Phase I Randomized, Double-Blind, Heterologous Prime-Boost Study of the Safety and Immunogenicity of Vi Polysaccharide Typhoid Vaccine After Priming by Live Attenuated Oral Vi+ Salmonella Typhi Strain CVD 909
Overview
- Phase
- Phase 1
- Intervention
- CVD 909
- Conditions
- Typhoid Fever
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- Safety: determined by symptom diaries, interim medical histories obtained by interview, by blood and stool cultures, and by clinical laboratory tests.
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
The purpose of this research study is to see if giving a typhoid vaccine by mouth (an experimental vaccine, CVD 909) before giving a vaccine shot (Typhim Vi) will result in a better immune response than giving Typhim Vi vaccine by itself. Another purpose is to see whether CVD 909 is safe. Typhim Vi has been shown to be safe and effective in preventing typhoid fever in older children and adults, but it does not work in children under age 2. Scientists at the University of Maryland think that young children could respond to Typhim Vi if they were given a dose of the other typhoid vaccine by mouth before they are given the Typhim Vi shot. Twenty-eight healthy adult volunteers, ages 18-40 years, will take part in this study. Study participation will last for up to 63 weeks, but most of the study visits will be in the first 6 weeks. Blood samples will be collected approximately 13 times. Four stool samples will be collected. Some volunteers may be followed for an additional 4 years.
Detailed Description
This is a phase I, randomized, double-blind, heterologous prime-boost study of the safety and immunogenicity of Vi polysaccharide typhoid vaccine after priming by live, attenuated oral Vi+ Salmonella Typhi strain CVD 909. The primary study objective is to determine the phase 1 safety of the prime-boost regimen of priming with CVD 909, a live attenuated Vi+ S. Typhi strain, followed by boosting with licensed parenteral Vi polysaccharide vaccine in healthy adult volunteers. The secondary objective is to compare the immunogenicity of licensed parenteral Vi polysaccharide vaccine in volunteers primed with a single oral dose of CVD 909 and in volunteers who are not primed with the oral vaccine. The outcome measures of interest are the seroconversion rate and titer of serum IgG anti-Vi antibodies, the timing of development and longevity of serum anti-Vi antibodies, the subclasses and avidity of antibodies developed, and the memory B and T cell responses elicited. The following immunologic outcome measures will be sought: rate and timing of seroconversion in each study arm after receiving Vi polysaccharide and analysis of immunoglobulin subclasses and avidity. This will assess the presence of priming and the rapidity of the anamnestic response. A successful priming would accelerate the response to the boost (Day 7 after Vi vaccine), and this response is expected to be more balanced, inducing both Th1/Th2-type immunity evidenced by the induction of both IgG1 and IgG2; geometric mean titer (GMT) of serum IgG anti-Vi antibodies on Days 7, 14, 21, and 35 post-Vi (Days 28, 35, 42, and 84 of the study). This will assess magnitude of response (another measure of priming); GMT of serum IgG Vi antibody in each study arm at multiple later time points up to 1 year after receiving parenteral Vi (week 55 of the study). This will assess the quality and duration of the antibodies; and peripheral blood mononuclear cells will be collected to measure cytokine production and cytotoxic T lymphocyte (CTL) activity, as well as the induction and maintenance of B and T cell memory responses and homing potential of antibody secreting cells (ASC) and T cells depending on cell numbers. Twenty-eight healthy adult volunteers, 18-40 years of age and from the Baltimore community, will be recruited to participate in this study, which will be conducted at the Center for Vaccine Development (CVD), University of Maryland School of Medicine. The volunteers will be randomized to receive either 5x10\^9 colony forming units of CVD 909 with buffer or buffer placebo alone. Three weeks later, all volunteers will receive 25 micrograms (0.5 ml) of licensed purified Vi polysaccharide vaccine by the intramuscular route. Blood for serum and antibody secreting cell responses to Vi, S. Typhi LPS, and O antigen will be drawn before and after the Vi boost. The patient participation duration is up to 63 weeks, with the option for prolonged immunologic follow-up for 4 additional years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 18 - 40 years, inclusive.
- •Good general health as determined by a screening evaluation within 30 days before administration of CVD 909 or placebo.
- •Expressed interest and availability to fulfill the study requirements.
- •Informed, written consent.
- •Agrees not to participate in another investigational vaccine or drug trial for the first 84 days of this study.
- •Agrees not to become pregnant from the time of study enrollment until at least 56 days after the administration of CVD 909 or placebo; if a woman is sexually active and capable of conception (i.e., no history of hysterectomy or tubal ligation), she must agree to use hormonal or barrier birth control. A woman is eligible if she is monogamous with a vasectomized male.
Exclusion Criteria
- •History of any of the following medical illnesses:
- •Gall bladder disease or gall stones without cholecystectomy
- •Heart disease (hospitalization for a heart attack, arrhythmia, or syncope)
- •Unconsciousness
- •Seizures (other than febrile seizures as a child less than 5 years old)
- •Recurrent infections (more than 3 hospitalizations for invasive bacterial infections such as pneumonia or meningitis)
- •Any current illness requiring daily medication other than vitamins, birth control, or stable regimen of anti-histamine medication for hay fever or anti-depressant
- •History of the following types of abdominal surgery:
- •Any major gastrointestinal surgery (e.g., intestinal resection or splenectomy)
- •A laparotomy for any reason (e.g., hysterectomy, Caesarean section, appendectomy, or herniorrhaphy) within the last 3 years
Arms & Interventions
1
14 subjects Oral CVD 909 with buffer on Day 0. Parental Vi polysaccharide vaccine on Day 21.
Intervention: CVD 909
1
14 subjects Oral CVD 909 with buffer on Day 0. Parental Vi polysaccharide vaccine on Day 21.
Intervention: Vi Polysaccharide
2
14 subjects oral buffer placebo. Parental Vi polysaccharide vaccine on Day 21.
Intervention: Placebo
2
14 subjects oral buffer placebo. Parental Vi polysaccharide vaccine on Day 21.
Intervention: Vi Polysaccharide
Outcomes
Primary Outcomes
Safety: determined by symptom diaries, interim medical histories obtained by interview, by blood and stool cultures, and by clinical laboratory tests.
Time Frame: During the 1st 14 days after ingestion of CVD 909 vaccine or placebo, during the 3 days after receiving parenteral Typhim Vi vaccine at Day 24, and interim medical history for safety at Day 42.
Secondary Outcomes
- Immunogenicity: assessed by specific antibody secreting cell assays.(Days 0 and 10 after oral administration of CVD 909 and Days 0 and 7 after administration of parenteral Vi.)
- The timing of development and longevity of serum anti-Vi antibodies.(Days 0 and 10 after oral administration of CVD 909 and Days 0 and 7 after administration of parenteral Vi.)
- The subclasses and avidity of antibodies developed.(Days 0 and 10 after oral administration of CVD 909 and Days 0 and 7 after administration of parenteral Vi.)
- Seroconversion rate and titer of serum IgG anti-Vi antibodies.(Days 0, 10, 14+/-2, 21+/-2, 28+/-2, 35+/-2, 42+/-2, and 84+/-7 and at 29+/-2 weeks and 55+/- 4 weeks, and every 6 months for 4 years for volunteers who remain seropositive at week 55 and agree to continue participation in the study.)