Influenza Virus Vaccine Plus Vitamin A and D Supplements for Prevention of Respiratory Virus Infections in Children

Study Overview
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Brief Summary
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Children are particularly vulnerable to respiratory virus infections, especially influenza. Vitamin A & D deficiencies are associated with vulnerability to infectious diseases of the respiratory tract. The central hypothesis of this protocol is that vitamin supplements will enhance antibody responses toward the flu vaccine in children. Children, 2-8 years old, will be randomized to receive influenza virus vaccine with a vitamin A+D supplement or influenza virus vaccine with placebo. Children will be tested for vitamin levels and immune responses before and after influenza virus vaccinations to determine if vitamin supplementation improves the influenza virus vaccine-induced immune response. PRIMARY OBJECTIVE: To assess the vaccine-induced and total antibody (including IgG and IgA) response after influenza virus vaccine administration and IgA/IgG plus IgA/IgM ratios at 28 and 56 days in sera SECONDARY OBJECTIVE: To assess the neutralizing response toward influenza virus vaccine in the sera.

Detailed Description
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Participants will be randomized to receive either an influenza virus vaccine plus Vitamins A & D or an influenza virus vaccine plus placebo. They will be stratified based on retinol binding protein (RBP) levels at screening, using a cut-off indicative of Vitamin A insufficiency (≤22,000 ng/ml). Co-enrolled sibling participants will be first stratified by RBP levels, then siblings within the same stratum will be equally assigned to different arms to provide greater assurance of balanced treatment assignment. Children will be tested for vitamin levels and immune responses before and after influenza virus vaccinations to determine if vitamin supplementation improves the influenza virus vaccine-induced antibody immune response. All participants will receive two doses of an influenza virus vaccination administered at least 28 days apart. Vitamin levels and antibody responses toward the vaccine will be measured on day 0 (baseline levels obtained where day 0 equals the first influenza virus vaccination administration), day 28, and day 56. Placebo or Vitamins A + D (at the levels of 20,000 IU and 2,000 IU, respectively) will be administered orally on the days of vaccination. Blood serum samples will be collected from participants on Day 0, prior to receiving influenza virus vaccine on Day 28, and during their Day 56 follow-up visit. Parents will be asked to fill out diary cards to indicate food intake for children during the study period along with an optional food frequency questionnaire given on day 56. Specific measurements on days 28, and 56 will include analyses of vaccine-specific and total IgA, IgG, and IgA/IgG plus IgA/IgM ratios in sera. Functional activities of antibodies toward influenza vaccine will also be measured.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled Study of Antibody Induction by Vitamin Supplementation at the Time of Influenza Virus Vaccinations in Children

Conditions
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Healthy Participants

Intervention / Treatment
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* Biological: Influenza virus vaccine
* Dietary Supplement: Vitamins A and D
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Resident of the Memphis area community. Parent or legal guardian willing and able to give informed consent and comply with study requirements. Exclusion Criteria: Current use of investigational or immunosuppressive drugs (e.g., steroids) at the time of enrollment. Currently taking a daily (routine) vitamin A, D, or multivitamin. Note: participants who report occasional or sporadic vitamin use will be allowed to enroll. History of lung disease, asthma, immunodeficiency, sickle cell disease, or any other serious underlying condition or disease in the opinion of the principal investigator. Evidence of developmental delay or evolving neurological disorders at screening. Current use of antibiotics or antivirals at enrollment. History of having a severe allergy to eggs or to any inactive ingredient in the influenza virus vaccine History of a life-threatening reaction to influenza vaccinations Currently wheezing at the time of enrollment History of heart, kidney, or lung conditions History of diabetes Use of an anti-influenza medication (including amantadine, rimantadine, oseltamivir, and zanamivir) within 14 days prior to enrollment Acute febrile [>100.0°F (37.8°C) oral] illness or acute respiratory illness (e.g., cough or sore throat) within 3 days prior to enrollment Previous receipt of current seasonal influenza vaccine

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 8 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Influenza Virus Vaccine Plus Vitamins A and D<br>Participants receive influenza virus vaccine and Vitamins A and D supplement on Day 0 and Day 28. | Biological: Influenza virus vaccine<br>* Children will have the first influenza virus vaccine dose (dose 1) administered on day 0 of the trial, and the second dose (dose 2) administered 28 days later.<br>* Other names: Fluzone®;Dietary Supplement: Vitamins A and D<br>* The chewable gummy contains either Vitamin A (20,000 International Units) and Vitamin D3 (2,000 International Units), which should be fully chewed under supervision of study staff with documentation in the participant's research record and eMAR (electronic medical administration record). The chewable gummy should be administered prior to receiving influenza virus vaccination.<br>* Other names: Nutritional Supplement;|
| Placebo Comparator: Influenza Virus Vaccine Plus Placebo<br>Participants receive influenza virus vaccine and matched placebo on Day 0 and Day 28. | Biological: Influenza virus vaccine<br>* Children will have the first influenza virus vaccine dose (dose 1) administered on day 0 of the trial, and the second dose (dose 2) administered 28 days later.<br>* Other names: Fluzone®;Other: Placebo<br>* The chewable gummy matched placebo will be formulated with gelatin base and tangerine oil and match the Vitamin A and D in shape, taste, texture, and appearance. Gummies should be fully chewed under supervision of study staff with documentation in the participant's research record and eMAR (electronic medical administration record). The chewable gummy should be administered prior to receiving influenza virus vaccination.<br>* Other names: Matched Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Positive Responses in Virus-specific Antibody in Sera | The percentage of 2X increases or conversion from undetectable to detectable response in virus-specific antibody toward any vaccine component after 2 immunizations in intervention and control groups will be reported. | Day 56 after vaccination | 
| Isotype Ratios on Day 56 | Isotype ratios will be summarized with descriptive statistics. | Day 56 after vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion at Day 56 After Vaccination, Overall | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval. The rate difference will be described with point estimate and 95% confidence interval. | Day 56 after vaccination | 
| Percentage of Participants With Seroconversion at Day 56 After Vaccination, by Vitamin A Levels at Screening | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval for participants sufficient and insufficient in vitamin A at screening. | Day 56 after vaccination | 
| HAI Titers at Day 56 After Vaccination, Overall |  | Day 56 after vaccination | 
| HAI Titers at Day 56 After Vaccination, by Vitamin A Levels at Screening |  | Day 56 after vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Vitamin Supplements, Influenza virus vaccine