1. Influenza Virus Vaccine Composition 2004-2005 Roland A. Levandowski, M.D. Division of Viral Products Prepared for Vaccines and Related Biological Products Advisory Committee 18-19 February 2004

2. Topics for VRBPAC 18-19 February 2004 For Committee Recommendation: – Selection of influenza A (H1 and H3) and B viruses for 2004-2005 For Committee Information – Vaccine effectiveness studies 2003-2004 – Avian Influenza (H5) 2003-2004 For Committee Discussion – Tissue culture isolates for influenza vaccines

3. Question for Committee Recommendation What strains should be recommended for the antigenic composition of the 2004-2005 influenza virus vaccine?

4. Review of Strain Selection for 2003-2004 A/New Caledonia/20/99 (H1N1)-like B/Hong Kong/330/01-like  B/Hong Kong/330/01  B/Hong Kong/1434/02 A/Moscow/10/99 (H3N2)-like  A/Panama/2007/99

5. Vaccine efficacy relates to: Vaccine immunogenicity (potency) Match of vaccine HA/NA with wild-type viruses – First evidence of reduced vaccine effectiveness because of antigenic drift 2 years after first vaccines licensed for use in United States – Antigenic drift of HA/NA continuous in influenza A and B viruses Why Change Strains in Influenza Vaccines?

6. Questions to Be Answered for Strain Changes Every Year Are new (drifted or shifted) influenza viruses present? Are these new viruses spreading in people? Do current vaccines induce antibodies against the new viruses (HA)? Are strains suitable for vaccines available?

7. Strain Selection 2003-2004: New Strains Present? Influenza A H1N1?NO  HA of all strains were similar to the vaccine strain

8. Strain Selection 2003-2004: New Strains Present? (Cont) Influenza A H3N2?YES  HA of most strains in early 2003 were similar to the vaccine strain  HA of a proportion were antigenically distinguishable  First identification of antigenically distinguishable A/Fujian-like viruses in February 2003

9. Strain Selection 2003-2004: New Strains Present? (Cont) Influenza B?NO  HA of majority of strains were similar to the vaccine strain  HA of small number (<<1%) of viruses were similar to older vaccine strain

10. Strain Selection 2003-2004: New Viruses Spreading? Influenza A H3N2?YES  A/Fujian-like viruses found in small proportion in Asia, Europe and North America in Feb-Mar 2003

11. Strain Selection 2003-2004: Viruses Inhibited by Current Vaccines? Influenza A H3N2?Partial NO  Majority of strains (A/Panama/2007/99-like): well-inhinbited  A/Fujian-like strains: some well-inhibited others poorly inhibited

12. Strain Selection 2003-2004: Strains Suitable for Manufacture Available? TIMINGNO  Manufacturing depends on egg-adapted strains (wild-type or high growth reassortant)  First A/Fujian-like variants identified February 2003  No A/Fujian-like egg isolates until April 2003  High growth reassortants first available end of June 2003

13. Implications of Strain Selection 1 Preparation of vaccines was on schedule The supply of vaccine matched the demand expected by previous years’ experiences

14. Implications of Strain Selection 2 Early widespread appearance of drift variant A/Fujian-like viruses with reports of mortality in children significantly increased vaccine demand – Excess supplies of inactivated and live vaccines in mid November were insufficient to avoid spot shortages after Thanksgiving Effectiveness of the vaccines against drift variant A/Fujian-like viruses was questioned – Effectiveness evaluation is an ongoing activity

15. Influenza Virus Vaccines Used in the United States Inactivated – Aventis-Pasteur, Inc.(Licensed 1970’s) – Evans Vaccines Ltd.(Licensed 1980’s) – Approx. production 2003: 83 million doses Live attenuated – MedImmune Vaccines Inc.(Licensed June, 2003) – Approx. production 2003: 4 million doses

16. Timelines for Vaccine Production

17. Time to First Trivalent Vaccine Lot after Strain Change

18. Relative Effort for Production of Monovalent Vaccine Components Per Cent of Total Inactivated Vaccine Monovalent Lots Submitted for Release 199819992000200120022003 H3251728211723 H13728474443 B385525354034 Strains changed BH1 and H3 BBNone

19. Timing of Submission of Influenza Vaccines for Release 2003

20. Cumulative Trivalent Influenza Vaccine Submitted for Release 2000-2003

21. Why are Influenza Vaccines Important? Economic consequences are high because of lost work Morbidity is high, particularly in the very young “Pneumonia and Influenza” category is among the top ten causes of death in the US Epidemics cause 20,000 to 40,000 deaths annually in US, mainly in the elderly Pandemics cause even higher losses: the pandemic of 1918 caused over 500,000 deaths in the US alone

22. Influenza Season Morbidity: Influenza-like Illness Baltimore 1918-1944 (H1N1) Source: Public Health Reports 1944; 59:1483

23. Influenza Season Morbidity: Pneumonia Baltimore 1918-1944 (H1N1) Source: Public Health Reports 1944; 59:1483

24. Influenza Season Morbidity: Hospitalizations Houston 1975-1976 Source: Epidemiol Rev 1982; 4:25

25. Influenza Season Mortality: Harris County, Texas 1977-1978 Source: Epidemiol Rev 1982; 4:25

26. Effect of Age on Influenza Morbidity and Mortality Influenza attack rates often highest in children < 10 years old Serious illness in all age brackets with the young and old most affected Mortality generally highest in the elderly, but also relatively high in young children and infants

