Influenza Virus Vaccine

Composition 2004-2005

Roland A. Levandowski, M.D.

Division of Viral Products

Prepared for Vaccines and Related Biological Products Advisory Committee18-19 February 2004

Topics for VRBPAC18-19 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

Question for Committee Recommendation

What strains should be recommended for the antigenic composition of the 2004-2005 influenza virus vaccine?

Review of Strain Selection for2003-2004

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

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 2003-2004:New Strains Present?

Influenza A H1N1? NO

HA of all strains were similar to the vaccine strain

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

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

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

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

Strain Selection 2003-2004: Strains Suitable for Manufacture Available?

TIMING NO

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

Week

0 2 4 6 8 10 12 14 16 18 20 22 24+

REFERENCE VIRUS REFERENCE REAGENTS

SEED VIRUS PREP MONOVALENT PRODUCTION STRAIN 1 STRAIN 2 STRAIN 3 TRIVALENT PRODUCTION FILLING VACCINE RELEASE VACCINE DISTRIBUTION

Relative Effort for Production of Monovalent Vaccine Components

Per Cent of Total Inactivated Vaccine

Monovalent Lots Submitted for Release

1998 1999 2000 2001 2002 2003

H3 25 17 28 21 17 23

H1 37 28 47 44 43 43

B 38 55 25 35 40 34

Strains changed

B H1 and H3

B B None

Timing of Submission of Influenza Vaccines for Release 2003

0

5

10

15

20

25

30

35

40

45

50

MAR APR MAY JUN JUL AUG SEP OCT NOV DEC

Month

Nu

mb

er

of

Lo

ts

Monovalent

Trivalent

Cumulative Trivalent Influenza Vaccine Submitted for Release 2000-2003

0

10

20

30

40

50

60

70

80

90

100

JUN JUL AUG SEP OCT NOV DECMonth

Cum

ulat

ive

Per

cen

t

2003 2002 2001 2000

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 1918-1944 (H1N1)

0

5

10

15

20

25

30

35

<5 5-9 10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-59

>60

Age (Yrs)

Cas

es p

er 1

0,00

0

1918-1919

1919-1920

1928-1929

1940-1941

1943-1944

Source: Public Health Reports 1944; 59:1483

Influenza Season Morbidity:Pneumonia

Baltimore 1918-1944 (H1N1)

Source: Public Health Reports 1944; 59:1483

0

1

2

3

4

5

<5 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-59 >60

Age (Yrs)

Ca

se

s p

er

10

,00

0

1918-1919

1919-1920

1928-1929

1940-1941

1943-1944

Influenza Season Morbidity: Hospitalizations

Houston 1975-1976

Source: Epidemiol Rev 1982; 4:25

0

20

40

60

80

100

120

140

160

180

<1 1-4 5-9 10-14 15-19 20-24 25-34 35-44 45-54 55-64 >65Age (Yrs)

Ho

spit

aliz

atio

ns

per

10,

000 A/Victoria/3/75 (H3N2)-like viruses

Influenza Season Mortality: Harris County, Texas 1977-1978

Source: Epidemiol Rev 1982; 4:25

0

2

4

6

8

10

12

14

16

18

20

<1 1-4 5-19 20-44 45-64 >65

Age (Yrs)

Dea

ths

per

10,

000

A/Texas/1/77 (H3N2)-like viruses

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

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

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

Influenza Vaccine EfficacyClinical 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 1943-1945

Influenza A Influenza B

cases cases

N n % N n %

Vaccine 6263 138 2.2 600 7 1.2

Placebo 6211 442 7.1 1100 109 9.9

Protective

Effectiveness 69% 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 878 35 5 2 0

Placebo 875 44 8 9 0.5

Protective Effectiveness

21 % 38 % 78 % 100 %

Source: Am J Hyg 1945; 42:57

Influenza Vaccine Efficacy 1943Other 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, 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)

Protective Immunity to H3N2 Drift Variant A/Victoria/3/75

Pre exposure HI titer

Antibody to <10 10 20 >40

Port Chalmers/73 N=154 52 54 28 20

Per cent ill 19 19 4 5

Per cent infected 39 30 18 10

Victoria/75 N=154 64 63 21 6

Per cent ill 19 14 5 0

Per cent infected 36 24 19 17

Source: J Hyg Camb 1981; 86:303

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

Protective Effectiveness againstDrift Variant A/Taiwan/1/86

Per Cent Infected

Age: 3-9 10-18 Total

Vaccine

Live Attenuated 18 24 21

Inactivated 26 0 17

Placebo 39 52 44

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

0

1

2

3

4

5

6

7

8

9

10

Week 1 (Outbreakstarts)

2 (Vaccinegiven)

3 4 5

Nu

mb

er

of

Cas

es Immunized Unimmunized

Source: JAGS 1989; 37:407

Effectiveness against Drift Variant: Nursing Home, Colorado, 1987

Effectiveness against Drift Variant: Nursing Home, Colorado, 1987

After Vaccine All Residents

Vaccine No Vaccine Vaccine No Vaccine

N 64 17 74 28

Febrile URI 13 10 20 20

Pneumonia 0 3 0 12

Death 0 2 0 7

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 CompositionNorthern 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 ”

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