Safety and immunogenicity of PanChol, a single-dose live-attenuated oral cholera vaccine: results from a phase 1a, double-blind, randomized, placebo-controlled trial
Escrito por Deborah R. Leitner, Stephen R. Walsh, Masataka Suzuki, Michaël Desjardins, Alisse Hannaford, Amy C. Sherman, Hannah Levine, Lena Carr, Elliot Hammerness, Akina Osaki, Emily Sullivan, Bryan Wang, George I. Balazs, Jun Bai Park Chang, Damien M. Slater, Nirajan Puri, Carole J. Kuehl, Wilbur H. Chen, Jason B. Harris, Steven Piantadosi, Lindsey R. Baden y Matthew K. Waldor
Publicado
14 de septiembre de 2025
Servidor
medRxiv
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 104 -1010 colony-forming-units (CFU) PanChol. Two dosing groups of 2×107 and 2×108 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 107 dose and in all 108 (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 ≥105 CFU, with no relationship to dose. All 45 vaccinees given ≥105 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.
Research in context
Evidence before this study
Cholera remains a global public health threat; killed oral cholera vaccines (OCVs) are important for control. However, they have limited efficacy in young children and require multiple doses for maximum efficacy. Live-attenuated OCVs, like natural infection, may induce protective immunity with a single dose. While other live-attenuated OCVs have been developed, none are WHO prequalified. We searched PubMed from inception to July 2025 for studies evaluating OCVs using the terms “live oral cholera vaccine trial O1”, yielding 25 non-review clinical trial articles. All tested live vaccines were derived from the extinct classical V. cholerae biotype or early El Tor biotype strains and were Inaba serotype. None were engineered to be resistant to reversion to toxigenicity.
Added value of this study
This first-in-human trial establishes that PanChol, a live-attenuated OCVs engineered from the current global pandemic El Tor V. cholerae O1 strain, is safe and immunogenic in an adult population in Boston, USA. Unlike previous live-attenuated vaccines, PanChol expresses both Inaba and Ogawa serotype antigens, is engineered for enhanced genetic stability, and resists toxigenic reversion. PanChol shedding, a marker for vaccine replication in the intestine, was detectable across doses 105 -1010 CFU. Whole genome sequencing of PanChol isolated from vaccinees’ stool confirmed the vaccine’s genomic stability. Across all doses, 100% of vaccinees seroconverted to both Inaba and Ogawa serotypes, demonstrating potent immunogenicity.
Implications of all the available evidence
PanChol’s favorable safety profile and immunogenicity support additional development as a new agent for cholera control. Since PanChol is derived from the current pandemic strain, and natural infection stimulates more potent immunity to cholera than killed vaccines, PanChol may offer effective single-dose protection for children. It may be beneficial for reactive vaccination campaigns and for alleviating the global shortage of killed OCVs. These positive results warrant the establishment of the vaccine’s safety and immunogenicity in cholera endemic settings and age de-escalation trials.