title: Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial.
abstract: Ricin is a potent toxin and potential bioterrorism weapon for which no specific licensed countermeasures are available. We report the safety and immunogenicity of the ricin vaccine RVEc™ in a Phase 1 (N=30) multiple-dose, open-label, non-placebo-controlled, dose-escalating (20, 50, and 100μg), single-center study. Each subject in the 20- and 50-μg dose groups (n=10 for each group) received three injections at 4-week intervals and was observed carefully for untoward effects of the vaccine; blood was drawn at predetermined intervals after each dose for up to 1 year. RVEc™ was safe and well tolerated at the 20- and 50-μg doses. The most common adverse events were pain at the injection site and headache. Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group. Immunogenicity of the vaccine was evaluated by measuring antibody response using the well standardized enzyme-linked immunosorbent assay (ELISA) and toxin neutralization assay (TNA). Of the subjects in the 20- and 50-μg dose groups, 100% achieved ELISA anti-ricin IgG titers of 1:500 to 1:121,500 and 50% produced neutralizing anti-ricin antibodies measurable by TNA. Four subjects in the 50-μg group received a single booster dose of RVEc™ 20-21 months after the initial dose. The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects. Each booster recipient developed a robust anamnestic response with ELISA anti-ricin IgG titers of 1:13,500 to 1:121,500 and neutralizing antibody titers of 1:400 to 1:3200. Future studies will attempt to optimize dose, scheduling, and route of administration. This study is registered at clinicaltrials.gov (NCT01317667 and NCT01846104).
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. Electronic address: phillip.r.pittman.civ@mail.mil.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Pittman
authors.affiliation: MedStar Georgetown University Hospital, 7503 Surratts Road, Clinton, MD 20735, USA.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Reisler
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Changhong Y
authors.initials: CY
authors.lastname: Lindsey
authors.affiliation: US Army, 10th Mountain Division, Fort Drum, NY 13602, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Güereña
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Rivard
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Denise P
authors.initials: DP
authors.lastname: Clizbe
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Chambers
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Norris
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000992:Antitoxins / Q000097:blood*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006261:Headache / Q000453:epidemiology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D010146:Pain / Q000453:epidemiology; D011041:Poisoning / Q000517:prevention & control*; D012276:Ricin / Q000276:immunology* / Q000633:toxicity*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D055815:Young Adult
chemical_list: D000992:Antitoxins; D007074:Immunoglobulin G; D014614:Vaccines, Synthetic; D012276:Ricin
keywords: Clinical trial; Dose; Immune response; Recombinant vaccine; Ricin vaccine; Safety