Background
Seasonal influenza affects 5–10% of the global population [
1], accounting for 290,000–650,000 annual deaths globally [
2,
3], not including secondary complications or underlying conditions exacerbated by influenza [
3]. In addition, a 2018 systematic review of randomised controlled trials designed to determine the incidence of influenza showed that 1 in 10 unvaccinated adults and 1 in 5 unvaccinated children were infected with influenza annually [
4]. Risk groups for severe influenza include individuals with chronic conditions (such as human immunodeficiency viruses [HIV]/acquired immunodeficiency syndrome [AIDS], asthma, chronic heart or lung diseases), older adults (typically those aged ≥ 65 years), pregnant women, and young children aged 6–24 months [
5]. Healthcare workers (HCW) also comprise a risk group, being at increased personal risk of exposure to infection and a potential source of further transmission [
6].
Increased general practitioner (GP) visits, hospitalisations, and deaths related to influenza infection are especially common in adults aged ≥ 65 years and in individuals with chronic conditions [
7]. In addition, pregnancy is associated with elevated risk of influenza-related death and intensive care unit admission [
8]. The incidence of influenza-related complications leading to hospitalisation also increases in at-risk individuals compared with individuals not at risk [
9]. Of those hospitalised, approximately 10% will be defined as complicated hospitalisations, which require mechanical ventilation support, lead to intensive care unit admission, or result in death [
10]. Complicated hospitalisations contribute substantially to the overall influenza-related healthcare burden due to excess consultations and hospitalisation costs, as well as the broader societal and economic burden associated with reduced productivity [
11‐
13].
Vaccination against seasonal influenza is effective in reducing both influenza disease burden in risk groups and the cost of annual influenza epidemics [
13]. In 2003, the World Health Organization (WHO) urged European Union (EU) and European Economic Area member states to achieve a 75% vaccination coverage rate (VCR) target among risk groups by 2010 [
14,
15]. Despite this target, VCRs in most countries across Europe remained suboptimal in all risk groups during the 2022‒2023 influenza season [
16]. As such, the WHO-recommended 75% target VCR remains unchanged. To appropriately allocate resources, understanding the public heath, economic, and broader benefits of vaccination is required; this can be accomplished by measuring achieved VCR and modelling the impact of increasing VCR [
17]. Although such analyses have proven beneficial in decision-making around the use of vaccine prioritisation strategies [
18], no up-to-date analyses have measured the benefits of increasing the influenza VCR in Europe. The potential public health and economic benefits of reaching a target seasonal influenza VCR of 100% for all risk groups across 25 EU member states have been estimated in 2006 [
13]. Achieving such a target would have led to an estimated approximate reduction in influenza cases of 7.22 million, 797,000 fewer hospital admissions and 68,500 fewer influenza related deaths for all 25 EU member states [
13]. A subsequent 2014 study, using an adapted version of the 2006 model [
17], estimated that achieving 75% VCR across 27 EU member states would increase the number of averted annual cases of influenza by 1.6–1.7 million and would prevent influenza-related costs of between €190 and €226 million. Updated data are needed to provide accurate estimates of the potential current health and economic benefits, along with a need for data that focus on the potential benefits in groups at risk from severe influenza.
This study aimed to provide estimates of the health and economic benefits associated with seasonal influenza immunisation at the 2021/2022 VCR in France, Italy, Spain and the UK, while exploring the potential further benefits achieved by reaching the WHO-recommended 75% VCR target in risk groups in these countries.
Discussion
Modelling the impact of influenza vaccination, particularly in high-risk groups, is important to support vaccine implementation and inform resource allocation. This epidemiological model based on the 2021/2022 VCR, showed that approximately 1.9 million influenza cases, 73,200 hospitalisations and 38,400 deaths were avoided across France, Italy, Spain and the UK. However, the weighted average 2021/2022 VCR (47%) was much lower than the WHO target of 75%. Increasing the seasonal influenza VCR to this 75% target in all WHO-recommended risk groups would achieve substantially greater public health and economic benefits in these countries, due to the reduction in influenza disease burden in risk groups and in the cost of annual influenza epidemics (due to reductions in lost productivity and absenteeism) [
17]. As part of its Global Influenza Strategy 2019–2030, the WHO aims to continue supporting countries to implement national immunisation policies for risk groups, as recommended by the Strategic Advisory Group of Experts on Immunization, and to monitor uptake through national databases [
29].
