FluPRINT Study: Characterisation of the Immune and Transcriptional Response to LAIV

Overview

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.

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.