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Systems Biology of Inactivated Rabies Vaccine in Healthy Adults With or Without Use of Broad Spectrum Antibiotics

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ClinicalTrials.gov Identifier: NCT03557008
Recruitment Status : Recruiting
First Posted : June 14, 2018
Last Update Posted : July 23, 2019
Sponsor:
Information provided by (Responsible Party):
Nadine Rouphael, Emory University

Brief Summary:

The study is a prospective randomized, unblinded study looking to enroll 54 subjects at Emory University. The use of antibiotics changes micro-organisms in the intestines. The change to micro-organisms in the intestines may change the body's vaccine immune response and alter the effectiveness of the rabies vaccine.

There will be two randomized groups (1:1 randomization). Group A will start taking an antibiotic regimen by mouth 3 days prior to vaccination and continue taking antibiotics the day of rabies vaccination and one day after vaccination for a total of 5 days. Group B will only receive the rabies vaccination and will not take any antibiotics. The dosage of each antibiotic is taken from their respective package inserts and does not exceed the maximum dose allowed for each antibiotic.

The purpose of the study is to look at certain markers (immune responses) in blood and lymph nodes after rabies vaccination with or without the use of antibiotics from day of vaccination to 28 days post vaccination in both groups.


Condition or disease Intervention/treatment Phase
Rabies Human Biological: Rabies Vaccine Drug: Metronidazole Drug: Vancomycin Drug: Neomycin Sulfate Phase 4

Detailed Description:

Vaccination has been one of the most important and cost-effective public health interventions to provide protection against infectious diseases. Since the introduction of the first vaccine in 1796, there have been countless advances in the field. However, numerous gaps remain to be addressed. An important gap is understanding the mechanisms that lead to suboptimal immune responses to vaccination. It has been shown that the magnitude of the immune response produced by vaccines is highly variable among individuals, with both genetic and environmental factors playing an important role. More recently, emphasis is being placed on the role of the microbiota in vaccine immunogenicity. The microbiome is the collection of all microbial cells in and on the human body, with the majority being in the gastrointestinal tract. Due to this link between microbiome and the immune system, it is important to further understand the impact of the microbiome on the immune response to vaccination. This can be done using systems vaccinology, which is the application of systems biology in vaccinology to predict vaccine efficacy. The aim is to find molecular signatures, or patterns of gene expression induced after vaccination, which can be used to correlate and predict the development of protective immunity. The goal of this study is to determine whether alteration of microbiota by antibiotic exposure can negatively impact the immunogenicity of rabies vaccine, and to assess the innate and adaptive immune mechanisms responsible for that phenomenon. The study also wants to evaluate the safety profile of the different antibiotics and the lymph node sampling methods.

Half of the study participants will receive the rabies vaccine alone and half will receive the rabies vaccine along with a 5 day course of antibiotics. The primary objective of this study is to compare antibody titers after vaccination with the rabies vaccine in adults with or without use of antibiotics.

Prior to the clinical trial portion of this study comparing the antibody titers between the study arms, the researchers will evaluate lymph node sampling methods. The study will determine whether Fine Needle Aspiration (FNA) or Core Needle Biopsy (CNB) is the best technique for sampling lymph nodes. Once the best technique is determined, the ideal timing of lymph node sampling will be examined by comparing follow up sampling at 1, 3 or 7 days after vaccination. The technique and timing found to be best will be used throughout the remainder of the trial.Subjects are followed on days 1, 3, 7, 14, 28, 180, and 365 post randomization. Any grade 2 solicited adverse event (AE) (until D28 or up to 7 days after lymph node sampling) or serious adverse event (SAE) (for the duration of the study) which may not have been reported by the subject by calling the site as directed at a prior visit.

Blood samples for immunologic testing will be collected at screening (from D -35 to D -2), on D0 (at vaccination), D1, D3, D7 (+/- 1 day), D14 (+/- 2 day), D28 (+/- 5 days), D29, D35 (+/- 1 day), D56 (+/- 5 days), D180 (+/- 14 days), D365 (+/- 14 days) post vaccination for both groups to study innate and/or adaptive immune responses.