27. A Brief History of Influenza Vaccine Efficacy 1941 - Request to license first inactivated vaccine in US deferred to obtain efficacy data 1942 - Small scale studies demonstrate efficacy against influenza A and B challenge 1943 - Large scale field studies demonstrate efficacy against circulating influenza viruses 1945 - Inactivated influenza vaccines licensed in US 1947 - Reduced vaccine effectiveness against drift variant 1948 - Global surveillance initiated to identify drift variants for use in vaccines

28. Influenza Vaccine Efficacy Randomized, placebo controlled field efficacy studies performed 1943-1945 Vaccines prepared as whole virus, formalin inactivated preparation Vaccine antigens – A/Puerto Rico/8/34 (H1N1), A/Weiss/43 (H1N1), B/Lee/40 Army Specialized Training Program centers at 8 universities >10,000 study participants

29. Influenza Vaccine Efficacy Clinical Aspects Influenza infection identified by culture and illness documented by daily observation Illness characterized by symptoms including: – Abrupt onset – Fever – Myalgias – Cough – Sore throat – Nasal symptoms Cases categorized by illness severity – Hospitalized if temperature > 100 F – X-ray to detect pneumonia

30. Vaccine Effectiveness against Clinical Influenza 1943-1945 Influenza AInfluenza B cases Nn%Nn% Vaccine62631382.260071.2 Placebo62114427.111001099.9 Protective Effectiveness69%88% Sources: JAMA 1944; 124:982 and JAMA 1945;131:273

31. Influenza Vaccine Efficacy 1943 Subanalysis: University of Michigan Per cent with Clinical Illness N Any respiratory Outpatient influenza Inpatient influenza Pneumonia Vaccine87835520 Placebo87544890.5 Protective Effectiveness 21 %38 %78 %100 % Source: Am J Hyg 1945; 42:57

32. Influenza Vaccine Efficacy 1943 Other Observations The placebo group was “diluted” by the presence of an immunized cohort which may have reduced transmission in the placebo group – the concept of “herd” immunity The differences in attack rates between vaccine and placebo were greatest at the peak of the epidemic and became less as the epidemic receded, possibly because susceptibles were cumulatively eliminated– another “herd” effect

33. Protective Immunity to Drift Variant: Family Study, Texas, 1976 37 families with 155 members, Houston Family Study A/Port Chalmers/1/73-like (H3N2) viruses caused an epidemic in 1975 and resulted in antibody production A/Victoria/3/75-like viruses (drift variants of A/PC/73) caused an epidemic in 1976 Virus isolation and serology to document infection No vaccine used (but contemporary vaccines were A/PC/73 for H3N2)

34. Protective Immunity to H3N2 Drift Variant A/Victoria/3/75 Pre exposure HI titer Antibody to<101020>40 Port Chalmers/73 N=15452542820 Per cent ill19 45 Per cent infected39301810 Victoria/75 N=1546463216 Per cent ill191450 Per cent infected36241917 Source: J Hyg Camb 1981; 86:303

35. Protective Immunity to Drift Variant: Family Study, Texas, 1986 98 families with 192 children 3-18 years old from the Houston Family Study Inactivated or live attenuated vaccines given contained A/Chile/1/83-like H1N1 viruses Single dose vaccine administered to all ages A/Taiwan/1/86-like viruses (drift variants of A/Chile/83) caused an epidemic in 1986-1987 Virus isolation and serology to document infection

36. Protective Effectiveness against Drift Variant A/Taiwan/1/86 Per Cent Infected Age:3-910-18Total Vaccine Live Attenuated182421 Inactivated26017 Placebo395244 Protective effect: 52% live attenuated 61% inactivated Source: J Infect Dis 1991; 163: 300

37. Protective Immunity to Drift Variant: Nursing Home, Colorado, 1986 Outbreak caused by H3N2 drift variant (A/Sichuan/2/87-like) of vaccine strain (A/Leningrad/6/86) 72% of residents immunized after outbreak started with peak of outbreak 2 weeks after immunization Retrospective analysis using nursing home documentation of fever, illness, pneumonia and death Serologic confirmation of infection in subset Source: JAGS 1989; 37:407

38. Effectiveness against Drift Variant: Nursing Home, Colorado, 1987

39. After VaccineAll Residents VaccineNo VaccineVaccineNo Vaccine N64177428 Febrile URI131020 Pneumonia03012 Death0207 Protect Effect: 65% Source: JAGS 1989; 37:407

40. Generalized Facts about Influenza Vaccine Effectiveness Vaccine protective effect is more obvious for more severe forms of illness and for complications related to influenza infection Vaccine shifts the spectrum of disease toward less severe consequences and milder illness Higher antibody titers are more likely to result in protection from clinical illness > infection Vaccine administered in an ongoing epidemic may reduce illness, pneumonia and death even when antigenic drift has occurred

41. WHO Recommendations for Influenza Vaccine Composition Northern hemisphere: 2004-2005 “ It is recommended that vaccines to be used in the 2004-2005 northern hemisphere influenza season contain the following:  an A/New Caledonia/20/99(H1N1)-like virus  an A/Fujian/411/2002(H3N2)-like virus  a B/Shanghai/361/2002-like virus ”

42. Question for Committee Recommendation What strains should be recommended for the antigenic composition of the 2004-2005 influenza virus vaccine? Based on Epidemiology and antigenic characteristics Serologic Responses Availability of candidate strains