Influenza viruses belong to the Orthomyxoviridae family, including the clinically relevant influenza A and B viruses.4 Influenza A and B viruses are relatively simple, consisting of a viral envelope, matrix protein and the virion core.7

The genome of influenza A and B viruses comprises eight negative-sense, single-stranded viral RNA segments, coated with multiple copies of Nucleoproteins (NPs) and bound by an RNA-dependent RNA polymerase heterotrimeric complex, forming the Ribonucleoprotein (RNP) complex.7 In addition to the RNP complex, the virion core also includes nuclear export and nonstructural proteins.7

The core is enclosed within the Matrix protein (M1) and the glycoprotein-studded phospholipid bilayer envelope.7 The viral envelope anchors the Hemagglutinin (HA) and Neuraminidase (NA) glycoproteins – the predominant viral surface proteins that act as key regulators of viral entry and exit from host cells and are thus immunologically important antigens.7 There are 18 HA subtypes and 11 NA subtypes that have been identified in influenza to date.8 In addition, the viral envelope is also associated with the M2 protein that forms a tetrameric ion channel.7

Influenza viruses constantly evolve at their surface glycoproteins via antigenic drift or shift, allowing the virus to remain a threat to the human population despite repeated exposure and immunity to prior variants.8

Antigenic drift is the process by which point mutations in the viral genome introduce minor changes into viral epitopes.8 In the influenza virus genome, frequent mutations are introduced during the replication cycle owing to the lack of proofreading mechanisms associated with viral RNA-dependent RNA polymerases.8 Viruses with antigenic drift are reported to preferentially escape preexisting immunity.8 Antigenic drift is the main cause of seasonal epidemics and is responsible for the need to update vaccine composition every influenza season.9

Antigenic shift results in an exchange of HA genes, NA genes or both.8 The emergence of such a novel strain could result in a global pandemic.8 The capacity of the influenza A virus to cause a pandemic is related to its genetic diversity and ability to switch host species.8 There have been four pandemics in the last 100 years: the pandemics of 1918, 1957, 1968 and 2009.8,9

At present, the A(H3N2), 2009 A(H1N1) and influenza B viruses circulate seasonally among humans, causing substantial morbidity and mortality.8 Vaccinating against circulating viruses is the best approach to reducing the seasonal influenza disease burden.4

Seasonal influenza A and B cause significant disease and mortality, especially among unvaccinated older adults (aged ≥ 65 years) and young children (aged < 5 years).4 In general, influenza A poses a higher disease burden than influenza B; a recent study estimated that 23 % of all annual influenza cases are due to influenza B virus.10 Influenza B can be more common and severe than influenza A in children, causing up to 52 % of all influenza-related deaths.11

A study by Iuliano and colleagues revealed that older adults living in LMICs had the highest proportion of influenza-related respiratory deaths, accounting for 77 % of deaths within this age group.1 Among adults aged < 65 years, up to 93 % of influenza-related respiratory mortality occurred in LMICs.1 In WHO geographic regions (regardless of income level), older adults residing in the Western Pacific and South-East Asia regions had the highest proportion of influenza-related respiratory mortality, accounting for 57 % of deaths within this age group.1 Meanwhile, Sub-Saharan Africa and Eastern Mediterranean had the lowest proportion of influenza-related respiratory mortality within this age bracket.1

A 2018 study showed a substantial proportion of influenza-related burden in children aged 0–59 months. Of the estimated 786,000 LRTI total hospital admissions in young children (the burden estimates were calculated by summing up estimates in three non-overlapping age groups and three income levels according to the World Bank classification), LMICs contributed about 86 % of admissions.12 Of about 20,800 in-hospital deaths in young children, up to 98 % occurred among infants under 6 months living in LMICs.12 Unsurprisingly, the in-hospital case fatality ratio among young children was higher in LMICs at 4.1 % than in HICs at 0.5 %.12

Post-acute conditions have also been reported after influenza infection. Evidence shows that influenza infection could trigger acute Myocardial Infarction (MI) and stroke.13 Specifically, a higher incidence ratio for acute MI was observed after influenza infection in individuals aged > 65 years than in those aged ≤ 65 years (7.31 vs. 2.38).14 A study conducted in Beijing from 2011 to 2018 to assess the excess Cardiovascular Disease (CVD) mortality attributable to influenza in older adults estimated the annual excess mortality rate per 100,000 population at 27–49 for ischemic heart disease, 14–22 for ischemic stroke and 54–96 for overall CVD.15 The excess mortality was estimated to result in 916–1640 influenza-related CVD deaths among those aged ≥ 65 years,15 further reinforcing the high actual burden of influenza.

