Oral cholera vaccination strategy: Self-administration of the second dose in urban Dhaka, Bangladesh.

Cholera remains a major public health problem in many developing countries including Bangladesh. The oral cholera vaccine (OCV) is now considered a key component of the public health response to cholera. Although maintaining cold chain and organizing human resource are the major challenges of vaccine delivery to the community. Here we applied an innovative approach to second dose OCV delivery to minimize financial and logistic burdens. The purpose of this study was to assess the feasibility and compliance of second dose self-administration when the second dose was provided in a plastic bag to first dose vaccine recipients as OCV is stable for up to 42 days at ambient temperatures. We aimed to deploy vaccines (N = 112,000) left over from other studies to 56,000 people aged ≥ one year living in Mirpur, Dhaka to see the feasibility of self-administration strategy. During vaccination, the first OCV dose (OCV1) was given from fixed sites and the second dose (OCV2) was provided in a plastic zip-lock bag for the participant to take the vaccine two weeks later at home. Participants were instructed to keep the vaccine away from light and in a dry cool place. Empty vials were collected following the end date of the scheduled second vaccination. Of the targeted population, 41,694 (74%) received the first OCV dose whereas an estimated 38,852 (93% of those receiving the first dose) received the second dose which represents a 7% drop out rate from OCV1 to OCV2. However the average two dose coverage was 69%. A survey of a subsample 2990 (from 8551) randomly selected households revealed that almost all respondents (98.75%) appreciated this new self-administration strategy and considered the strategy to be more practical and convenient than the usual method. This simplified, self-administered delivery strategy provides an ideal alternative for second-dose OCV delivery in hard-to-reach populations and resource-poor settings.

Feasibility and effectiveness of oral cholera vaccine in an urban endemic setting in Bangladesh: a cluster randomised open-label trial.

BACKGROUND: Cholera is endemic in Bangladesh with epidemics occurring each year. The decision to use a cheap oral killed whole-cell cholera vaccine to control the disease depends on the feasibility and effectiveness of vaccination when delivered in a public health setting. We therefore assessed the feasibility and protective effect of delivering such a vaccine through routine government services in urban Bangladesh and evaluated the benefit of adding behavioural interventions to encourage safe drinking water and hand washing to vaccination in this setting. METHODS: We did this cluster-randomised open-label trial in Dhaka, Bangladesh. We randomly assigned 90 clusters (1:1:1) to vaccination only, vaccination and behavioural change, or no intervention. The primary outcome was overall protective effectiveness, assessed as the risk of severely dehydrating cholera during 2 years after vaccination for all individuals present at time of the second dose. This study is registered with ClinicalTrials.gov, number NCT01339845. FINDINGS: Of 268,896 people present at baseline, we analysed 267,270: 94,675 assigned to vaccination only, 92,539 assigned to vaccination and behavioural change, and 80,056 assigned to non-intervention. Vaccine coverage was 65% in the vaccination only group and 66% in the vaccination and behavioural change group. Overall protective effectiveness was 37% (95% CI lower bound 18%; p=0·002) in the vaccination group and 45% (95% CI lower bound 24%; p=0·001) in the vaccination and behavioural change group. We recorded no vaccine-related serious adverse events. INTERPRETATION: Our findings provide the first indication of the effect of delivering an oral killed whole-cell cholera vaccine to poor urban populations with endemic cholera using routine government services and will help policy makers to formulate vaccination strategies to reduce the burden of severely dehydrating cholera in such populations. FUNDING: Bill & Melinda Gates Foundation.

Safety and immunogenicity study of a killed bivalent (O1 and O139) whole-cell oral cholera vaccine Shanchol, in Bangladeshi adults and children as young as 1 year of age.

BACKGROUND: Safety and immunogenicity study of an oral, killed, bivalent whole-cell, cholera vaccine, Shanchol was carried out in Bangladeshi participants. This study was conducted prior to initiating a feasibility study in Bangladesh. STUDY PARTICIPANTS: The double-blind, randomized placebo controlled study was carried out in adults (18-45 years), toddlers (2-5 years) and younger children (12-23 months). Two doses of the vaccine/placebo were given 14 days apart. RESULTS: Shanchol did not elicit major adverse events in any age group. Vibriocidal antibody responses in adults were 60% against Vibrio cholerae O1 Inaba, 72% against V. cholerae O1 Ogawa and 21% against V. cholerae O139. In toddlers, responses were 84%, 75% and 64% and in younger children it was 74%, 78% and 54% against Inaba, Ogawa and O139 serotypes. The responses in all ages were higher in vaccinees compared to pre-immune titers or to responses in placebo recipients (P<0.001). Plasma IgA antibody response to O1 Inaba LPS was seen in 61%, 73% and 45% of adults, toddlers and younger children, respectively. CONCLUSIONS: The safety and immunogenicity data for Shanchol is promising and warrants future use in large scale trial in cholera endemic areas, high risk Bangladeshi population and in other countries in the region.

Antigen-specific memory B-cell responses in Bangladeshi adults after one- or two-dose oral killed cholera vaccination and comparison with responses in patients with naturally acquired cholera.

