Introduction
Influenza is a respiratory infection associated with significant clinical, humanistic, and economic burden for patients, caregivers, and healthcare systems worldwide [
1]. Each year there are an estimated 5 million cases of severe illness worldwide, and up to 650,000 deaths attributed to influenza [
2,
3]. With over half the world’s population falling in the 18–64 age bracket, significant heterogeneity appears in this demographic, from large variations in age, health status, and virus exposure, as well as socio-economic status and access to healthcare facilities [
4]. Given that this group encompasses the majority of the working population, influenza can be especially disruptive, causing prolonged absence from the workplace, and reduced productivity and the ability to care for others (i.e., dependents) [
2]. Furthermore, the impact of influenza in the 18–64 population is not equal with, for example, influenza incidence rates varying across differing age groups within the population. The median incidence of influenza in the United States (US) over the past decade in the 18- to 49- and 50- to 64-year-old populations were 6.8% and 11.6%, respectively [
5]. Although the trend in influenza vaccine uptake has slightly increased over the past decade in the US, only 37.2% of adults who were 18–49 years old and 54.2% of adults aged 50–64 years old received the influenza vaccine in the 2020–2021 season [
6].
Vaccines are central to the prevention and control of influenza [
1]. Although there appears to be a lack of perceived need for vaccination in the 18–64 population exemplified by large organizations, including the World Health Organization (WHO), who only recommend annual vaccination against influenza to those aged ≥ 65 years and to those deemed at high-risk of severe influenza illness in the 18–64 population [
7]. This includes individuals with chronic medical diseases, such as asthma, diabetes, heart or lung diseases, or HIV/AIDs, as well as those with increased exposure to influenza, such as healthcare workers and pregnant women [
7]. In accordance, many national healthcare bodies also use these recommendations. The French, Spanish, and South African healthcare bodies recommend that all people ≥ 65 years of age receive the influenza vaccination annually [
8,
9]. The UK National Health Service prioritize persons ≥ 65 years and those ≥ 18 years of age at high clinical risk of severe illness for vaccination; however, this is extended to those ≥ 50 years later in the influenza season, depending on vaccine availability [
10]. Thus, the perceived importance of influenza vaccination varies across age groups. This is further reflected in the low vaccine uptake rates in the 18–49 and 50–64 populations (37.2% and 45.9%, respectively), but high uptake, 73.9%, within the US ≥ 65 population, in the 2021–2022 influenza season [
11]. Importantly, although influenza vaccines do not strictly prevent transmission and infection, they do reduce the severity and incidence of further complications, thus mitigating the risk of hospitalization and death [
2,
7].
A unified, global approach to increase recognition of the importance of influenza vaccine uptake in the 18–64 population may reduce the risk of hospitalization and death in this large, working-age population [
7]. Furthermore, increased vaccination in the 18–64 population may mitigate workplace and productivity disruption, thus alleviating wider clinical, humanistic, and economic burden to patients, caregivers, and healthcare systems worldwide.
Currently, the global distribution of influenza vaccines comprises of those that are egg-derived [
12], yet they present substantial challenges in terms of time for vaccine production. Additionally, fluctuating effectiveness and longevity of protection may result from both viral drift, manifested by differences in seasonal vaccine antigen and circulating antigen, and through adaptation of viral antigens produced in the eggs [
1,
12,
13]. Consequently, these limitations can reduce vaccine effectiveness (VE) and, thus, contribute to increased burden of influenza that year, severely impacting patients, caregivers, and healthcare systems worldwide. There is an ongoing need to further mitigate disease burden year-on-year through modifying the current approach to influenza prevention.
Two alternatives to vaccine development are recombinant and messenger ribonucleic acid (mRNA) techniques. Recombinant influenza vaccines are not limited by antigen mutation, and have demonstrated improved vaccine efficacy over egg-based vaccines [
14]. However, reports of suboptimal immunogenicity have impacted mass uptake [
15]. Novel mRNA technology has further demonstrated precise targeting of strains, plus improved accuracy and VE, due to reduced antigen mismatch, throughout the recent COVID-19 pandemic [
15,
16]. During this time, widespread utilization of mRNA vaccine technology demonstrated the proficiency of rapid, large-scale manufacturing of vaccines. These factors may help confront concerns with more traditional methods of vaccine production, provide greater protection against influenza, and alleviate further influenza disease burden [
15].