Seasonal influenza also exacts a heavy socioeconomic toll on healthcare systems and society. The proportion of costs attributable to influenza is particularly high among working adults, primarily as a result of workplace absence, reduced patient and caregiver productivity, and increased healthcare resource utilization. A study in South Africa from 2013 to 2015 estimated the mean annual total cost of influenza‐associated illness at USD 270.5 million, with indirect costs accounting for 44 % of the total cost.16 Similarly, a systematic review of 11 studies conducted in Thailand estimated the total cost of influenza at USD 31.1–83.6 million per year, with 50 %–53 % of the economic burden attributable to lost productivity.17

An influenza surveillance system is indispensable in monitoring influenza epidemiology and disease burden. The WHO Global Influenza Surveillance and Response System (GISRS) – through a network of national influenza centers, collaborating centers and reference laboratories worldwide – is especially critical in the surveillance, detection, preparedness and response to pandemic influenza and informing forecasting for strain composition for seasonal influenza vaccines.18

The Global Initiative on Sharing All Influenza Data (GISAID) was later established to promote the rapid sharing of genetic and associated influenza virus data.19 The repository data is particularly valuable to help detect emerging strains and guide the selection of vaccine strains.19 More recently, the Global Influenza Hospital Surveillance Network (GIHSN) was developed to study the burden of severe influenza and estimate the effectiveness of seasonal influenza vaccines across seasons in different countries.20 The network uses a standard protocol and a common approach to case selection for testing and data selection, thereby avoiding potential biases.20

The WHO's Global Influenza Strategy 2019–2030 highlights the need to strengthen global influenza surveillance and monitoring. The document also called for a better understanding of the disease and its economic burden in LMICs, to guide the establishment or expansion of seasonal influenza prevention and control strategies.21 Despite influenza surveillance systems being a key component to successful influenza control and prevention, there is a clear disparity across WHO member states, particularly between HICs and LMICs.22 A 2021 study comparing national influenza surveillance systems revealed considerable variability between three Asia Pacific countries with different levels of development, with Australia demonstrating the broadest scope and most detailed influenza surveillance, followed by China and Malaysia.22

The WHO's Global Influenza Strategy 2019–2030 also encourages LMICs to use innovative modeling and data sources to improve the forecasting of influenza seasonality, inform influenza vaccine strain selection and recommend appropriate vaccination timing.21 Analysis of FluNet data from 2011 to 2016 confirmed that temperate regions of the northern and southern hemispheres showed a distinct seasonal peak during their respective winters, while influenza activity in tropical and sub-tropical countries could be seen throughout the year in various patterns.23 The dichotomy of influenza seasonality has been used to guide the vaccine strain selection meeting and manufacturing cycle (Fig. 1)24 and inform vaccination strategies.23 Currently, the GISRS scientific committee convenes a meeting twice a year (in February for the northern hemisphere and in September for the southern hemisphere) to provide recommendations on vaccine strains for the next influenza season.24

Fig. 1.

WHO timeline for vaccine strain selection meeting and manufacturing cycle.24 Analytical and Bioanalytical Chemistry. Antigenic characterization of influenza and SARS-CoV-2 viruses. Volume 414, 2021, 2841–2881, Wang Y, Tang CY, Wan XF. (Copyright© Springer-Verlag GmbH Germany, part of Springer Nature 2021) "With permission of Springer".

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The three types of influenza vaccines currently approved for use include Inactivated (IIV), Live-Attenuated (LAIV) and Recombinant (RIV) influenza vaccines (Table 1).25 All three vaccine platforms are available as trivalent (containing two influenza A subtypes and one influenza B lineage) or quadrivalent (containing two influenza A subtypes and two influenza B lineages) formulations.

Influenza vaccines are traditionally produced using Candidate Vaccine Viruses (CVVs) grown in embryonated chicken eggs.26 At present, almost all seasonal influenza vaccines are produced using egg-based technology due to the infrastructure availability and vast manufacturing requirement to meet the global annual demand for seasonal influenza vaccines.26 While egg-based vaccines are generally more cost-effective than their egg-free alternatives, the reliance on eggs makes them susceptible to egg supply shortage.26 Furthermore, the production of an egg-based vaccine can take about 6 months, giving time for antigenic drift away from CVVs to occur in circulating strains.24 Additionally, egg-adaptation changes in the virus could affect antigenicity and reduce Vaccine Effectiveness (VE) by an estimated 4 %–16 %.27 Moreover, egg-based vaccines are contraindicated in individuals with a history of severe allergic reactions to eggs.26

One way to improve the traditional egg-based influenza vaccines involves delivering a higher dose of viral antigens (i.e., four-fold higher than the standard vaccine) or incorporating adjuvants (such as emulsion-based MF59 adjuvant) into the vaccine formulation.26 Both strategies can enhance immune responses in older adults or individuals with weaker immune system, leading to improved VE.26 However, concerns related to egg-based technology remain.

