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FLUENZ A Live Attenuated Influenza

Vaccine (LAIV)

Agenda

FLUENZ

Product characteristics

Indication

Mode of Action

Others

Efficacy

Safety

Practical information.

Product characteristics

4

55

• FLUENZ nasal spray, suspension

• Influenza vaccine (live attenuated nasal)

• Trivalent (A/H1N1, A/H3N2, B)

• 0.2 mL intranasal spray (0.1 mL per nostril)

• Contains no preservatives (e.g., no thimerosal) or adjuvants (e.g. alum or squalene)

• Storage at 2-8 ºC

• Approved in U.S., Hong Kong, South Korea, Israel, UAE, Macau for 2-49 years, Canada for 2-59 years, Europe for 2-17 years.

• FLUENZ /FluMist has been used in the US since 2003.

FLUENZ

Ref. SmPC FLUENZ

FLUENZ SmPC

Therapeutic indication

FLUENZ is indicated for the prophylaxis of influenza in individuals 24 months to less than 18 year of age

The use of FLUENZ should be based on official recommendations

6

Ref. SmPC FLUENZ

Special warnings & precautionsContraindications

• Should not be administered to children

with severe asthma or active wheezing as not adequately studied

• Vaccine recipients should attempt to avoid close association with severely immunocompromised individuals

Children and adolescents:•hypersensitivity to: the active substances, any of the excipients, gentamicin or to egg proteins

Children and adolescents: •clinically immunodeficient due to conditions or immunosupp. therapy•receiving salicylate therapy

7

For additional information, see SmPC

Ref. SmPC FLUENZ

FLUENZ SmPC

Extensive documentation behind EMA approval

Clinical efficacy or immunogenicity data from 43 studies• > 64.000 subjects• 31 studies included paediatric subjects

Efficacy in paediatric subjects were assessed in 9 studies:• > 20.000 children• 6 placebo-controlled• 3 TIV (trivalent inactivated influenza vaccine) controlled

Safety data• > 28,500 subjects 2 to 17 years of age from clinical studies• > 52,500 children and adolescents from post authorisation safety studies

Flumist on the US market since 2003. > 39 million doses have been distributed

Fluenz Summary of Product Characteristics, http://www.ema.europa.eu, 2011-03-17Assessment report Fluenz, 2011-09-26http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001101/WC500103711.pdf

AstraZeneca

Mode of administration

LAIV vaccine is sprayed directly into the nasal cavity1

Needle-free

Active inhalation/sniffingnot required

Intranasal administration enables induction of immunity at the site of virus entry2

Induces a broad innate, mucosal and systemic response2

Designed to more closely mimic the immune response generated by wild-type influenza2

9

1. FLUENZ SmPC2. Tosh P et al. Mayo Clin Proc 2008; 83: 77–84.

Types of influenza vaccine approved in the EU

CONFIDENTIAL – For Internal Use Only 10

Please refer to the specific prescribing information for each manufacturer’s influenza vaccine as not all influenza vaccines are indicated for all ages

Live attenuated influenza vaccine, intranasal

Attenuated vaccine with multiple antigens3,4*

LAIV

Trivalent inactivated influenza vaccine, intramuscular

HA is the only standardised component; other antigens

may be present1,2*

TIV

HA: haemagglutinin; M1, M2: matrix proteins; NA: neuraminidase; NP: nucleoprotein.*Image adapted from: Clinical Virology. 6th ed. 1997:911–942.4

HAHA

HA

HANA

NP

1. Fluarix [Summary of Product Characteristics]. GlaxoSmithKline plc. 2. Fluvirin [Summary of Product Characteristics]. Novartis Vaccines and Diagnostics Ltd. 3. FLUENZ SmPC4. Hayden FG et al. Clinical Virology. 6th ed. 1997;911–942.

LAIV is engineered to prevent influenza infection

Attenuated virus: disease-causing properties removed so as not to cause illness

Cold-adapted: replicates efficiently only in the cooler areas of the nasopharynx

Temperature-sensitive: does not replicate efficiently in warmer areas of the lower respiratory tract where influenza viruses typically replicate

11

1. Cox RJ, et al. Scand J Immunol. 2004;59:1-152. SmPC FLUENZ3. Assessment report Fluenz, 2011-09-264. Maassab HF, DeBorde DC. Vaccine. 1985b;3(5):355-369

FLUENZ creates a broad immune response.

