Efficacy of WRSs2, a live-attenuated Shigella sonnei vaccine, against shigellosis in a controlled human infection model in the USA: a phase 2, double-blind, randomised, placebo-controlled trial

Background: Despite long-standing research, no licensed vaccine exists for shigella, a leading cause of bacterial diarrhoea and dysentery. WRSs2 is a live-attenuated Shigella sonnei vaccine candidate which has previously shown safety and immunogenicity. In this trial, we evaluated its safety and efficacy in a controlled human infection model. Methods: In this phase 2, double-blind, randomised, placebo-controlled trial at two sites in the USA, healthy adults aged 18–49 years were assigned using a site-stratified permuted-block schedule. The original three-arm design allocated participants 1:1:1 to two-dose WRSs2 (10⁶ colony-forming units [CFU]), one-dose placebo followed by one-dose WRSs2 (10⁶ CFU), or two-dose placebo; doses were given 28 days apart. After 69 participants were enrolled, a Data and Safety Monitoring Board (DSMB)-triggered safety review and protocol amendment resulted in subsequent participants being assigned 2:1 to two-dose WRSs2 (5 × 10⁵ CFU) or placebo. Participants were challenged orally 28 days after the second vaccination with approximately 1·5 × 10³ CFU of S sonnei 53G. The primary endpoint was endpoint review committee-adjudicated shigellosis in challenged participants. Safety was assessed in all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT04242264. The trial is complete. Findings: Between Oct 11, 2022, and Jan 9, 2024, 108 participants were enrolled, with 22 assigned to two-dose 10⁶CFU, 26 to two-dose 5 × 10⁵ CFU, 23 to one-dose 10⁶ CFU, and 37 to placebo. 73 participants underwent challenge (16, 18, 13, and 26 participants in the respective groups). Endpoint review committee-adjudicated shigellosis occurred in three (9%) of 34 participants given pooled two-dose vaccine and 21 (81%) of 26 placebo recipients (vaccine efficacy 89% [95% CI 71–96]; p<0·0001). Six participants had grade 3 post-vaccination adverse events, prompting two DSMB reviews; after the first review, the protocol was amended to reduce the vaccine dose and revise eligibility criteria. There was no change after the second review. No vaccine-related serious adverse events or deaths occurred. Interpretation: In adults in the USA, WRSs2 provided high-level protection against S sonnei shigellosis. Although protection was substantial, the occurrence of a few self-limiting grade 3 adverse events indicates that further optimisation is needed to better define the safety–efficacy balance. These findings support further clinical development of live-attenuated shigella vaccines. Funding: US National Institutes of Health with pharmaceutical support from the US Department of Defense.