Impact case study database

The reverse genetics technology covered by the patent to Fodor, Brownlee and colleagues [1] is used by AstraZeneca to manufacture its seasonal flu vaccine each year, ensuring that it contains the most relevant and up-to-date virus strains [A]. The technology was licensed to MedImmune Inc. (now part of AstraZeneca) to improve production of the initially licensed trivalent formulation vaccine, branded as FluMist in the U.S. and Fluenz in Europe, which is a live attenuated influenza vaccine (LAIV) and given intranasally. The technology was first applied to generate FluMist as trivalent (LAIV) vaccine for the 2008 and following seasons. In 2012, it was used to generate the quadrivalent vaccine (FluMist Quadrivalent, LAIV4) protecting against four flu virus strains. FluMist Quadrivalent and Fluenz Tetra, licensed in the US and Europe respectively, have been in use worldwide since 2013.

Prior to 2008, LAIV vaccine virus strains were generated by an inefficient empirical process of natural genetic reassortment between the wild-type influenza virus and the LAIV Master Donor Virus. The helper-free reverse genetics technology in the patent granted to the University of Oxford researchers [1] was described by AstraZeneca as vital to the success of FluMist and Fluenz:

*“This technology has been of critical importance to the success of Flumist/Fluenz as it is a quicker, simpler and more robust way of generating the vaccine strains than previous technology. This is important as the timelines to manufacture seasonal influenza vaccines are incredibly challenging. This technology has increased the speed of the vaccine to market, ensuring that the maximum number of patients are able to receive the vaccine before the start of the Flu season.*” [Ai]

The REF2014 impact case study described the health benefits from use of FluMist in the U.S. from 2008 to July 2013, the economic benefits to MedImmune from FluMist sales and the impact of the reverse genetics technology for the production of vaccines against the 2009 swine-origin pandemic influenza virus. This impact case study describes wider health benefits to populations from use of FluMist and Fluenz in national childhood vaccination programmes the UK and other countries from August 2013 to 2020.

In 2012, the Joint Committee on Vaccination and Immunisation (JCVI) recommended the stepwise roll-out of a universal childhood influenza vaccine programme with the trivalent vaccine Fluenz [B]. The programme was recommended to cover all children 2-17 years of age because children experience some of the highest rates of infection during seasonal epidemics and also play a key role in the spread of the virus. Recommendation of the programme was based on its predicted direct and indirect impact, with the aim to provide individual protection to children themselves and, by reducing transmission across all age groups, protection to vulnerable members of the population. The commonly used trivalent inactivated influenza vaccine was documented to have poor immunogenicity in children and therefore the intranasally administered LAIV, which early efficacy studies suggested provides excellent protection for children, was recommended. The LAIV vaccine is suitable for all children except those who are clinically immunosuppressed.

Flu vaccination has been offered to children in a phased roll-out since 2013. The programme was initiated with the trivalent LAIV and then changed to LAIV4 following European approval in 2013. Fluenz was introduced in the 2013-14 flu season, UK-wide, to all children aged 2 and 3 years [C]. The vaccine was subsequently rolled out to include older children, starting in 2014/15 with school year 1 and expanding by a single year group each season up to the current 2020/21 season when it has been offered to children who have just started secondary school in year 7. The programme combined stepped roll-out nationally with geographical school-based pilots covering the full 4-11 age range and additionally, in some cases, secondary school children (11-13 years). Over 20,000,000 children in the UK aged 2-17 have been vaccinated since the programme was rolled out in 2013 [A]. Vaccine uptake has generally increased over the period of introduction of the vaccine and ranges from 30% to 80% [D]. The intranasal formulation may have helped to make vaccination more acceptable in this age group by overcoming needle phobia, which is estimated to affect at least 10% of children.

Since its introduction in 2013/14, the programme has been shown to positively impact influenza-related outcomes in children and the community as a whole, with the greatest impact observed in pilot areas where children in **all primary school years have been offered vaccination. Early results from the school-based pilot in England in the 2013/14 season followed by an evaluation of the impact of the programme and continuation of the pilots in the 2014/15 season informed the programme’s national roll-out. The early results indicated that the programme in the pilot areas had a significant impact on flu in multiple age groups [E]. Evaluation of the 2014/15 season confirmed this [F]; vaccinating primary school-aged children resulted in direct protection in children aged 5–10 years, with significant reductions in cumulative GP influenza-like illness (ILI) consultations (94% reduction), emergency department respiratory attendances (74% reduction) and confirmed influenza hospital admissions (93%) as well as a reduction in excess respiratory mortality. These changes were also associated with indirect protection of other age groups. Information captured by the Royal College of General Practitioners network for the 2014/15 season showed that cumulative GP ILI consultation rates in individuals aged 50-70 years were lower in pilot areas that vaccinated primary and secondary (children aged 11–13 years) school children compared with non-pilot areas (consultation rate: 3.4 per 100,000 versus 17.4 per 100,000, respectively); similar results were also seen for swab positivity (7.7% positive versus 29.5% positive, respectively) [D]. These changes were accompanied by a significant reduction in cumulative GP ILI consultations at a population level i.e. in individuals aged 17 years or more (59% reduction) [F].

