Comprehensive Notes on Influenza

Why is Influenza Important?

• Pandemics cause widespread illness and death over 1-2 years.
• Epidemic influenza causes widespread illness and death over many years.
• It is the most serious respiratory virus infection due to:
  • Direct virus-related disease
  • Secondary bacterial infections
  • Exacerbations of pre-existing chronic illness
• Immunity is transient, leading to regular reinfections.
• It is preventable and treatable.

Clinical Illness Due to Influenza

• Uncomplicated illness:
  • Acute onset of high fever, sore throat, muscle aches, headache, malaise, nausea, diarrhea.
• Complications:
  • Pneumonia: primary viral and secondary bacterial
  • In children: Croup, tracheobronchitis, bronchiolitis, otitis media
  • Myocarditis and myositis
  • Febrile seizures, encephalopathy, Guillain-Barre, Reye’s syndrome
• Exacerbations of underlying disease:
  • Chronic lung diseases, including asthma
  • Cardiovascular disease
  • Diabetes
  • Neurological disease
• Death

Influenza Virus Types

• Influenza A:
  • Crosses species
  • Antigenic drift and shift
  • Seasonal epidemics and pandemics
  • Subtypes H1-H16, only H1, 2, 3 in human viruses
• Influenza B:
  • Does not cross species
  • Antigenic drift, but not shift
  • Seasonal epidemics, but not pandemics
  • No subtypes - two distinct lineages until ?2021 - probably now single lineage
• Influenza C:
  • Does not cross species
  • Mild respiratory illness
  • No antigenic drift or shift
  • No subtypes
  • May not be a true influenza virus

Influenza: Circulating Types/Subtypes

• Timeline of influenza types and subtypes:
  • A/H2N2: Around 1880
  • A/H3N8: Around 1889
  • A/H1N1: 1918 (Pandemic), 1977, 2009 (Pandemic)
  • A/H2N8
  • A/H3N2: 1968 (Pandemic)
  • B: Victoria and Yamagata lineages
• Influenza B/Yamagata is probably now extinct.

Evolution of Influenza A

• Involves humans, pigs, migratory water birds.
• Point mutations lead to antigenic drift.
• Reassortment leads to antigenic shift.
• Recombination and multiple mutations also contribute.
• Pandemic strains arise through antigenic shift.

Influenza Virus Structure

• Key components:
  • Neuraminidase (N) or Sialidase
  • Nucleoprotein (RNA)
  • Lipid Envelope
  • Capsid
  • Hemagglutinin (H)
• Hemagglutinin is important for survival and replication.

Antigenic Drift

• Red sections (receptor binding site) are the targets for neutralizing antibodies and the dominant sites for antigenic drift.

Genetic Change in Influenza Viruses

• Antigenic drift (Influenza A and B):
  • Point mutations: minor change in HA producing low to moderate antigenic change that is sufficient to reduce protection from previous infection or vaccination
• Antigenic shift (Influenza A only):
  • Reassortment: Exchange of segments of the genome between human/avian/mammalian influenza viruses resulting in a new human pathogenic strain (1957, 1968, 2009)
  • Major mutations or recombination: Multiple mutations and/or recombination of sections of RNA within the segments. Produces a mixing of human, animal and avian gene sequences resulting in a human pathogenic strain with major antigenic change (1918).

Antigenic Shift: Leaping the Species Barrier

• Examples:
  • 1918 H1N1: 50 million extra deaths
  • 1957 H2N2: 2 million extra deaths
  • 1968 H3N1: 2 million extra deaths
  • 2009 H1N1: 0.3 million extra deaths

Mortality Due to Pandemic Influenza

• Death rates vary:
  • 1918: 50 million excess deaths
  • 1968: 2 million excess deaths
  • 2009: 1 million excess deaths
• 1918 virus produced more fulminant illness with a peak of deaths in young adults as well as the very young and the elderly.

