Cholera vaccine (recombinant, live, oral) effervescent powder and powder for oral suspension

BACKGROUND: Cholera still affects millions of people worldwide, especially in lower- and middle-income countries (LMICs). The Global Task Force on Cholera Control (GTFCC) has identified surveillance and oral cholera vaccines as two critical interventions to actualise the global roadmap goals-reduction of cholera-related deaths by 90% and decreasing the number of cholera endemic countries by half by 2030. Therefore, this study aimed to identify facilitators and barriers to implementing these two cholera interventions in LMIC settings. METHODS: A scoping review using the methods presented by Arksey and O'Malley. The search strategy involved using key search terms (cholera, surveillance, epidemiology and vaccines) in three databases (PubMed, CINAHL and Web of Science) and reviewing the first ten pages of Google searches. The eligibility criteria of being conducted in LMICs, a timeline of 2011-2021 and documents only in English were applied. Thematic analysis was performed, and the findings were presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension. RESULTS: Thirty-six documents met the predefined inclusion criteria, covering 2011 to 2021. There were two themes identified regarding the implementation of surveillance: timeliness and reporting (1); and resources and laboratory capabilities (2). As for oral cholera vaccines, there were four themes identified: information and awareness (1); community acceptance and trusted community leaders (2); planning and coordination (3); and resources and logistics (4). Additionally, adequate resources, good planning and coordination were identified to be operating at the interface between surveillance and oral cholera vaccines. CONCLUSION: Findings suggest that adequate and sustainable resources are crucial for timely and accurate cholera surveillance and that oral cholera vaccine implementation would benefit from increased community awareness and engagement of community leaders.

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BACKGROUND: A single-dose regimen of inactivated whole-cell oral cholera vaccine (OCV) is attractive because it reduces logistical challenges for vaccination and could enable more people to be vaccinated. Previously, we reported the efficacy of a single dose of an OCV vaccine during the 6 months following dosing. Herein, we report the results of 2 years of follow-up. METHODS: In this placebo-controlled, double-blind trial done in Dhaka, Bangladesh, individuals aged 1 year or older with no history of receipt of OCV were randomly assigned to receive a single dose of inactivated OCV or oral placebo. The primary endpoint was a confirmed episode of non-bloody diarrhoea for which the onset was at least 7 days after dosing and a faecal culture was positive for Vibrio cholerae O1 or O139. Passive surveillance for diarrhoea was done in 13 hospitals or major clinics located in or near the study area for 2 years after the last administered dose. We assessed the protective efficacy of the OCV against culture-confirmed cholera occurring 7-730 days after dosing with both crude and multivariable per-protocol analyses. This trial is registered at ClinicalTrials.gov, number NCT02027207. FINDINGS: Between Jan 10, 2014, and Feb 4, 2014, 205 513 people were randomly assigned to receive either vaccine or placebo, of whom 204 700 (102 552 vaccine recipients and 102 148 placebo recipients) were included in the per-protocol analysis. 287 first episodes of cholera (109 among vaccine recipients and 178 among placebo recipients) were detected during the 2-year follow-up; 138 of these episodes (46 in vaccine recipients and 92 in placebo recipients) were associated with severe dehydration. The overall incidence rates of initial cholera episodes were 0·22 (95% CI 0·18 to 0·27) per 100 000 person-days in vaccine recipients versus 0·36 (0·31 to 0·42) per 100 000 person-days in placebo recipients (adjusted protective efficacy 39%, 95% CI 23 to 52). The overall incidence of severe cholera was 0·09 (0·07 to 0·12) per 100 000 person-days versus 0·19 (0·15 to 0·23; adjusted protective efficacy 50%, 29 to 65). Vaccine protective efficacy was 52% (8 to 75) against all cholera episodes and 71% (27 to 88) against severe cholera episodes in participants aged 5 years to younger than 15 years. For participants aged 15 years or older, vaccine protective efficacy was 59% (42 to 71) against all cholera episodes and 59% (35 to 74) against severe cholera. The protection in the older age groups was sustained throughout the 2-year follow-up. In participants younger than 5 years, the vaccine did not show protection against either all cholera episodes (protective efficacy -13%, -68 to 25) or severe cholera episodes (-44%, -220 to 35). INTERPRETATION: A single dose of the inactivated whole-cell OCV offered protection to older children and adults that was sustained for at least 2 years. The absence of protection of young children might reflect a lesser degree of pre-existing natural immunity in this age group. FUNDING: Bill & Melinda Gates Foundation to the International Vaccine Institute.

