Randomized Double-Blind Placebo-Controlled Multicentered Trialof the Efficacy of a Single Dose of Live Oral Cholera Vaccine CVD103-HgR in Preventing Cholera following Challenge with Vibriocholerae O1 El Tor Inaba Three Months after Vaccination

摘要

CVD 103-HgR is a live oral cholera vaccine strain constructed by deleting 94% of the gene for the enzymatically active A subunit of cholera toxin from classical Inaba Vibrio cholerae O1 569B; the strain also contains a mercury resistance gene as an identifying marker. This vaccine was well tolerated and immunogenic in double-blind, controlled studies and was protective in open-label studies of volunteers challenged with V. cholerae O1. A randomized, double-blind, placebo-controlled, multicenter study of vaccine efficacy was designed to test longer-term protection of CVD 103-HgR against moderate and severe El Tor cholera in U.S. volunteers. A total of 85 volunteers (50 at the University of Maryland and 35 at Children's Hospital Medical Center/University of Cincinnati) were recruited for vaccination and challenge with wild-type V. cholerae El Tor Inaba. Volunteers were randomized in a double-blind manner to receive, with buffer, a single oral dose of either CVD 103-HgR (2 × 10⁸ to 8 × 10⁸ CFU) or placebo (killed E.coli K-12). About 3 months after immunization, 51 of thesevolunteers were orally challenged with 10⁵ CFU ofvirulent V. cholerae O1 El Tor Inaba strain N16961,prepared from a standardized frozen inoculum. Ninety-onepercent of the vaccinees had a ≥4-fold rise in serum vibriocidalantibodies after vaccination. After challenge, 9 (39%) of the 23placebo recipients and 1 (4%) of the 28 vaccinees had moderate orsevere diarrhea (≥3-liter diarrheal stool) (P <0.01; protective efficacy, 91%). A total of 21 (91%) of 23 placeborecipients and 5 (18%) of 28 vaccinees had any diarrhea(P < 0.001; protective efficacy, 80%). Peak stoolV. cholerae excretion among placebo recipients was 1.1× 10⁷ CFU/g and among vaccinees was 4.9 ×10² CFU/g (P < 0.001). This vaccine couldtherefore be a safe and effective tool to prevent cholera intravelers.