Influenza A/H1N1 2009 Pandemic

• It wasn’t a different HA subtype, but was completely different from the circulating subtype. It did replace the previous A/H1, but not the A/H3.
• Overall, it was a mild pandemic:
  • 150,00-575,00 deaths worldwide, 0.001%-0.007% of the worlds’ population - compared with 0.03% for the 1968 pandemic and 1-3% for 1918 pandemic
• Disease patterns were different:
  • Direct viral pneumonia, rather than secondary bacterial pneumonia, was more common than in non-pandemic pneumonia
  • Children were commonly hospitalized, but severe disease and death was uncommon
  • 80% deaths occurred in people under 65 y.o., compared with 30% in seasonal influenza - people aged 65 years and over were spared
  • There was an increase in severe disease in young adults and middle-aged adults
• It became our seasonal influenza A/H1 strain and now undergoes the expected antigenic drift.

Excess Respiratory Deaths in Pandemics: 2009 vs 1918 Modelling

• 125,000-200,000 pandemic respiratory deaths due to influenza globally for the last 9 months of 2009, ~75% under 65 y of age.
• Compared with pre-pandemic seasonal influenza estimates 150,000– 250,000 with only 19% in persons <65 y.
• In 2009, the older population was less susceptible to infection because they were more likely to have had exposure to H1N1 viruses during or after the 1918 pandemic, prior to the 1957 H2 pandemic. Their immune memory gave partial protection against H1N1/2009 strain.
• But if they did get infected, they had a higher death rate than younger people

Impact of Seasonal Influenza

• Epidemic influenza is responsible for more illness and deaths than pandemic influenza
• Some epidemic seasons are worse than pandemic seasons
• The majority of illness and death due to influenza is due to the secondary illnesses such as pneumonia and the exacerbation of underlying illnesses such as cardiovascular disease, chronic respiratory conditions, diabetes and other metabolic disorders

Influenza Seasonality

• In temperate parts of the world influenza is a seasonal disease peaking in the winter months
• In tropical and subtropical areas, it has more variable pattern – may be two seasons or continuous low-level influenza
• Estimated that over 250,00 people die each year from influenza, including 2-3000 in Australia – recognised to be an underestimate

Australian Influenza Surveillance

• It's not the same everywhere.

Influenza Seasonality Varies with Climate and Weather

• Temperate weather patterns:
  • Late spring/winter/autumn activity
• Tropical and subtropical:
  • Variable patterns in different regions
  • Single season but not necessarily in summer
  • Double season – winter plus summer/spring
  • Continual activity in equatorial areas

Seasonal Comparisons for Western Australia

• WA has a small summer influenza season comprising influenza in the tropical and subtropical north, and influenza in returned travelers
• Seasonal peaks vary in size and timing, sometimes dramatically (2019)

Influenza 2020 - What Happened to It?

• Notifications of laboratory-confirmed influenza, Australia, 01 January 2017 to 25 September 2022, by month and week of diagnosis

Influenza 2020 – Minimal Influenza and Likely Extinction of a Lineage

• Influenza activity dropped dramatically in April 2020 and did not reappear in significant numbers until 2022
• It was not due to any reduction in testing
• It coincided with travel restrictions and other public health measure related to the COVID-19 pandemic control
• The Yamagata lineage of influenza B has disappeared since the pandemic, despite the reappearance of the other influenza lineages

Impact: Influenza Pyramid

• The total societal impact determined direct and indirect effects: serious, moderate and minor illness; social and financial impacts.
• Severe disease, hospitalization and death due to seasonal influenza is highest in the elderly and the very young.
• The major burden of disease is indirect morbidity and mortality due to exacerbation of underlying illness

Influenza Mortality Varies with Patient Age and Influenza Type/Subtype

• Overall A/H3N2 causes the largest numbers of hospitalizations and deaths, mainly in the 60+ age group, then in young children
• A/H1N1 has a broader mortality range, especially relatively more in the 40-60 y.o. age group
• Influenza B causes few deaths, most of which are in the 60+ age group

