TY800 Dose Escalation (Typhoid)
Condition: Typhoid and Paratyphoid Fevers
MeSH terms: Typhoid Fever; Paratyphoid Fever
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Ty800; Placebo
Intervention type(s): Biological; Drug
Intervention description(s): Live attenuated Ty800 S typhi oral vaccine is co-administered with a sodium bicarbonate buffer solution. Dosages: 5 X 10^7 cfu, 5 X 10^8 cfu, and 5 X 10^9 cfu.; 150 mL of the prepared sodium bicarbonate buffer solution. Placebo will look and taste essentially like the study product.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Typhoid fever, S typhi, vaccine