Influenza vaccine

The influenza vaccine is a preventive immunization designed to protect against seasonal influenza viruses, primarily the influenza A and B types that cause annual epidemics, by stimulating the immune system to produce antibodies against specific viral strains.^[1] Administered annually due to the rapid mutation of influenza viruses, it is recommended by the U.S. Centers for Disease Control and Prevention (CDC) for everyone aged 6 months and older, with rare exceptions such as severe allergic reactions to vaccine components, to mitigate the risk of flu-associated illness, hospitalization, and death.^[2] The World Health Organization (WHO) similarly prioritizes vaccination for high-risk groups including health workers, older adults, pregnant women, and young children, emphasizing its role in reducing severe outcomes in vulnerable populations.^[3] The development of the influenza vaccine traces back to the 1940s, when Thomas Francis Jr. and Jonas Salk, supported by the U.S. Army, created the first inactivated influenza vaccine at the University of Michigan, which was licensed for military use in 1945 and extended to civilians in 1946.^[4] This breakthrough followed the devastating 1918 influenza pandemic and aimed to address recurring seasonal threats, with early trials demonstrating protective efficacy against inactivated strains in the 1950s.^[5] Over decades, vaccine technology evolved to include live attenuated formulations licensed in the 2000s, alongside advancements like recombinant and cell-based production methods to improve accessibility and accommodate allergies, such as to eggs.^[6] Contemporary influenza vaccines are categorized into several types, including inactivated influenza vaccines (IIVs) delivered as injections, recombinant influenza vaccines (RIVs) produced without eggs or viruses, and live attenuated influenza vaccines (LAIVs) administered nasally for healthy non-pregnant individuals aged 2-49 years.^[6] Specialized formulations, such as high-dose IIVs and adjuvanted vaccines, are tailored for adults aged 65 and older to enhance immune response in this high-risk group, while cell-based and jet-injector options address production and administration preferences.^[6] For the 2025-2026 Northern Hemisphere season, all U.S.-approved vaccines are trivalent, targeting two influenza A subtypes (H1N1 and H3N2) and one B/Victoria lineage strain, as recommended by the WHO and FDA based on global surveillance of circulating viruses.^[7][8] Vaccine effectiveness varies annually depending on the match between vaccine strains and circulating viruses, age, and health status, but meta-analyses indicate overall protection of 40-60% against medically attended influenza illness in adults, with higher efficacy (up to 67% in some seasons) against hospitalization in older adults and 75% against influenza B in children.^[1][9] In the 2019-2020 season, for instance, U.S. vaccination prevented an estimated 7.5 million illnesses, 3.7 million medical visits, 105,000 hospitalizations, and 6,300 deaths, underscoring its public health impact despite imperfect strain matching.^[10] Safety profiles are robust, with mild side effects like soreness or low-grade fever common, and serious adverse events rare; annual dosing remains critical as immunity wanes over time.^[11]

History

Origins and early development

The discovery of the influenza virus as the causative agent of swine influenza was made by Richard E. Shope in 1931, who demonstrated through experimental transmission in pigs that a filterable agent, distinct from bacteria, was responsible for the disease.^[12] Building on Shope's work, British researchers Wilson Smith, Christopher H. Andrewes, and Patrick P. Laidlaw achieved a breakthrough in 1933 by isolating the human influenza A virus using ferrets as an animal model; they successfully transmitted the virus from infected human nasal washings to ferrets, confirming its viral nature and enabling further study.^[5] A major challenge in vaccine development was the need for a reliable method to propagate the virus in large quantities. In 1931, Ernest W. Goodpasture pioneered the technique of cultivating viruses on the chorioallantoic membrane of embryonated chicken eggs, which was adapted for influenza virus growth by 1936, providing a scalable system for virus production free from bacterial contamination.^[13] This advancement facilitated the work of Thomas Francis Jr. and Jonas Salk, who in the late 1930s and early 1940s developed the first inactivated influenza vaccine by chemically treating virus grown in eggs to render it non-infectious while preserving its immunogenicity; their efforts were spurred by the U.S. military's need to protect troops during World War II.^[4] Early human trials underscored the vaccine's promise amid wartime outbreaks. In 1943, the U.S. Army conducted a large-scale field trial vaccinating 12,500 soldiers against influenza A, which demonstrated approximately 70% efficacy in reducing clinical illness compared to unvaccinated controls, marking one of the first demonstrations of influenza vaccine effectiveness in humans.^[14] These results led to the U.S. approval of the first commercial inactivated influenza vaccine in 1945, initially prioritizing military use but soon extending to civilians, establishing the foundation for annual influenza immunization programs.^[15]

Key milestones and acceptance

The 1957 Asian flu pandemic, caused by the H2N2 influenza A virus, prompted significant enhancements in global influenza surveillance and vaccine production capabilities. In response, the World Health Organization (WHO) expanded its international surveillance network to monitor circulating strains more effectively, enabling faster identification and response to emerging threats. This effort, coupled with scaled-up vaccine manufacturing in the United States and other countries, increased production from limited wartime levels to millions of doses, though coverage remained inadequate, limiting overall impact during the pandemic that caused an estimated 1.1 million deaths worldwide.^[16][17] In 1968, the first split-virus influenza vaccine was licensed in the United States, marking a key advancement in reducing reactogenicity compared to earlier whole-virus formulations, which often caused more frequent local and systemic side effects. This chemical disruption of the virus preserved key antigens like hemagglutinin while minimizing inflammatory components, improving tolerability particularly in children and adults. Building on this, subunit vaccines—purified preparations focusing primarily on hemagglutinin and neuraminidase proteins—were developed and introduced in the 1970s, further enhancing safety profiles and immunogenicity in primed populations without the need for full viral particles.^[18][19] The 1976 swine flu vaccination campaign in the United States represented a massive public health mobilization, with approximately 40 million people vaccinated in response to fears of a potential H1N1 pandemic. Launched under the National Influenza Immunization Program, it aimed to immunize the entire population rapidly but was suspended in December 1976 after reports of Guillain-Barré syndrome emerged, with an estimated excess risk of about 1 case per 100,000 doses, highlighting early challenges in balancing urgency with safety monitoring.^[20][21] The development of quadrivalent influenza vaccines addressed limitations in trivalent formulations by including strains from both influenza B lineages (Victoria and Yamagata), providing broader protection against mismatched B strains that had caused up to 50% of seasonal epidemics in some years. The U.S. Food and Drug Administration (FDA) approved the first quadrivalent vaccine, FluMist Quadrivalent, in March 2012, followed by inactivated versions like Fluzone Quadrivalent in 2013. The European Medicines Agency (EMA) granted marketing authorization for Fluenz Tetra, a live attenuated quadrivalent vaccine, in December 2013, facilitating its rollout across Europe.^[22][23] Global acceptance of influenza vaccination grew substantially in the late 20th and early 21st centuries, driven by evolving recommendations from health authorities. In 1980, the WHO began emphasizing annual vaccination campaigns for high-risk groups as part of its broader influenza control strategy, aligning with national programs to promote routine immunization. In the United States, the Advisory Committee on Immunization Practices (ACIP) expanded its guidance in 2010 to recommend annual influenza vaccination for all adults and children aged 6 months and older without contraindications, shifting from targeted to universal coverage to reduce community transmission and burden.^[24] Recent milestones include the 1997 approval of adjuvanted influenza vaccines enhanced for elderly populations in Europe, such as those incorporating MF59 to boost immune responses in older adults with immunosenescence, and high-dose formulations like Fluzone High-Dose approved by regulatory bodies to deliver four times the antigen of standard vaccines for improved protection in those aged 65 and older. By 2025, mRNA-based influenza vaccines advanced significantly, with Moderna's mRNA-1010 completing Phase 3 trials demonstrating a relative vaccine efficacy of 26.6% (95% CI, 16.7%-35.4%) against laboratory-confirmed influenza compared to standard-dose vaccines in adults aged 50 and older, alongside superior immunogenicity across all strains and a favorable safety profile.^[25][26][27]

