Introduction
Influenza is a respiratory infection associated with a significant clinical burden globally [
1]. Annually, there are an estimated one billion cases of influenza in the general population, of which three to five million cases are severe [
2]. The clinical burden is exacerbated by limited regional access to annual influenza vaccines, including limited coverage within some racial and ethnic groups [
3,
4]. Furthermore, inadequate influenza surveillance infrastructure, testing practices, and healthcare services can exacerbate influenza clinical burden in low- and middle-income countries (LMICs) [
5].
Older adults aged ≥ 65 years are at an increased risk of severe influenza symptoms and the development of serious complications due to chronic comorbidity and age-associated decline in immune function, i.e., immunosenescence [
6]. The US Centers for Disease Control and Prevention (CDC) estimated that 70–85% of influenza-related deaths and 50–70% of influenza-related hospitalizations during the 2010–2011 and 2019–2020 seasons were among those aged ≥ 65 years [
7]. Similar estimates were reported from the World Health Organization (WHO) and European Centre for Disease Prevention and Control (ECDC) [
8,
9]. Older adults are a heterogenous population, in terms of general lifestyle (active to sedentary), their health status, living arrangements, healthcare support requirements, and access to healthcare resources. To improve clinical outcomes through targeted vaccination of those most at risk, a better understanding of how these risk factors influence severe influenza-related clinical outcomes in older adults is needed.
Influenza vaccines are fundamental to disease prevention and have been licensed in the USA and Europe since the 1960s [
1,
10]. The WHO recommends annual vaccination of individuals at greatest risk of developing serious complications from seasonal influenza infection and lists older adults among the priority groups for vaccination [
8]. Despite adults aged ≥ 65 years being identified as a high-risk group, there is disparate influenza vaccination coverage in this population globally [
11]. Globally in 2019, influenza vaccination coverage rates among adults aged ≥ 65 years were estimated to range from the lowest in Turkey at 5.9% to highest in South Korea at 85.8% [
11].
Egg-derived influenza vaccines are the most distributed influenza vaccines globally [
12]. However, these traditional vaccines display limited vaccine effectiveness (VE), in terms of strength and longevity of immunogenicity, and breadth of protection across influenza strains [
13]. This was evident in countries with widespread vaccination coverage of adults aged ≥ 65 years, such as 67.5% in the USA in 2020, where a substantial influenza-associated clinical burden persists [
11,
12].
Suboptimal protection against influenza infection and high clinical burden may be partially explained by antigen mismatch between circulating influenza strains and seasonal influenza vaccines [
14]. Circulating influenza strains vary by season and region, and influenza vaccines are produced annually based on predictions of the most prevalent circulating viruses for the coming season [
15]. Influenza A(H3N2), which older adults are known to be more vulnerable to, is consistently one of the most common circulating strains and frequently mutates genetically and antigenically [
15]. As such, many genetically distinct subtypes of influenza A(H3N2) co-circulate annually around the world [
16]. Considerable antigenic drifting of A(H3N2) viruses, among others, results in variable influenza VE due to strain mismatch. For example, between 2012 and 2020, the US CDC estimated that influenza VE among adults aged ≥ 65 years ranged from 12% [95% confidence interval (CI) − 31 to 40] to 66% (95% CI 36–82] in the 2018–2019 and 2015–2016 seasons, respectively [
17].
Egg-derived influenza vaccine production takes approximately 6 months and this time lapse exacerbates antigen mismatch between vaccines and circulating strains. The delay can result in poor protection against seasonal influenza, potentiating the clinical burden of disease in older adults [
18] . A next generation of influenza vaccines that facilitate improved strain matching and rapid manufacture are necessary to improve influenza VE. Novel vaccine platforms, such as mRNA technology, are well placed to address limitations associated with traditional influenza vaccines. The mRNA manufacturing process allows the precise targeting of multiple influenza subtype strains and is not subject to egg-adapted antigenic changes. Moreover, mRNA vaccines can be rapidly manufactured, which facilitates strain matching nearer the start of the influenza season [
19]. Currently, several promising multivalent mRNA influenza vaccines are undergoing early phase clinical trials [
20,
21].
The aims of this review were threefold: to characterize the clinical burden of influenza in adults aged ≥ 65 years, to enhance our understanding of the strengths and limitations of currently used influenza vaccines, and to understand how the unique features of mRNA vaccines may be harnessed to reduce the clinical disease burden in this population.
