Immunological investigation for the implementation of Live Attenuated Influenza Vaccination

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Each year flu affects 5-10% of adults and 20-30% of children, causes 250-500,000 deaths and places a huge strain on health services. The conventional inactivated injectable vaccine is targeted to vulnerable groups, especially the elderly (who are at highest risk of dying from flu), but is only 50-60% effective. An alternative, potentially better strategy is a live vaccine in the form of a weakened flu virus; it is given conveniently as a nasal spray and is 80% effective in children. Since flu spreads across communities mostly through children, protecting them by vaccination can stem the spread, thereby providing community-wide protection (known as 'herd immunity'). With this rationale, the UK Department of Health (DH) launched the first publicly-funded nationwide vaccination programme with this vaccine, offering it yearly to all children at an annual cost of c. £100m. The phased roll-out, managed and monitored by Public Health England (PHE), started in 2013 with 2-3 year old children. The live vaccine has been used in the USA since 2003 but has become less effective since 2010. Last year surveillance indicated that it was no longer protecting children against the predominant flu strain, and the USA public health agency therefore discontinued its use. In the UK, results show that the live vaccine has so far been protecting vaccinated children and unvaccinated elderly through herd immunity, but it has been less effective than expected.Identifying the reasons for this reduced (and in the USA, absent) effectiveness is recognised by DH, PHE and the World Health Organization (WHO) as an urgent public health priority. This proposal addresses this issue and aims to answer the key questions for optimal implementation of this live vaccine.The National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU) in Respiratory Infections is a partnership between Imperial College London (IC) and PHE. For this proposal, our HPRU brings together the UK's top flu experts. We have worked closely together to enrol and follow-up different groups of children receiving the live nasal spray vaccine into our observation studies. We have systematically stored all relevant blood and nasal swab samples, creating a globally unique 'biobank' which enables us to address the important knowledge gaps above.As a nasal spray, this live vaccine causes a mild transient infection in the nose inducing a wide range of immune responses, similar to natural infection. In contrast to the UK, most US children receiving the vaccine have received it in previous years. The leading hypothesis for the vaccine's underperformance is that in children who are already repeatedly vaccinated with the weakened vaccine virus, the immunity induced is sufficient to prevent the localised transient nasal infection, but is not strong enough to protect against infection by natural flu.The children in our studies include those never previously vaccinated as well as previously vaccinated children (up to 3 previous vaccinations). This enables us to:-compare the effect of prior vaccination on how well the vaccine induces a local infection, assessed by measuring the amount of vaccine virus shed from the nose after vaccination-measure how well it stimulates immunity by a range of blood tests-evaluate which immune responses induced by prior vaccination prevent this beneficial local infection and immune stimulation. For this winter, the strain of flu in the vaccine has been replaced in line with WHO's recommendation for the new natural flu strain that is expected to dominate. We will also compare nasal replication and immune stimulation induced by this new vaccine strain with that induced by the previous vaccine strain.