Influenza Transmission and Incubation

• Incubation period: 1-4 days (typically 2 days)
• Viral shedding can begin before symptom onset
• Peak viral shedding on first day of symptoms
• Adults typically shed viruses for 4-7 days
• Children may shed viruses for longer periods
• Transmission: person-to-person
  • Large droplets <2 meters: Coughing, talking, sneezing
  • Aerosols/ droplet nuclei
  • Contact/ Fomites

Influenza Treatment and Prevention

• Vaccination
• Antiviral agents
• Non-pharmacological interventions
  • Avoidance of exposure
  • Personal hygiene
  • Community mitigation strategies

Influenza Vaccination

• Vaccination prevents milder illness in the community, complications of influenza, and influenza-related hospitalization and death.
• Severe illness is more likely in those aged 65y.o. or more, and people with pre-existing chronic illnesses.
• Reduces the impact of influenza on individual health by:
  • Reducing the risk of infection
  • Reducing the severity of illness in those who are infected
• Reducing the risk and impact of influenza in the community is achieved by:
  • Vaccinating the individual to protect them
  • Reducing the likelihood of them infecting others
• Vaccinate those who have contact with people at high risk of serious illness
  • health care workers, close contacts of risk groups for severe disease
• Universal vaccination of young children
  • protects them individually and reduces the spread within the community (herd immunity)

Influenza Vaccination

• Influenza vaccine effectiveness overall is about 50-60%
• This varies with:
  • How well the strains chosen for the vaccines match the strains that circulates in the following season
  • Whether the virus changes during the production of the vaccine – occurs with some vaccines produced in eggs – called egg adaptation
  • Age and other illnesses which cause a poorer immune responses
  • The amount of antigen or the presence of adjuvants that increase immune responses

Influenza Vaccines in Australia

• Nearly all licensed vaccines are made from virus grown in eggs, then inactivated and “split”. A vaccine grown in cell-cultures is also available, but currently not subsidized
• Nearly all are quadrivalent vaccines containing antigens from influenza A/H1, influenza A/H3, influenza B Yamagata lineage and influenza B Victoria lineage
• Vaccines with increased immunogenicity – better responses in the 65+ age group - two types:
  • Those containing a higher amount of antigen
  • Those with an adjuvant that boosts immune responses
• Protective levels are best from about 2 weeks to 6 months after vaccination.
• Live-attenuated vaccines used overseas, none yet licensed in Australia

Influenza Vaccine Production

• Influenza viruses are forwarded from National Influenza Centers and other laboratories to the WHO Collaborating Centre for Influenza Reference and Research in Melbourne.
• They undertake antigenic typing
• WHO has two meetings each year to select the best strains for inclusion in the upcoming season
  • meet in September for Southern hemisphere season and February for Northern hemisphere season
• Allows 6 months for vaccine formulation, testing and production
  • potentially shorter time for cell culture-based vaccines and for the RNA vaccines in development

NHMRC Recommendations for Influenza Vaccination

• Those at increased risk of more severe illness:
  • All persons aged 65 years or over
  • All children aged 6 months to 4 y.o.
  • All ATSI children aged 6 months and over, and 15 years and over
  • Adults and children (6 months or over) with specified medical conditions associated with increased risk of influenza disease and severe outcomes
    • cardiovascular, respiratory, metabolic, etc.
  • Pregnant women and those likely to be pregnant during the influenza season
  • Residents of nursing homes and other LTRCF
  • Homeless people
• People liable to infect high risk individuals
  • Health care workers
  • Family members of high-risk individuals
• Those in green are funded under the National Immunization Program