Vaccine types

Inactivated vaccines

Inactivated influenza vaccines, the most widely used type globally, contain killed influenza viruses that cannot replicate or cause infection but elicit an immune response through antibodies against viral antigens. These vaccines are produced by propagating influenza viruses in embryonated chicken eggs or mammalian cell lines, such as Madin-Darby Canine Kidney (MDCK) cells, followed by chemical inactivation using agents like formaldehyde or beta-propiolactone to render the viruses noninfectious. They exist in three primary forms: whole virus vaccines, which include the entire inactivated virion; split virus vaccines, which disrupt viral particles with detergents like Triton X-100 to reduce reactogenicity; and subunit vaccines, which purify key surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Whole virus formulations are no longer available in the United States, having been largely replaced by split and subunit types due to lower side effect profiles.^[28][29][30] Administration of inactivated influenza vaccines occurs via intramuscular injection, typically in the deltoid for adults and older children or the anterolateral thigh for infants and young children, using a 22- to 25-gauge needle of appropriate length to ensure muscle penetration. The standard dose volume is 0.5 mL for persons aged 3 years and older, delivering 15 μg of HA per strain, while certain formulations allow a 0.25 mL dose (7.5 μg HA per strain) for children aged 6 through 35 months to minimize discomfort.^[31][32] Traditional inactivated vaccines were formulated as trivalent (TIV), targeting two influenza A subtypes—H1N1pdm09 and H3N2—and one influenza B lineage, typically Victoria. Quadrivalent inactivated vaccines (QIV), introduced to address B lineage mismatches, include an additional B/Yamagata strain for broader coverage, though for the 2025–2026 season, trivalent formulations are recommended due to the global disappearance of circulating B/Yamagata viruses.^[33][7] Adjuvanted inactivated vaccines incorporate immune enhancers to improve immunogenicity, especially in older adults with waning immune responses. Fluad, for instance, uses the MF59 adjuvant—an oil-in-water emulsion of squalene, polysorbate 80, and sorbitan trioleate—first approved in 1997 to augment antibody titers against influenza in persons aged 65 years and older. High-dose inactivated vaccines, such as Fluzone High-Dose approved for adults 65 and older, contain 60 μg of HA per strain (four times the standard amount), which clinical trials showed provided 24.2% higher relative efficacy (95% CI: 9.7–36.5) against laboratory-confirmed influenza with illness symptoms compared to standard-dose versions.^[34][35] Cell-based inactivated vaccines like Flucelvax, approved by the FDA in 2012, are grown in MDCK cells rather than eggs, circumventing egg-adaptive mutations in HA that can alter antigenicity and reduce antibody effectiveness against circulating strains. This production method also makes Flucelvax suitable for egg-allergic individuals, as it contains no egg proteins.^[36][37]

Live attenuated and recombinant vaccines

Live attenuated influenza vaccines (LAIVs), such as FluMist, utilize cold-adapted, temperature-sensitive mutant strains of influenza virus that replicate preferentially in the cooler temperatures of the nasal passages, mimicking natural infection to stimulate both systemic and mucosal immune responses.^[38] These viruses are administered intranasally via a prefilled sprayer delivering 0.2 mL total (0.1 mL per nostril), allowing replication in the nasopharynx to induce protective immunity without causing disease in the lower respiratory tract.^[31] Unlike inactivated vaccines, which serve as the standard injected option, LAIVs promote mucosal antibody production and T-cell responses at the site of viral entry.^[38] The U.S. Food and Drug Administration (FDA) first approved FluMist in 2003 for healthy individuals aged 5–49 years, with subsequent expansion to ages 2–49; however, the Advisory Committee on Immunization Practices (ACIP) temporarily did not recommend its use during the 2016–2017 and 2017–2018 seasons due to observed low effectiveness against certain strains, resuming recommendations for the 2018–2019 season following strain updates and improved performance data.^[39][40][41] Recombinant influenza vaccines, exemplified by Flublok, are produced by expressing hemagglutinin (HA) proteins in insect cell cultures using a baculovirus vector system, resulting in an egg-free product that avoids potential adaptations from egg-based propagation.^[42] This method ensures precise genetic control over antigen composition, reducing risks of antigenic mismatch seen in traditional vaccines.^[43] The FDA approved Flublok in 2013 initially for adults aged 18 and older, with expansion in 2025 to include those aged 9 and older; it is administered as a 0.5 mL intramuscular injection containing 135 mcg total HA (45 mcg per strain for trivalent formulations).^[44] Key advantages include suitability for individuals with egg allergies and potentially higher immunogenicity due to the absence of egg-related impurities, leading to robust antibody responses.^[43][45]

