Typhoid and Paratyphoid Fevers Clinical Trial
Official title:
A Randomized, Double-Blind, Placebo-Controlled, Dose Escalation, In-Patient Phase I/II Study to Determine the Safety and Immunogenicity of Ty800 in Healthy Adult Subjects
The purpose of this research study is to determine whether a new vaccine for typhoid fever is safe and effective. This study will also look at what effects (good and bad) this new vaccine, Ty800, has on the volunteers. The study will determine the highest dose of Ty800 that can be given without causing severe side effects. About 54 healthy males and females, ages 18-45 inclusive, in the Cincinnati metropolitan area will be enrolled in this study. They will be in the study for approximately 7 months, which includes a one month screening period, study product administration on Day 0, a 10-day hospital stay, an outpatient period on Days 9-28 with 4 follow-up visits, and safety follow-up phone calls at 2 and 6 months after hospital discharge. Researchers hope that this trial will help produce a vaccine that combines a high level of durable protective immunity with simplicity of administration and minimal reaction to the vaccine.
Typhoid fever is a generalized infection of the reticuloendothelial system (spleen, liver, and bone marrow), gut-associated lymphoid tissue and gall bladder caused by Salmonella enterica serovar Typhi (S typhi). Humans are the only known natural host and reservoir for S typhi. Typhoid bacilli are transmitted by the fecal-oral route by contaminated drinking water or food. The ideal typhoid vaccine would combine high levels of durable protective immunity with simplicity of administration and minimal reactogenicity. The primary objective of this study is to assess the safety of Ty800 oral typhoid vaccine when administered as a single dose over a range of doses (5 x 10^7, 5 x 10^8, and 5 x 10^9 cfu) in healthy adult subjects compared to placebo. The primary endpoint is safety of Ty800 at the dose levels administered compared to placebo as determined by absence of bacteremia, absence of the diagnosis of typhoid fever as confirmed by a positive blood culture for the Ty800 vaccine organism, and by verifying that the null phoP/phoQ phenotype is retained by the isolated shed vaccine organism. Safety variables will be assessed by the reported incidence of adverse events (AE), blood cultures, and changes in vital signs, physical examination, and routine laboratory parameters over time at each vaccine dose level compared to placebo. The secondary objectives of this study are: to evaluate the immunogenicity of a single oral dose administration of Ty800 over a range of doses in healthy adult subjects; to evaluate the Ty800 vaccine dose response by comparing the immunogenicity profiles of each dose level; and to evaluate the shedding profile of Ty800 by determining the quantity and duration of shedding for each dose level. The tertiary objectives of this study include: evaluating, in a substudy, single nucleotide polymorphisms (SNPs) in candidate genes, e.g., IL-8 and interferon gamma, that may influence the immune response or persistent shedding of the vaccine organism and evaluating the induction of memory B cells in the vaccinated subjects. This study is a randomized, double-blind, placebo-controlled, dose escalation, inpatient phase I/II clinical trial. Three dose levels of Ty800 a vaccine will be evaluated and compared to placebo. Prior to randomization and administration of study vaccine, subjects will undergo screening evaluations. Healthy subjects meeting study eligibility criteria will be admitted to an inpatient facility with appropriate isolation containment the day prior to randomization, and they will remain in the unit for approximately 10 consecutive days. Three cohorts of 18 volunteers, representing 3 escalating doses of Ty800 typhoid vaccine will be challenged. In each cohort, 12 volunteers will receive Ty800 as a single oral dose, and 6 volunteers will receive placebo. Dose escalation will occur in a stepwise fashion and will be dependent upon the assessment of safety parameters and by meeting criteria for advancement to the next dose. Participants will be involved in study related procedures for up to 7 months. ;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention