Influenza Vaccines

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Influenza Vaccines

• MedCh 401
• Lecture 5

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Occurrence of Influenza in U.S.

• 48 million cases per year
• 3.9 million hospitalized
• 20,000 deaths
• gt40,000 deaths in bad epidemic year
• gt90 in persons gt65 years of age
• Seasonal disease - winter in N. Hemisphere

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Influenza virus

• Orthomyxovirus
• Single-stranded RNA genome
• lacks proof-reading ability of DNA genomes
• Segmented genome
• increases potential for genetic reassortment
• Continuous evolution of genome and antigens

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Influenza virus

• Highly infectious
• Affects all age groups
• Most common cause of lower respiratory tract
  infections
• Three antigen types

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Influenza Antigen types

• Type A
• infection occurs most frequently
• accounts for majority of morbidity and mortality
• moderate to severe illness
• perpetuated in nature by wildfowl
• usually not pathogenic to natural host
• normally dont change or evolve

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Influenza Antigen Types II

• Type B
• responsible for regional epidemics
• less severe disease than A
• affects primarily children
• affects humans only
• Type C
• rarely causes epidemics
• associated with sporadic human cases

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Influenza A subtypes

• Determined by surface antigens
• Hemagglutinin - virus attachment to cells
• H1
• H2
• H3
• Neuraminidase - virus penetration into cells
• N1
• N2

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Reassortant viruses

• Natural and induced process
• Process is used to increase replication of new
  viruses (e.g., vaccine strains) to high titers
• Produced by
• simultaneous infection of check embryo with
  antigenically dissimilar parental viruses
• select by passage of post-reassortment virus with
  antibody suppressing antigens of high-yield donor

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Antigenic drift

• Minor change in surface antigens
• Antigenic mutants of surface antigens H and N
  emerge by cumulative point mutations
• Are selected by antibody to previous predominant
  virus
• Continuous process
• Occurs in types A, B, C

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Antigenic Shift

• Due to recombination between Type A viruses
• Major changes (H, N) from currently circulating
  virus
• Spread rapidly due to lack of protection in
  population
• Often causes pandemic
• May or may not cause more severe disease

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Influenza Prevalence

• 1918-1919 - H1N1
• severe
• highly infectious
• 20 million deaths worldwide
• 1957 - H2N2
• mild
• 1-4 million deaths worldwide
• 1968 - H3N2
• Moderate
• Current strains - H3N2 and H1N1

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Definitions

• Epidemic
• Outbreak of an infectious disease that spreads
  rapidly
• Occurrence of an infectious disease at a higher
  rate than normal
• Increase in morbidity over normal incidence
• Severity of disease may or may not increase
• Mortality may or may not increase (but often does
  with flu epidemics)

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Definitions

• Pandemic
• Epidemic over a wide geographic area and
  affecting a large proportion of the population
• Morbidity increases over larger population area
• Mortality may or may not rise

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Flu vaccines

• Trivalent
• Manufactured each year for specific viruses
• Expire in June of each year

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Flu Vaccines
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Types of Manufacturing Processes

• Chicken embryo process
• takes 10 weeks
• campaign-based
• high yield (millions of doses)
• Cell culture
• continuous process
• lower yield (lt 1 million doses)

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Whole virus Flu Manufacturing I

• Grow and purify each virus individually
• Harvest culture fluid
• sP inactivate with formaldehyde
• Concentrate with centrifugation
• Purify with sucrose gradients
• GSK, sP solubilize virus with detergent
• Novartis inactivate with b-propriolactone

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Whole virus Flu Manufacturing II

• Further purification
• GSK inactivation with sodium deoxycholate and
  formaldehyde
• All three purified, inactivated strains are
  formulated into split virus solutions

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Live Flu vaccine production

• Grow genetically attenuated viral strains in cell
  culture
• Purify
• Formulate

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Flu Vaccines
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Flu Symptoms

• Incubation period 1-4 days
• Abrupt onset of fever, myalgia, sore throat, dry
  cough, headache
• 50 of people develop these classical symptoms
• Viremia rare
• Viral shedding in respiratory secretions for 5-10
  days

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Transmission

• Person-to-person
• Respiratory droplets
• Animal to human rare

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Flu

• Deaths commonly due to pneumonia from secondary
  infections
• S. pneumonia
• H. influenzae
• S. aureus

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Flu Pandemics

• Less seasonally restricted than normal flu
• Are random events
• May or may not demonstrate increased mortality