A Phase II Randomized, Double-Blinded, Comparative Clinical Trial for a Group B Streptococcus Serotype III-Tetanus Toxoid (GBS III-TT) Vaccine to Prevent Vaginal Acquisition of GBS Type III
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 667
- Locations
- 6
- Primary Endpoint
- The Time to First Vaginal Swab That is Type III GBS Culture Positive, With All Previous Cultures Negative for Type III GBS, Not Just the Immediately Preceding Culture.
Study Overview
Brief Summary
The group B streptococcus (GBS) vaccine study is being done to see if a single vaccination with a GBS type III vaccine can stop women from getting GBS type III bacteria in the vagina. Approximately 600 women, ages 18-40, will be enrolled from the clinical sites participating in this study. Participants will be non-pregnant, sexually active (sex with a male at least once in the last 4 months), and GBS negative in the vagina or rectum at the screening visit. Participants will be randomly assigned to receive the experimental GBS type III vaccine or a licensed vaccine containing Tetanus and Diphtheria Toxoids (Td). Participants will be followed at one month, 2 months and every other month thereafter following vaccination (for vaginal and rectal swab collection and a blood draw) for 1½ years or a total of 10 post vaccination visits.
Detailed Description
Vaginal colonization is the single most important risk factor for transmission of group B Streptococcus (GBS) from mothers to neonates, resulting in neonatal sepsis and/or meningitis. The long-term goal of this study is to determine whether vaccine-induced serum antibody to type III GBS will be sufficient to prevent vaginal acquisition of type III GBS. This study is linked to Division of Microbiology and Infectious Diseases protocol 04-018. It is a randomized, double-blinded, comparative clinical trial among young (18-40 years old), non-pregnant, sexually active women who are not currently colonized vaginally or rectally with type III GBS, it will be conducted to evaluate the efficacy of a GBS type III-TT vaccine for prevention of type III GBS vaginal acquisition. The observation period for each patient will be 18 months following vaccination. The specific objectives are: enroll 600 women (previously screened within last 14 days in a GBS Screening Protocol) identified as GBS type III negative, vaginally and rectally; vaccinate 600 women randomized to a 1:1 ratio with 50 micrograms of type III GBS polysaccharide conjugated to tetanus toxoid (GBS III-TT) or licensed vaccine containing Tetanus and Diphtheria Toxoids adsorbed for adult use (Td); measure reactogenicity by subject report in a 7-day symptom diary and by 1-2 day follow-up telephone call; evaluate women at 1, 2, 4, 6, 8, 10, 12, 14, 16 and 18 months for serum antibody response. Blood will be obtained at each of these clinic follow-up visits and serum will be used to compare type III GBS specific antibody levels at baseline and follow-up; assess vaginal and rectal acquisition by GBS at months 1, 2, 4, 6, 8, 10, 12, 14, 16 and 18 months using specimens obtained at the clinic visits; compare women receiving GBS III-TT vaccine to women receiving Td vaccine with respect to the time to first vaginal culture positive for type III GBS; assess the relationship between person-level covariates, including features of the decrease of type III GBS antibody levels over time, and the time to first vaginal culture positive for type III GBS; and assess the effect of vaginal colonization by hydrogen peroxide (H2O2)-producing Lactobacillus, sexual activity, antibiotic usage, rectal colonization with GBS and demographic features as risk factors for acquisition of type III GBS, independent of serum antibody levels. The primary study endpoint will be the time to the first vaginal swab that is type III GBS culture positive, with all previous cultures negative for type III GBS, not just the immediately preceding culture. The secondary endpoints include: the proportion of vaginal swabs that are type III GBS culture positive; the proportion of subjects whose vaginal cultures are type III GBS culture negative throughout the study; the frequency of vaginal colonization with GBS serotypes Ia, Ib, II and V; the measurement of serum immunoglobulin (Ig)G antibody levels to type III GBS at 1, 2, 4, 6, 8, 10 12, 14, 16 and 18 months following vaccination; the measurement of post-vaccination antibody levels to type III GBS, stratified by pre-vaccination levels of native antibody; the frequency of local and systemic symptoms attributable to vaccination; and the density of type III GBS cultured from vaginal swabs at culture positive visits.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 40 Years (Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Participated in and completed the group B Streptococcus (GBS) Screening Protocol
- •Non-pregnant women
- •Aged 18-40 years at time of the screening protocol
- •Currently sexually active at time of enrollment (sex with a male at least once in the last 4 months)
- •Current use of effective birth control methods and stated intention to use the method for at least the next 30 days
- •Provision of written informed consent
- •Intention to stay in the geographical area for the next 18 months
- •Access to telephone
Exclusion Criteria
- •Group B Streptococcus (GBS) positive by culture (vaginal and/or rectal), or culture positive for streptococcal strains that cross-react with GBS typing sera (vaginal and/or rectal).