Methods
Search Strategy
The search strategy was designed to capture publications reporting data that described the clinical burden of influenza in older adults (those ≥ 65 years of age) and that were published in English between January 1, 2012 and February 9, 2022. Recognizing that there are substantial differences in global influenza surveillance infrastructure, testing practices and reporting, healthcare services, and administration, we carefully selected countries in disparate regions to achieve a considered global overview—specifically limited to France, Germany, Italy, Spain, the United Kingdom (UK), USA, Canada, China, Japan, Brazil, Saudi Arabia, and South Africa.
An electronic database search was designed following guidance from the Cochrane Handbook for Systematic Reviews of Interventions [
22] and conducted on February 9, 2022 in Embase, Medline, Econlit, PsycINFO, and Evidence-Based Medicine Reviews (EBMR) via the OVID® platform.
Bibliographies of relevant systematic literature reviews (SLRs), meta-analyses, and economic analyses identified in the database search were reviewed to ensure all studies that met study inclusion criteria had been captured. The SLR search strategy is presented in Appendix B in the supplementary material.
The database searches were supplemented by searching conference proceedings, and gray literature. Conferences were selected from current infectious disease congresses following critical review of the quantity and relevance of influenza data presented in the previous 2 years. Consequently, conference proceedings from the International Society for Pharmacoeconomic and Outcomes Research (ISPOR), European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), American Thoracic Society (ATS), and IDWeek (joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medical Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP)) dating from the January 1, 2020 to February 9, 2022 were included in the search. Gray literature that reported the most recent epidemiological data from the WHO, ECDC, and the US CDC were included.
This review was based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Study Eligibility Criteria
All retrieved studies were screened against the Population, Intervention, Comparison, Outcomes, and Study (PICOS) criteria outlined in Table
1. It was hypothesized that these outcomes would capture the most frequent and severe influenza-related outcomes, to comprehensively reflect the spectrum of clinical burden of influenza in adults ≥ 65 years. Studies that did not explicitly report data for ≥ 65 years and that reported aggregated data across age groups spanning from < 65 years to ≥ 65 years were excluded.
Table 1
Eligibility criteria
Population(s) | People aged ≥ 65 years with laboratory confirmed seasonal influenza or symptomatic ILI | Studies reporting data from people aged < 65 years Studies reporting data from people without influenza or symptomatic ILI Studies reporting data from people with pandemic influenza Studies reporting data from people co-infected with influenza and COVID-19 where COVID-19 is not specifically stated as a secondary infection |
Interventions | Any/none | N/A |
Comparisons | All | N/A |
Outcomes | Prevalence and incidence Breakthrough cases Symptoms Morbidity and mortality Treatment, escalation, and long-term care Hospitalizations and ICU visits Complications and secondary infections Vaccine effectiveness (individuals aged ≥ 65 years who received their annual influenza vaccination) | Studies reporting clinical outcomes not mentioned in inclusion criteria |
Time | Studies published from January 2012 to February 2022 | N/A |
Study design | Randomized controlled trials Non-randomized interventional studies Observational studies SLRs and meta-analyses | Editorials Case studies Letters to journals Non-systematic literature reviews Conference minutes |
Other | Human studies English language | Animal studies Duplicates |
The search date parameters spanned the outbreak and height of the COVID-19 pandemic. As the biology and literature relating to co-infection of influenza and SARS-CoV-2 pathogen has not yet been established, data reporting influenza and COVID-19 co-infection were excluded. Additionally, to ensure influenza was the primary study focus, data reporting respiratory infections such as pneumonia were only included if explicitly reported as secondary infection to influenza.
Study Selection and Data Extraction
Abstract and full-text screening were conducted by two independent reviewers, with any differences and uncertainties resolved by a third reviewer. Data extraction was conducted by one reviewer and verified by a second reviewer. Data were extracted into a concise data extraction form (DEF) developed within Microsoft Excel. For each of the included studies, publication information, study characteristics and methods, population and subgroup characteristics, as well as clinical outcomes of interest (Table
1) were extracted. Older adults are a heterogenous population and therefore clinical outcome data across relevant subgroups were captured where available (age, living arrangements, comorbidities, employment status, vaccination status). The DEF was designed to enable direct comparison of clinical outcomes between these subgroups. For the gray literature reporting epidemiological outcomes, prevalence and incidence rates, as well as influenza-associated hospitalization and mortality rates were extracted. A risk of bias assessment was performed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists [
23].