The mediators of protective immunity against cholera are currently unknown, but memory B-cell responses may play a central role in facilitating long-term and anamnestic responses against Vibrio cholerae, the cause of cholera. We compared memory B-cell responses in adults with natural cholera in Bangladesh (n = 70) to responses in Bangladeshi adults after one-dose (n = 30) or two-dose (n = 30) administration of an oral killed cholera vaccine, WC-rBS (Dukoral; Crucell), assessing the responses at the acute stage of disease or prevaccination and then on days 3, 30, 90, 180, 270, and 360. Individuals with natural cholera developed prominent vibriocidal and plasma anti-cholera toxin B subunit (CtxB) and lipopolysaccharide (LPS) IgG and IgA responses, but these responses returned to baseline by 1 year of follow-up. Vaccinees developed plasma anti-CtxB and anti-LPS IgG and IgA responses that were generally comparable to those in individuals recovering from natural disease, but vibriocidal responses were lower in vaccinees than in infected patients. Individuals recovering from natural disease developed memory B-cell IgG and IgA anti-CtxB and anti-LPS responses by day 30, and these responses were detectable through at least days 180 to 360. In contrast, we detected no IgA or IgG memory B-cell responses to LPS in vaccinees; anti-CtxB IgA responses were only detectable on day 30, and anti-CtxB IgG responses were detectable until days 90 to 180, compared to days 270 to 360 in patients. These findings may explain in part the relatively short-term protection afforded by oral cholera vaccination compared to natural disease.

Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea.

Information is limited on the effect of zinc on immune responses in children with diarrhea due to enterotoxigenic Escherichia coli (ETEC), the most common bacterial pathogen in children. We studied the immunological effect of zinc treatment (20 mg/d) and supplementation (10 mg/d) in children with diarrhea due to ETEC. A total of 148 children aged 6-24 mo were followed up for 9 mo after a 10-d zinc treatment (ZT; n = 74) or a 10-d zinc treatment plus 3-mo supplementation (ZT+S; n = 74), as well as 50 children with ETEC-induced diarrhea that were not treated with zinc (UT). Fifty control children (HC) of the same age group from the same location were also studied. Serum zinc concentrations were higher in both the ZT (P < 0.001) and ZT+S groups (P < 0.001) than in the UT group but did not differ from the HC group. We found higher serum complement C3 immediately after zinc administration in both ZT (P < 0.001) and ZT+S (P < 0.001) groups than in the UT group. Phagocytic activity in children in both ZT (P < 0.01) and ZT+S (P < 0.01) groups was greater than in the UT group. However, oxidative burst capacity was lower in zinc-receiving groups (ZT, P < 0.001 and ZT+S, P < 0.001) than in the UT group. The naïve:memory T cell ratio in both ZT (P < 0.05) and ZT+S (P < 0.01) groups was higher than in the UT group from d 2 to 15. Increased responses, including complement C3, phagocytic activity, and changes in T cell phenotypes, suggest that zinc administration enhances innate immunity against ETEC infection in children.

Development of Peru-15 (CholeraGarde), a live-attenuated oral cholera vaccine: 1991-2009.

Epidemics of severe dehydrating cholera are on the increase in resource-limited settings around the world. Adults, children and young infants are all at risk of these infections. Considerable efforts have been made for the development of safe and efficacious oral cholera vaccines over the last three decades. Whole-cell-inactivated as well as live oral cholera vaccines have been developed and tested in different field settings to determine the efficacy and/or effectiveness of such vaccines for reducing life-threatening disease. This review follows the trail of the development of CholeraGarde, a live-attenuated Vibrio cholerae O1 vaccine candidate of the El Tor biotype and Inaba serotype. CholeraGarde, also well known as Peru-15, was derived from V. cholerae O1 strain C6709, a clinical isolate from Peru. The vaccine has now been tested in over 500 individuals, adults and children and shows a good safety and immunogenicity profile. At a dose of around 10(8) CFU, it is immunogenic in adults in the USA, as well as in adults, children and infants in Bangladesh. The vaccine has been tested in infants of 9 months of age where a single 10(8) CFU dose was safe and immunogenic while a tenfold lower dose was not. Excretion of the strain was higher in adults in the USA and low in Bangladeshi participants in all age groups. Phase II studies of CholeraGarde are ongoing in cholera-endemic countries to concomitantly administer it to infants with the parenteral measles vaccine. Studies on HIV-positive individuals are also ongoing to determine safety, immunogenicity and contraindications, if any. Phase III studies are being targeted to determine the protective efficacy of CholeraGarde and for further development of a single-dose vaccine that will protect infants and also other age groups from endemic and epidemic cholera.

A comparison of clinical and immunologic features in children and older patients hospitalized with severe cholera in Bangladesh.

BACKGROUND: : Infection with Vibrio cholerae induces protection from subsequent severe disease, suggesting that an effective vaccine could be an important preventive strategy. Available vaccines provide less protection against cholera than natural infection, particularly in children. METHODS: : We examined a cohort of 121 children (2 years-12 years of age) and 276 older patients (>12 years of age) hospitalized with cholera in Dhaka, Bangladesh over a 4-year period, to compare clinical features in older patients and children and immune responses to key antigens. RESULTS: : Older patients had more severe disease. Children with cholera were more commonly retinol deficient, while zinc deficiency was equally prevalent in both groups. Children developed higher vibriocidal and serum immune responses to the B subunit of cholera toxin (CTB). In contrast, older patients mounted higher immune responses to 2 other key V. cholerae antigens, the lipopolysaccharide (LPS) and toxin coregulated pilus antigens (TcpA). We compared immune responses following infection with those occurring after receipt of a live, oral vaccine in both children and older patients in Bangladesh, during a similar time period. The response rates for vibriocidal and LPS antibodies were higher after infection than after vaccination. Both vaccinated older patients and children responded poorly to CTB and TcpA. CONCLUSIONS: : Although children developed vigorous vibriocidal and CTB-specific responses following infection, they had lessened responses to LPS and TcpA compared with older patients, as well as lessened responses to vaccination. More studies need to be carried out to determine factors, including micronutrient interventions that can improve responses in children to both natural infection and vaccination.