CVD 909 Vi Prime Boost Study

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Brief Title

CVD 909 Vi Prime Boost Study

Official Title

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

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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Safety: determined by symptom diaries, interim medical histories obtained by interview, by blood and stool cultures, and by clinical laboratory tests.

Secondary Outcome

 Immunogenicity: assessed by specific antibody secreting cell assays.

Condition

Typhoid Fever

Intervention

CVD 909

Study Arms / Comparison Groups

 1
Description:  14 subjects Oral CVD 909 with buffer on Day 0. Parental Vi polysaccharide vaccine on Day 21.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

21

Start Date

February 2006

Completion Date

August 2008

Primary Completion Date

September 2007

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

          -  Diabetes

          -  Cancer

          -  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

          -  Laparoscopic abdominal surgery within the past year

          -  A large abdominal scar of unclear origin

          -  Evidence of gastrointestinal disease, as indicated by any of the following:

          -  Usual bowel habit of more than 3 bowel movements each day

          -  Recurrent diarrhea (greater than 5 episodes during the past 6 months, each lasting at
             least 3 days, with at least one week between episodes)

          -  Lactose intolerance

          -  Frequent indigestion or heartburn that requires daily antacids or other medical
             therapy

          -  Diagnosed by a doctor as having irritable bowel disease, Crohn's disease, ulcerative
             colitis, celiac disease, stomach or intestinal ulcers in the past 10 years

          -  Blood in the stool during the past year (other than occasional small amount from
             straining)

          -  Any clinically significant abnormality detected on physical examination, including:

          -  Murmur (other than a functional murmur)

          -  Focal neurological deficit suggesting a pathologic process

          -  Hepatosplenomegaly

          -  Lymphadenopathy

          -  Jaundice

          -  Hypertension (BP greater than 150/90 mm Hg on two separate days) or hypotension (BP
             less than 85/55 mm Hg)

          -  Any lab abnormality, as listed below:

          -  WBC outside the normal range

          -  Hemoglobin outside the normal range

          -  Platelet count outside the normal range

          -  Creatinine outside the normal range

          -  Fasting glucose greater than 115 mg/dl (if screening greater than 115 mg/dl)

          -  AST or ALT outside the normal range (may be repeated once if outside this limit)

          -  Positive serology for hepatitis C or HIV antibody or hepatitis B surface antigen

          -  Stool culture positive for Salmonella spp, Shigella spp, Campylobacter jejuni, V.
             cholerae, or pathogenic protozoa

          -  For women, positive serum pregnancy test within 7 days and urine pregnancy test within
             24 hours of administering CVD 909 and within 24 hours of administering Vi vaccine

          -  Nursing mother

          -  Oral temperature greater than 37.8ºC or symptoms of an acute self-limited illness such
             as an upper respiratory infection or gastroenteritis on the day of administration of
             CVD 909 or placebo

          -  Immunization against typhoid fever or history of typhoid fever

          -  Allergy to quinolones (including ciprofloxacin) or sulfa drugs (Including
             trimethoprim/sulfamethoxazole)

          -  Medical, occupational, or family problems as a result of alcohol or illicit drug use
             during the past 12 months

          -  Failure to pass written examination about study purpose, background, and procedures
             (70% correct answers required to pass)

          -  Receipt of an investigational vaccine or drug within 28 days before administration of
             CVD 909

          -  Commercial food-handlers

          -  Health care workers who are engaged in patient care during the study

          -  Day care providers

          -  Subject with a household contact who is less than 2 years of age, who is
             immunocompromised or pregnant, or who works as a commercial food-handler

          -  Use of antibiotics within 7 days of CVD 909 or placebo vaccination

          -  Other condition that in the opinion of the investigator would jeopardize the safety or
             rights of a volunteer participating in the trial or would render the subject unable to
             comply with the protocol.
      

Gender

All

Ages

18 Years - 40 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

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Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00326443

Organization ID

05-0009

Secondary IDs

Typhoid CVD 36000


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

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Verification Date

February 2010