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

2. 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

3. 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

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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

12. 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

13. 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

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

15. Flu Vaccines
19May06
KL Vadheim Lecture 4

16. 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

17. 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

18. 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

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

20. Flu Vaccines
19May06
KL Vadheim Lecture 4

21. 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

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

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

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