A review of clinical impact of the programme across all UK nations over six influenza seasons provided further data about vaccine effectiveness and influenza-related outcomes in different age groups [D]. Vaccine effectiveness against laboratory-confirmed influenza in children aged 2-17 in primary care in the UK varied from year to year. Whilst the data were not available for the first two seasons, the vaccine prevented 58% of flu cases in 2015/16, 66% of flu cases in 2016/17, 27% of flu cases in 2017/18, 49% of flu cases in 2018/19 and 45% of flu cases in 2019/20 [D,G]. In the 2015/16 season, vaccinating primary school-aged children was associated with lower ILI GP consultations and swab positivity in children of primary school age and those aged <5 years for pilot versus non-pilot areas. In addition, these changes were associated with significant indirect protection of the wider population, with reductions in the adjusted cumulative primary care indicators for ILI (63% reduction) and swab positivity (estimated 48% reduction) in individuals aged 17 years or more from pilot areas compared with those from non-pilot areas. In Northern Ireland, significant reductions were observed in GP in-hours consultations and out-of-hour calls for ILI both overall (61% reduction in GP in-hours; 51% reduction in out-of-hours) and in children aged <14 years (38% reduction in GP in-hours; 39% reduction in out-of-hours), in seasons with full implementation of the programme (2014/15 to 2016/17) compared with pre-programme seasons (2010/11 to 2012/13).

There is also evidence that vaccination in young children through the programme may contribute to a reduction in prescribing of amoxicillin in children. Amoxicillin is one of the most prescribed antibiotics in primary care and is indicated for two common complications of influenza: community-acquired pneumonia and acute otitis media. Whilst further studies are needed to confirm the size of the effect, a study in 2017 found a 12.8% to 14.5% reduced rate of amoxicillin prescribing during periods of LAIV-induced immunity in preschool children [H].

As the UK’s programme expanded beyond the pilot areas and to older children, it has become more challenging to fully capture the benefits of the vaccination programme especially those on the wider community. Nevertheless, the data available to date demonstrate a positive impact of the UK’s programme for a range of key surveillance indicators. In addition, an economic analysis of influenza vaccination in England found that vaccination (across all age groups) helped to avert between 5,678 and 8,800 premature deaths per year [l].

Cost-effectiveness studies were amongst those that provided evidence supporting extending the UK influenza vaccination programme to children in 2012. These studies continue to support the vaccination of children to optimise the benefits of influenza vaccination programmes. A recent cost-benefit assessment of influenza vaccination in England concluded that “ public policy should focus on improving coverage rates among young people aged 15 years or under, as the most efficient approach to improving overall benefits relative to costs” [I].

Influenza vaccination of healthy children with Flumist/Fluenz has been introduced through national vaccination programmes in the United States, Canada, Finland and other European countries, and South Korea. Up to 22,000,000 doses of Flumist/Fluenz are manufactured in Liverpool, UK each season and used to vaccinate people in the US, Europe, Israel, Canada and South Korea [A].

FluMist has been used in the US since before 2013 in children from the age of 2 upwards. FluMist Quadrivalent is approved for use in healthy individuals aged 2-49 and was first introduced in the 2013/14 season. The US Advisory Committee on Immunization Practices recommends annual influenza vaccination for everyone aged 6 months and older with any licensed, influenza vaccine that is appropriate for the recipient’s age and health status. FluMist has been used in most seasons since 2013/14 and from 2018/19 onwards [J].

In Finland, influenza vaccine has been given free of charge to all eligible children (6-35 months) since 2007. To enhance vaccine uptake, Fluenz (Fluenz Tetra) was introduced in the 2015/16 season. Since then, all 2-year-old children have been eligible for vaccination with either Fluenz or trivalent inactivated influenza vaccine, without a recommended preference. Vaccination coverage has increased steadily following Fluenz introduction – from 11% of children aged 6–35 months in 2014/15 to 24% in 2017/18 [K]. Vaccine effectiveness of Fluenz measured over three seasons (2015/16 to 2017/18) was comparable with that in the UK – between 20% and 54%. Since the 2018/19 season, children aged between 2 and 6 years have been offered the Fluenz vaccine free of charge as part of the national vaccination programme. For the 2020/21 season, 116,000 doses of Fluenz were procured for the programme which is sufficient for four out of ten children in this age range [L].

With COVID-19 putting pressure on hospitals in winter 2020/21, Ireland offered Fluenz for the first time to children aged between 2 and 12 years from October to December 2020 [M].