FluPRINT Study: Characterisation of the Immune and Transcriptional Response to LAIV
Condition: Immunization
Study type: Interventional

Summary: 
      In 2013 the UK government introduced the nasal flu spray vaccine (Fluenz Tetra®) for use in
      children from 24 months to less than 18 years of age. This is a licensed vaccine that is
      safe, effective and like the injectable vaccine, needs to be given yearly. There is evidence
      that the nasal spray flu vaccine can offer better protection for children than the injectable
      flu vaccine but it is not yet fully understood why this is so. When the immune system
      responds to an infection or a vaccine, specific 'immune response' genes are activated or
      'switched on'. This process is called gene expression and different types of immune responses
      cause the activation of different genes.This study is looking at how specific parts of the
      immune system like B and T cells respond to the nasal spray vaccine and how and what genes
      are activated by the vaccine. B cells make antibodies, a part of our immune system that helps
      to protect against invaders such as viruses or bacteria. The next time our bodies are exposed
      to the same invader, our B cells make antibodies that can recognise and stop the invader
      going on to cause an infection. Our T cells can help B cells to make antibodies and also help
      to direct the body to attack the invader instead of causing harm to healthy cells.
    

Detailed description: 
      Influenza infection is related to significant morbidity and mortality in children. Although
      usually causing a self-limiting illness, the increased risk for children of hospitalisation
      and further complications, ranging from secondary pneumonia to death, reflect the need to
      focus on prevention. The commonly used trivalent inactive influenza vaccine (TIV) has been
      documented to have poor immunogenicity in children. The live attenuated influenza vaccine
      (LAIV) was introduced with the idea to induce superior protection than TIV. Early efficacy
      studies suggested that LAIV provides superior protection to TIV in children, however the
      mechanisms of action at a molecular and immunological level are not yet well described. This
      study aims to understand how the LAIV works from a gene expression and immunological
      perspective using a systems biology approach and relate these findings to adaptive immune
      responses and immunogenicity. Success of this study will yield the first comprehensive
      picture of cellular and molecular signature that underlie a successful response to LAIV
      vaccination in children.

      The LAIV was introduced to provide broader protection by stimulation of both antibody and T
      cell responses. At present the two major obstacles in the widespread use of LAIV are concerns
      raised over its effectiveness and the lack of defined immunological correlates of protection.
      In this study, by identifying key genes and immune cells that are participating in the
      vaccine-induced responses, the investigators aim to understand molecular and immunological
      mechanism of LAIV.

      In 2016 the Centers for Disease Control and Prevention in the Unites States (US) recommended
      against the use of LAIV due to its poor effectiveness in their analysis of the 2015/2016
      season. However, the same vaccine, in the same season had high effectiveness as assessed by
      two public health authorities in UK and Finland. Currently the reason for this discrepancy is
      not known. The annual childhood influenza vaccine programme in UK started in the 2013/2014
      influenza season by the introduction of the newly licensed LAIV. Eligible healthy children
      were offered a single dose of LAIV, while children in a clinical risk group up to 9 years of
      age were offered two doses of vaccine. By the 2016/2017 season, the LAIV became a licensed
      vaccine in the UK for children and adolescents from 2 to 18 years of age. The UK has found
      evidence of LAIV effectiveness in 2015/2016 season of 58% and therefore it continues to
      recommend its use.

      In this study, the investigators will administer LAIV to cohorts of children and investigate
      the immunological basis for the observed variability and define the role of adaptive immunity
      by applying the systems biology tools and machine learning algorithms for predictive
      modelling. Tracing the influenza vaccine imprint on immune system, termed FluPRINT, by the
      proposed project will help to identify cellular signatures of vaccine-induced protection in
      young children, which is of critical importance for the development of a new generation of
      influenza vaccines that will be more effective in this target population.

      This project will cover an issue that has been poorly studied in humans and that is the role
      of influenza-specific T cells after vaccination. Correlating the cellular signature and T
      cell repertoire after vaccination with the vaccine efficacy is a novel approach to the
      current problem about usage of LAIV. Results obtained are expected to increase the
      understanding of the mechanisms of influenza vaccine effectiveness, by exploring for the
      first time the impact of vaccines on the influenza-specific T cell repertoire in children
      while their adaptive immune system is still being developed.

      Despite many years on the market, no correlates of protection for LAIV have been defined.
      Recent studies using systems biology and computational methods identified baseline frequency
      of B and T cells to predict antibody responses on day 28 after TIV vaccination. A similar
      approach to define cellular signatures driving immunity to LAIV has not yet been reported.
      The current study aims to assess the detailed phenotypical and functional analysis of immune
      cells (focusing on T and B cells) combined with the molecular signature which will provide
      insights into LAIV's mechanisms of protection. To comprehensively probe the phenotypic and
      functional profiles of different immune cells, in the proposed study the investigators will
      analyse blood samples in children aged 4-6 years before and 28 days after LAIV vaccination
      using mass cytometry (CyTOF), Luminex and transcriptome analysis which will be correlated
      with HAI titers. This study will be an exploratory study with between 30 and 40 children
      allocated to 4 groups; Group 1: up to 10 children aged 4-6 years that never received LAIV
      before. Group 2: up to 10 children aged 4-6 years that received LAIV once before, Group 3: up
      to 10 children aged 4-6 years that were vaccinated twice before and Group 4: up to 10
      children aged 4-6 years vaccinated 3 or 4 times.
    

Intervention name(s): Fluenz Tetra nasal spray suspension
Intervention type(s): Other
Intervention description(s): Prophylaxis of influenza in children and adolescents from 24 months to less than 18 years of age. Single dose vaccine, administered as a nasal spray (0.2 ml administered as 0.1 ml per nostril).
Other intervention name(s): Influenza vaccine (live attenuated, nasal)
Intervention MeSH terms: Vaccines
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Open-label study of healthy and immunocompetent children aged 4 to 6 years
Masking: None (Open Label)
Primary purpose: Other