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

Phase 2

Completed

Conditions: Healthy Participants

Interventions: Biological: Influenza virus vaccine
Dietary Supplement: Vitamins A and D
Other: Placebo

Registration Number: NCT02649192

Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 87

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Influenza Virus Vaccine Plus Vitamins A and D	Vitamins A and D	Participants receive influenza virus vaccine and Vitamins A and D supplement on Day 0 and Day 28.
Influenza Virus Vaccine Plus Vitamins A and D	Influenza virus vaccine	Participants receive influenza virus vaccine and Vitamins A and D supplement on Day 0 and Day 28.
Influenza Virus Vaccine Plus Placebo	Influenza virus vaccine	Participants receive influenza virus vaccine and matched placebo on Day 0 and Day 28.
Influenza Virus Vaccine Plus Placebo	Placebo	Participants receive influenza virus vaccine and matched placebo on Day 0 and Day 28.

Primary Outcome Measures

Name	Time	Method
Isotype Ratios on Day 56	Day 56 after vaccination	Isotype ratios will be summarized with descriptive statistics.
Percentage of Participants With Positive Responses in Virus-specific Antibody in Sera	Day 56 after vaccination	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Seroconversion at Day 56 After Vaccination, by Vitamin A Levels at Screening	Day 56 after vaccination	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.
Percentage of Participants With Seroconversion at Day 56 After Vaccination, Overall	Day 56 after vaccination	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.
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