a New Era Begins

Live attenuated intranasal Influenza Vaccine

Some Considerations for Evaluation of a Live Vaccine

• Safety

• Efficacy

• Risk:Benefit

• Basis of Attenuation

• Transmission/ genetic stability

• Time to Development

• Cost

Structure of Influenza Virus(Type A and B)

Viral Genome 8 Negative-Sense RNA Segments

Viral Non-EnvelopeProteins: PB1, PB2, PA Polymerase Complex

NP

Matrix (M1)

Non-StructuralProteins

NS1, NEP

M2

Neuraminidase (NA)

Viral Envelope Proteins:

Hemagglutinin (HA)

Influenza Epidemiology / Burden of Disease

Influenza

Most common medically attended acute respiratory illness

Fever, chills, myalgia, cough, sore throat, nasal congestion, headache, malaise

Annual U.S. disease burden 20-50M people infected 20,000-50,000 deaths 70M lost work days and 38M lost school days Societal costs nearly $12B

MMWR 2001; American Lung Association, 3/01

Influenza-related Morbidity and Mortality

<5 5-9 10-14 15-19 20-24 25-34 35-44 45-54 55-64 >65

Pneumonia-Influenza Mortality

120

80

40

0

Age (Years)

80

40

0

30

20

10

0

Per 100,000

Per 10,000

Per 100

Hospitalizations

Medically Attended Illness

Rates

Glezen WP. Epidemiol Rev. 1996; 18(1),64-76.

20

60

Vaccination is primary method for prevention of disease Trivalent inactivated vaccine given IM Recommended 6-24 months, >50 years Virus “drift” dictates annual vaccination

Two manufacturers Aventis Pasteur Chiron (Powderject/Evans/Medeva)

80- 90M doses sold annually in U.S. Growing at 7%

Inactivated Influenza Vaccine

Current Trivalent Inactivated Influenza Vaccine (TIV)

93 million doses of TIV sold in U.S. for 2002/2003, but

25M-50M annual influenza infections in the US

70M lost work days, 38M missed school days

Limitations of TIV vaccine program

150 million healthy people not vaccinated

<10% of healthy children, < 30% of healthy adults <30% of high risk children

Annual injection required

A live Flu vaccine meets a major public health need

Ease/ acceptance of administration

Live, cold-adapted, attenuated influenza virus Live, cold-adapted, attenuated influenza virus vaccine: current indication –healthy individuals 5-vaccine: current indication –healthy individuals 5-49 years of age49 years of age

Delivered by large particle intranasal mistDelivered by large particle intranasal mist

Trivalent blend of 10Trivalent blend of 107.07.0 infectious particles of each infectious particles of each strain: A/H1N1, A/H3N2, Bstrain: A/H1N1, A/H3N2, B

Induction of systemic IgG/IgA, local secretory IgA Induction of systemic IgG/IgA, local secretory IgA and cytotoxic T cell responsesand cytotoxic T cell responses

> 20 clinical trials completed; >25,000 subjects> 20 clinical trials completed; >25,000 subjects

First live attenuated Nasal Flu Vaccine- FluMist™

1967 1985 1989 19951976

Johnson1963 - 69

Nixon1969 - 74

Ford1974 - 77

Carter1977 - 81

Reagan1981 - 89

Bush1989 - 93

Clinton1993 - 01

By 2002, 25 separate influenza strains in over 28,000 people tested as CAIV reassortants

John Maassab describes cold

adapted influenza viruses

First human studies

with 6:2 CAIV reassortants

Four year efficacy study of

CAIV/TIV

First FluMisttm trial

2003

Bush, Jr.2001-

Live Influenza Vaccine Milestones:The First 36 years

FDA VRBPAC Review - #1

FDA VRBPA Review - #2

Licensure

6/17/03

Avironformed

Derivation of Cold-Adapted A & B Master Donor Viruses

Maassab, Nature; 1967

36oC

33oC

30oC

25oC

PCK CellsMultiplePassagesAt Reduced Temperatures

Plaque Purify 25oCPCK CellsPlaque Purify

EggAmplificationMDV- ca,ts,att

WT

Derivation of New Master Virus Strain

6:2 Master Virus Strain (ca, ts, att)