While our previous work characterized the global burden of influenza among adults aged ≥ 65 years, less is known about the impact of influenza within the 18–64 population [
17]. Therefore, by conducting this SLR, we sought to gain a better understanding of the clinical, humanistic and economic burden of influenza exclusively within the 18–64 population, and to identify potential limitations of current vaccines in this population.
Discussion
This SLR aimed to characterize the clinical, humanistic, and economic burden of primary influenza among adults in the general population aged 18–64 years. Although the clinical burden in this age group was widely reported, limited evidence was identified for the humanistic and economic burden.
The data identified in this SLR reflect a trend of increased influenza-associated clinical burden with increased age among those aged 18–64 years, including hospitalizations [
22‐
26,
28], ICU admissions [
26,
34], mortality [
26,
34,
39], ER/outpatient visits [
34], and use of mechanical ventilation [
26,
39]. Of note, in studies that stratified by age, the ‘older’ age range with greater associated burden was most frequently 50–64 years [
22,
23,
25,
26,
34,
39].
Seasonal differences in circulating influenza strain are determined by multiple factors including population-level natural and vaccine-induced immunity, surveillance, and the transmissibility of the dominant strain (most prevalent circulating strain during the influenza season). When stratified by influenza strain, higher rates of hospitalization, ICU admission, and mechanical ventilation were reported for influenza A or A subtypes (H1N1 and H3N2) than influenza B, and were reported to be exacerbated among adults aged 45–64 years [
25,
39,
54]. Poor influenza outcomes have been associated with influenza A(H3N2), especially among older populations [
17].
Similar to older adults, people aged 18–64 years with underlying comorbidities (e.g., type 2 diabetes mellitus, IBD, IPA, immunosuppressed) were at higher risk of influenza-related hospitalizations, ICU admission, and mortality compared to otherwise healthy individuals [
36,
38,
40,
41]. The increased incidence of early onset chronic conditions such as type 2 diabetes and obesity among younger adults, largely due to lifestyle choices, means increased prevalence of comorbidities among patients aged 18–64 years [
55,
56]. Further, data from the WHO suggest that the extent of influenza-related clinical burden is often underreported, and is far more detrimental to patients and healthcare systems than realized, due to influenza-related deaths from other diseases (e.g., cardiovascular) not being acknowledged [
57]. Overall, with increased risk of comorbidity and general declining health in older age, extension of influenza vaccination prioritization to at least the 50–64 population may reduce the risk of hospitalization and death in this population.
Limited humanistic data were identified in the SLR that reported influenza-related outcomes (
n = 5). Unlike the identified clinical burden, these studies did not stratify the humanistic burden within the adult population by age. Considering the trend of increased influenza burden with increased age, age-related differences in humanistic burden among adults aged 18–64 years warrant further investigation [
7].
Interestingly, Tsuzuki et al. reported no significant difference in symptom duration, QALYs lost, or QoL score between vaccinated and unvaccinated patient subgroups [
44], while Yoshino et al. reported a significantly higher HRQoL score for the physical component of the SF-8 questionnaire (
p = 0.001) among vaccinated adults compared with unvaccinated adults [
45]. Of note, these studies were both conducted in Japan with overlapping study periods (2018–2020), but the former among patients with influenza-like-illness and the latter among adults with laboratory-confirmed influenza [
44,
45]. These findings highlight the ambiguity surrounding the benefits of influenza vaccination for assessing both the humanistic and overall burden within the general population aged 18–64 years.
Limited evidence of the economic burden in adults was identified (
n = 16). Indirect costs associated with influenza were more frequently reported than direct costs (
n = 6 vs.
n = 3, respectively), suggesting that the impact of absenteeism and reduced productivity is more relevant and burdensome within the working population of adults [
44,
46,
48,
50‐
52]. However, these identified studies still provide a limited overview of indirect costs considering the size and breadth of the working adult population aged 18–64 years.
