Influenza Vaccines MedCh 401 Lecture 5 19May06 KL Vadheim Lecture 4

Occurrence of Influenza in U.S. ~48 million cases per year ~3.9 million hospitalized 20,000 deaths >40,000 deaths in bad epidemic year >90% in persons >65 years of age Seasonal disease - winter in N. Hemisphere 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Influenza virus Highly infectious Affects all age groups Most common cause of lower respiratory tract infections Three antigen types 19May06 KL Vadheim Lecture 4

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 don’t change or evolve 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Influenza A subtypes Determined by surface antigens: Hemagglutinin - virus attachment to cells H1 H2 H3 Neuraminidase - virus penetration into cells N1 N2 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Influenza Prevalence 1918-1919 - H1N1 1957 - H2N2 1968 - H3N2 severe highly infectious ~20 million deaths worldwide 1957 - H2N2 mild 1-4 million deaths worldwide 1968 - H3N2 Moderate Current strains - H3N2 and H1N1 19May06 KL Vadheim Lecture 4

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) 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Flu vaccines Trivalent Manufactured each year for specific viruses Expire in June of each year 19May06 KL Vadheim Lecture 4

Flu Vaccines 19May06 KL Vadheim Lecture 4

Types of Manufacturing Processes Chicken embryo process takes 10 weeks campaign-based high yield (millions of doses) Cell culture continuous process lower yield (< 1 million doses) 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Live Flu vaccine production Grow genetically attenuated viral strains in cell culture Purify Formulate 19May06 KL Vadheim Lecture 4

Flu Vaccines 19May06 KL Vadheim Lecture 4

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 19May06 KL Vadheim Lecture 4

Transmission Person-to-person Respiratory droplets Animal to human rare 19May06 KL Vadheim Lecture 4

Flu Deaths commonly due to pneumonia from secondary infections: S. pneumonia H. influenzae S. aureus 19May06 KL Vadheim Lecture 4

Flu Pandemics Less seasonally restricted than normal flu Are random events May or may not demonstrate increased mortality 19May06 KL Vadheim Lecture 4