Antivirals for Influenza

• Neuraminidase Inhibitors:
  • Active against all known strains of human and animal influenza
  • Block release of virus from infected cells
• Matrix protein inhibitors:
  • Only for influenza A
  • High levels of resistance, including A/H1N1 2009
  • No longer recommended as first-line treatment
• Polymerase inhibitors:
  • Active against all known strains of human and animal influenza
  • Inhibit RNA polymerase

Influenza Antivirals in Current Clinical Use

• M2 inhibitors:
  • Active Against: Influenza A
  • Target: M2 ion channel. Inhibits uncoating
  • Drugs: Amantadine#, Rimantadine#
• Neuraminidase inhibitors:
  • Active Against: All influenza viruses
  • Target: Inhibits viral neuraminidase. Prevents release of progeny virions
  • Drugs: Oseltamivir, Zanamivir, Peramivir
• Polymerase inhibitors:
  • Active Against: Influenza A, B
  • Target: Inhibits viral RNA polymerase
  • Drugs: Baloxivir marboxil

Neuraminidase and Polymerase Inhibitors for Influenza

• Active against all known influenza A & B viruses, but no other viruses
• Commence within 48 hours of onset of illness - the earlier the better. Later therapy for severely ill and immunocompromised
• Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir):
  • Reduces duration of uncomplicated influenza illness, reduce complications, including pneumonia, reduce viral shedding
  • Prophylactic use is 50-70% effective in preventing influenza infection and 80-90% effective in preventing clinical illness
• Polymerase inhibitors (baloxavir-marboxil):
  • Reduces duration of uncomplicated influenza illness, reduces viral shedding
  • Resistance viruses emerge during treatment, but little clinical impact

Aerosols, Droplets, Fomites and PPE

• Influenza virus transmission mainly large particles, aerosols and fomites
• Handwashing, protective clothing and masks
  • Water-repellent surgical mask
    • Low risk contact
  • P2 mask
    • High-risk contacts
• Non-pharmaceutical public health measures put in place for SARS- CoV-2 control were shown to stop spread of influenza and other respiratory viruses
  • border closures, restrictions on movements, quarantining, social distancing, restrictions of social gatherings, school closures, etc.

Zoonotic Influenza Update WHO

• From 20 January to 19 March 2025, based on reporting date, the detection of influenza A(H5N1) in five humans, influenza A(H9N2) virus in four humans, influenza A(H1N1) variant ((H1N1)v) virus in one human, and influenza A(H1N2)v virus in one human were reported officially.
• Circulation of influenza viruses with zoonotic potential in animals: High pathogenicity avian influenza (HPAI) events in poultry and non-poultry continue to be reported to the World Organisation for Animal Health (WOAH).

Zoonotic Influenza A/H1

• Current outbreak of Highly Pathogenic Avian Influenza H5N1 since 2016
• Evolved from H5N1 virus that appeared in Hong Kong markets in 1997, and now persistently circulates in domestic and wild birds
• Very high mortality rates in animal populations
• Multiple human infections detected, but no evidence yet for human-to-human transmission
• None of these strains yet detected in Australian animals, but rare human cases diagnosed here travellers from overseas – none with US lineage

Human Infections with H5N1 HPAI in the USA from Dairy Cows

• Specific lineage – Avian influenza A(H5N1) virus from clade 2.3.4.4.b – this has D701N genetic mutation in the polymerase basic 2 (PB2) protein (E627K) that has previously been associated with more efficient virus replication in people and other mammals
• Infects dairy cows, with highest viral load in milk – replicates in mammary gland cells
• Spread to farm cats by ingestion of raw milk inactivated by pasteurization
• Human infections in USA:
  • 70 cases, 1 death
  • Nearly all mild illness, conjunctivitis common
  • Contact with dairy herds, chicken farms
• No proven person-to-person spread

Avian H5/HPAI Pandemic 2016 Onwards

• Potential to spread from Antarctica to Australia via migratory bird populations
• Spread to large range of wild mammals, primarily by predation