We found that the introduction of quadrivalent influenza vaccines to the seasonal influenza vaccination programme in England can be cost-effective for all targeted cohorts, though the cost-effectiveness of the programme implemented is highly dependent on the increased cost of replacing trivalent vaccines with their quadrivalent counterparts. Increasing the eligibility for quadrivalent vaccination programmes further than just the paediatric programme reduces the additional amount that the National Health Service (NHS) should pay to procure each vaccine dose. Indeed, if only trivalent vaccines were available for individuals aged 17 years and younger, then the maximum incremental cost per dose of QIIV vaccines for high-risk and elderly individuals would increase to £3.55 and £0.29 respectively. This increases further to a minimum of £3.76 and £0.41 respectively if no paediatric influenza vaccination programme had been implemented at all, but these latter estimates are likely to be underestimates, as they ignore the substantial change in the population-wide burden of influenza A attributable to the LAIV/TIIV paediatric programme [5, 19].
The maximum incremental cost per dose of the quadrivalent vaccine for high-risk and elderly individuals reduces further from £1.84 and £0.20 if the paediatric influenza vaccination programme is ultimately implemented for all age groups in schools as planned. This is due to two factors: first the heterogeneous burden of influenza B in the population is concentrated in the younger age groups, so a vaccination programme that targets all children of ages 2–16 years will reduce a large proportion of this total burden. Second, the well-demonstrated indirect effect of vaccinating children to protect other age groups reduces the potential impact of any vaccination programme in the remaining population, thereby reducing the amount that should be spent on those vaccination programmes after a successfully implemented paediatric programme. Any additional resources required to implement the paediatric influenza vaccination programme would be the same whether the programme used a trivalent or quadrivalent live attenuated vaccine, so we did not consider this potential additional cost in our analysis.
Strengths and weaknesses of this study
This study uses a dynamic transmission model that was fitted to 14 years of surveillance data, and it uses the same cost-effectiveness framework that was used to support the decision to implement a nationwide seasonal influenza vaccination programme for healthy children , providing a consistent approach to understanding the impact of an evolving vaccination programme. This approach, as outlined in the previous publications, accounts not just for the direct protection inferred on vaccinated individuals but also the indirect protection inferred on unvaccinated individuals in the population. The model also uses the same data  on social contacts to account for mixing patterns in the population, an important inclusion to understanding infectious disease dynamics .
We assumed that existing trivalent vaccines were poorly matched to the dominant circulating B strain in each influenza season. Whilst this assumption allowed us to maintain a consistent modelling approach with that of Baguelin et al., we recognise that it presents the best-case scenario for introducing quadrivalent vaccines. In addition, other countries have reported that some vaccines were well matched against the dominant circulating influenza B strains with little activity for the unmatched B strain [21, 22], which would reduce the maximum incremental cost per dose of quadrivalent vaccines in our analysis. However, our approach allows us to report the maximum incremental cost in the best possible scenario for quadrivalent vaccines with the understanding that any previous years with a better strain match in vaccines will reduce the cost-effectiveness of quadrivalent vaccines. Indeed, the estimated proportion of influenza B infections between 2000 and 2010 caused by vaccine mismatched strains was 52.4% , presenting an encouraging opportunity for quadrivalent vaccines to reduce the public health impact of seasonal influenza.
We did not consider extending eligibility to children aged younger than 2 years old, in contrast to paediatric vaccination programmes in some other countries. The live attenuated vaccine is not licensed for children in this age group; and the effectiveness of inactivated vaccines is lower ; and implementation of a programme using an injectable vaccine would represent a considerable additional workload for a policy that has not been recommended in the UK.
Our economic evaluation of the vaccination programmes followed the guidelines recommended by the National Institute for Health and Clinical Excellence (NICE) in evaluating the costs of the programme from the perspective of the health care provider . We took a conservative approach in assessing the potential additional expenditure appropriate to reducing the disease burden caused by influenza B strains. We considered vaccination programmes with at least 90% of all simulations below the WTP threshold as cost-effective, with a WTP threshold of £20,000 per QALY as recommended by NICE. We also reported our results for other WTP thresholds should that advice change in the future.
Our sensitivity analysis reported that our model estimates are most sensitive to the estimated efficacy of the QLAIV in preventing influenza B infection, but the manufacturers of the vaccine have not confirmed these estimates and have instead hypothesised that the similarity in manufacturing processes between the LAIV and QLAIV implies that there is no difference. Greater clarity on the estimated efficacy of the QLAIV in preventing influenza B infection would greatly improve the accuracy of our estimates.
A recent systematic review of economic evaluations assessing the impact of quadrivalent influenza vaccines compared the modelling approaches and results of 16 analyses published before September 2016 . The authors reported that 13 of these analyses were funded by vaccine manufacturers, two did not specify the funding source and the one remaining study was publicly funded. Our independent study is therefore a helpful addition to the literature on the cost-effectiveness of quadrivalent vaccines that is so dominated by industry-funded studies. In addition, the review of de Boer et al. calls for more extensive use of dynamic transmission models to fully understand the impact of quadrivalent vaccines in influenza vaccination programmes, an approach that we adopted here using the fluEvidenceSynthesis R package.
Relation of this study to other studies
The review of de Boer et al. reported that the range of incremental cost per dose of quadrivalent vaccines over existing trivalent equivalents for all studies was $1.25 to $7.14 in 2015 US dollars , though there was variation in the perspective for which economic evaluations were performed, the WTP thresholds for each country and the requirement of the proportion of simulations that should be below those WTP thresholds. Many studies reported that quadrivalent vaccines are cost-effective with an emphasis of the sensitivity of these estimates to the parameters for the cost of vaccines and the efficacy of vaccines considered against the circulating influenza B strains. We adopted a conservative approach to our economic evaluation and feel that our conservative incremental cost-per-dose estimates for each proposed programme compare well to those of the studies featured in this review, with similar findings from our sensitivity analysis to those featured in the review.
Possible explanations and implications for clinicians and policymakers
Extending a QIIV programme to include clinical risk individuals younger than 65 years old in England is more likely to be cost-effective than extending further to also include all elderly individuals. However, the maximum incremental cost per dose of the quadrivalent vaccines is just £1.84, meaning that the current policy of reimbursing GPs and pharmacists for administering QIIVs to clinical risk groups is likely to be cost-effective if the incremental reimbursement cost is less than this value and less than £0.20 per dose if extended further to all elderly individuals. This result is influenced by the heterogeneous burden of influenza B infection in England , with children shouldering the largest proportion of this burden; therefore, directly protecting the elderly from infection with QIIV offers a smaller return than the QLAIV programme in schools.
Unanswered questions and future research
We did not address the issue of adverse events arising from vaccination using the QIIV and QLAIV and assumed that these risks were negligible, as clinical trials suggest that the quadrivalent vaccines have similar safety profiles to those of the trivalent vaccines [11, 27, 28]. We did not consider the implications of infection from natural exposure to influenza B, nor did we attempt to estimate the impact of repeated vaccination on the immunogenic response in the patient.