New Wild Type StrainMaster Donor Virus

Co-infect CellsCo-infect Cells

Six genes from Six genes from MDVMDV

confer confer ca, ts, att ca, ts, att phenotypephenotype

Hemagglutinin and Hemagglutinin and Neuraminidase Genes Neuraminidase Genes

from Wild Typefrom Wild Type

• In a Time & Motion study* of 497 pediatric subjects receiving intranasal flu vaccine, 12/497, or 2% cried

* Unpublished data

Intranasal Administration of FluMist tm

Clinical Studies

Flumisttm

Efficacy Trial Healthy Children Study AV006

Randomized, double-blind, placebo-controlled two year trial

1,602 healthy children ages 15-71 months at entry

Active surveillance with illness cultures

Primary endpoint: culture-confirmed influenza

Circulating strains

A/Wuhan/359/95 (H3N2) and B/Beijing/184/93-like in Year 1

A/Sydney/05/97 (H3N2), a mismatched strain in Year 2

Safety of FluMist in Indicated Populations (Ages 5-49 years)

Generally safe and well tolerated

Most common side effects are mild and temporary Runny nose and other various cold-like

symptoms

No related serious adverse events

Pediatric Efficacy Trial (AV006): Results

Year 1 Year 2* Years 1 & 2Virus (n = 1602) (n = 1358)

A 95% 87%* 92%

B 91% 100% 91%

Either 93% 87% 92%

*H3N2 mismatched

Belshe et al. N Engl J Med. 1998; 338:1405Belshe et al. J Pediatr. 2000; 136:168

0

20

40

60

80

100

Vaccine (A/Wuhan) Variant (A/Sydney)

FluMist TIV

% S

e ro c

o nve

rsio

n (>

=4-

fold

ris

e)

HAI Antibody to H3N2 StrainsTwo dose regimen in seronegative children

Belshe et al., 2000Belshe et al., 2000

P<0.001

0

10

20

30

40

50

60

70

80

90

Panama Wyoming Panama Wyoming

CAIV-T TIV

% S

er o

con

vers

ion

(>

=4

- fo l

d

rise

)

P<0.001P<0.001

P<0.001

Antibody to H3N2 After One Dose of CAIV-T or TIV in Seronegative

Infants

--------HAI assay------- ----Neutralization assay---

Wyoming strain is a Fujian-like antigenic variant to the Panama Wyoming strain is a Fujian-like antigenic variant to the Panama vaccine strainvaccine strain

FluMist Effectiveness Against Febrile Upper Respiratory Illness in

Healthy AdultsEndpoint Reduction p-valuea

Occurrence of: 21.9 % 0.010

Episodes of: 23.6 % <0.0001

Daysb of: 24.8 % <0.0001

Illness Associated Days of:Missed Work Health-care Provider VisitsPrescription AntibioticsOTC Medication Use

28.4 %40.9 %45.2 %28.0 %

<0.0001<0.0001<0.0001<0.0001

a Unadjusted for multiple comparisons.b Days per 1,000 participants per 7-week outbreak period.

Medically Attended Events in Children and Adolescents - Kaiser Study (AV019)

Randomized 2:1, double-blind, placebo-controlled

Safety of FluMist in 9,689 children

Outcomes examined from diagnosis in database over 42 days

>1,500 comparisons made without statistical adjustment

Emergency Department, Clinic, Hospital, and Combined

1-17 years, 1-8 years, 9-17 years, 18-35 mo., 12-17 mo.

Occurrence of Asthma (AV019)

Age FluMist n/N

Placebo n/N

Rate per 1000 person-months FluMist / Placebo

Binomial Relative Risk

(90% CI)

1 – 17 58 / 6473 30 / 3216 4.58 / 4.770.96 (0.66, 1.40)

P=.422

1 – 8 45 / 3769 21 / 1868 5.05 / 4.761.06

(0.69, 1.66) P=.418

18–35 mos.

16 / 728 2 / 369 9.30 / 2.294.06

(1.29, 17.86) P=.019

12–17 mos.

