Safety and immunogenicity of PanChol, a single-dose live-attenuated oral cholera vaccine: results from a phase 1a, double-blind, randomized, placebo-controlled trial

Background Current whole-cell killed oral cholera vaccines have utility but require multiple doses and have limited efficacy in young children. PanChol is a single-dose live-attenuated cholera vaccine derived from the 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 minimize reactogenicity and prevent toxigenic reversion. We assessed safety and immunogenicity in a first-in-human trial. Methods In a dose-escalation phase at Brigham and Women's Hospital (Boston, MA, USA), seven cohorts received one dose of 10 4 -10 10 colony-forming-units (CFU) PanChol. Two dosing groups of 2*10 7 and 2*10 8 were subsequently evaluated in a double-blind, placebo-controlled module. Fecal shedding was assessed until day five; safety and immunogenicity were monitored for six months. This trial is registered with ClinicalTrials.gov, NCT05657782 . Findings Between Dec 2022 and Feb 2025, 57 healthy adults were enrolled (dose-escalation: n=21; expansion n=28 vaccine and n=8 placebo recipients). PanChol was safe and well-tolerated at all doses, and no safety concerns were identified including no vaccine-related serious adverse events. In the dose-escalation phase, 81% (17/21) of participants had 39 unsolicited adverse events (AE). In the randomized module, at least one AE occurred in 64% (9/14) at 10 7 dose and in all 10 8 (13/13) and placebo (7/7) recipients. Most AEs were mild and only four were >grade 2 (all unrelated to vaccine). Shedding was detected in 44 recipients of ≥10 5 CFU, with no relationship to dose. All 45 vaccinees given ≥ 10 5 CFU seroconverted vibriocidal antibodies to both serotypes, with comparable mean titers across doses. IgM responses targeting Inaba or Ogawa polysaccharides were detected in 44 and 41 vaccinees respectively, and anti-toxin IgG responses were measured in 21 vaccinees. Antibody lymphocyte supernatant assays demonstrated mucosal IgA to these antigens and to colonization factor, TcpA. Interpretation A single oral dose of PanChol induced 100% vibriocidal seroconversion over a 100,000-fold dose range with no safety concerns. These findings support further development of PanChol as a new tool for cholera prevention, including studies in endemic settings and in children. Funding: Wellcome Trust.