Influenza Immunity in Children

Understanding How the Initial Encounter With Influenza Virus Poises Children for Protective Immunity

This study evaluates how different methods of early exposure to influenza (natural infection, live attenuated influenza vaccination, inactivated influenza vaccination) initially stimulate immunity and poise the immune system to respond to a future challenge with the inactivated influenza vaccine.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Biological: Seasonal IIV 0.25 mL dose; Other: Natural influenza infection; Biological: Seasonal IIV 0.5 mL dose

Detailed Description

The proposed research addresses the fact that, despite high childhood morbidity from influenza and broad recommendations for vaccination, very little is known about how anti-influenza immunity is shaped by the method of initial exposure. The objective of this research is to understand how CD4 T cell and B cell responses are altered by the method of initial influenza priming, with the long-term goal of determining how a child's initial influenza encounter poises the immune system to respond to subsequent influenza challenges. The investigators central hypothesis is that differences in the mode of influenza antigen exposure in early childhood will generate long lasting, detectable changes in memory CD4 T cell and B cell specificity and function that influence the response to future influenza vaccinations and infections. This hypothesis will be tested by comparing 1) CD4 T cell and 2) antibody responses in cohorts of children initially exposed to influenza through either natural infection or inactivated or live attenuated vaccination. A combination of multiparameter assays will be used to determine the phenotype and functional potential of hemagglutinin (HA)- and nucleoprotein (NP)-specific CD4 T cells. The breadth and avidity of the neutralizing and non-neutralizing antibody responses and its distribution against head and stalk epitopes will also be evaluated. By determining how initial priming shapes the specificity and functional potential of the anti-influenza CD4 T cell and antibody responses, the investigators will gain the knowledge necessary to optimize current influenza vaccination strategies and develop novel influenza vaccines able to provide highly efficacious universal protection against both seasonal and potentially pandemic viral strains.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 8 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age

  • Between 6 and 12 months to participate in the vaccination arm of cohort 1 (cohort 1A)
  • Between 3 and 12 months to participate in the natural infection arm of cohort 1 (cohort 1B)
  • Between 13 and 35 months of age to participate in either the vaccination or natural infection arm of cohort 2
  • Between 36 months and 5 years of age to participate in either the vaccination or natural infection arm of cohort 3
  • Between 6 years and 8 years of age to participate in either the vaccination or natural infection arm of cohort 4
• Gestational age of ≥37 weeks at birth
• Parent/guardian can provide informed consent
• Available for the duration of the study
• History of previous IIV administration ONLY for participation in the vaccination arm of cohorts 2, 3, or 4
• Acute illness documented to be due to influenza virus ONLY for participation in the natural infection arms of cohorts 1-4

Exclusion Criteria:

• Immunosuppression as a result of an underlying illness or condition (including HIV or a primary immunodeficiency syndrome)
• Active neoplastic disease
• Use of potentially immunosuppressive medications currently or within the past year (including chemotherapeutic agents) or chronic (>2 weeks) use of oral or inhaled steroid therapy
• A diagnosis of asthma requiring chronic controller medication
• Previous administration of influenza vaccine in the current influenza season ONLY for subjects receiving an influenza vaccination
• Receipt of immunoglobulin or another blood product within the year prior to study enrollment
• An acute illness within the previous 3 days or temperature >38o on screening EXCEPT for participation in the natural infection arms of cohorts 1-4
• A contraindication to influenza vaccination EXCEPT infants between 3 and 5 months presenting with natural influenza infection whose only contraindication is their current age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 6-12 months Seasonal IIV; Children 6 - 12 months of age vaccinated with seasonal IIV	Biological: Seasonal IIV 0.25 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: Inactivated influenza vaccine
Experimental: 3-12 months natural infection; Children 3-12 months of age presenting with natural influenza infection	Other: Natural influenza infection; Children enrolled on presentation to their primary care provider with a natural influenza infection; Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine
Experimental: 13-35 months Seasonal IIV; Children 13-35 months of age vaccinated with seasonal IIV	Biological: Seasonal IIV 0.25 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: Inactivated influenza vaccine
Experimental: 13-35 months natural infection; Children 13-35 months of age presenting with natural influenza infection	Other: Natural influenza infection; Children enrolled on presentation to their primary care provider with a natural influenza infection; Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine
Experimental: 3-5 years Seasonal IIV; Children 3-5 years of age vaccinated with seasonal IIV	Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine
Experimental: 3-5 years natural infection; Children 3-5 years of age presenting with natural influenza infection	Other: Natural influenza infection; Children enrolled on presentation to their primary care provider with a natural influenza infection; Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine
Experimental: 6-8 years Seasonal IIV; Children 6-8 years of age vaccinated with seasonal IIV	Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine
Experimental: 6-8 years natural infection; Children 6-8 years of age presenting with natural influenza infection	Other: Natural influenza infection; Children enrolled on presentation to their primary care provider with a natural influenza infection; Biological: Seasonal IIV 0.5 mL dose; Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age; Other Names: inactivated influenza vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent of IFNg+ CD69+ CD4 T Cells Between Acute (H3N2) Infected and Vaccinated Subjects	% H3- and nucleoprotein (NP)-specific CD4 T cells were measured using intracellular cytokine staining	Visit 2 (day 8-14 post enrollment)
Mean Percent of IFNg+ CD69+ CD4 T Cells Between Acute (H3N2) Infected and Vaccinated Subjects	% H3- and nucleoprotein (NP)-specific CD4 T cells were measured using intracellular cytokine staining	Visit 3 (day 20-28 post enrollment)
Mean Percent of IFNg+ CD69+ CD4 T Cells Between Acute (H3N2) Infected and Vaccinated Subjects	% H3- and nucleoprotein (NP)-specific CD4 T cells were measured using intracellular cytokine staining	Visit 4 (day of vaccination year 2)
Mean Percent of IFNg+ CD69+ CD4 T Cells Between Acute (H3N2) Infected and Vaccinated Subjects	% H3 protein- and nucleoprotein (NP)-specific CD4 T cells were measured using intracellular cytokine staining	Visit 5 (day 8-14 post-vaccination year 2)
Mean Percent of IFNg+ CD69+ CD4 T Cells Between Acute (H3N2) Infected and Vaccinated Subjects	% H3 Protein- and nucleoprotein (NP)-specific CD4 T cells were measured using intracellular cytokine staining	Visit 6 (day 20-28 post-vaccination year 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Percent of IFNg+ CD69+ CD4 T Cells Between Vaccinated Subjects in Different Age Subsets	CD4 T cell quantity and specificity will be measured using intracellular cytokine staining. We report here the mean change in percent of cells reactive to the influenza HA protein and H3 protein.	Baseline to day 24 study year 1
Mean Change in Percent of IFNg+ CD69+ CD4 T Cells Between Vaccinated Subjects in Different Age Subsets	CD4 T cell quantity and specificity will be measured using intracellular cytokine staining. We report here the mean change in percent of cells reactive to the influenza HA protein and H3 protein.	Baseline to day 24 study year 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Day 10 and Day 24 in PBMC Gene Expression	Changes in PBMC gene expression patterns due to prior influenza exposure will be assessed using RNA-seq analysis	Days 10 and 24 post vaccination

Collaborators and Investigators

• Sponsor: University of Rochester
• Investigators: Principal Investigator: Jennifer L Nayak, MD, University of Rochester

Publications and helpful links

General Publications

• Shannon I, White CL, Yang H, Nayak JL. Differences in Influenza-Specific CD4 T-Cell Mediated Immunity Following Acute Infection Versus Inactivated Vaccination in Children. J Infect Dis. 2021 Jun 15;223(12):2164-2173. doi: 10.1093/infdis/jiaa664.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): July 3, 2020
• Study Completion (Actual): July 3, 2020

Study Registration Dates

• First Submitted: September 18, 2015
• First Submitted That Met QC Criteria: September 22, 2015
• First Posted (Estimate): September 24, 2015

Study Record Updates

• Last Update Posted (Actual): September 2, 2021
• Last Update Submitted That Met QC Criteria: August 5, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: children; infants; natural influenza infection; live attenuated influenza vaccination (LAIV); inactivated influenza vaccination (IIV)
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: RSRB00058437