Production and annual reformulation

Strain selection process

The World Health Organization's Global Influenza Surveillance and Response System (GISRS), established in 1952, coordinates a global network of 149 National Influenza Centres across 115 countries to monitor influenza viruses year-round.^[46] This system collects and analyzes thousands of virus samples from patients with influenza-like illness, using tools like FluNet for virological data and FluID for epidemiological surveillance to track virus evolution and circulation patterns.^[46] Surveillance emphasizes antigenic and genetic characterization, focusing on hemagglutinin (HA) and neuraminidase (NA) genes to detect changes such as antigenic drift that could impact vaccine performance.^[47] Twice-yearly consultations, convened by WHO in February for the Northern Hemisphere and September for the Southern Hemisphere, bring together experts from WHO Collaborating Centres and Essential Regulatory Laboratories to recommend vaccine strains.^[47] These meetings evaluate global surveillance data to select up to four strains—typically two influenza A subtypes (H1N1 and H3N2) and one or two influenza B lineages (Victoria and/or Yamagata)—prioritizing those most likely to circulate in the upcoming season.^[48] Selection criteria include phylogenetic analysis of HA and NA gene sequences to identify dominant clades, assessment of antigenic similarity between candidate vaccine viruses and circulating strains via hemagglutination inhibition assays, and consideration of production adaptations such as egg passage versus cell-based propagation to minimize antigenic changes.^[46] For instance, in the 2025-2026 Northern Hemisphere season, the recommended H3N2 strain focused on a clade 3C.2a1b representative, like A/Croatia/10136RV/2023, to better match evolving variants.^[8] Challenges in strain selection arise from rapid viral evolution and production constraints, as seen in the 2014-2015 season when egg adaptation of the H3N2 vaccine strain (A/Texas/50/2012-like) led to antigenic mismatch with circulating viruses, primarily due to mutations in the HA receptor-binding site.^[49] This highlighted the need for diverse production platforms to avoid such adaptations. Since March 2020, GISRS has integrated co-surveillance for SARS-CoV-2 into its protocols, enhancing detection of respiratory pathogens and preparing for potential hybrid threats by incorporating COVID-19 testing into sentinel influenza specimen algorithms.^[50]

Manufacturing methods

The primary manufacturing methods for influenza vaccines rely on propagating the virus or its components in biological systems to produce sufficient antigen for immunization. Traditional egg-based production remains the cornerstone, accounting for nearly 90% of global supply, while cell-based, recombinant, and emerging platforms offer alternatives to address limitations like supply chain vulnerabilities and antigenic mismatches.^[51] Egg-based manufacturing involves inoculating fertilized hen eggs with selected influenza virus strains, typically in the allantoic cavity, followed by incubation at 33–35°C for 2–3 days to allow viral replication. The virus is then harvested from the allantoic fluid, purified, inactivated with chemicals like formaldehyde, and split into components such as hemagglutinin (HA) and neuraminidase (NA) using detergents. This method yields approximately 1–2 doses per egg and has been the dominant approach since the 1940s, enabling large-scale production but requiring millions of eggs annually and risking mutations during egg adaptation.^[52][53] Cell-based production circumvents egg-related issues by cultivating influenza viruses in mammalian cell lines, such as Madin-Darby canine kidney (MDCK) or Vero cells, within bioreactors. The process mirrors egg-based methods in virus propagation, harvesting, inactivation, and purification but allows faster scale-up and consistent yields without reliance on poultry supplies. For example, Seqirus' Flucelvax uses MDCK cells and has been approved for use in multiple countries, demonstrating improved antigenic matching in seasons where egg-based vaccines underperform.^[36][54] Recombinant vaccines produce HA proteins directly using genetic engineering in host systems, avoiding live virus cultivation altogether. Insect cell lines, such as Spodoptera frugiperda (Sf9) cells infected with baculovirus vectors encoding HA genes, express the protein, which is then purified and formulated without eggs or whole viruses. This method, exemplified by Sanofi's Flublok, provides precise control over antigen composition, reduces contamination risks, and supports rapid adaptation to new strains.^[42][55] Emerging platforms include plant-based systems, where HA or virus-like particles (VLPs) are expressed in transgenic plants like Nicotiana benthamiana; Medicago completed phase 3 trials for a quadrivalent VLP vaccine around 2020, showing immunogenicity comparable to egg-based options, though it has not yet received regulatory approval for seasonal use as of 2025.^[56] Yeast-based approaches, using organisms like Saccharomyces cerevisiae or Kluyveromyces lactis to express HA or multivalent subunits, are in preclinical and early development stages, offering potential for cost-effective, scalable production. Additionally, mRNA platforms, such as Pfizer/BioNTech's candidate, encode HA and other antigens in lipid nanoparticles and entered phase 3 trials by 2025, promising quicker manufacturing timelines similar to COVID-19 vaccines.^[57][58] Global production capacity for seasonal influenza vaccines stands at approximately 1.53 billion doses annually as of 2025, with pandemic surge capacity exceeding 8 billion monovalent doses if needed. In the United States, manufacturers project supply of up to 154 million doses for the 2025–2026 season, bolstering national stockpiles for emergency response.^[59][60][7] Quality control in manufacturing ensures potency, purity, and safety through standardized assays. Hemagglutinin content is quantified using the single radial immunodiffusion (SRID) assay, the regulatory gold standard since 1979, which measures HA diffusion in agarose gels with strain-specific antisera to confirm doses meet 15 μg HA per strain for trivalent vaccines. Sterility testing, per pharmacopeial standards, verifies absence of contaminants like bacteria or endotoxins via culture and biochemical methods.^[61][62][63]

Efficacy and effectiveness

Overall effectiveness metrics

The effectiveness of influenza vaccines is typically measured through vaccine efficacy (VE) in randomized controlled trials, which assesses the reduction in laboratory-confirmed influenza cases among vaccinated versus unvaccinated participants under ideal conditions. Meta-analyses of trials in healthy adults have shown VE ranging from 40% to 60% against antigenically matched strains.^[64] A systematic review pooling data from multiple randomized trials reported an overall VE of 48% (95% CI: 42-54%) against laboratory-confirmed influenza, with higher estimates in seasons of good strain matching.^[65] In real-world settings, observational studies estimate vaccine effectiveness (VE) using test-negative designs, accounting for factors like population immunity and circulating strains. These studies often report VE of 20% to 50% across seasons, with lower values in periods of antigenic mismatch between vaccine and circulating viruses; for example, during the 2014-2015 Northern Hemisphere season, VE was only 19% due to poor H3N2 strain matching.^[66] For the 2024-2025 Northern Hemisphere season, interim estimates indicated VE of 32-60% against outpatient medically attended influenza and 63-78% against hospitalization.^[67] However, a Cleveland Clinic observational study of healthcare workers during the 2024-2025 season found vaccination associated with higher risk of influenza-positive tests, contrasting CDC interim estimates of moderate protection against medically attended illness; limitations include restriction to relatively healthy working-age healthcare personnel, limiting generalizability to broader populations; absence of data on disease severity or hospitalization outcomes; potential testing biases, as vaccinated individuals may be more likely to seek testing; predominance of one standard trivalent vaccine type; and possible residual confounding in the observational design. Critics note the study does not assess reductions in severe outcomes like hospitalization or death.^[68] This protection against severe outcomes indirectly reduces the risk of rare complications such as influenza-associated encephalopathy.^[69] For the 2025 Southern Hemisphere season, VE was 50.4% against outpatient visits.^[70] Key metrics include absolute risk reduction, which varies by season but typically prevents 1-2% of influenza cases in vaccinated populations, and the number needed to vaccinate (NNV), estimated at 30 to 70 individuals to avert one laboratory-confirmed case in adults.^[71] Several factors influence these metrics, including age-adjusted VE, which declines with increasing age, and the degree of strain matching, where better antigenic similarity strongly correlates with higher protection. Adjuvanted vaccines, such as those with MF59, provide an additional 10-15% boost in VE compared to standard inactivated vaccines, particularly in older adults, by enhancing immune responses.^[72] Long-term surveillance through the CDC's U.S. Flu VE Network, operational since 2004, has tracked annual estimates across multiple seasons and sites, revealing an overall VE range of 10% to 60% depending on strain circulation and match quality.^[66]

