Yellow Fever Virus Vaccine and Immune Globulin Study
Condition: Viremia
MeSH terms: Viremia; Yellow Fever
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine whether immune globulin can limit the amount of
      yellow fever vaccine virus present in the blood after vaccination without compromising the
      immunity associated with the yellow fever vaccine. The study will enroll 80 participants in
      two groups of 40 each. The first group will receive the yellow fever vaccine with salt-water
      placebo. The second group will receive yellow fever vaccine with immune globulin. The amount
      of vaccine virus and immune response in both groups will be compared. Yellow fever vaccine
      has been used to protect humans against Yellow Fever Vaccine disease since the 1930s.
    

Detailed description: 
      This double-blind, randomized outpatient study is designed to determine if human immune
      globulin (IG) will limit the viremic response to 17D yellow fever vaccine without
      compromising immunogenicity. The yellow fever 17D vaccine YF-VAX® is manufactured in the
      United States. The IG, Gama STAN S/D®, is manufactured in the U.S. The study will be
      conducted in 80 healthy adults 18-40 years of age in the U.S. Participants will be randomized
      to receive YF-VAX® plus saline (40 subjects), or YF-VAX® plus Gama STAN S/D® (40 subjects).
      The dose of Gama STAN S/D® will be that used for the prevention of hepatitis A, i.e. 0.06
      mL/kg. The lot of Gama STAN S/D® will have been tested and shown to contain yellow fever
      neutralizing antibodies at a log neutralizing index of >0.7. Saline will be given to blind
      the vaccine administrator and vaccinee as to their treatment group. A stratified
      randomization procedure will be used to ensure equal distribution of study medications to
      participants by gender. Safety and tolerability will be assessed by comparison of the
      incidence of adverse events across the two treatment groups.

      The hypothesis being tested is whether co-administration of yellow fever antibody and yellow
      fever vaccine (passive-active immunization) results in effective immunization while reducing
      viremia. The effectiveness of use of Gama STAN S/D® in combination with YF-VAX® will be
      assessed by a reduction in the viremic response in the vaccinee. Viremia is a measure of
      replication of YF 17D virus in host tissues, and absence of viremia indicates that virus
      replication in host tissues is abrogated. Abrogation of virus replication is expected to
      limit the potential for dissemination of virus and virus invasion of and damage to vital
      organs, including the liver and brain. The methods used to quantify viremia will be reverse
      transcriptase-polymerase chain reaction (RT-PCR) and direct plaquing in Vero cell monolayers.
      In addition, sera collected pre-vaccination and on blood draws post-vaccination will be
      tested for yellow fever neutralizing antibodies to measure immunogenicity. The method used to
      detect neutralizing antibodies will be a plaque-reduction neutralization test (PRNT)
      performed in Vero cell culture using the constant serum-varying virus technique standardized
      by the U.S. Food and Drug Administration (Beaty et al., 1989). The PRNT has been recently
      validated and used to support Phase 3 clinical trials of YF-VAX® (Monath et al. 2002a). The
      primary endpoint will be the comparison of the proportion of subjects without prior yellow
      fever immunization in each treatment group who have measurable vaccine virus after
      vaccination. The T-cell activation, cytokine response, dendritic cell response and kinetics
      and phenotype of natural killer (NK) cells will also be characterized.

      Study participants will be excluded who have significant underlying medical conditions, a
      history of sensitivity to IG, or established contraindications to yellow fever vaccine,
      including immunosuppression, thymus disorder, pregnancy, or egg hypersensitivity. These
      exclusion criteria represent the major contraindications to the use of Gama STAN S/D® and all
      yellow fever vaccines, including YF-VAX®.

      The study consists of a Screening Period and a Treatment Period. During the Screening Period
      (Days -30 to -1), informed consent is obtained, eligibility for study entry is assessed and
      baseline tests are performed. Subjects who satisfy all inclusion/exclusion criteria are
      eligible to enter the Treatment Period and are randomized to one of the two treatment groups.
      On Day 0 subjects will receive either YF-VAX® plus saline, or YF-VAX® plus Gama STAN S/D®.
      Subjects return to the clinic for daily visits on day 1, 2, 3, 5, 7, 9, 11, 14, 30, and 91.
      The total duration of participation for an individual subject is approximately 91 days.

      Safety assessments in vaccinated subjects include adverse event reporting and clinical
      laboratory evaluations. To ensure thorough reporting of adverse events during the time
      interval in which adverse events associated with yellow fever vaccination might be expected
      to occur, subjects will be required to complete a study diary for Days 0-28. The study diary
      will record both local reactions (i.e., pain, redness, and swelling) and systemic reactions
      (i.e., feeling ill [malaise], headache, muscle aches, fever, chills, rash, tiredness, and
      other general symptoms). These are the principal symptoms and side effects known to be
      associated with yellow fever 17D vaccine. At each visit, study personnel will perform
      clinical evaluations and at days 7, 14 and 30 the study staff will review the diary card and
      follow up on any adverse events that occurred since vaccination.

      A sample size for efficacy of 80 participants including 40 subjects in the group receiving
      YF-VAX® plus saline and 40 subjects receiving YF-VAX® plus Gama STAN S/D® provides 80% power
      in a one-sided test at significance level alpha of 0.05, assuming 93% of subjects not
      receiving immune globulin will exhibit detectable viremia and a reduction of 35% (to 61% of
      subjects) following administration of immune globulin.
    

Intervention name(s): YF-VAX® plus saline; 17D YF Vaccine plus Ig,
Intervention type(s): Biological; Biological
Intervention description(s): YF-VAX® plus saine; 17D YF Vaccine plus Ig, one vaccine on day 0
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Yellow Fever Virus Vaccination