- •Pregnancy (all women will receive a urine pregnancy prior to vaccination).
- •Any condition which in the opinion of the investigator would pose a health risk to the subject or interfere with the evaluation of the vaccine.
- •Serious underlying disease, which is known at the time of vaccination (including: immunodeficiency, active or chronic hepatitis, immunosuppressive conditions which require systemic steroid therapy, or treatment for a malignancy during the past year).
- •Receipt of any vaccine, blood product, or experimental medicine within the past 30 days with the exception of a licensed inactivated influenza vaccine.
- •Plans to receive any vaccine, blood product, or experimental medicine in the next 30 days with the exception of a licensed inactivated influenza vaccine.
- •Use of any antimicrobial agent(s) (vaginal or systemic) for treatment of any condition within 7 days prior to study enrollment (including: Monistat, Gyne-Lotrimin, et cetera )
- •History of hypersensitivity to tetanus toxoid vaccine.
- •Tetanus toxoid immunization within the previous 12 months.
- •Previous participation in a study in which participants received tetanus toxoid vaccine or vaccine against Group B Streptococcus.
- •Spontaneous or surgical menopause.
- •Nursing mother.
- •Hypersensitivity to thimerosal.
Outcomes
Primary Outcomes
The Time to First Vaginal Swab That is Type III GBS Culture Positive, With All Previous Cultures Negative for Type III GBS, Not Just the Immediately Preceding Culture.
Time Frame: Time from vaccination to acquisition of vaginal type III GBS, up to 18 months post-vaccination.
Time to first acquisition of vaginal type III GBS was calculated as time from vaccination to the mid-point of the interval of ascertainment, censored by either the end of the follow-up period, or the first of 2 or more consecutive missed visits. Vaginal type III GBS status at missed visits prior to censoring was imputed from the subsequent visit.
Secondary Outcomes
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 18 Post-Vaccination(Prior to and 18 months following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 6 Post-Vaccination(Prior to and 6 months following vaccination)
- Mean Fold-Rise in Serum IgG Antibody Levels to Type III GBS Post-Vaccination(Prior to and at 1, 2, 4, 6, 8, 10, 12, 14, 16, and 18 months following vaccination.)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 1 Post-Vaccination(Prior to and 1 month following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 4 Post-Vaccination(Prior to and 4 months following vaccination)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 0(Month 0 prior to vaccination)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 1 Post Vaccination(Month 1)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 2 Post Vaccination(Month 2)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 8 Post Vaccination(Month 8)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 14 Post Vaccination(Month 14)
- Geometric Mean Concentration (GMC) of Serum Immunoglobulin G (IgG) Antibody Levels to Type III GBS Post-Vaccination.(Prior to and at 1, 2, 4, 6, 8, 10, 12, 14, 16, and 18 months following vaccination.)
- Number of Participants With Any Solicited Local and Systemic Symptoms.(Safety surveillance during the 1st 7 days.)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 12 Post-Vaccination(Prior to and 12 months following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 14 Post-Vaccination(Prior to and 14 months following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 2 Post-Vaccination(Prior to and 2 months following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 8 Post-Vaccination(Prior to and 8 month following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 10 Post-Vaccination(Prior to and 10 months following vaccination)
- Number of Participants With a Four-Fold or Greater Rise in Serum IgG Antibody to Type III GBS at Month 16 Post-Vaccination(Prior to and 16 months following vaccination)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 10 Post Vaccination(Month 10)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 4 Post Vaccination(Month 4)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 1(Month 1)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 4(Month 4)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 8(Month 8)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 6 Post Vaccination(Month 6)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 10(Month 10)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 18(Month 18)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 12 Post Vaccination(Month 12)
- Number of Participants Whose Vaginal Cultures Are Type III GBS Culture Negative Throughout the Study.(Every 2 months from time of vaccination up to 18 months post-vaccination.)
- Number of Participants Whose Vaginal Cultures Were Type III GBS Culture Positive.(Every 2 months from time of vaccination up to 18 months post-vaccination.)
- Number of Participants Whose Vaginal Cultures Were Persistently Type III GBS Culture Positive for Three or More Consecutive Visits(Every 2 months from time of vaccination up to 18 months post-vaccination.)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 0(Month 0)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 2(Month 2)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 12(Month 12)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 16 Post Vaccination(Month 16)
- Number of Participants With a Serum IgG Antibody to Type III GBS Post-Vaccination of 5 µg/mL or Greater at Month 18 Post Vaccination(Month 18)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 6(Month 6)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 14(Month 14)
- The Density of Type III GBS Cultured From Vaginal Swabs at Month 16(Month 16)