Effectiveness in specific populations

In children aged 6 months to 18 years, influenza vaccines demonstrate vaccine effectiveness (VE) of 50-80% against influenza-associated hospitalization, with higher estimates observed in recent seasons for preventing emergency department visits and urgent care encounters.^[73][74] For children receiving the vaccine for the first time, a two-dose priming regimen in the initial season enhances the immune response approximately twofold compared to a single dose, leading to sustained protection in subsequent years.^[75] This approach is particularly beneficial for young children under 9 years, where priming improves antibody titers and reduces the risk of severe outcomes like pediatric intensive care unit admissions by up to 74%.^[76] Among adults aged 18-64 years, overall VE ranges from 40-60% against influenza-associated acute respiratory illness in outpatient settings and hospitalization, varying by season and strain match.^[67][64] Evidence on VE in obese individuals is mixed: some studies indicate approximately a 20% lower effectiveness due to impaired immune responses,^[77] while more recent analyses find no significant association with obesity.^[78] For older adults aged 65 years and above, standard influenza vaccines show lower VE of 20-40% against infection and hospitalization, primarily attributable to immunosenescence, which diminishes antibody production and T-cell responses.^[79] High-dose or adjuvanted formulations address this by eliciting stronger immune responses, improving VE to around 50% and preventing an estimated 1.5 million influenza illnesses annually in the United States among this population.^[72][80] In pregnant individuals, influenza vaccination yields a VE of approximately 50% against maternal influenza illness, significantly lowering the risk of severe disease during pregnancy.^[81] Maternal immunization also reduces influenza-associated hospitalizations in infants during the first 6 months of life by approximately 40-50%, through passive antibody transfer, with the World Health Organization recommending vaccination at any trimester to maximize this protection.^[82][83] Individuals with immunocompromising conditions exhibit reduced VE of 30-50% for inactivated influenza vaccines, owing to impaired humoral and cellular immunity, though vaccination remains recommended to mitigate severe outcomes.^[32] Live attenuated influenza vaccines are contraindicated in this population due to the risk of vaccine-derived disease from replication-competent virus.^[32]

Safety profile

The safety of influenza vaccines has been well-established through the administration of hundreds of millions of doses in the United States alone over the past 50 years, and billions worldwide over more than six decades, supported by extensive pharmacovigilance and research confirming a favorable risk-benefit profile.^[84][85]

Common side effects

Common side effects of influenza vaccines are typically mild and self-limiting, occurring shortly after administration and resolving within 1-2 days without intervention. For inactivated influenza vaccines administered via injection, the most frequent local reactions include soreness at the injection site, affecting 10-64% of recipients, and redness or swelling, reported in approximately 5-20% of cases.^[86] These reactions result from the immune response to the vaccine components and are more common in first-time vaccinees or children.^[30] Systemic reactions to inactivated vaccines, such as fatigue, headache, and muscle aches, occur in 10-15% of individuals, while low-grade fever is less common, affecting 1-10% of children and less than 1% of adults. For live attenuated influenza vaccines (LAIV) given intranasally, common local effects include nasal congestion or irritation in 20-58% of recipients, alongside sore throat in 5-20%.^[87][88] Systemic symptoms like mild fever, headache, and fatigue mirror those of inactivated vaccines but may appear slightly more frequently in children due to viral replication.^[84] Data from the Vaccine Adverse Event Reporting System (VAERS) indicate that mild events, including these local and systemic reactions, are reported at rates of approximately 0.12 to 2 per 1,000 doses, with higher incidence among first-time pediatric vaccinations.^[89] Management generally involves symptomatic relief with acetaminophen for fever or discomfort, as no long-term sequelae are associated with these reactions.^[90] In 2025 clinical trials of self-amplifying mRNA influenza vaccines, the safety profile remains comparable to traditional inactivated vaccines, with injection site pain and fatigue as the most common solicited reactions (affecting 90-93% of participants, mostly mild and resolving in 2-4 days).^[91]

Rare adverse events and contraindications

Rare adverse events associated with influenza vaccines include Guillain-Barré syndrome (GBS), anaphylaxis, and oculorespiratory syndrome (ORS). GBS, a rare neurological disorder, was linked to an increased risk during the 1976 swine influenza vaccination program in the United States, with approximately one excess case per 100,000 doses administered.^[20] Current estimates indicate that the risk of GBS following seasonal influenza vaccination is about 1 to 2 cases per million doses, a rate comparable to the background incidence in unvaccinated individuals.^[92] This small elevated risk is outweighed by the greater GBS incidence associated with influenza infection itself.^[93] Anaphylaxis, a severe allergic reaction, occurs at a rate of approximately 1.3 cases per million doses of influenza vaccine, predominantly in individuals with egg allergies due to the egg-based production of many formulations.^[94] These reactions typically manifest shortly after vaccination and can be effectively managed with prompt administration of epinephrine, with most cases resolving without long-term sequelae.^[95] Oculorespiratory syndrome (ORS), characterized by red eyes, facial swelling, and respiratory symptoms, emerged as a rare adverse event during influenza vaccination campaigns in Canada in the early 2000s, linked to specific vaccine lots.^[96] Its incidence has since declined substantially through manufacturing improvements, now occurring at rates below 1 per million doses.^[97] Contraindications for influenza vaccination are limited and primarily apply to specific formulations. Egg allergy of any severity is not a contraindication or precaution for any licensed influenza vaccine. Individuals with egg allergies should receive an age- and health status-appropriate influenza vaccine in any setting where vaccines are administered, with standard post-vaccination observation.^[98] A history of GBS within 6 weeks following a previous influenza vaccination is a precaution, warranting individualized assessment of benefits and risks, though benefits generally outweigh risks as of the 2025-2026 season.^[75][99] Live attenuated influenza vaccines (LAIV) are contraindicated in pregnant individuals and those with immunosuppression, as the vaccine contains weakened live virus that could pose risks in these groups.^[100] Global safety monitoring of influenza vaccines is conducted through systems like the World Health Organization's VigiBase, a pharmacovigilance database aggregating adverse event reports worldwide. As of 2025, analyses of data from recent seasons, including the introduction of mRNA-based influenza vaccines, have identified no new safety signals beyond established rare events.^[101]

