Abstract
BACKGROUND: 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 Vibrio cholerae 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. METHODS: 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 V cholerae 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 10(6)-10(10) colony-forming units (CFU) of PanChol. A dose de-escalation (10(4) CFU and 10(5) 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 × 10(7) CFU or 2 × 10(8) 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 V cholerae 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. FINDINGS: 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 10(7) CFU PanChol, 14 to 10(8) 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 10(7) CFU, in 12 (86%) of 14 participants given 10(8) 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 10(7) CFU recipient). Shedding was detected in no placebo recipients, in one (33%) of three recipients of 10(4) CFU PanChol, and in 44 (96%) of 46 recipients of at least 10(5) CFU (two recipients of 10(8) CFU did not shed PanChol). All 45 vaccinees given at least 10(5) CFU PanChol who had samples available past day 7 seroconverted vibriocidal antibodies to both serotypes. INTERPRETATION: 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. FUNDING: Wellcome Trust.