Discussion
There are limited existing SLRs which focused on exploring the clinical burden of influenza in a single country or region with scope not limited to those aged ≥ 65 years and including other high-risk subpopulations. The focus of this SLR was to enhance our understanding of the current clinical burden of influenza among adults aged ≥ 65 years from a global perspective, and the potential clinical benefit of harnessing mRNA vaccine technology.
Data identified in this SLR reflect the substantial clinical burden of influenza among adults aged ≥ 65 years, characterized by high rates of hospitalizations, escalation of care (such as ICU admissions) and mortality. These outcomes were also reported to worsen with increasing age—people aged ≥ 75 years were more likely to be hospitalized for influenza than those aged ≥ 65–74 years [
29,
38,
39,
50], with some indication that the hospitalization risk continues to increase with age [
29,
43]. Furthermore, people with influenza aged ≥ 75 years were more likely to die than those aged 65–74 years [
2,
24,
39,
44,
46,
50,
65,
66,
67,
68,
69]. Older adults (aged ≥ 65 years) are a growing subpopulation [
92], and have greater healthcare needs, which frequently require hospitalization. These findings suggest that influenza infection exacerbates the existing clinical burden and highlights the need for improved influenza VE and vaccination coverage in this age group.
Older adults are a heterogenous population in terms of health and care requirements. Various comorbidities are common among adults aged ≥ 65 years [
92], placing them at a higher risk for several conditions and contributing to their increased vulnerability to influenza. The literature identified in this SLR largely suggested that the burden of disease is exacerbated in older adults with comorbidities. Existing cardiovascular diseases, respiratory diseases, immunosuppressive conditions, diabetes mellitus, metabolic conditions, kidney diseases, and neurological conditions were all associated with increased risk of poor clinical outcomes among patients aged ≥ 65 years with influenza. The high prevalence of these comorbidities among older adults in the general population puts this population at risk of serious influenza infection, hospitalization, and death, highlighting the need for effective vaccination programs is this population [
92]. Older adults also vary widely in terms of working and living arrangements. Although few data were identified, and were limited to Canada, the findings of this SLR suggested that long-term care residents with influenza were more likely to be hospitalized than community residents, even when stratified by age group [
54]. These findings are consistent with CDC guidance, which states that people who live in nursing homes or other long-term care facilities are at higher risk of serious influenza complications [
93]. This is an important trend, considering that from 2011 to 2026, there is a projected 71% increase in the number of Canadian residents aged ≥ 65 years who will require continuing care [
94]. Therefore, greater understanding of the variable risk of influenza infection based on living arrangements in Canada and across regions would improve targeting of the most at-risk adults aged ≥ 65 years for influenza vaccination. No data characterizing differences in influenza clinical outcomes between minority and ethnic groups or employment status (e.g., retired, semi-retired, working) were identified. Therefore, further research across countries and older adult subpopulations may enhance the understanding of differential risk within the ≥ 65 years population.
While this SLR aimed to characterize the burden of disease across countries, the majority of identified studies were limited to North America and Europe, with a good representation of high-income countries in the Northern Hemisphere. Conversely, the data identified for Southern Hemisphere countries were limited and confined to Brazil and South Africa, both upper-middle-income countries. The high volume of burden data available for countries such as the USA could be due to the sophisticated influenza surveillance programs in these high-income countries. No differences between Northern and Southern hemisphere countries were identified, with all studies in this SLR reporting high clinical burden in the older population. However, as representative data for Southern Hemisphere countries was lacking, in-depth comparisons could not be made. Given the hemispheric differences in seasonality, circulating strains, and vaccination recommendations [
95], further investigation into the differences in clinical burden of influenza across these regions is needed to characterize the specific burden of influenza among adults aged ≥ 65 years in the Southern Hemisphere.