Stool samples will be collected in both groups at screening (from D -35 to D -2), on D0 (at vaccination), D1, D3, D7 (+/- 1 day), D14 (+/- 2 day), D28 (+/- 5 days), D29, D35 (+/- 1 day), D56 (+/- 5 days), D180 (+/- 14 days), D365 (+/- 14 days) post vaccination to study the gut microbiome. For Group A, stools will be screened for Clostridium difficile carriage by PCR at screening (from D-35 to D-2).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Longitudinal and Randomized
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Prospective Randomized Open Label Trial to Study the Systems Biology of Inactivated Rabies Vaccine in Healthy Adults With or Without Use of Broad Spectrum Antibiotics
Actual Study Start Date : July 5, 2018
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics Rabies

Arm Intervention/treatment
Active Comparator: Rabies Vaccine with Antibiotics
Participants in this group will receive the rabies vaccines as well as an antibiotic regimen consisting of metronidazole, vancomycin, and neomycin sulfate.
Biological: Rabies Vaccine
A single 1.0 milliliter (mL) dose of Imovax® will be given to participants on Day 0 and Day 28 of the study.
Other Name: Imovax

Drug: Metronidazole
The antibiotic regimen will be given for five days beginning 3 days prior to vaccination, on the vaccination day, and one day after vaccination for a total for 5. The regimen will include 500 milligrams (mg) of Flagyl taken by mouth three times a day.
Other Name: Flagyl

Drug: Vancomycin
The antibiotic regimen will be given for five days beginning 3 days prior to vaccination, on the vaccination day, and one day after vaccination for a total for 5. The regimen will include 125 mg of Vancocin taken by mouth four times a day.
Other Name: Vancocin

Drug: Neomycin Sulfate
The antibiotic regimen will be given for five days beginning 3 days prior to vaccination, on the vaccination day, and one day after vaccination for a total for 5. The regimen will include 500 milligrams (mg) of Neomycin sulfate taken by mouth three times a day.
Other Name: Mycifradin

Active Comparator: Rabies Vaccine
Participants in this group will receive the rabies vaccine.
Biological: Rabies Vaccine
A single 1.0 milliliter (mL) dose of Imovax® will be given to participants on Day 0 and Day 28 of the study.
Other Name: Imovax




Primary Outcome Measures :
  1. Antibody Titers [ Time Frame: Day 28 ]
    The comparison of antibody titers will be examined by direct comparison of antibody titers expressed in international units (IU) per milliliter (mL) of blood. The first data analysis route is directly comparing the means of the antibody titers between the two groups at 28 days after vaccination. Rabies antibody titer levels range from 0.1 to 15.0 IU/mL and titer levels of at least 0.5 IU/mL indicate there has been an adequate immune response after rabies vaccination.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy individuals aged 18-49 years.
  • Able to understand and give informed consent.
  • Women of child-bearing potential (not surgically sterile via tubal ligation, bilateral oophorectomy or hysterectomy or who are not postmenopausal for ≥1 year) must agree to practice adequate contraception that may include, but is not limited to, abstinence, monogamous relationship with vasectomized partner, barrier methods such as condoms, diaphragms, spermicides, intrauterine devices, and licensed hormonal methods for 28 days before and 28 days after Rabies vaccination.

Exclusion Criteria:

  • Receipt of the following:

    • Receipt of blood products 3 months prior to vaccination or expected receipt through 12 months after vaccination.
    • Receipt of any live virus vaccines within 28 days prior to vaccination or expected receipt within 28 days after vaccination.
    • Receipt of any inactivated vaccine within 14 days or expected receipt within 14 days after vaccination.
    • Receipt of any antibiotic 3 months prior to vaccination or expected receipt 28 days after vaccination.
    • Receipt of probiotics and prebiotics 3 months prior to vaccination or expected receipt 28 days after vaccination.
    • Receipt of proton pump inhibitors, H2 receptor blockers, or antacids 3 months prior to vaccination or expected receipt 28 days after vaccination.
  • Presence of co-morbidities or immunosuppressive states such as:

