Interferon as a Mucosal Adjuvant for Influenza Vaccine Given Intranasally

Study Overview
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Brief Summary
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Influenza is a virus infection that causes sickness from the nose to the lungs. It is thought that type 1 interferon (a protein that helps the immune system fight viruses) will make flu vaccines more effective. This study will determine if type 1 interferon added to a specific flu vaccine will help the immune system of healthy adults fight off infection better than vaccine alone. Ninety volunteers, ages 18-40, will participate in this study. They will attend 3 study visits and have a final follow-up study visit, email, or phone call about six months after the vaccination. Volunteers will receive a single dose of study vaccine sprayed into the nose. Study procedures including blood samples and nasal washes (the inside of the nose is washed out) will be collected to evaluate immune system responses.

Detailed Description
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Influenza is primarily a virus infection of the respiratory tract mucosa from the nose to the terminal bronchioles. Immunity to influenza virus infection is mediated primarily by antibody in respiratory secretions at the mucosal surface. To meet the need for improved inactivated vaccines, one potential approach is to increase the frequency and magnitude of antibody in secretions by administering inactivated influenza virus vaccine (IVV) intranasally and to optimize responses by including a mucosal adjuvant. The primary hypothesis of this study is that Type 1 interferon (IFN) will provide an adjuvant effect at the respiratory mucosal surface for production of IgA and/or IgG antibody to the influenza strains when added to IVV and administered intranasally. The primary objective of the study is to determine whether including type 1 IFN with IVV, administered intranasally, to healthy adults will enhance antibody responses in nasal secretions compared to intranasal administration of IVV alone. This is a single-center, randomized, double-blind, clinical trial to determine if type 1 IFN will act as a mucosal adjuvant for antibody responses to influenza viruses after administration with IVV intranasally. Subjects will be healthy adults between the ages of 18 and 40. The study will enroll 30 subjects in each of three groups, a group given 0.6 ml of IVV, a group given 0.6 ml of IVV containing 1M units of IFN and a group given 0.7 ml of IVV containing 10M units of IFN. The vaccine or vaccine/interferon combination will be administered to the subjects intranasally once. Blood and nasal secretions will be obtained before vaccination and again two and four weeks after immunization. Each subject will be asked to complete a memory aid for seven days and to report any unexpected adverse events (AEs) to study personnel. The subject will report to the clinic or be contacted by phone or e-mail at six months after vaccination regarding occurrence of any unreported serious adverse events (SAEs). The three nasal secretions will be used for testing for IgA and IgG antibody to the A/H1N1 and A/H3N2 HA in enzyme-linked immunosorbent assay (ELISA) tests. The three blood samples will be tested in HAI and neutralization tests for antibody to the A/H1N1 and A/H3N2 vaccine antigens.

Official Title
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Type 1 Interferon as a Mucosal Adjuvant for Influenza Vaccine Given Intranasally