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Although measuring vaccine efficacy through the conventional phase III study design, randomized, double-blinded controlled trial serves as the “gold standard”, effectiveness studies, conducted in the context of a public health program, seek to broaden the understanding of the impact of a vaccine in a real world setting including both individual and population level impacts. Cholera is an acute diarrheal infection caused by the ingestion of food or water contaminated with the bacterium Vibrio cholerae. Since the 1980s, either killed or live oral cholera vaccines (OCVs) have been developed and efficacy and effectiveness studies have been conducted on OCV. Although the results of OCV effectiveness studies sometimes showed outliers, the tendency seen is for effectiveness of the vaccine used in public health settings to be somewhat higher than estimated in randomized controlled trials due to the influence of indirect herd protection. Efficacy and Effectiveness studies both generate important information about the vaccine performance characteristics and its impact when used in real world populations at risk for the disease.

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Abstract Background Oral cholera vaccine (OCV) and incremental improvements in household water, sanitation, and hygiene (WASH) within cholera-endemic areas can reduce cholera risk. However, we lack empiric evaluation of their combined impact. Methods We evaluated a cluster-randomized, placebo-controlled trial of OCV (Shanchol) in Kolkata, India. The study population included 108 777 individuals, and 106 879 nonpregnant individuals >1 year of age were eligible to receive 2 doses of OCV or placebo. We measured cholera risk in all household members assigned to OCV vs placebo and in all members of households with “Better” vs “Not Better” WASH, where WASH was classified according to validated criteria. Protection was measured by Cox proportional hazard models. Results Residence in an OCV household was associated with protective effectiveness (PE) of 54% (95% CI, 42%–64%; P < .001) and was similar regardless of Better (PE, 57%; 95% CI, 26%–75%; P = .002) or Not Better (PE, 53%; 95% CI, 40%–64%; P < .001) household WASH. Better WASH household residence was associated with PE of 30% (95% CI, 5%–48%; P = .023) and was similar in OCV (PE, 24%; 95% CI, −26% to 54%; P = .293) and placebo (PE, 29%; 95% CI, −3% to 51%; P = .069) households. When assessed conjointly, residence in OCV households with Better WASH was associated with the greatest PE against cholera at 69% (95% CI, 49%–81%; P < .001). Conclusions These findings suggest that the combination of a vaccine policy and improved WASH reduces cholera risk more than either would alone, although the magnitude of either intervention was not affected by the other. Future randomized trials investigating OCV and WASH interventions separately and together are recommended to further understand the interaction between OCV and WASH.

