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

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

Question for Committee Recommendation What strains should be recommended for the antigenic composition of the influenza virus vaccine?

Review of Strain Selection for 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

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?

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?

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

Strain Selection : 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

Strain Selection : 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

Strain Selection : 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

Strain Selection : 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

Strain Selection : 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

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

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

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

Timelines for Vaccine Production

Time to First Trivalent Vaccine Lot after Strain Change

Relative Effort for Production of Monovalent Vaccine Components Per Cent of Total Inactivated Vaccine Monovalent Lots Submitted for Release H H B Strains changed BH1 and H3 BBNone

Timing of Submission of Influenza Vaccines for Release 2003

Cumulative Trivalent Influenza Vaccine Submitted for Release

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

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

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

Influenza Season Morbidity: Hospitalizations Houston Source: Epidemiol Rev 1982; 4:25

Influenza Season Mortality: Harris County, Texas Source: Epidemiol Rev 1982; 4:25

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

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

Influenza Vaccine Efficacy Randomized, placebo controlled field efficacy studies performed 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

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

Vaccine Effectiveness against Clinical Influenza Influenza AInfluenza B cases Nn%Nn% Vaccine Placebo Protective Effectiveness69%88% Sources: JAMA 1944; 124:982 and JAMA 1945;131:273

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

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

Protective Immunity to Drift Variant: Family Study, Texas, 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)

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

Protective Immunity to Drift Variant: Family Study, Texas, 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 Virus isolation and serology to document infection

Protective Effectiveness against Drift Variant A/Taiwan/1/86 Per Cent Infected Age: Total Vaccine Live Attenuated Inactivated26017 Placebo Protective effect: 52% live attenuated 61% inactivated Source: J Infect Dis 1991; 163: 300

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

Effectiveness against Drift Variant: Nursing Home, Colorado, 1987

After VaccineAll Residents VaccineNo VaccineVaccineNo Vaccine N Febrile URI Pneumonia03012 Death0207 Protect Effect: 65% Source: JAGS 1989; 37:407

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

WHO Recommendations for Influenza Vaccine Composition Northern hemisphere: “ It is recommended that vaccines to be used in the 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 ”

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