Conditions
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Influenza

Intervention / Treatment
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* Biological: Trivalent inactivated influenza virus vaccine (2006-2007 formulation)
* Biological: Type 1 interferon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant female (as indicated by a negative urine pregnancy test immediately prior to vaccine administration) between the ages of 18 and 40 years. Women of childbearing potential who are at risk of becoming pregnant must agree to practice adequate contraception (e.g., barrier method, abstinence, and licensed hormonal methods) for at least 3 months after immunization. Is in good health, as determined by vital signs (heart rate, blood pressure, oral temperature), medical history and a targeted physical examination based on medical history. Able to understand and comply with planned study procedures. Provides informed consent prior to any study procedures and is available for all study visits. Exclusion Criteria: Has a known allergy to eggs, chicken protein or other components of the vaccine. Has a positive urine pregnancy test prior to vaccination (if female of childbearing potential), is lactating, or has the intention to become pregnant within 3 months of receipt of vaccine. Is undergoing immunosuppression as a result of an underlying illness or treatment. Has an active neoplastic disease or a history of any hematologic malignancy. Is using oral or parenteral steroids or other immunosuppressive or cytotoxic drugs. Has used any nasal or aerosol treatments in the past 2 weeks or likely to use any in the next 2 weeks. Has a diagnosis of hay fever or asthma. Has a history of receiving immunoglobulin or other blood product within the 3 months prior to enrollment in this study. Has a diagnosis of schizophrenia, bipolar disease or other major psychiatric diagnosis. Has received any other licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to enrollment in this study. Has an acute or chronic medical condition that, in the opinion of the investigator, would render vaccination unsafe or would interfere with the evaluation of responses (this includes, but is not limited to: known chronic liver disease, significant renal disease, unstable or progressive neurological disorders, diabetes mellitus, and transplant recipients). Has a history of severe reactions following immunization with contemporary influenza virus vaccines. Has an acute illness, including an oral temperature greater than 100.4 degrees F, within 1 week prior to vaccination. Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to vaccination in the study, or expects to receive an experimental agent during the 6-month study period. Is planning to enroll in another clinical trial at any time during the study period. Has known active human immunodeficiency virus, hepatitis B or hepatitis C infection. Has a history of alcohol or drug abuse in the last 5 years. Has a history of Guillain-Barre syndrome. Has received the 2006-2007 formulation influenza vaccine by injection or by nose drops (fall of 2006 or since). Has any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: 0.6 ml of IVV<br>30 subjects to receive 0.6 ml of inactivated influenza virus vaccine (IVV). | Biological: Trivalent inactivated influenza virus vaccine (2006-2007 formulation)<br>* Commercially available trivalent inactivated influenza virus vaccine without or with 1 of 2 dosages of commercially available type 1 interferon administered once by nasal instillation. Dosages: 0.6 ml of IVV or 0.7 ml of IVV.<br>|
| Experimental: Group 3: 0.7 ml of IVV + 10M units of IFN<br>30 subjects to receive 0.7 ml of IVV containing 10M units of interferon (IFN). | Biological: Trivalent inactivated influenza virus vaccine (2006-2007 formulation)<br>* Commercially available trivalent inactivated influenza virus vaccine without or with 1 of 2 dosages of commercially available type 1 interferon administered once by nasal instillation. Dosages: 0.6 ml of IVV or 0.7 ml of IVV.<br>Biological: Type 1 interferon<br>* Commercially available lyophilized IFN; dosages 1 M unit (Mu) of IFN; 10 M units (Mu) of IFN.<br>|
| Experimental: Group 2: 0.6 ml of IVV + 1M unit of IFN<br>30 subjects to receive 0.6 ml of IVV containing 1M units of interferon (IFN). | Biological: Trivalent inactivated influenza virus vaccine (2006-2007 formulation)<br>* Commercially available trivalent inactivated influenza virus vaccine without or with 1 of 2 dosages of commercially available type 1 interferon administered once by nasal instillation. Dosages: 0.6 ml of IVV or 0.7 ml of IVV.<br>Biological: Type 1 interferon<br>* Commercially available lyophilized IFN; dosages 1 M unit (Mu) of IFN; 10 M units (Mu) of IFN.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody Responses in Nasal Secretions to Influenza A/H1N1 and A/H3N2 at 14 Days After Intranasal Immunization. | Number of subjects (frequency) responding with a four-fold or greater increase (magnitude) in titer at day 14 after immunization, relative to pre-immunization levels | 14 days after immunization. | 
| Antibody Responses in Nasal Secretions to Influenza A/H1N1 and A/H3N2 at 28 Days After Intranasal Immunization | Number of subjects (frequency) responding with a four-fold or greater increase (magnitude) in titer at day 28 after immunization, relative to pre-immunization levels. | 28 days after immunization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local and/or Systemic Solicited Symptoms After Intranasal Immunization. | Number of participants (frequency) reporting solicited (systematically collected on a Memory Aid) reactogenicity events of any severity and number reporting severe occurrences. | 0-7 days following immunization | 
| Serum Antibody Responses (Hemagglutination Inhibition (HAI) and Neutralization) to Influenza A/H1N1 and A/H3N2 at 14 Days After Intranasal Immunization. | Number of subjects (frequency) responding with a four-fold or greater increase (magnitude) in titer at 14 days after immunization, relative to pre-immunization levels. | 14 days after immunization. | 
| Unsolicited Adverse Events After Intranasal Immunization | Number of subjects (frequency) with spontaneous reports of Adverse Events of any severity and severe or higher severity, during the 28 days after vaccination regardless of relatedness. Events reported by more than 5.6% of subjects in any group are reported by MedDRA Preferred Term. | Non-serious AEs are collected through 28 days after vaccination. Serious AEs are collected through 180 days after vaccination. | 
| Serum Antibody Responses (Hemagglutination Inhibition (HAI) and Neutralization) to Influenza A/H1N1 and A/H3N2 at 28 Days After Intranasal Immunization. | Number of subjects (frequency) responding with a four-fold or greater increase (magnitude) in titer at 28 days after immunization, relative to pre-immunization levels. | 28 days after immunization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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interferon, vaccine, influenza