Genetic and Environmental Factors in the Response to Influenza Vaccination

Study Overview
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Brief Summary
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The purpose of the study is to investigate and compare the immune responses to influenza vaccination in monozygotic (identical) and dizygotic (fraternal) twins to determine the roles of genetics and environment in the response to flu vaccination.

Detailed Description
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This is a phase 1 study of 120 healthy 12-49 year old adolescents and adult volunteers who are given licensed seasonal influenza vaccine. There are no exclusions for gender, ethnicity or race. The volunteers will be enrolled into one of 3 groups: Group A: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+ 7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group B: Up to 40 healthy dizygotic (DZ) twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group C: Up to 40 healthy monozygotic (MZ) twin volunteers, 12-49 years old, will be randomized within the twin pair to receive either inactivated influenza vaccine quadrivalent (IIV4) or live, attenuated influenza vaccine quadrivalent (LAIV4). Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). This group was terminated in 2016 due to ACIP recommendations against the use of LAIV but was reopened in 2018 with the availability of LAIV4. Each twin is counted as a single participant. All reporting numbers reflect the number of participants, not the number of twin pairs.

Official Title
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Genetic and Environmental Factors in the Response to Influenza Vaccination

Conditions
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Influenza, Healthy

Intervention / Treatment
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* Biological: FluMist® Quadrivalent
* Biological: Fluzone® Quadrivalent vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Otherwise healthy, 12-49 years old, identical (MZ) or fraternal (DZ) twins. Willing to complete the informed consent process (including assent for minors 12-17 years of age, inclusive). Availability for follow-up for the planned duration of the study at least 28 days after immunization. Acceptable medical history by review of inclusion/exclusion criteria and vital signs. Exclusion Criteria Prior off-study vaccination with the current year's seasonal influenza vaccine. Allergy to egg or egg products, or to vaccine components, (including gentamicin, gelatin, arginine or MSG in LAIV) Life-threatening reactions to previous influenza vaccinations. Asthma (If yes, not eligible for Group C). Active systemic or serious concurrent illness, including febrile illness on the day of vaccination. History of immunodeficiency (including HIV infection). Known or suspected impairment of immunologic function, including, but not limited to, clinically significant liver disease, diabetes mellitus treated with insulin, moderate to severe renal disease, or any other chronic disorder which, in the opinion of the investigator, might jeopardize volunteer safety or compliance with the protocol. Blood pressure >150 systolic or >95 diastolic at first study visit and the day of vaccination. Hospitalization in the past year for congestive heart failure or emphysema. Chronic Hepatitis B or C. Recent or current use of immunosuppressive medication, including systemic glucocorticoids (corticosteroid nasal sprays and topical steroids are permissible in all groups; inhaled steroid use is not permissible). In close contact with anyone who has a severely weakened immune system and requires a protective environment (If yes, may be ineligible for Group C; exposure to such persons should be avoided for 7 days after receipt of LAIV). Malignancy, other than squamous cell or basal cell skin cancer (includes solid tumors such as breast cancer or prostate cancer with recurrence in the past year, and any hematologic cancer such as leukemia). Autoimmune disease (including rheumatoid arthritis treated with immunosuppressive medication such as Plaquenil, methotrexate, prednisone, Enbrel) which, in the opinion of the investigator, might jeopardize volunteer safety or compliance with the protocol. History of blood dyscrasias, renal disease, or hemoglobinopathies requiring regular medical follow up or hospitalization during the preceding year. Use of any anti-coagulation medication such as Coumadin or Lovenox, or anti-platelet agents such as aspirin (except up to 325 mg. per day), Plavix, or Aggrenox must be reviewed by investigator to determine if this would affect the volunteer's safety. For children or adolescents through 17 years of age, receiving aspirin therapy or aspirin-containing products (If yes, not eligible for Group C). Receipt of blood or blood products within the past 6 months or planned used during the study. Medical or psychiatric condition or occupational responsibilities that preclude participant compliance with the protocol. Receipt of inactivated vaccine 14 days prior to study enrollment, or planned vaccinations prior to completion of last study visit (  28 days after study vaccination). Receipt of live, attenuated vaccine within 60 days prior to enrollment of planned vaccination prior to completion of last study visit (  28 days after study vaccination). Need for allergy immunization (that cannot be postponed) during the study period. Has taken an influenza antiviral medication within 48 hours prior to study vaccination (If yes, not eligible for Group C). History of Guillain-Barré syndrome Pregnant woman Lactating woman (If yes, not eligible for Group C). Use of investigational agents within 30 days prior to enrollment or planned use during the study. Donation of the equivalent of a unit of blood within 6 weeks prior to enrollment or planned donation prior to completion of the last visit. Any condition which, in the opinion of the investigator, might interfere with volunteer safety, study objectives or the ability of the participant to understand or comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 49 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: MZ twins (IIV4)<br>Group A: Up to 40 healthy monozygotic (MZ) individual twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4) Fluzone® Quadrivalent vaccine. Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Fluzone® Quadrivalent vaccine<br>* IIV4 vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>|
| Experimental: Group B: DZ twins (IIV4)<br>Group B: Up to 40 healthy dizygotic (DZ) individual twin volunteers, 12-49 years old, will be given inactivated influenza vaccine quadrivalent (IIV4) Fluzone® Quadrivalent vaccine. Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), and Day 6-8 and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Fluzone® Quadrivalent vaccine<br>* IIV4 vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>|
| Experimental: Group C: MZ twins (IIV4 or LAIV4)<br>Group C: Up to 40 healthy monozygotic (MZ) individual twin volunteers, 12-49 years old, will be randomized within the twin pair to receive either inactivated influenza vaccine quadrivalent (IIV4) Fluzone® Quadrivalent vaccine or live, attenuated influenza vaccine quadrivalent (LAIV4) FluMist® Quadrivalent. Each volunteer will complete a total of 3 visits: Day 0 (pre-immunization), Day 6-8 and Day 28+7 post-immunization. All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). This group was terminated in 2016 due to ACIP recommendations against the use of LAIV but may be reopened in 2018 pending LAIV4 availability. | Biological: FluMist® Quadrivalent<br>* LAIV4 vaccine dosage is 0.2 mL. Vaccine will be administered as an intranasal spray. Each sprayer contains a single dose of FluMist® Quadrivalent; approximately one-half of the contents should be administered into each nostril. 0.1 mL (i.e., half of the dose from a single FluMist sprayer) is administered into each nostril while the recipient is in an upright position. Insert the tip of the sprayer just inside the nose and rapidly depress the plunger until the dose-divider clip stops the plunger. The dose divider clip is removed from the sprayer to administer the second half of the dose (0.1 mL) into the other nostril.<br>Biological: Fluzone® Quadrivalent vaccine<br>* IIV4 vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemagglutination inhibition (HAI) titers in response to influenza vaccination. |  | Day 0 to Day 28 | 
| Interferon-gamma (IFN-γ) production by T cells |  | Day 0 to Day 28 | 
| IFN-γ production by Natural Killer (NK) cells. |  | Day 0 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequencing of T-cell receptor (TCR)ab and Immunoglobulin Genes | B and T cells will be sequenced for their antibody repertoires. | Day 0 to Day 28 | 
| Natural Killer (NK) repertoire. | Mass cytometry will be used to assess the NK cell repertoire. | Day 0 to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inactivated influenza vaccine quadrivalent, Live, attenuated influenza vaccine quadrivalent, Monozygotic twins, Dizygotic twins, Adults, Adolescents