The SLR was, however, able to consider the potential impact of income status on country-level differences in influenza burden. Disparities in disease burden by income status were reported by a global modeling study which reported the lowest mortality rates in high-income countries (South Korea and Japan) and the highest in the upper-middle-income countries included in this SLR (Brazil, China, and South Africa) [
2]. Two further studies compared data for Southern Brazil and the USA; mortality was similarly higher in Southern Brazil than in the USA in the first [
65], while the second reported fewer hospitalizations in Southern Brazil than the USA [
60]. Drivers for the lower hospitalization in Brazil were suggested, including a lower bed density in countries with lower income [
60]. This can contribute to fewer hospitalizations which may therefore skew the burden of disease data where hospitalization data is used as a proxy. Differences in surveillance and reporting methodology and circulating strain may also have contributed to country-level differences. Improved and standardized influenza surveillance infrastructure and reporting practices would facilitate better comparisons of the true burden of disease across countries.
Moreover, studies were often conducted across single or few cities within countries or regions, and therefore were unlikely to provide an accurate representation of the clinical burden at a national or regional level. This is due to population differences, variability in the level of available healthcare, and potential differences in climates across countries. Climatic differences in particular can affect the seasonality and transmission dynamics of influenza, thereby contributing to differences in influenza burden within countries or regions [
90]. This is particularly relevant in countries where both temperate and tropical climates exist. The timing of the WHO influenza vaccination recommendations often does not correspond to the dynamics of the tropical regions in areas such as South America, China, and Africa as influenza activity is often out of phase with other dynamics in the hemispheric group [
96]. Suboptimal recommendations and subsequent vaccine-induced protection across such regions may explain why these areas were found to be at high risk of clinical burden of influenza in the studies included in this SLR. This highlights the need to tailor vaccine formulation and timing of administration to each geographic area to better protect against influenza each season.
Understanding the seasonal nature and variability of influenza is vital to optimize vaccination strategies. This SLR emphasized the differential impact of influenza among adults aged ≥ 65 years between seasons with high levels of seasonal variability in clinical outcomes including hospitalizations and mortality identified across the literature. The seasonal differences are likely driven by a variety of factors including the level of natural and vaccine-induced immunity in the population, differential surveillance and reporting across seasons, and the seasonal dominant strain and its transmissibility. Influenza A(H3N2) is often associated with more severe flu seasons and is known to result in poor outcomes among the older adult population [
25,
30,
34,
36,
37,
38,
41].
Multiple studies in this SLR found that seasons dominated by A(H3N2) were associated with high rates of hospitalization and mortality and more severe infection, resulting in ICU admissions [
25,
30,
34,
36,
37,
38]. The substantial burden exerted by A(H3N2) may, in part, be due to the frequency that A(H3N2) mutates genetically and antigenically, which is higher than other common influenza subtypes [
97]. The mutagenic nature of A(H3N2) increases the likelihood of antigen mismatch and suboptimal VE, which in turn increases the risk of influenza-associated hospitalization/ICU admission and mortality in seasons dominated by the A(H3N2) strain [
97]. This challenge was discussed across several studies included in this SLR where the mismatched Northern Hemisphere vaccine in specific seasons was concluded to drive the peaks in clinical burden observed [
40,
48,
88]. The clinical burden generated by influenza A(H3N2) may therefore persist despite vaccination in the ≥ 65 years population due to a mismatch between seasonal vaccines and circulating strains and subsequent suboptimal vaccine-induced immunity.
As a result of the increased risk of developing serious influenza-associated outcomes and complications among older adults, the WHO recommends that this population receive an annual influenza vaccination [
8]. While vaccination coverage varies across regions, adults aged ≥ 65 years are a priority group for influenza vaccination, globally [
7]. However, as found in this SLR, the clinical burden of influenza persists among older populations despite the availability of seasonal vaccine, which further suggests that there may be limitations in the current influenza vaccination programs and formulations. High-dose vaccines were developed to address reduced protection against severe influenza outcomes offered by standard-dose influenza vaccines in adults aged ≥ 65 years [
7]. Currently available influenza vaccines have been shown to reduce the burden of influenza-related morbidity and mortality [
98].
Despite the evolution of influenza vaccine formulations (first inactivated influenza vaccine [
99], egg-derived and cell-based [
100], addition of a fourth strain in recent years, and development of adjuvanted and recombinant vaccines [
101,
102], and different dose formulations), we continue to see a significant clinical disease burden. Although currently available influenza vaccines have been shown to reduce the burden of influenza-related morbidity and mortality, the findings of this review demonstrate that a high clinical burden of influenza persists among older populations. The continued clinical burden of influenza disease and limitations of current vaccines support the entry and positioning of mRNA vaccine technology as a potential solution.
