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.

Abstract

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. 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. 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. 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. US National Institutes of Health with pharmaceutical support from the US Department of Defense.