1 / 171 3 / 90 2.51 / 14.430.17

(0.01, 1.17) P=0.67

Asthma by Day Following Vaccination for Asthma by Day Following Vaccination for Participants 18Participants 18––35 Months of Age35 Months of Age

Relative Risk: 4.06 - but no temporal relationship within 42 days

0

1

2

3

4

5

6

0 4 8 12 16 20 24 28 32 36 40

Day post Vaccination

Flu

Mis

t

0

1

2

3

Pla

ce

bo

FluMist

Placebo

Viruses detection rates in asthma/wheezing episodes in children

0

10

20

30

40

50

Picorn

a

Corona

Influ

enza

Paraf

luRSV

Oth

er

No Viru

s

% E

pis

od

es

Adapted from S Johnston, et al, BMJ,1995.

Genetic Basis of Attenuation

Flumisttm

Derivation of Cold-Adapted A & B Master Donor Viruses

36oC

33oC

30oC

25oC

PCK CellsMultiplePassagesAt Reduced Temperatures

Plaque Purify 25oCPCK CellsPlaque Purify

EggAmplificationMDV- ca,ts,att

WT

Sequence

Sequence

5 Amino Acid Changes Confer ts and att Phenotypes

PB2

PB1

PA

NP

M

NS

821(N)

1195 (K)

1766(E)

146(D)

PB2

PB1

PA

NP

M

NS

821(S)

1195 (E)

1766(G)

146(G)

non-ts ts

2005(T)

2005(A)

Shedding / Transmission

Flumisttm

Shedding and Infectivity of CAIV

Following challenge, % shedding, mean peak titer and mean duration of shedding are higher in young children than adults

HID50 lower in young children compared to adults

Population % SheddingMean Peak Titer

(Log 10 TCID50/mL)

Mean Duration

(days)

Children 67 - 91 2.1 – 3.4 4.5 – 9.0

Adults 14 - 60 0.7 – 1.8 0.6 – 1.9

Virus Shedding

Population HID50 (Log10 TCID50)

Children 2.5 – 4.6

Adults 4.9 – 6.4

Virus Infectivity

Reviewed In Murphy, Inf. Dis. In Clin Prac, 1993

Reviewed In Murphy & Coelingh, Viral Immunol, 2002

Finnish Daycare TrialWyeth, unpublished data

Randomized (1:1), double-blind, placebo-controlled

197 children age 8 months - 36 months

51 playgroups

Average of 4.1 study children per playgroup

Children attended daycare > 3 days/week and > 4 hours/day

Each placebo child exposed to an average of 1.9 vaccinees

Shedding of influenza A and B in Children – Finnish Trial

0

10

20

30

40

50

60

70

0 4 8 12 16 20 24

Days Post Vaccination

% S

ub

ject

s

A

B

Type B Shed from Vaccinee

Type B Shed from Placebo

Calculated transmission

probability0.006

Coding Changes Observed in Viruses Shed from Children Do Not Overlap with

ts or att loci

PB2

PB1

PA

NP

M

NS

821(N)

1195 (K)

1766(E)

146(D)

2005(T)

340(V)

198(E)

1304(C/S)

789(F-M2)

PB2

PB1

PA

NP

M

NS

499(H/Q)

399(V/A)

1286(P/H)

571(M/V)

718(M)

MDV-A MDV-Bts/att locus

Coding change observed in >1 clinical isolate

1320(V/M)

Conclusions/ Issues1) Flumisttm is safe and effective in healthy children and adults

2) Flumisttm phenotypes (ts, att) are multigenic and stable

3) Flumisttm has a low transmission rate

4) The road from invention to licensure is long and unpredictable, as is the road to acceptance

5) Major issues to be resolved :

a. Relationship of Flumisttm to asthma

b. Safety and efficacy in 50-64 year olds

c. reverse genetics to select new vaccines

d. concurrent vaccination: safety/ efficacy

e. cost

f. Heterotypic immunity

Optimal Indication for a Live Attenuated Influenza Vaccine

Healthy children and healthy adults ages 6 months to 65

years

“The End of the Vaccination Man Era”

Acknowledgements

A) Medimmune Vaccines C) Investigator Community

K Coelingh

G. Kemble B. Belshe

R. Spaete K. Nichol

E. Hoffmann S. Black

H. Jin J. Maassab

P. Mendelman Others

Clinical Group

B) NIH

B. Murphy

R. Chanock

The VTEUs

Others