Influenza Virus

Influenza A virus (Alphainfluenzavirus influenzae) is the most medically significant influenza type, capable of causing both seasonal epidemics and pandemics in humans. It is classified into subtypes based on the combination of its surface proteins hemagglutinin (HA) and neuraminidase (NA). To date, 18 HA subtypes (H1-H18) and 11 NA subtypes (N1-N11) have been identified. The major subtypes currently circulating seasonally in humans are A(H1N1) and A(H3N2). Wild waterfowl serve as the natural reservoir for influenza A viruses, and nearly all HA and NA subtype combinations have been found in avian species.

Influenza B virus (Betainfluenzavirus influenzae) primarily infects humans and is classified not by subtype but by lineage. Two lineages have been recognized — B/Victoria and B/Yamagata — although B/Yamagata has not been detected globally since March 2020 and is considered to have undergone probable extinction (Caini et al., Lancet Microbe, 2024). Non-pharmaceutical interventions during the COVID-19 pandemic were identified as the primary driver of its disappearance; while B/Victoria resurged after measures were relaxed, B/Yamagata did not recover. All influenza vaccines have consequently transitioned to trivalent formulations excluding B/Yamagata from the 2025-2026 season onward (FDA, 2025; CDC, 2026). Influenza B evolves more slowly both genetically and antigenically than influenza A and, lacking an animal reservoir, cannot undergo antigenic shift and does not cause pandemics.

Influenza C virus (Gammainfluenzavirus influenzae) infects humans and swine, causing mild upper respiratory infections or asymptomatic infections. Its genome consists of 7 segments (compared to 8 for types A and B), and it possesses a single hemagglutinin-esterase-fusion (HEF) protein that performs the functions of both HA and NA. It does not cause seasonal epidemics or pandemics and is of low public health significance.

Influenza D virus (Deltainfluenzavirus influenzae), the most recently discovered type, was first identified in 2011 and primarily infects cattle and swine. Human infection is rare, though serological evidence of exposure has been reported in livestock workers. Like influenza C, it has 7 genome segments. Its capacity to cause disease in humans has not been established.

Influenza viruses are pleomorphic enveloped viruses that exist in two morphological forms: spherical and filamentous. Spherical virions have a diameter of approximately 80-120 nm, while filamentous forms have a diameter of approximately 80 nm and can extend from 300 nm to several micrometers in length. Laboratory-adapted strains are predominantly spherical, but clinical isolates more commonly exhibit filamentous morphology. The virion surface is studded with HA and NA glycoprotein spikes protruding approximately 7-14 nm, with HA outnumbering NA by a ratio of roughly 4-5:1.

Hemagglutinin (HA) is the most abundant surface glycoprotein (approximately 500 copies per virion) and exists as a homotrimer. HA initiates viral entry by binding sialic acid receptors on host cell surfaces and mediates membrane fusion upon endosomal acidification. HA consists of HA1 (receptor-binding domain) and HA2 (fusion domain), and cleavage by host proteases is essential for activation of infectivity.

Neuraminidase (NA) is a tetrameric enzymatic glycoprotein that cleaves sialic acid residues, facilitating the release of newly formed virions from host cells and promoting transit through the mucus layer. NA is the molecular target of the antiviral drugs oseltamivir (Tamiflu) and zanamivir (Relenza).

The M1 (matrix 1) protein forms a layer beneath the viral envelope, providing structural stability and playing essential roles in virion assembly and budding. The M2 protein functions as a tetrameric proton ion channel that transmits endosomal acidification into the virion interior during uncoating, facilitating the dissociation of M1 from vRNPs. The NS1 protein is a major virulence factor that antagonizes the host interferon response, while NEP (NS2) mediates the nuclear export of vRNPs.

Influenza A and B viruses possess a genome of 8 segments of negative-sense single-stranded RNA, while influenza C and D have 7 segments. The total genome size is approximately 13.5 kb (types A and B). Each RNA segment exists as a viral ribonucleoprotein (vRNP) complex, associated with nucleoprotein (NP) and the RNA-dependent RNA polymerase (RdRp) complex comprising PB1, PB2, and PA subunits.

The eight RNA segments of influenza A virus encode the following proteins.

The influenza virus replication cycle consists of the following stages. First, during the attachment phase, HA binds sialic acid receptors on the host cell surface. Human-adapted viruses preferentially bind alpha-2,6-linked sialic acid, while avian-adapted viruses prefer alpha-2,3-linked sialic acid. Second, the virus is internalized via receptor-mediated endocytosis. Third, endosomal acidification (pH ~5) triggers a conformational change in HA that initiates fusion between the viral envelope and endosomal membrane, while simultaneously the M2 ion channel allows proton influx, releasing vRNPs. Fourth, vRNPs are transported to the nucleus, where viral RNA transcription and replication occur — a distinctive feature of influenza among RNA viruses, most of which replicate in the cytoplasm. Fifth, viral mRNAs are translated in the cytoplasm, and new vRNPs are assembled and exported from the nucleus. Finally, viral proteins and vRNPs are assembled at the plasma membrane, and NA cleaves sialic acid to allow new virions to bud from the cell.

