lot stability of the whole cell/recombinant B subunit cholera vaccine, 2 lots manufactured in June 1991 and February 1992 were tested in January 1995. Two oral doses of vaccine or placebo given 2 weeks apart were given with buffer to 216 Peruvian adults and children. Symptoms were elicited for 3 days after each dose. Serum and plasma specimens obtained from each volunteer before vaccination and 10-14 days after the second dose were tested for vibriocidal and anti-cholera toxin antibodies. The vaccine was well-tolerated. Nearly half of the 100 vaccinees had pre-vaccination vibriocidal titers > or = 1:40. Elevated titers were observed in 22% of 37 children 2-5 years of age compared with 66% of 63 vaccinees 6-65 years (P or =2-fold serum vibriocidal response was observed in 55% of 100 vaccinees and 6% of 32 placebo recipients. An elevated pre-vaccination titer ( or =2-fold increase in vibriocidal titer (51% versus 59%, difference not significant), but did change the proportion responding with a > or =4-fold increase (41% versus 22%; P 90% of the vaccinees; > or =4-fold responses were seen in 65-70% of the vaccinees with a 6-8-fold increase over baseline. Plasma specimens were as good as sera for determining anti-toxic antibodies by ELISA, but were less satisfactory for determining vibriocidal antibody titers.