An SLR of the economic burden of influenza among adults aged 18–64 years conducted by Courville et al. also identified an evidence gap and a focus on indirect costs in this population [
58]. Currently, the WHO does not explicitly recommend seasonal vaccination against influenza in the 18–64 population. However, the organization does recognize that it can be cost-saving for patients and healthcare systems globally [
59]. Interestingly, more evidence for influenza-associated direct costs has previously been reported among adults aged ≥ 65 years [
17]. These SLRs in older populations reported influenza-related hospitalization, ICU admission, and ER/outpatient visits, which were also clinical outcomes reported among the 18–64 years population in this SLR. Thus, this suggests that the limited evidence of influenza-related direct costs identified in this SLR is not representative of the actual burden exerted by adults aged 18–64 years. In addition, studies investigating influenza-associated costs in those aged ≥ 65 years have demonstrated the economic benefits of preventive healthcare given the rising cost of care and limited availability of resources. These findings suggest that influenza vaccination among adults aged 18–64 years would help to reduce the burden exerted on healthcare providers.
Overall, limited and contradictory reports of influenza vaccination protection highlighted a need for further research into the benefits of seasonal influenza vaccination in adults aged 18–64 years. Given the size and breadth of this population, who form most of the global workforce, prolonged absence from the workplace has the potential to disrupt the economy and to burden healthcare providers [
2].
However, seasonal influenza vaccination is currently available across several countries for adults aged 18–64 years [
10,
11], but with consistently poor uptake rates. For example, vaccination coverage among US adults aged 18–64 years peaked at 43.0% between 2015–2016 and 2021–2022. Although peak uptake rate over the same period when limited to adults aged 50–64 years increased to 54.2%, these figures suggest that this population still perceives an influenza vaccination as of low importance [
60].
Influenza vaccination uptake between age groups was also differentially affected by the COVID-19 pandemic. Between 2019–2020 and 2021–2022, influenza vaccination uptake increased among adults aged 50–64 years (50.6% vs. 52.4%, respectively) and decreased among adults 18–49 years (38.4 vs. 37.1%). These differences are likely due to a combination of factors, including increased distrust of vaccinations during the COVID-19 pandemic, non-prioritization while lockdown measures were in place among younger adults, and an increased feeling of vulnerability among adults aged 50–64 years. The decision to receive an influenza vaccination within the 18–64 population relies heavily on factors such as underlying comorbidities and increased occupational exposure, while attitude and trust toward healthcare, associated costs, and level of education tend to drive adults in this age group to choose not to receive a vaccination [
61]. Interestingly, among unvaccinated groups, lack of knowledge was the greatest barrier to influenza vaccination [
61].
A combined lack of trust in vaccine effectiveness and a perceived low risk of personal illness are reported drivers of poor influenza vaccine uptake rates [
61,
62], partly owing to limitations and suboptimal effectiveness of traditional influenza vaccines. Novel vaccine production methods such as using mRNA technology may offer a solution to overcome limitations associated with current vaccine production methods [
63]. The recent COVID-19 pandemic offered insight into the potential use of mRNA vaccines, highlighting the proficiency of rapid, large-scale manufacture of vaccines, and eliciting a wealth of safety and efficacy data. Improved perception of influenza vaccination effectiveness and a greater understanding of the risks of influenza illness, combined with extension of influenza vaccination prioritization to at least the 50–64 population, are necessary to reduce the risk of hospitalization and death in this population. With increased risks of comorbidity and overall declining health in older age, these aspects of vaccination are important to take into consideration, as they contextualize the burden of influenza and indicate areas to address to minimize influenza-related clinical burden within the 50–64 years population.
Study Limitations
A potential limitation of this SLR was that, during the screening process, studies that did not explicitly report data for adults aged 18–64 years within the title and/or abstract were excluded. As such, studies may have been excluded due to uncertainty of the population of interest if not disclosed within the abstract. In addition, due to the broad inclusion criteria, the ability to identify clear trends and make direct comparisons between study results were impeded by heterogeneity in study design, outcomes, and population characteristics.
Finally, the limiting of study scope to include studies reporting data for Brazil, Canada, China, France, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, UK, and the US may not be fully representative of the global burden of influenza in adults aged 18–64 years.