Older adults represented the greatest clinical and economic burden in terms of influenza cases, hospitalisations and deaths. Given local vaccine recommendations and the contribution of older adults to the total estimated clinical and economic outcomes, an analysis scenario applying QIV-HD in older adults was considered relevant. The efficacy of QIV-HD relative to QIV-SD was 24%, in the prevention of laboratory-confirmed cases of influenza or influenza-like illness, in older adults (aged ≥ 65 years old) [
23]. This suggests that one quarter of all breakthrough influenza could be prevented if QIV-HD was used over QIV-SD, and evidences the potential alleviation of economic burden within the population. Previous studies have indicated that using QIV-HD over QIV-SD may be cost-effective in several European settings for this at-risk population [
30,
31], and may contribute to additional public health and economic benefits beyond those calculated in this study, such as reduced rates of influenza-related secondary bacterial infections, functional decline and poor pregnancy outcomes, and improved child education and macroeconomic stability due to reduced absenteeism [
32].
Given the increasingly ageing population (population aged ≥ 65 years is projected to increase by 12% between 2022 and 2030) [
33], a growing prevalence of chronic underlying conditions and emerging respiratory virus threats, the need to protect vulnerable adults across Europe is imperative [
34]. Given these trends, modelled estimates in this study may represent only a fraction of the future influenza-related burden and costs of disease.
Compared with the previous findings [
17], our model found an increased public health burden, which may be possible to avert by achieving the WHO target of 75% VCR. Achieving a 75% VCR in the four selected countries led to 54% fewer influenza cases (compared with achieving the 75% VCR in the Preaud et al. model from 2014 [
17]), 5% more GP visits, 134% fewer hospital admissions and 90% fewer deaths. Prevention of these additional influenza cases and events through achieving the 75% VCR also translates into 205% and 29% lower direct and indirect cost savings, respectively, compared with the previous model [
17]. These differences may be explained by the higher proportion of older adults in the current population versus the previous study population, use of epidemiological excess rates, a higher vaccine efficacy for QIV-SD versus trivalent inactivated vaccine standard dose (TIV-SD), and fewer GP visits.
In this study population, older adults represented a large proportion of the influenza cases, hospitalisations, GP visits, and nearly all of the deaths avoided at the 2020/2021 VCR or by achieving a 75% VCR. Older adults and individuals with chronic conditions accounted for the largest proportion of the avoidable economic burden of influenza. Therefore, it is imperative that HCWs prioritise vaccination of these subgroups, to maximise the public health impact and reduce the economic burden [
35].
Influenza is a leading cause of work absenteeism, yet is frequently overlooked by conventional surveillance systems, which rely on healthcare data from GP or hospital records [
36,
37]. Capturing data on individuals who do not seek medical attention will therefore enhance influenza reporting [
36,
37]. Uhart et al. modelled the distribution of cost savings from a societal perspective if the QIV-SD vaccine was used instead of TIV-SD across Europe [
38]. In Europe, the VCR in working adults remains far lower than the VCR seen among older adults in a context where, unlike in the United States (US) and Canada, there is no universal influenza vaccination reimbursement [
39].
This study utilised an influenza VCR considered to be reflective of a post-COVID-19 scenario. COVID-19 vaccination and surveillance provided an opportunity to improve other adult immunisation programmes, reinforce infrastructures and assess potential synergies between COVID-19 and influenza management strategies, including enhanced epidemiological surveillance [
19]. Well-established adult influenza vaccination programmes proved to be a key component of the success of the response to the COVID-19 pandemic by facilitating access to and acceptance of mass vaccination campaigns [
40], highlighting that implementing annual adult immunisation programmes could be mutually beneficial in protecting vulnerable adults against a variety of respiratory pathogens, including influenza, severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), pertussis, pneumococcal diseases and respiratory syncytial viruses. As suggested by the Board of the Vaccination Calendar for Life in Italy, an innovative and concerted model based on co-administration of adult vaccines should ensure immunisation reaches vulnerable populations, in social and health residential facilities, and at home [
41].
