S. administered as 2 doses, 1C2 weeks apart; 3 doses are required for children 2C6 years of age. Shanchol (Shantha), made up of inactivated O1 and O139, is administered as 2 doses, 2 weeks apart. Dukoral is mainly used to immunize travelers from Europe, whereas Shanchol is intended for control of cholera in developing-country populations. For travelers on short notice to areas of intense cholera transmission, an OCV that rapidly confers protection after a single dose would be advantageous [1]. Such a vaccine would also be useful for reactive mass vaccination to control cholera in explosive unsettled virgin ground epidemics where administering 1 dose is logistically challenging [2]. CVD 103-HgR is usually a live attenuated serogroup O1, serotype Inaba, classical biotype strain in which the toxigenic A1 (ADP-ribosylating) subunit of CT was deleted and only the nontoxic, immunogenic B (binding) subunit of CT is usually synthesized [3C5]. The original manufacturer of Neferine CVD 103-HgR, the Swiss Serum and Vaccine Institute (SSVI), commercialized the vaccine as Orochol (Switzerland, New Zealand, Australia, and several other countries) and as Mutacol (Canada) to protect travelers, and initiated the licensure process for the US Food and Drug Administration (FDA). FDA licensure was never completed, as SSVI became Berna Biotech in 2000 and manufacture ceased when Crucell acquired Berna Biotech in 2004. In 2009 2009, PaxVax, Inc obtained rights to redevelop CVD 103-HgR. PXVX0200, prepared from new CVD 103-HgR grasp and working cell banks, exhibited safety and immunogenicity results similar to the former CVD 103-HgR formulations [6]. The present study, designed with guidance from the FDA, represents the pivotal efficacy trial for FDA licensure of PXVX0200. We used a closely monitored human contamination model involving the ingestion of virulent O1 El Tor Neferine Inaba strain N16961, 10 days or 3 months after vaccination. The primary endpoint for efficacy was the prevention of moderate (3.0 L) to severe (5.0 L) cholera diarrhea. Without rehydration therapy, this endpoint would represent potentially life-threatening fluid losses, as the total adult plasma volume approximates 3 L. To identify a possible correlate of protection, we explored the relationship between the vibriocidal antibody responses following vaccination and the clinical outcome of diarrhea following challenge. METHODS Neferine Study Design This study was approved by institutional review boards at the 3 centers (Baltimore, Maryland; Cincinnati, Ohio; and Burlington, Vermont). Written informed consent was obtained from healthy adults 18C45 years of age screened for eligibility (shown in http://clinicaltrials.gov/show/”type”:”clinical-trial”,”attrs”:”text”:”NCT01895855″,”term_id”:”NCT01895855″NCT01895855). Because blood group O individuals are at higher risk for severe cholera (cholera gravis) [7C9], the study populace was enriched for blood group O volunteers to assess vaccine efficacy in these high-risk hosts. Eligible volunteers randomized (1:1) to PXVX0200 vaccine or placebo fasted 60 minutes before and after ingesting the blinded product. Following vaccination, daily oral temperatures and solicited adverse events (AEs) were recorded over 7 days, including diarrhea, abdominal pain, nausea/vomiting, anorexia, headache, and tiredness. The occurrence of unsolicited AEs was recorded through 28 days after vaccination or challenge, whichever was later, and serious AEs through day 180. Blood Bmp1 was collected on days 0, 7, 10, 28, and 180 for participants who were not challenged. Neferine Volunteers challenged at day 10 postvaccination had blood collected on days 0, 7, 10 (before challenge), 38 (28 days after challenge), and 180, while volunteers challenged 3 months postvaccination had blood collected on days 0, 7, 10, 28, 90 (before challenge), 118 (28 days after challenge), and 180. Vaccine Single-dose PXVX0200 sachets with lyophilized powder containing approximately 5 108 colony-forming models (CFU) of Neferine CVD 103-HgR were produced according to current good manufacturing practice (cGMP) by PaxVax, Inc. An accompanying buffer powder sachet contained.