Immunological investigation for the implementation of Live Attenuated Influenza Vaccination

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.

The UK launched universal annual childhood vaccination with quadrivalent live attenuated influenza vaccine (LAIV4) in 2013, with phased roll-out to progressively older children each year. Although LAIV has higher vaccine effectiveness (VE) in children than inactivated influenza vaccine (IIV), it was recently found to have lost VE against pH1N1 in the USA resulting in its discontinuation. In the UK, VE against pH1N1 has been lower than expected and lower than IIV but the programme continues. This marked reduction of VE to pH1N1 (but not the other subtypes in LAIV4) suggests a mechanism specific to pH1N1 while the complete loss of VE in the USA suggests a mechanism that is accentuated specifically in US children (the only population to have been vaccinated annually for several years). We hypothesise that:
(a) there is reduced local in vivo nasal replication of pH1N1 resulting in impaired vaccine take (and consequently impaired immunogenicity and VE)
(b) pre-existing LAIV-induced pH1N1-specific immunity exacerbates the reduced take and immunogenicity.
Our aim is to identify the reasons for loss of VE by testing these hypotheses and thereby to inform optimal implementation of LAIV. Given that evidence for annual vaccination is scarce and that correlates of protection are unknown, we will also generate data on longevity of LAIV-induced immunity to inform vaccination schedule and shed light on protective correlates by studying vaccine failures.
With Public Health England (PHE), we have recruited 3 unique child cohorts undergoing LAIV vaccination but with differing vaccination histories. We will conduct the most comprehensive study of LAIV immunogenicity to date, quantifying vaccine take and correlating it with LAIV-induced cell-mediated immunity, mucosal IgA, humoral immunity and blood transcriptome. The causes of impaired vaccine take and immunogenicity will be investigated by correlating these with prior LAIV vaccination status and pre-existing LAIV-induced immu

Human health, wellbeing and productivity
Influenza causes a huge burden of ill-health, mortality (especially in the elderly and other vulnerable groups) and lost productivity through days off work due to sickness. By informing the optimal implementation of the national childhood live attenuated influenza vaccine (LAIV) programme, our research has real potential to reduce all these adverse consequences of seasonal influenza. Due to the 'herd immunity' effect of vaccinating children, the protection conferred by LAIV is population-wide, including prevention of hospital admissions and deaths in vulnerable groups. Since several other countries are considering introduction of childhood LAIV vaccination, the impact on human health will extend far beyond the UK.

Cost savings to healthcare systems
Seasonal influenza illness consumes very substantial healthcare resources and routinely stretches primary and secondary care service to the limit, sometimes resulting in hospitals exceeding capacity and closing their doors in the winter. An effectively implemented childhood LAIV vaccination programme, with its population-wide protective effect, could substantially reduce these pressures. NHS England recognises implementation of this programme as "an important contribution to increasing resilience across the system through the winter period" (Flu Plan Winter 2017/18, NHS England/DH/PHE).

Scientific knowledge
As detailed in the section on Academic Beneficiaries, our proposal addresses key knowledge gaps in the type of immunity induced by LAIV. By generating the most comprehensive picture of LAIV-induced immunity to date, this proposal will drive the whole field forward. The resultant advances in our understanding of the durability and protective correlates of LAIV-induced immunity will be invaluable to the global influenza immunology and influenza vaccine communities. The outputs will thus inform the development of (potentially patentable) improvements to LAIV as a seasonal influenza vaccine and, more generally, will enable advances in translational influenza virology and mathematical modelling of influenza infection dynamics.

Improving economic competitiveness through innovation
Although LAIV protects children against antigenically-drifted seasonal influenza strains and animal models against antigenically-shifted pandemic strains, little is known about the LAIV-induced heterosubtypic cellular immunity that mediates this in humans. By systematically delineating the extent of this, we will gain key insights into the potential of LAIV as a pre-pandemic vaccine, providing the necessary immunological data and rationale for development of LAIV into a universal influenza vaccine. These discoveries, which are likely to be patentable, would provide an important commercial opportunity for UK vaccine and biotech companies.

Creating a skilled workforce and future public health leaders
The NIHR Health Protection Research Unit (HPRU) that is hosting this work is an interdisciplinary melting pot that is nurturing and inspiring the next-generation of public health researchers. The current proposal will (a) provide high-level training and scientific development for the 3 scientists to be funded by the grant, (b) deliver two PhD projects which will be jointly supervised by IC and PHE scientists and (c) nurture the career development of all Imperial College (IC) and PHE influenza researchers and paediatricians involved in the HPRU through provision of a unique series of rich datasets covering all aspects of the immunology of LAIV in the relevant UK target population.

Education
The HPRU is very active in knowledge transfer and sharing, engaging widely with the public (eg through IC and PHE communications channels) and with our cohort participants (eg ongoing close multi-level engagement with the schools from which cohort X was recruited). These activities are detailed in the Engagement, Communication and Dissemination Plan.