Recommendations and guidelines

International and WHO recommendations

The World Health Organization (WHO) recommends annual influenza vaccination as a key public health intervention to reduce severe illness, hospitalization, and death from seasonal influenza, particularly among high-risk populations. According to the WHO's 2022 position paper, updated through 2023 consultations, vaccination is advised for pregnant women at any stage of pregnancy, children aged 6–59 months, older adults (typically those aged 65 years and above), healthcare workers, and individuals with underlying chronic medical conditions such as cardiovascular disease, diabetes, or immunosuppression.^[102] This guidance emphasizes prioritizing these groups to mitigate disease burden, with annual administration required due to antigenic drift in circulating strains.^[102] The WHO's Strategic Advisory Group of Experts on Immunization (SAGE) further delineates prioritization tiers for resource-limited settings, stratifying target populations based on influenza disease burden, vulnerability, and transmission risk. Tier 1 includes pregnant women, infants under 6 months (via maternal vaccination), and individuals with severe chronic conditions; Tier 2 encompasses older adults, children 6–59 months, and healthcare workers; while Tier 3 covers healthy adults aged 18–65 years and schoolchildren as needed.^[103] SAGE also supports the integration of influenza vaccines with other respiratory virus immunizations, such as COVID-19 and respiratory syncytial virus (RSV) vaccines, to enhance programmatic efficiency and coverage, particularly in co-administration scenarios during overlapping seasons. The influenza vaccine is distinct from the COVID-19 vaccine, as it targets influenza viruses rather than SARS-CoV-2, offers no cross-protection against COVID-19, and requires separate administration for protection against both diseases, though the two can be given during the same visit.^{[104][105][106]} Regional bodies aligned with WHO adapt these recommendations to local contexts. The Pan American Health Organization (PAHO) endorses seasonal influenza vaccination policies across the Americas, with several Southern Cone countries (e.g., Argentina, Brazil, Chile, Paraguay, and Uruguay) implementing universal programs for children under 2 years of age since 2010 to address high pediatric burden and improve herd immunity.^[107] Similarly, the WHO European Region promotes tailored strategies through its European Technical Advisory Group of Experts on Immunization, focusing on enhancing uptake among older adults and those in long-term care facilities while aligning with national surveillance data for strain-specific adaptations.^[108] Under the International Health Regulations (2005) framework, WHO coordinates global pandemic preparedness, including the maintenance of influenza vaccine stockpiles for rapid deployment during outbreaks. These stockpiles, primarily comprising H5N1 avian influenza vaccines, support equitable access for low-resource countries and are replenished through donor pledges.^[109] In 2025 updates, WHO has endorsed cell-based influenza vaccines for improved antigenic match to circulating strains, recommending distinct virus components (e.g., A/Wisconsin/67/2022-like H1N1 for cell-based formulations) to overcome limitations of egg-based production, such as adaptation-induced mutations.^[8]

National variations

In the United States, the Advisory Committee on Immunization Practices (ACIP) has recommended annual influenza vaccination for all persons aged 6 months and older without contraindications since the 2010-2011 season, marking a shift to universal coverage to reduce overall disease burden. Children eligible through the Vaccines for Children (VFC) program receive free vaccines, while Medicare Part B covers the full cost for adults aged 65 and older, including high-dose formulations preferred for this group. In the United Kingdom, the Joint Committee on Vaccination and Immunisation (JCVI) advises free influenza vaccination for individuals under 65 at clinical risk, pregnant women, and all those aged 65 and older, with a phased expansion to broader populations. A school-based program targeting children aged 2 to 17 has been implemented since 2013, using live attenuated influenza vaccine (LAIV) as the preferred option for healthy children aged 2 to 17 due to its efficacy profile in this demographic.^[110] Canada's National Advisory Committee on Immunization (NACI) endorses annual vaccination for everyone aged 6 months and older, promoting a universal approach while allowing provincial adaptations in delivery. For instance, Ontario operates school-based immunization programs for children, enhancing accessibility, and NACI specifically recommends high-dose inactivated vaccines for adults aged 65 and older to improve immunogenicity and protection.^[111][112] Australia's Australian Technical Advisory Group on Immunisation (ATAGI) provides free seasonal influenza vaccines to at-risk groups, including those with chronic conditions, Indigenous populations, pregnant women, and close contacts of vulnerable individuals, while encouraging vaccination for all aged 6 months and older. Vaccines are formulated for Southern Hemisphere strains, with campaigns typically starting in autumn to align with the local season, and co-administration with COVID-19 boosters is promoted to streamline protection against respiratory viruses.^[113] Within the European Union, the European Medicines Agency (EMA) and its Committee for Medicinal Products for Human Use (CHMP) ensure harmonized approvals and strain recommendations for influenza vaccines, such as the trivalent formulations endorsed for the 2025-2026 Northern Hemisphere season, but implementation varies by member state through national health authorities. For example, in Germany, the Standing Committee on Vaccination (STIKO) strongly recommends annual vaccination for healthcare workers in care homes to protect residents, though it remains voluntary without a federal mandate.^[114][115]