    • Chronic medical problems including (but not limited to) insulin dependent diabetes, severe heart disease (including arrhythmias), severe lung disease, auto immune diseases, thrombocytopenia and grade 4 hypertension. Grade 4 hypertension per CTCAE criteria is defined as Life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive).
    • Chronic neurologic conditions including seizure disorder, Parkinson's disease, myasthenia gravis, neuropathy, or history of encephalopathy, meningitis or ototoxicity.
    • Any history of gastrointestinal disease including (but not only): documented bacterial gastroenteritis or gastroenteritis associated with fever or associated with presence of blood/mucus in stools in the last 3 months; inflammatory bowel disease, and/or gastrointestinal surgery.
    • Any history of kidney or liver diseases.
    • Alcohol abuse, drug abuse, or psychiatric conditions that in the opinion of the investigator would preclude compliance with the trial or interpretation of safety or endpoint data.
    • Any history of lymphoma involving axillary nodes or any history of breast cancer.
    • Impaired immune function or known chronic infections including, but not limited to, known HIV, tuberculosis, hepatitis B or C; organ transplantation (bone marrow, hematopoietic stem cell, or solid organ transplant); immunosuppression due to cancer; current and/or expected receipt of chemotherapy, radiation therapy, steroids (i.e., more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more in the past 90 days , or high dose inhaled corticosteroids); and any other immunosuppressive therapies (including anti-TNF therapy), functional or anatomic asplenia, or congenital immunodeficiency. Subjects receiving > 20 mg/day of prednisone or its equivalent daily or on alternate days for more than 2 weeks may enter the study after therapy has been discontinued for more than 3 months and Subjects are excluded if on high dose intranasal steroids defined as > 960 mcg/day of beclomethasone dipropionate or equivalent.
    • Pregnancy or breast feeding
  • Conditions that could affect the safety of the volunteers, such as:

    • Severe reactions to prior vaccinations, including anaphylaxis
    • History of Guillain-Barré syndrome
    • History of bleeding disorders or current use of warfarin, aspirin, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs) or other blood thinner/anticoagulant medications in the past week (for subjects undergoing lymph node sampling)
    • Use of anticonvulsants
    • Use of digoxin or other forms of digitalis
    • Any allergy to any component of the vaccine or lidocaine (for subjects undergoing lymph node sampling)
    • Allergy to vancomycin, metronidazole or neomycin as well as other aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin)
  • Volunteers with any acute illness, including any fever (> 100.4 F [> 38.0C], regardless of the route) within 3 days prior to vaccination.
  • Social, occupational, or any other condition that in the opinion of the investigator might interfere with compliance with the study and vaccine evaluation.
  • Positive C difficile testing by PCR at screening or history of C difficile infection.
  • Any grade 2 safety lab test results at screening
  • Previously received any rabies vaccine or immunoglobulin.
  • Are at high risk of exposure to rabies: veterinarians, animal handlers, rabies laboratory workers, spelunkers, frequent contact with rabies virus or with possibly rabid animals, international travelers who are likely to come in contact with animals in parts of the world where rabies is common, and rabies biologics production workers.
  • Bilateral inflammatory process of upper arms in the past 2 weeks.
  • Prior breast or axillary biopsy and/or surgery.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03557008


Contacts
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Contact: Nadine Rouphael, MD 404-712-1435 nroupha@emory.edu
Contact: Eileen Osinski 404-712-1371 gosinsk@emory.edu

Locations
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United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Nadine Rouphael, MD    404-712-1435    nroupha@emory.edu   
The Hope Clinic of the Emory Vaccine Center Recruiting
Decatur, Georgia, United States, 30030
Contact: Nadine Rouphael, MD    404-712-1435    nroupha@emory.edu   
Principal Investigator: Nadine Rouphael, MD         
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Nadine Rouphael, MD Emory University

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Responsible Party: Nadine Rouphael, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT03557008     History of Changes
Other Study ID Numbers: IRB00101567
First Posted: June 14, 2018    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nadine Rouphael, Emory University:
Rabies Vaccine
Antibiotics
Biopsy

Additional relevant MeSH terms:
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Rabies
Immunologic Factors
Rhabdoviridae Infections
Mononegavirales Infections
RNA Virus Infections
Virus Diseases
Anti-Bacterial Agents
Metronidazole
Vancomycin
Neomycin
Antibiotics, Antitubercular
Vaccines
Physiological Effects of Drugs
Anti-Infective Agents
Antitubercular Agents
Antiprotozoal Agents
Antiparasitic Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action