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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 6-12 months Seasonal IIV | Experimental | Children 6 - 12 months of age vaccinated with seasonal IIV |
|
| 3-12 months natural infection | Experimental | Children 3-12 months of age presenting with natural influenza infection |
|
| 13-35 months Seasonal IIV | Experimental | Children 13-35 months of age vaccinated with seasonal IIV |
|
| 13-35 months natural infection | Experimental | Children 13-35 months of age presenting with natural influenza infection |
|
| 3-5 years Seasonal IIV | Experimental | Children 3-5 years of age vaccinated with seasonal IIV |
|
| 3-5 years natural infection |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Seasonal IIV 0.25 mL dose | Biological | Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
|
| 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) |
| 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 |
| 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 |
Inclusion Criteria:
Age
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:
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| Name | Affiliation | Role |
|---|---|---|
| Jennifer L Nayak, MD | University of Rochester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Rochester | Rochester | New York | 14642 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33074330 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Acute | Children enrolled on presentation to their primary care provider with a natural influenza infection. |
| FG001 | Vaccinated | Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 6-12 Months of Age: Vaccinated | Children 6 - 12 months of age vaccinated with seasonal IIV Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG001 | 3-12 Months of Age: Acute |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | 6 acute participants were infected with influenza strains that were not H3 and therefore were not included in the data analyzed for the primary outcome. Only vaccinated participants that age matched to the acute subjects were analyzed, resulting in 16 acutely infected and 28 vaccinated subjects included in the data analysis. | Posted | Mean | Standard Deviation | percentage of T cells | Visit 2 (day 8-14 post enrollment) |
|
up to 18 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 6-12 Months: Vaccinated | Children 6 - 12 months of age vaccinated with seasonal IIV Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jennifer Nayak | University Of Rochester | 5852767404 | Jennifer_Nayak@URMC.Rochester.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 21, 2016 | Jul 8, 2021 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 4, 2015 | Jul 2, 2021 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
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| Experimental |
Children 3-5 years of age presenting with natural influenza infection |
|
| 6-8 years Seasonal IIV | Experimental | Children 6-8 years of age vaccinated with seasonal IIV |
|
| 6-8 years natural infection | Experimental | Children 6-8 years of age presenting with natural influenza infection |
|
|
| Natural influenza infection | Other | Children enrolled on presentation to their primary care provider with a natural influenza infection |
|
| Seasonal IIV 0.5 mL dose | Biological | Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
|
|
| 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 |
Children 3-12 months of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG002 | 13-35 Months of Age: Vaccinated | Children 13-35 months of age vaccinated with seasonal IIV Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG003 | 13-35 Months of Age: Acute | Children 13-35 months of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG004 | 3-5 Years of Age: Vaccinated | Children 3-5 years of age vaccinated with seasonal IIV Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG005 | 3-5 Years of Age: Acute | Children 3-5 years of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG006 | 6-8 Years of Age: Vaccinated | Children 6-8 years of age vaccinated with seasonal IIV Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG007 | 6-8 Years of Age: Acute | Children 6-8 years of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
| BG008 | Total | Total of all reporting groups |
| participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Vaccinated |
Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age |
|
|
|
| Primary | 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 | 6 acute participants were infected with influenza strains that were not H3 and therefore were not included in the data analyzed for the primary outcome. Only vaccinated participants that age matched to the acute subjects were analyzed, resulting in 16 acutely infected and 28 vaccinated subjects included in the data analysis. | Posted | Mean | Standard Deviation | Percentage of T cells | Visit 3 (day 20-28 post enrollment) |
|
|
|
|
| Primary | 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 | 6 acute participants were infected with influenza strains that were not H3 and therefore were not included in the data analyzed for the primary outcome. Only vaccinated participants that age matched to the acute subjects were analyzed, resulting in 16 acutely infected and 28 vaccinated subjects included in the data analysis. | Posted | Mean | Standard Deviation | Percentage of T cells | Visit 4 (day of vaccination year 2) |
|
|
|
|
| Primary | 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 | 6 acute participants were infected with influenza strains that were not H3 and therefore were not included in the data analyzed for the primary outcome. Only vaccinated participants that age matched to the acute subjects were analyzed, resulting in 16 acutely infected and 28 vaccinated subjects included in the data analysis. | Posted | Mean | Standard Deviation | Percentage of T cells | Visit 5 (day 8-14 post-vaccination year 2) |
|
|
|
|
| Primary | 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 | 6 acute participants were infected with influenza strains that were not H3 and therefore were not included in the data analyzed for the primary outcome. Only vaccinated participants that age matched to the acute subjects were analyzed, resulting in 16 acutely infected and 28 vaccinated subjects included in the data analysis. | Posted | Mean | Standard Deviation | Percentage of T cells | Visit 6 (day 20-28 post-vaccination year 2) |
|
|
|
|
| Secondary | 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. | Statistical analysis was completed on all patients who attended all six clinical visits in addition to those who had 3 or more visits that had withdrawn later. | Posted | Mean | Standard Deviation | Mean Percent change | Baseline to day 24 study year 1 |
|
|
|
| Secondary | 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. | Statistical analysis was completed on all patients who attended all six clinical visits in addition to those who had 3 or more visits that had withdrawn later. | Posted | Mean | Standard Deviation | Mean Percent Change | Baseline to day 24 study year 2 |
|
|
|
| Other Pre-specified | 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 | Not Posted | Days 10 and 24 post vaccination | Participants |
| 0 |
| 13 |
| 0 |
| 13 |
| 0 |
| 13 |
| EG001 | 3-12 Months: Acute | Children 3-12 months of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 8 | 0 | 8 | 0 | 8 |
| EG002 | 13-35 Months: Vaccinated | Children 13-35 months of age vaccinated with seasonal IIV Seasonal IIV 0.25 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 30 | 0 | 30 | 0 | 30 |
| EG003 | 13-35 Months: Acute | Children 13-35 months of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 19 | 0 | 19 | 0 | 19 |
| EG004 | 3-5 Years: Vaccinated | Children 3-5 years of age vaccinated with seasonal IIV Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 18 | 0 | 18 | 0 | 18 |
| EG005 | 3-5 Years: Acute | Children 3-5 years of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 12 | 0 | 12 | 0 | 12 |
| EG006 | 6-8 Years: Vaccinated | Children 6-8 years of age vaccinated with seasonal IIV Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 23 | 0 | 23 | 0 | 23 |
| EG007 | 6-8 Years: Acute | Children 6-8 years of age presenting with natural influenza infection Natural influenza infection: Children enrolled on presentation to their primary care provider with a natural influenza infection Seasonal IIV 0.5 mL dose: Fluzone (Sanofi Pasteur) 0.25 mL administered intramuscularly to children between 6 and 35 months of age | 0 | 9 | 0 | 9 | 0 | 9 |
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| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
p-value for NP reactivity, difference of Acute Infected vs. Vaccinated. |
| Other |
p-value for NP reactivity, difference of Acute Infected vs. Vaccinated. |
| Other |
p-value for NP reactivity, difference of Acute Infected vs. Vaccinated. |
| Other |
p-value for H3 reactivity, difference of Acute Infected vs. Vaccinated. |
| Other |
| H3 |
|
| H3 |
|