Uptake and implementation

Target groups and barriers

The primary target groups for influenza vaccination include individuals at higher risk of severe complications from the flu, such as adults aged 65 and older, children under 5 years (specifically 6 months to 4 years), pregnant women, immunocompromised persons, and those with chronic medical conditions like diabetes or heart disease.^[116] Healthcare workers are also prioritized due to their potential to transmit the virus to vulnerable patients in clinical settings.^[117] These recommendations from health authorities like the CDC and WHO emphasize annual vaccination for these groups to reduce hospitalization and mortality risks.^[48] Vaccination coverage goals in the United States aim for 80% among healthy persons and 90% among high-risk groups and healthcare professionals, levels estimated as sufficient to establish herd immunity against influenza.^[118][119] In Europe, the target is 75% coverage among risk groups, particularly the elderly, which is generally considered insufficient for achieving herd immunity.^[120] Global influenza vaccination coverage remains low, with rates often below 10% in low- and middle-income countries compared to 40-50% in high-income nations for general adult populations (higher, up to 70%, among older adults).^[121][122] In the United States, adult coverage for the 2023-2024 season reached 44.9%, with higher rates among older adults (69.7% for those 65+) but lower among younger adults (around 32% for ages 18-49).^[123] For the 2024-2025 season, preliminary estimates indicate overall adult coverage of approximately 46% as of mid-season, similar to the previous year.^[124] Key barriers to achieving higher coverage include vaccine hesitancy, with about 30% of unvaccinated individuals citing fears of side effects as a primary concern, alongside access challenges in rural or underserved areas where transportation and clinic availability limit opportunities.^[125] Common misconceptions, such as the belief that the flu vaccine causes influenza, further contribute to reluctance, despite evidence that inactivated vaccines cannot cause the disease.^[126] Uptake disparities persist among subgroups, particularly racial and ethnic minorities in the US, where Black and Hispanic adults exhibit lower vaccination rates than White adults (e.g., 44.5% vs. 49.7% in 2023-2024), influenced by systemic factors like healthcare access and historical mistrust.^[127][128] Among healthcare workers, despite mandates in many facilities, coverage varies widely at 40-75%, with the 2023-2024 season averaging 75.4%, highlighting ongoing gaps even in high-priority professional groups.^[129] As of 2025, post-COVID-19 trust erosion has exacerbated hesitancy toward routine vaccines like influenza, with spillover effects reducing confidence in public health recommendations and contributing to stagnant or declining uptake in some populations.^[130] Conversely, heightened fears of avian H5N1 outbreaks have boosted awareness and vaccination interest in parts of Asia, where regional coverage remains under 1% but shows potential for improvement amid ongoing zoonotic threats.^[131]

Strategies for improving coverage

Public health campaigns have employed various reminder systems to boost influenza vaccination uptake, with automated text message reminders proving particularly effective. For instance, short message service (SMS) reminders sent close to appointment times have been shown to increase vaccination rates by approximately 10% among eligible adults, serving as a low-cost intervention that enhances compliance without requiring extensive resources.^[132] In the United Kingdom, school-based vaccination clinics have significantly improved coverage among children, achieving rates of around 60-64% in primary school-aged groups during recent seasons, by integrating immunization directly into educational settings and reducing logistical barriers for families.^[133] Mandates and incentives represent another key approach to elevating vaccination rates, particularly in high-risk settings. In the United States, employer-mandated influenza vaccination policies for healthcare workers have been associated with substantial increases in uptake, often achieving coverage over 90% as shown in meta-analyses, superior to voluntary programs.^[134] Additionally, financial incentives, including lotteries in some programs and cash rewards in trials, have been linked to rises in vaccination rates of about 10-15% among targeted populations, though effects vary by implementation scale.^[135][136] Improving access to vaccination sites has addressed geographic and convenience-related barriers, expanding delivery beyond traditional clinics. Since 2000, pharmacist-administered influenza vaccines in the US have accounted for approximately 20-25% of total doses in recent seasons, correlating with overall coverage improvements from 32% in 2003 to 40% in 2013.^[137][138] Post-COVID-19, drive-thru vaccination sites have further enhanced uptake, offering contactless administration that boosts participation through reduced wait times and heightened convenience, as demonstrated in successful Veterans Affairs programs vaccinating hundreds in single events.^[139] Educational initiatives focus on countering misinformation and building trust in underserved communities. Social media campaigns targeting influenza vaccine myths—such as unfounded concerns about side effects—have effectively shifted attitudes, with multi-platform science-based messaging increasing positive perceptions and vaccination intent among hesitant groups.^[140] Complementing this, community outreach programs in low-uptake areas, including student-led efforts in urban settings, have lowered barriers through targeted education and on-site clinics, resulting in higher immunization rates among vulnerable populations like low-income families.^[141] As of 2025, innovations continue to evolve strategies for broader coverage. Digital applications for vaccine tracking and reminders, integrated with mobile health tools, enable personalized scheduling and real-time updates, facilitating sustained engagement in vaccination programs.^[142] Furthermore, combination influenza-COVID-19 vaccines under development, such as those from Pfizer-BioNTech and Sanofi, aim to streamline protection by reducing the need for multiple visits, with phase 3 trials showing robust immune responses and potential availability to simplify annual immunization routines.^[143][144]

Economic and global aspects

Cost-effectiveness analysis

Cost-effectiveness analyses of influenza vaccination programs typically employ health economic metrics such as the incremental cost-effectiveness ratio (ICER), which measures the additional cost per quality-adjusted life year (QALY) gained compared to no vaccination. In high-income settings, these analyses often yield ICERs ranging from $10,000 to $50,000 per QALY gained, indicating favorable economic value relative to common willingness-to-pay thresholds of $50,000–$100,000 per QALY. For elderly populations, vaccination is frequently dominant, meaning it both improves health outcomes and reduces overall costs by averting expensive hospitalizations and productivity losses.^{[145][146][147]} Markov simulation models are widely used to evaluate these programs, incorporating parameters like vaccine effectiveness (VE), disease incidence, and healthcare costs. These models account for U.S. hospitalization costs averaging $11,000–$14,000 per influenza case (2022–2023 data), alongside broader societal expenses such as outpatient visits and lost workdays.^[148] In the U.S., for the 2023–2024 season, vaccination prevented an estimated 9.8 million illnesses.^[149] In low- and middle-income countries, a 2023 systematic review found that 88% of target-group-specific scenarios for influenza vaccination were cost-effective or cost-saving.^[150] Sensitivity analyses highlight vulnerabilities: antigenic mismatch between vaccine strains and circulating viruses can reduce cost-effectiveness by up to 30% by lowering VE. Adjuvanted vaccines, while initially more expensive, demonstrate improved cost-effectiveness through higher VE in older adults, often resulting in net savings over standard formulations. A 2024 analysis of enhanced influenza vaccines indicated that broader-spectrum options, akin to combination approaches, could improve ICERs by 15–25% via greater protection against variants.^{[151][152][153]}

