Assessment of Viral Shedding Week Following Administration of Live Attenuated Influenza Vaccine in Children

Study Overview
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Brief Summary
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LAIV shedding studies in children could be an important way to confirm whether impediments to viral replication do indeed explain these observed reductions in vaccine effectiveness (VE), whether prior vaccination has any influence on replication and what future implications (if any) this might have for the UK paediatric LAIV programme. LAIV virus replication in children will be dependent on virological and host factors. The virus factors include replicative fitness of individual strains and the susceptibility to inhibition by other replicating strains (ability to compete). Host factors which may influence this include pre-existing specific immunity as a result of prior infection or previous vaccination (with either LAIV or IIV), and innate immune factors including mucosal immunity. There is significant variability in shedding across viral subtypes in studies done to date, so there is a need to obtain local data in a small pilot observational study which will look in detail at virus shedding by sequential daily virus samples, something not possible on a larger scale. The data generated will inform future LAIV studies in the UK in terms of optimum time of sample collection for viral shedding studies, which are likely to be required on a regular basis, to supplement field studies of vaccine effectiveness. This study will enrol up to 30 children that will allow these factors to be assessed. Both written informed consent from parent/ guardian and written assent from the child will be in place prior to any study procedure. All participants will have a baseline assessment of pre--existing influenza immunity (blood test, oral fluid collection and nasal swabs), followed by a single dose of LAIV. Parents will then be asked to take nasal swabs at home on days 1, 2, 3, 4, 5, 6, 7, 8, with further nasal swab, blood test and oral fluid collection in hospital 4 weeks later, in order to assess for immune responses to LAIV.

Official Title
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Assessment of Viral Shedding Week Following Administration of Live Attenuated Influenza Vaccine in Children: FluSHED-2 Study

Conditions
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Influenza Vaccines

Intervention / Treatment
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* Biological: Live attenuated influenza vaccine (LAIV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children age 6 years to 15 years +364 days of age on enrolment Children eligible to receive LAIV in accordance with current UK vaccine policy Written informed consent given by parent/ guardian and assent from child Exclusion Criteria: Contraindications to LAIV (notwithstanding allergy to egg protein), which include: Hypersensitivity to the active ingredients, gelatin or gentamicin (a possible trace residue) Previous systemic allergic reaction to LAIV Previous allergic reaction to an influenza vaccine (not LAIV) is a relative contra-indication, which must be discussed with the CI to confirm patient suitability Children/adolescents who are clinically immunodeficient due to conditions or immunosuppressive therapy such as: acute and chronic leukaemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high-dose corticosteroids*. Children / adolescents younger than 18 years of age receiving salicylate therapy because of the association of Reye's syndrome with salicylates and wild-type influenza infection. Pregnancy (determined by history). Where this cannot be confirmed, a urine pregnancy test will be performed. High---dose steroids is defined as a treatment course for at least one month, equivalent to a dose greater than 20mg prednisolone per day (any age), or for children under 20kg, a dose greater than 1mg/kg/day. NB: LAIV is not contraindicated for use in individuals with asymptomatic HIV infection; or individuals who are receiving topical/inhaled/low-dose oral systemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. for adrenal insufficiency.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All children<br>Administration of live attenuated influenza vaccine (LAIV) | Biological: Live attenuated influenza vaccine (LAIV)<br>* Single dose of LAIV<br>* Other names: Fluenz Tetra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of type-specific vaccine virus shedding in 2018/19 following LAIV administration (average shedding) | Kinetics of type-specific vaccine virus shedding in 2018/19 in the eight days following LAIV administration, assessed by Area under the curve (AUC) between days 0 and 8 calculated as average pfu/ml per day on logged data (with a minimum limit set at 1pfu (0 on the log scale)) | 8 days post LAIV | 
| Kinetics of type-specific vaccine virus shedding in 2018/19 following LAIV administration (peak day of shedding) | Kinetics of type-specific vaccine virus shedding in 2018/19 in the eight days following LAIV administration, assessed by day of peak shedding, for each individual strain | 8 days post LAIV | 
| Kinetics of type-specific vaccine virus shedding in 2018/19 following LAIV administration (number of days of detectable shedding) | Kinetics of type-specific vaccine virus shedding in 2018/19 in the eight days following LAIV administration, assessed by the number of days of detectable shedding for each strain | 8 days post LAIV | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative analysis of immunogenicity: serological | Haemagglutination inhibition (HAI) and Microneutralisation (MN) assay titres at each time point (day 0, 28) as well as ratios day 28/day 0 and proportions above thresholds and seroconverting | 1 month | 
| Quantitative analysis of immunogenicity: Oral fluids | Haemagglutination inhibition (HAI) titres in oral fluids at each time point (day 0, 28) | 1 month | 
| Quantitative analysis of immunogenicity: nasal IgA | Influenza-specific nasal IgA titres at each time point (day 0, 28) | 1 month |