Seasonal variation observed in both high-dose and standard-dose influenza VE [
103,
104,
105,
106] suggests that the differences are driven in part by seasonal factors, such as the prevalent circulating strain. In this SLR, the mismatch of seasonal influenza vaccines and circulating strains was reiterated across the findings of several studies, demonstrating suboptimal vaccine-induced immunity against dominant strains. Mismatch is particularly evident when genetic and antigenic variations occur after seasonal predictions have been made and vaccine manufacture has begun, which in some seasons can result in inadequate vaccine-induced protection. Moreover, studies reporting influenza VE for France, Germany, Italy, Spain, and UK have found a lower VE associated with increasing age and variable effectiveness against severe influenza-related outcomes in patients aged ≥ 65 years [
45,
87,
107,
108,
109,
110]. These findings suggested that current influenza vaccines are suboptimal within a population with high morbidity and mortality. This was mirrored by the high rates of hospitalization and mortality in older adults seen across European countries included in this SLR. Limitations of current vaccines therefore persist despite strain prediction methods across a range of global regions, highlighting the need for more consistently effective seasonal vaccines. To overcome the limitations of antigen mismatch, the development of “universal” influenza vaccines that target antigenic determinants is needed [
13]. New technologies may improve influenza VE by offering a solution for the challenges experienced with strain predictions and the time taken to develop traditional vaccines. Novel vaccine production methods such as using mRNA technology offers precise targeting of the antigenic determinants of multiple regional-specific influenza subtype strains and rapid manufacture. The manufacturing benefits of mRNA technology would facilitate strain prediction nearer the start of the influenza season, which is currently difficult considering the production demands for national antigen-based influenza vaccination schemes. Further, mRNA vaccines are not subject to limitations affecting traditional egg- and cell-based influenza vaccines, such as egg-adapted changes, which frequently alter immunogenicity and result in suboptimal VE [
19].
The COVID-19 pandemic has generated an unprecedented wealth of data reporting the real-world safety and effectiveness of mRNA vaccines and has provided a clinical proof of concept to support mRNA-based influenza vaccines [
111]. Post-authorization safety surveillance from the distribution of four billion doses of mRNA-based COVID-19 vaccines has not uncovered a major safety signal (only very rare reports of myocarditis in select age groups and anaphylaxis) and provides reassurance about the safety profile of this novel vaccine platform [
111]. Several promising multivalent mRNA influenza vaccines are currently undergoing early phase clinical trials [
20,
21] Although further research is required, early data considered in the context of the findings of this SLR suggest the novel mRNA vaccine technology may avoid some of the manufacturing limitations seen with current influenza vaccines, and attenuate the high clinical burden of seasonal influenza among adults aged ≥ 65 years.
A potential limitation of this SLR was the age restriction applied to the study population. The search strategy relied on relevant literature being appropriately indexed, with influenza and age stratification of outcomes present in the study title or abstract. Only data explicitly reported for adults aged ≥ 65 years was extracted. This may have led to the exclusion of data for the older adult population that was defined by a different threshold (e.g., 60–80 years). To refine the scope of the search, studies that made no reference to age stratification or older age/elderly patients were excluded at abstract screening stage. In addition, any studies that only referred to patient populations as “older” or “elderly” adults without specifying an age range of at least ≥ 65 years were excluded at full-text stage. It should be noted that co-infection data for influenza and other respiratory diseases (e.g., pneumonia, COVID-19, respiratory syncytial virus) were also excluded from this SLR to refine search scope and ensure that influenza remained the primary focus. However, as these respiratory infections often co-exist with influenza and are common among older adults, it is likely that the clinical burden of disease reported here is underestimated.
The lack of reported vaccination status in many of the included studies may have also limited interpretation of current vaccination efficacy on influenza-related outcomes captured in this SLR. Furthermore, limited available data for the countries within study scope (particularly for Southern Hemisphere countries) and disparate influenza vaccination surveillance and reporting practices limited direct comparison of clinical outcomes across different regions.
This SLR also did not identify any data reporting long-term sequelae of influenza in the included studies. While long-term complications of influenza may be present among those recovering from infection, this was not a focus of the studies reviewed. To date, there is no published literature reporting the clinical burden of long-term sequelae of influenza in older populations. Therefore, further empirical investigation into the prolonged clinical burden of influenza in this population is warranted.