Following the COVID-19 pandemic and vaccine rollouts, lessons can be learned in terms of how to drive vaccine uptake, particularly for vulnerable populations [
42]. Countries such as the UK, Portugal and Spain achieved record influenza VCRs during the 2020/2021 and 2021/2022 influenza seasons, thus increasing the benefits of influenza prevention at a time when healthcare systems were particularly under stress [
43]. Furthermore, the experience of the pandemic has highlighted the importance of identification of risk groups, namely, people more at risk of experiencing complications from infectious diseases, therefore warranting increased vaccination efforts, and reinforcing the importance of high adult vaccination coverage as a tool for pandemic preparedness. The US Biomedical Advanced Research and Development Authority has recently set goals of accelerating vaccine development and production, as well as improving vaccine performance [
44,
45]. Newly introduced influenza vaccines have been shown to provide better protection for vulnerable populations with HD vaccines showing increased benefits in older adults [
25]. In parallel, the medical community is looking towards a future research and development roadmap for novel influenza vaccines, which it expects, among other improvements, to lead to better protection and reduced production times [
46].
Several limitations apply to our analysis. Due to its static nature, our model does not account for the impact of vaccination on the reduction of the force of infection (i.e., the rate at which susceptible individuals in population acquire an infection disease), also called the indirect effect of vaccination, benefiting primarily the unvaccinated population. Hence, our result may be considered as an underestimation of the true potential impact of influenza vaccination. Also, as QIV-SD efficacy data were not uniformly available for all selected risk groups, a proxy based on TIV-SD efficacy in randomised trials (estimated by meta-analysis in Cochrane reviews) had to be used, adjusting for the benefit of protection against both B lineages [
47]. In addition, due to data paucity, several of the influenza VCRs and epidemiological and cost inputs that were used may not precisely match the risk group, period, and country considered; in those cases, a potential underestimation of the real burden can exist, as the study prioritised conservative assumptions. Influenza is also a significant driver of emergency visits and intensive care admissions, but available data (from surveillance systems and literature) does not allow for accurate evaluation of the overall impact on healthcare systems and the proportion of these events potentially avoided by vaccination [
48]. When combined with COVID-19, respiratory syncytial virus and other pathogens, influenza exerts a compounded pressure during winter and contributes to the overall saturation and disruption of healthcare systems, another aspect that was not modelled in this study [
49,
50]. Lastly, the estimated cost of vaccine acquisition provided in this study should be noted as a limitation. The cost of vaccine acquisition is a single component of the resources necessary for vaccine implementation, with additional resources required for vaccine application and immunisation campaigns. Due to the complexities associated with obtaining the necessary local data to provide accurate estimates, the estimated costs are unlikely to reflect the real value of vaccine acquisition for payors and could be easily misinterpreted in the context of this research.
Conclusions
Across France, Italy, Spain and the UK, the seasonal influenza VCR remains below the 75% target recommended by the WHO, with substantial heterogeneity across countries and risk groups [
17,
51,
52]. Despite suboptimal coverage, vaccination had a considerable positive impact on reducing overall influenza-related burden, resulting in cost savings.
By achieving the recommended 75% VCR, twice as many influenza cases could be prevented, avoiding thousands of hospitalisations and physician visits, and thereby reducing the burden on healthcare systems. Importantly, this study revealed that older adults account for the majority of preventable cases and deaths, along with those with chronic conditions, highlighting the need for health authorities and HCWs to prioritise these populations during their efforts to increase influenza vaccination uptake. By doing so, the public health and economic burdens associated with influenza could be substantially reduced. With an ageing population, pressured healthcare systems and budget constraints, the economic benefits of reducing influenza cases and the associated complications are of paramount importance.
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