Access and equity issues

Global disparities in influenza vaccine access are pronounced, with approximately 80% of pandemic influenza vaccine production capacity concentrated in high-income countries, limiting supply for low- and middle-income countries (LMICs).^[154] Seasonal influenza vaccine production, while stable at around 1.53 billion doses annually since 2019, remains heavily skewed toward high- and upper-middle-income nations, which account for over 95% of demand and consumption. As of March 2025, global production capacity remains at 1.53 billion doses annually, but challenges in equitable distribution to LMICs persist, hindering achievement of the aspirational goal of 1 billion doses annually for LMICs by 2025.^{[155][59][156]} This concentration exacerbates supply gaps during peak seasons or outbreaks, as LMICs rely on imports, facing logistical delays and shortages that hinder timely distribution.^[157] Affordability further compounds these challenges, with vaccine prices varying starkly by region. In the United States, wholesale costs for seasonal influenza vaccines range from $14 to $20 per dose for standard formulations through federal programs (2025–2026), though private sector prices can reach $69 for standard formulations or higher for specialized types.^[158][159] In contrast, economic costs in African countries like South Africa average $9 to $11 per dose when including delivery and program expenses, often exceeding $10 in unsubsidized markets due to import dependencies and limited economies of scale.^[160] Bulk procurement mechanisms help lower prices for LMICs, though specific influenza vaccine pricing data varies.^[161] Equity issues are evident in both routine and emergency responses. The 2024 avian influenza (H5N1) outbreak highlighted favoritism toward wealthy nations, where stockpiles and procurement deals—such as the European Union's acquisition of 40 million doses for 15 high-income countries—prioritized advanced economies, sidelining LMICs despite their higher vulnerability to spillover risks.^[162][163] Gender disparities persist globally, with pregnant women underserved in over 40% of countries due to low integration of maternal influenza vaccination into routine programs, resulting in coverage rates below 20% in many LMICs and exposing this high-risk group to severe outcomes.^[164][165] To address these inequities, the World Health Organization (WHO) has established technology transfer hubs to bolster local production in LMICs, including facilities in Indonesia through Bio Farma and in South Africa via partnerships like Biovac, as part of the Global Action Plan for Influenza Vaccines (GAP) initiative launched in 2006.^[166][167] These hubs facilitate knowledge sharing and pilot-scale manufacturing, enabling countries to produce influenza vaccines domestically and reduce reliance on imports. Complementing this, WHO's broader mRNA technology transfer program, with a hub in South Africa, aims to enhance regional capacity for future influenza threats, targeting sustainable production by 2025.^[168] The consequences of these access barriers are stark, particularly in pandemics, where unvaccinated regions experience mortality rates up to 20 times higher than vaccinated areas due to overwhelmed health systems and higher case fatality among vulnerable populations.^[169] For instance, during severe outbreaks, influenza vaccination has been associated with 40-50% reductions in all-cause mortality in covered populations, underscoring the amplified risks in underserved LMICs.^[170]

Research and future developments

Universal and next-generation vaccines

Universal influenza vaccines aim to provide broad, long-lasting protection against diverse influenza strains by targeting conserved viral components, such as the hemagglutinin (HA) stalk domain, rather than the rapidly mutating head region.^[171] One prominent approach involves chimeric hemagglutinin (cHA) constructs, developed under the National Institute of Allergy and Infectious Diseases (NIAID), which replace the variable HA head with stable variants to refocus immune responses on the conserved stalk.^[172] Phase 2 clinical trials of cHA-based vaccines, including live-attenuated and inactivated formulations, have demonstrated induction of broadly cross-reactive antibodies, with preclinical models showing significant protection against heterologous group 1 and 2 influenza viruses in the presence of pre-existing immunity.^[173] These candidates elicit stalk-specific neutralizing antibodies that persist for months, offering potential heterosubtypic coverage beyond seasonal strains. Next-generation platforms, such as mRNA-based vaccines, leverage rapid manufacturing and modular design to enhance universality. Moderna's mRNA-1010, a quadrivalent candidate incorporating HA sequences from multiple strains, advanced to Phase 3 trials in 2024, demonstrating superior immunogenicity compared to licensed vaccines and relative vaccine efficacy (rVE) of 26.6% (95% CI: 16.7%-35.4%) against influenza illness, with 33.7% (95% CI: 12.0%-50.0%) against medically-attended cases, in analyses reported in 2025.^[174][175] This platform enables production in as little as 6 weeks, addressing delays in egg-based methods, and supports incorporation of conserved epitopes like the HA stalk for broader protection.^[176] Similarly, experimental mRNA vaccines encoding chimeric HA and matrix protein 2 (M2) have shown preclinical cross-protection against major influenza A subtypes through enhanced T-cell and antibody responses.^[177] Nanoparticle and mosaic vaccine strategies further advance cross-group immunity by presenting multiple conserved antigens in structured arrays. Self-assembling HA stem nanoparticles, resembling ferritin scaffolds, have elicited cross-group 1 neutralizing antibodies in Phase 1 trials, with preclinical data indicating protection against both influenza A group 1 and 2 viruses via Fc-mediated effector functions.^[178] DARPA-funded initiatives, including nanoparticle platforms under the Pandemic Prevention Platform (P3) program, have supported preclinical development of mosaic vaccines displaying diverse HA variants, achieving broad heterosubtypic efficacy in animal models without adjuvants.^[179] These approaches mimic viral geometry to boost mucosal and systemic immunity. Despite progress, challenges persist, including original antigenic sin or immune imprinting, where prior exposures bias responses toward non-conserved epitopes, potentially reducing efficacy against novel strains.^[171] Regulatory goals, such as the NIAID target of at least 75% vaccine effectiveness (VE) against symptomatic influenza across age groups, remain unmet in advanced trials, necessitating strategies like prime-boost regimens to overcome imprinting.^[180] In 2025, advancements include BARDA's $19.5 million funding for Osivax's Oil-in-Water Nano-Emulsion platform, a Phase 2 candidate targeting nucleoprotein for T-cell mediated protection, and integration of AI-driven epitope prediction tools to identify conserved targets with high immunogenicity.^[181][182]