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<h2>Summary</h2><h3>Background</h3> Killed whole-cell oral cholera vaccines can be used to prevent cholera but require multiple doses and have limited efficacy in young children. PanChol is a single-dose, live-attenuated, oral cholera vaccine derived from a current seventh pandemic <i>Vibrio cholerae</i> O1 strain. It co-expresses Inaba and Ogawa antigens, over-expresses the non-toxic cholera toxin B subunit, and is designed to minimise reactogenicity and be incapable of toxigenic reversion. We aimed to assess safety and immunogenicity of PanChol in a first-in-human trial. <h3>Methods</h3> This phase 1a trial was conducted at the Brigham and Women's Hospital (Boston, MA, USA) and involved an open-label fixed dose-escalation module, followed by a randomised, double-blind, placebo-controlled dose-expansion module. Eligible participants were healthy adults aged 18–55 years without a previous <i>V cholerae</i> infection or cholera vaccination or a history of gastrointestinal disorders. In the open-label dose-escalation phase, eligible participants were enrolled into one of five cohorts receiving one dose of oral 10⁶–10¹⁰ colony-forming units (CFU) of PanChol. A dose de-escalation (10⁴ CFU and 10⁵ CFU) module was added after protocol amendment. In the subsequent randomised, double-blind module, participants were randomly assigned (7:7:4) to one of two dosing groups of one oral dose of PanChol (2 × 10⁷ CFU or 2 × 10⁸ CFU) or one oral dose of placebo (matching diluent). The list of assignments was generated from a custom program written by the statistician using blocked random assignments with a hidden block size (two blocks of 18). The co-primary outcomes were safety, including solicited, unsolicited, and serious adverse events following a single-dose of PanChol, and seroconversion (four-fold rise in titre over baseline) of vibriocidal titres to both Inaba and Ogawa <i>V cholerae</i> at 14 days post-vaccination (day 15). Safety was assessed in all participants who received the study product, and immunogenicity was assessed in all vaccine recipients who had samples available past day 7. Stool shedding of PanChol organisms was assessed as a secondary outcome in all participants. This trial is registered with ClinicalTrials.gov, NCT05657782, and is ongoing. <h3>Findings</h3> Between Dec 13, 2022, and Feb 7, 2025, 57 healthy adults were enrolled, including 15 in the dose-escalation module (three in each group), six in the dose de-escalation module (three in each group), and 36 in the dose-expansion module (14 assigned to 10⁷ CFU PanChol, 14 to 10⁸ CFU PanChol, and eight to placebo); all participants received the allocated intervention. 27 (47%) of 57 participants were male, 30 (53%) were female, and the median age was 30·6 years (IQR 25·1–45·1); the majority were White (35 [61%]) and not Hispanic or Latino (51 [89%]). 34 (69%) of 49 PanChol recipients reported at least one solicited adverse event, compared with three (38%) of eight placebo recipients. Most solicited adverse events in PanChol recipients were mild and transient. The most common solicited adverse event was diarrhoea, reported in 19 (39%) of 49 PanChol recipients (15 mild and four moderate) and in three (38%) of eight recipients of placebo (one severe and two mild). In the dose-escalation and dose de-escalation modules, 18 (86%) of 21 participants had 39 unsolicited adverse events. In the randomised module, at least one unsolicited adverse event occurred in ten (71%) of 14 participants given 10⁷ CFU, in 12 (86%) of 14 participants given 10⁸ CFU, and in seven (88%) of eight placebo recipients. Most unsolicited adverse events were mild and only four were higher than grade 2, all of which were deemed unrelated to vaccination. One unsolicited adverse event was deemed related to vaccination (mild gassy sensation on day 3 in a 10⁷ CFU recipient). Shedding was detected in no placebo recipients, in one (33%) of three recipients of 10⁴ CFU PanChol, and in 44 (96%) of 46 recipients of at least 10⁵ CFU (two recipients of 10⁸ CFU did not shed PanChol). All 45 vaccinees given at least 10⁵ CFU PanChol who had samples available past day 7 seroconverted vibriocidal antibodies to both serotypes. <h3>Interpretation</h3> A single oral dose of PanChol was safe and well tolerated at all doses and induced 100% vibriocidal seroconversion over a 100 000-fold dose range. These findings support the progression of PanChol into later phase clinical trials, including studies in endemic settings and in children. <h3>Funding</h3> Wellcome Trust.

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Cholera, a diarrheal disease primarily affecting vulnerable populations in developing countries, is estimated to cause disease in more than 2.5 million people and kill almost 100,000 annually. An oral cholera vaccine (OCV) has been available globally since 2001; the demand for this vaccine from affected countries has however been very low, due to various factors including vaccine price and mode of administration. The low demand for the vaccine and limited commercial incentives to invest in research and development of vaccines for developing country markets has kept the global supply of OCVs down. Since 1999, the International Vaccine Institute has been committed to make safe, effective and affordable OCVs accessible. Through a variety of partnerships with collaborators in Sweden, Vietnam, India and South Korea, and with public and private funding, IVI facilitated development and production of two affordable and WHO-prequalified OCVs and together with other stakeholders accelerated the introduction of these vaccines for the global public-sector market.

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Vibrio cholerae is the causative agent of cholera and annually leads to death of thousands of people around the globe. Two factors in the pathogenesis of this bacterium are its pili and flagella. The main subunits of pili TcpA, TcpB, and FlaA are the constituent subunit of flagella. In this study, we studied the ability of pili and flagella subunits to stimulate immune responses in mice. After amplification of TcpA, TcpB, and FlaA genes using PCR, they were cloned in expression plasmids. After production of the above-mentioned proteins by using IPTG, the proteins were purified and then approved using immunoblot method. After injection of the purified proteins to a mice model, immune response stimulation was evaluated by measuring the levels of IgG1 and IgG2a antibody titers, IL5 and IFN- γ . Immune response stimulation against pili and flagella antigens was adequate. Given the high levels of IL5 titer and IgG1 antibody, the stimulated immune response was toward Th1. Humoral immune response stimulation is of key importance in prevention of cholera. Our immunological analysis shows the appropriate immune response in mice model after vaccination with recombinant proteins. The high level of IL5 and low level of IFN- γ show the activation of Th2 cell response.

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