The mutation rate of influenza virus is approximately 2.3 x 10-5 substitutions per nucleotide per replication cycle, which is high among RNA viruses. This is because the RNA-dependent RNA polymerase lacks proofreading capability. The combination of a high mutation rate and immune selection pressure enables rapid antigenic variation. Additionally, the segmented genome allows reassortment when different viruses co-infect the same cell, potentially generating entirely novel viral combinations.

Antigenic drift is the gradual accumulation of point mutations in the HA and NA genes, resulting in progressive antigenic change. Under immune selection pressure, mutations accumulate at antibody-binding sites (antigenic epitopes), and variants capable of evading pre-existing immunity are selected. This continuous drift necessitates annual review and updating of seasonal influenza vaccine composition. The H3N2 subtype undergoes antigenic drift more rapidly than H1N1, and influenza B evolves more slowly than influenza A (Petrova & Russell, Nature Reviews Microbiology, 2018).

Antigenic shift is the abrupt antigenic change that occurs when different influenza A viruses co-infect the same host cell and undergo reassortment of genome segments. When a virus with a novel HA and/or NA subtype emerges, the majority of the population is immunologically naive, creating conditions for a pandemic. All influenza pandemics of the 20th and 21st centuries resulted from antigenic shift. Influenza B, lacking an animal reservoir, cannot undergo antigenic shift and does not cause pandemics.

Typical influenza symptoms include sudden onset of fever (38-40°C), chills, headache, myalgia, arthralgia, and fatigue, accompanied by respiratory symptoms such as dry cough, sore throat, and nasal congestion. However, only approximately 50% of infected individuals exhibit these classic symptoms. In children, gastrointestinal symptoms including nausea, vomiting, and diarrhea are more common. In most healthy adults, symptoms resolve spontaneously within 7-10 days, though cough and fatigue may persist for several weeks.

The incubation period averages approximately 2 days (range: 1-4 days). Infected individuals begin shedding virus approximately 1 day before symptom onset and remain infectious for 5-7 days after symptom onset. Children and immunocompromised individuals may shed virus for longer periods. Infectiousness is highest during the first 2-3 days following symptom onset.

Severe complications include viral pneumonia, secondary bacterial pneumonia (particularly Streptococcus pneumoniae and Staphylococcus aureus), acute respiratory distress syndrome (ARDS), myocarditis, encephalitis, rhabdomyolysis, and multi-organ failure. High-risk groups include adults aged 65 and older, children under 5 (especially under 2), pregnant women, individuals with chronic pulmonary or cardiovascular disease, diabetes, immunocompromised patients, and obese individuals (BMI >= 40).

Reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for influenza diagnosis, offering high sensitivity and specificity with the ability to distinguish virus type (A, B) and subtype (H1, H3, N1, N2, etc.). Multiplex RT-PCR can simultaneously detect influenza and other respiratory viruses (RSV, SARS-CoV-2, etc.). Rapid influenza diagnostic tests (RIDTs) provide results within 15-30 minutes with sensitivity of 50-70% and specificity exceeding 90%. Virus culture is used for detailed antigenic characterization and antiviral susceptibility testing, and is essential for surveillance and vaccine strain selection.

Seasonal influenza epidemics occur primarily during winter months in temperate regions (November-March in the Northern Hemisphere, May-September in the Southern Hemisphere), while year-round transmission occurs in tropical regions. WHO estimates approximately 1 billion annual infections, 3-5 million severe cases, and 290,000-650,000 respiratory-associated deaths globally (WHO, 2025). In the United States, the 2024-2025 season was a high-severity season with an estimated 51 million influenza illnesses, 23 million medical visits, 710,000 hospitalizations, and 45,000 deaths (CDC, 2026).

The major influenza pandemics since the 20th century are summarized below.

The 1918 Spanish Flu remains one of the deadliest pandemics in human history, infecting approximately one-third of the world's population and killing an estimated 50 million or more people. Unusually, it caused high mortality among healthy adults aged 20-40, which is believed to be related to an exaggerated immune response ("cytokine storm") (Taubenberger & Morens, Emerging Infectious Diseases, 2006).