Pandemic preparedness and novel technologies

Pandemic preparedness for influenza relies on accelerating vaccine development to counter emerging threats, particularly from novel strains like avian H5N1. DNA and viral vector platforms enable rapid prototyping, with DNA-based candidates producible in as little as one week following pathogen identification, far outpacing traditional methods.^[183] For instance, viral vector vaccines can be developed in about three weeks, supporting quick deployment in outbreaks. The Coalition for Epidemic Preparedness Innovations (CEPI) funds initiatives under its 100 Days Mission, aiming to deliver safe, effective vaccines within 100 days of identifying a new pathogen, including influenza variants.^[184] This framework emphasizes platform technologies to bridge gaps in response time and global access. Synthetic genomics has transformed influenza vaccine production by enabling the creation of custom viral strains through reverse genetics. In 2012, researchers at the J. Craig Venter Institute demonstrated the synthetic generation of influenza vaccine viruses entirely from sequence data, bypassing the need for live virus isolation and reducing production timelines for pandemic response. This approach, building on earlier synthetic biology advancements from Venter's work since 2005, is now a standard method for rapidly adapting vaccines to novel strains.^[185] Novel technologies further enhance agility, such as virus-like particles (VLPs), which mimic viral structure without replication. Novavax's VLP-based influenza vaccines, produced using recombinant baculovirus systems, have shown immunogenicity in phase 2 trials and offer a scalable alternative for pandemic scenarios.^[186] Additionally, computational tools like AlphaFold2 facilitate the design of stable hemagglutinin (HA) antigens; a 2022 study rationally engineered an HA stem vaccine using AlphaFold predictions, yielding a thermostable candidate with broad potential.^[187] Ongoing pandemic simulations and initiatives test these technologies' scalability. In 2024, the World Health Organization (WHO) conducted PanPRET-1 exercises across multiple countries to refine national pandemic plans, including vaccine deployment strategies for respiratory threats like influenza.^[188] Complementing this, WHO launched a project to advance mRNA vaccine candidates against human H5N1 influenza, focusing on technology transfer to enable rapid manufacturing in low- and middle-income countries.^[189] CEPI supports mRNA platform scale-up for influenza preparedness, targeting production capacities sufficient for billions of doses in outbreak scenarios.^[190] However, challenges persist with traditional egg-based production, which delayed the 2009 H1N1 vaccine rollout by approximately six months due to cultivation limitations.^[191] Recent efforts address this; in January 2025, the U.S. Department of Health and Human Services awarded Moderna $590 million to accelerate H5N1 mRNA vaccine trials, though the contract was terminated in May 2025.^[192][193] These efforts underscore a shift toward agile platforms.

Veterinary applications

Use in livestock and poultry

Influenza vaccines play a critical role in controlling avian influenza outbreaks in poultry production, particularly through the use of H5 and H7 subtype vaccines. Recombinant herpesvirus of turkeys (HVT) vector vaccines expressing hemagglutinin (HA) antigens from H5 or H7 strains have been developed to provide protective immunity against highly pathogenic avian influenza (HPAI) viruses, such as H5N1. These vaccines induce both humoral and cellular responses, offering advantages over traditional inactivated vaccines by allowing early administration in ovo or at day-old chicks without interfering with maternal antibodies. In Egypt, where H5N1 has been endemic since 2006, mass vaccination programs began in 2007, administering billions of doses of H5 vaccines since 2007, including routine use of recombinant HVT-H5 vaccines since 2012. This strategy has achieved 70-90% protection against morbidity and mortality in commercial broilers, significantly reducing viral shedding and limiting the spread of clade 2.2.1 H5N1 strains.^{[194][195][196]} For swine, inactivated bivalent vaccines targeting H1N1 and H3N2 subtypes are widely employed to mitigate respiratory disease and economic losses in pig herds. Following the 2009 H1N1 pandemic, which introduced novel strains into U.S. swine populations, vaccination became routine in breeding and finishing herds, with formulations updated to include pandemic-associated antigens. These vaccines reduce clinical signs, lung pathology, and viral replication, substantially decreasing nasal shedding by up to 90% in challenged pigs compared to unvaccinated controls. Autogenous vaccines, customized from local herd isolates, are also common, particularly in the European Union pork industry, where they incorporate farm-specific H1N1, H1N2, and H3N2 strains into inactivated whole-virus preparations to address antigenic drift and enhance herd protection. Such tailored approaches have helped stabilize production in large-scale operations by limiting intra-herd transmission.^[197][198] Despite these benefits, influenza vaccination in livestock raises one-health concerns, including the risk of reverse zoonosis where human influenza strains transmit to pigs or poultry, potentially creating reservoirs for reassortment and novel variants. Pigs, in particular, act as mixing vessels for human and swine viruses, with documented cases of seasonal H1N1 and H3N2 transmission from humans to swine herds, necessitating integrated surveillance and vaccination of both humans and animals to curb bidirectional spillover. As of 2025, mRNA-based vaccines for poultry are advancing in trials, demonstrating complete protection against divergent H5N1 strains in chickens and enabling faster adaptation to emerging outbreaks through rapid sequence-based manufacturing. These platforms show promise for on-demand responses, reducing the time from strain identification to deployment compared to traditional methods.^{[199][200][201][202]}

Use in companion animals

Influenza vaccines for companion animals primarily target equine influenza virus (EIV) in horses and canine influenza virus (CIV) in dogs, with limited options for cats due to rare natural infections. These vaccines focus on preventing respiratory disease in pets and working animals, emphasizing individual health rather than large-scale production. In horses, inactivated polyvalent vaccines protect against the primary EIV strain, H3N8, which causes outbreaks in stabled or traveling animals.^[203] The American Association of Equine Practitioners (AAEP) recommends vaccination for all horses at risk of exposure, such as those in competitive or communal settings, with annual boosters to maintain immunity.^[204] Studies indicate these vaccines achieve efficacy rates of 70-90% in reducing clinical signs and viral shedding in challenged horses.^[205] For dogs, recombinant or inactivated vaccines address CIV strains H3N8 and H3N2, which emerged from equine and avian origins, respectively. The first U.S. approval came in 2007 for the H3N8 vaccine (Vanguard ciV), followed by bivalent formulations like Nobivac Canine Influenza for broader protection.^[206] These vaccines are particularly recommended for dogs in high-density environments, such as shelters, to curb outbreaks that can spread rapidly among unvaccinated populations.^[207] Vaccine efficacy against clinical disease is approximately 60%, with two-dose protocols providing partial protection against infection and significantly reducing severity.^[208] Vaccination options for cats remain experimental and unlicensed for routine use, as feline influenza infections are uncommon and typically linked to avian strains like H5N1 in endemic regions. Research has evaluated subunit vaccines based on recombinant hemagglutinin (HA) proteins from H5N1, demonstrating protection against lethal challenge in cats by eliciting cross-clade immunity and reducing viral replication.^[209] Inactivated H5N6 vaccines have also shown efficacy in preventing clinical signs and limiting shedding in experimentally infected cats.^[210] These approaches are targeted at high-risk areas with H5N1 circulation but are not commercially available.^[211] Administration protocols vary by species and vaccine type. In horses, inactivated vaccines are given intramuscularly (IM), typically starting with two to three initial doses spaced 3-4 weeks apart for naive animals, followed by annual boosters.^[212] For dogs, subcutaneous (SQ) injection is standard, with two doses administered 3 weeks apart to establish immunity.^[213] Intranasal options exist for horses but are less common for initial series due to slower onset.^[204] As of 2025, research into universal equine influenza vaccines, such as those using chimeric HA stems from H3N8 strains, is advancing in preclinical trials, aiming for broader heterosubtypic protection in horses.^[214] For dogs, vaccine uptake has risen following widespread CIV outbreaks in 2023, with self-reported coverage reaching about 29% among U.S. pet owners, driven by increased awareness in boarding and shelter settings.^[215]