Egg-free production methods, using cell-based or recombinant technologies, have also been developed and approved to overcome some drawbacks of egg-based vaccines. Cell-based technology involves growing CVVs in mammalian cells, while the more innovative RIV is produced using baculovirus vectors expressing recombinant HA protein subunit in insect cells.26 Neither approach uses eggs; this insulates them from egg supply shortages, egg-adaptive mutations and egg allergies.26

The overall efficacy and/or effectiveness of licensed influenza vaccines varies each year and depends on several key factors, with estimates ranging between 19 % and 52 % from 2011 through 2022 in the US.28 A meta-analysis conducted in China also revealed a moderate overall VE of 36 % from 2010 through 2018.29 Key factors affecting the efficacy (based on Randomized Controlled Trials [RCTs]) and/or effectiveness (based on real-world data) of influenza vaccines include recipient age and health status,28 vaccine manufacturing process27 and degree of strain match in an influenza season.30,31

Given the high mutation rate of the influenza virus, WHO continues to recommend annual influenza vaccination using the most recent vaccine formulation for high-risk individuals, including adults aged ≥ 65 years, children aged 6–59 months, pregnant women, individuals with chronic medical conditions and healthcare workers.4 The WHO recommends prioritizing these high-risk groups in countries considering initiating or expanding their seasonal influenza vaccination program or when vaccine supply is limited.4 While the WHO noted that the quadrivalent formulations are expected to provide broader protection against influenza B viruses than trivalent formulations, countries should consider whether potential health gains outweigh the costs of switching to quadrivalent vaccines.4

Although the WHO recommends that all countries implement a seasonal influenza vaccination program, analysis of the WHO/UNICEF Joint Reporting Forms on Immunization in 2018 revealed a substantial variation in the execution of national influenza vaccination policies across WHO regions and World Bank income group levels.68 Policies were more frequently reported among HICs, while more than half of LMICs had no national policy.68 The Americas, Europe and Western Pacific had the highest percentages of countries with national policies, at 89 %, 89 % and 62 %, respectively. South-East Asia (27 %) and Africa (11 %) reported the lowest.68 Of the 56 countries that reported having a policy targeting all high-risk groups in 2018, 38 were in the Americas and Europe.68 HICs showed greater prioritization of all high-risk groups than LMICs (Fig. 2).68 Half of the countries reported using trivalent influenza vaccines in 2018, with most LMICs still preferring the trivalent formulation.68

Fig. 2.

WHO member states with national influenza vaccination policies in 2018 according to risk-group prioritization. .68

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Nevertheless, a recent meta-analysis estimated the pooled global VCR at only 26 % for pregnant women, 37 % for healthcare workers and 42 % for individuals with chronic diseases.69 The VCRs pooled from 25 countries in adults aged ≥ 60 years and children aged ≤ 14 years were 51 % and 29 %, respectively.69 The analysis also revealed substantial variation in VCRs among high-risk groups between countries/regions.69 The striking differences in VCR across WHO regions may be driven primarily by the global inequity in vaccine access.5

Although the past decade has seen marked improvements in the formulation of influenza vaccines, current approaches still offer moderate and variable protection and require regular reformulation.

To address the needs unmet by current vaccines, next-generation influenza vaccines should offer improved efficacy and/or effectiveness that is preferably consistent across influenza seasons, while demonstrating good safety, tolerability and acceptability profiles.67 Less complex manufacturing technology could help reduce the production time and also make future influenza vaccines affordable across socioeconomic strata.26,70

An ideal vaccine candidate should also provide long-lasting protection against the virus. Next-generation influenza vaccines should give broad protection against a wide range of influenza viruses, including group 1 or 2 influenza A, influenza B lineages or all influenza A/B viruses.67

New strategies to improve existing vaccine platforms have been investigated in the last few years, including nucleic acid, viral vector, and Virus-Like Particle (VLP)–based vaccines. Table 2 outlines the theoretical advantages and disadvantages of these novel technologies.67,70,75,76

Of the novel platforms currently in clinical development (Table 3), two potential RNA vaccine candidates have recently entered phase 3 trials based on promising preliminary phase 2 results. One such trial is by Moderna, which started recruiting participants on 6 June 2022 (NCT04956575).77 The phase 3 trial was designed to investigate the immunogenicity and safety of the mRNA-1010 seasonal influenza vaccine in 6102 adults aged ≥ 18 years (NCT05415462).78 The trial was completed in September 2023.78 The interim analysis of the phase 2 trial showed that mRNA-1010 elicited antibody titers, consistently exceeding the 1:40 threshold level for all four strains across all vaccine doses and age groups.77

Pfizer/BioNTech also commenced their phase 3 trial in 2022, following the readout of the interim phase 2 trial results. The phase 2 trial showed that, in healthy adults aged ≥ 65 years, quadrivalent modified mRNA (modRNA) induced substantially greater CD4+ and CD8+ responses to all four influenza strains than the licensed SD-IIV4 (NCT05052697).79 The phase 3 study was designed to evaluate the efficacy, safety and tolerability of modRNA in 46,180 healthy adults (NCT05540522).80 At the time of this writing, the phase 3 trial is still active but no longer recruiting; it is expected to be completed by March 2024.80