Highly pathogenic avian influenza A(H5N1) was first identified in humans in Hong Kong in 1997. According to WHO cumulative data as of December 19, 2025, a total of 993 confirmed human cases have been reported worldwide since 2003, with 477 deaths, yielding a case fatality rate of approximately 48% (WHO, December 2025). Sustained human-to-human transmission has not been documented. However, beginning in March 2024, unprecedented outbreaks of H5N1 were identified in U.S. dairy cattle herds, with over 1,070 herd infections confirmed across more than 16 states by May 2025, along with 71 confirmed human infections in the United States (CDC, 2025). Active surveillance and control measures subsequently reduced these outbreaks substantially, but widespread circulation in wild bird populations persists worldwide.

FDA-approved influenza antiviral drugs include neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) and the cap-dependent endonuclease inhibitor baloxavir marboxil. Oseltamivir (Tamiflu), the most widely used oral agent, reduces symptom duration by approximately 1 day and lowers the risk of complications when administered within 48 hours of symptom onset. Zanamivir (Relenza) is an inhaled formulation, peramivir (Rapivab) is given intravenously, and baloxavir (Xofluza) offers the advantage of a single oral dose treatment.

The M2 ion channel inhibitors amantadine and rimantadine, once used against influenza A, are no longer recommended because virtually all currently circulating influenza A viruses carry the M2 resistance mutation S31N.

Seasonal influenza vaccination is the most effective preventive measure. Vaccine types include inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV), and live attenuated influenza vaccine (LAIV). Beginning with the 2025-2026 season, all influenza vaccines contain three antigens — A(H1N1), A(H3N2), and B/Victoria — in a trivalent formulation (FDA, 2025; CDC, 2026). Vaccine effectiveness varies depending on the antigenic match between vaccine strains and circulating viruses, generally providing 40-60% protection against symptomatic infection. Effectiveness against severe disease, hospitalization, and death is higher.

WHO and national health authorities recommend annual influenza vaccination for high-risk groups including adults 65 and older, children 6 months to 5 years, pregnant women, individuals with chronic medical conditions, healthcare workers, and residents and staff of long-term care facilities.

Development of a universal influenza vaccine is actively underway. Current vaccines target the variable head region of HA and require annual updates, whereas universal vaccines targeting conserved antigens such as the HA stalk, M2e, or neuraminidase could provide broad, durable protection. As of February 2026, CIDRAP's Universal Influenza Vaccine Technology Landscape documents numerous candidate vaccines in clinical trials, and mRNA-based seasonal influenza vaccines (such as Moderna's mRNA-1010) have reported Phase 3 clinical trial results (CIDRAP, 2026). In December 2025, WHO released updated Preferred Product Characteristics to guide the development of next-generation influenza vaccines (WHO, 2026).

Hand hygiene, respiratory etiquette, mask wearing, avoiding contact with symptomatic individuals, and ventilation are effective in reducing transmission. Symptomatic individuals are recommended to self-isolate until at least 24 hours after fever resolves.

Wild waterfowl (ducks, geese, swans) are the principal natural reservoir hosts of influenza A viruses, and nearly all HA (18) and NA (11) subtype combinations have been identified in these species. Most avian influenza viruses cause asymptomatic intestinal infections in wild birds and are transmitted via the fecal-oral route. Migratory bird flyways play a critical role in the long-range geographic dissemination of the virus.

Domestic poultry (chickens, turkeys) are highly susceptible to avian influenza. Low pathogenicity avian influenza (LPAI) causes mild symptoms, but highly pathogenic avian influenza (HPAI, particularly certain H5 and H7 subtypes) causes acute systemic infection with mortality approaching 100% in poultry, inflicting massive economic losses.

Swine are an important host for influenza A viruses, with H1N1, H1N2, and H3N2 as the major circulating subtypes. Pigs express both alpha-2,3- and alpha-2,6-linked sialic acid receptors, enabling simultaneous infection by both avian and human viruses. This makes swine a "mixing vessel" for reassortment, a critical pathway for the emergence of novel pandemic viruses. The 2009 H1N1 pandemic virus was the product of complex reassortment involving gene segments from swine, avian, and human influenza viruses (Neumann et al., Nature, 2009).

Influenza A virus infections have also been reported in horses (H3N8, H7N7), dogs (H3N8, H3N2), cats, and marine mammals (seals, whales). Beginning in March 2024, unprecedented outbreaks of H5N1 were confirmed in U.S. dairy cattle herds, representing the first known involvement of cattle as significant hosts. The initial outbreaks were caused by the B3.13 genotype, and a novel D1.1 genotype was subsequently identified in dairy cattle in early 2025 (USDA, 2025). Although active control measures substantially reduced these outbreaks, the event underscored the unpredictable host-range expansion capacity of influenza viruses.