Mucosal and systemic immune response

mucosal IgA, systemic IgG and influenza specific T-cells2)

Resembles natural response to infection- engineered not to cause disease1

12

1. Cox RJ, et al. Scand J Immunol 2004;59:1-15.2. Tam JS, et al. Pediatr Infect Dis J 2007;26(7):619-6283. Ambrose C, et al. Pediatri Infect Dis J 2008; 27:744-8.4. Honolulo HI, Halloran ME, et al. Am J Epidemiol. 2003;158:305-3115. Gaglani M, et al. Pediatr Infect Dis J 2001;20:1155-11606. Fluenz: EPAR – Public assessment report. Published: 17/03/2011

Efficacy

13

Study Region Age range NInfluenza season

D153-P502 Europe 6–35 months 1,6162000/20012001/2002

D153-P504 Africa, Latin America 6–35 months 1,88620012002

D153-P513 Asia/Oceania 6–35 months 2,107 2002

D153-P522Europe, Asia/Oceania, Latin

America11–24 months 1,150 2002/2003

D153-P501 Asia/Oceania 12–35 months 2,7642000/20012001/2002

AV006 USA 15–71 months 1,2591996/19971997/1998

Key studies conducted in children* – Placebo-controlled trials

14

*LAIV is not approved for children under 24 months of age

Ref. FLUENZ SmPC

Summary of 6 randomized studies:High FLUENZ efficacy in pediatric population.

15

PlaceboLAIV

60% reduction(95% CI: 51, 68)

77% reduction(95% CI: 72, 80)

87% reduction(95% CI: 81, 90)

5.7%

3.1%

1.6%

14.6% 14.5%

12.6%

0

2

4

6

8

10

12

14

16

One dose in first season(previously unvaccinated)

Two doses in first season(previously unvaccinated)

Revaccination with one dose

in second season(previously vaccinated)

Incid

en

ce o

f in

flu

en

za

(matc

hed

str

ain

s),

%Efficacy of one and two doses of LAIV vs. placebo on

culture-confirmed influenza for antigenically similar subtypes

*LAIV is not approved for children under 24 months of age

Rhorer J et al. Vaccine 2009; 27: 1101–1110.

Key studies conducted in children* – TIV-controlled trials

16

*LAIV is not approved for children under 24 months of age

FLUENZ [Summary of Product Characteristics]. AstraZeneca Ltd.

Study Region Age range NInfluenza season

MI-CP111 USA, Europe, Asia/Oceania 6–59 months 7,852 2004/2005

D153-P514 Europe 6–71 months 2,085 2002/2003

D153-P515 Europe6–17 years with

asthma2,211 2002/2003

3.9%

2.8%

4.5%

8.6%

5.8%

6.6%

Higher efficacy relative to TIV for all strains regardless of match

17

32% reduction(95% CI: 1, 54)

52% reduction(95% CI: 25, 71)

6–71 months2 6–17 years3

55% reduction(95% CI: 45, 63)

Age

0

1

2

3

4

5

6

7

8

9

10

6–59 months1

Incid

en

ce o

f in

flu

en

za(m

atc

hed

str

ain

s),

%3 randomised studies: all strains regardless of match

13,000 children 6 months to 17 years*

TIVLAIV

*LAIV is not approved for children under 24 months of age1. Belshe RB et al. New Engl J Med 2007; 356: 685–696.2. Ashkenazi S et al. Pediatr Infect Dis J 2006; 25: 870–879. 3. Fleming D et al. Pediatr Infect Dis J 2006; 25: 860–869.

Mismatched strains: Comparison of LAIV vs. placebo or TIV

18

86% reduction in attack rate

(95% CI: 75, 92)

79% reduction in attack rate

(95% CI: 71, 86)

6% reduction in attack rate

(95% CI: −32, 33)

MismatchedA/H3N2 (1997/1998)

Study AV006

MismatchedA/H3N2 (2004/2005)

Study CP111

Mismatched B(2004/2005)Study CP111

1.6%0.9%

1.7%

11.6%

4.5%

1.8%

26–85 months1 6–59 months2 6–59 months2

0

2

4

6

8

10

12

14

Incid

en

ce o

f cu

ltu

re-c

on

firm

ed

in

flu

en

za,

%

Placebo recipientsLAIV recipientsTIV recipients

Incidence of culture-confirmed influenza in children aged 6–85 months* in

2 randomised studies

*LAIV is not approved for children under 24 months of age1. Belshe RB et al. J Pediatr 2000; 136: 168–175.2. Belshe RB et al. N Eng J Med 2007; 356: 685–696.

Cochrane reviewEfficacy LAIV and TIV.

Children > 2 år

LAIV vs placebo TIV vs placebo

Efficacy 82% (95% CI: 71%-89%) 59% (95% CI: 41%-71%)

Cochrane review: Jefferson et al. Vaccines for preventing influenza in healthy children.Cochrane Database Syst Rev. 200816;(2):CD004879

FLUENZ has shown to protect over time

FLUENZ gave 73% efficacy against matched influenza strains over a 12 months period1,2

FLUENZ protected against late influenza outbreaks 2

1. Ambrose C, et al. Pediatri Infect Dis J 2008;27:744-7482. Tam J, et al. Pediatr Infect Dis J 2007;26:619-6283. Fluenz SmPC

LAIV shows an increase in efficacy over time relative to TIV

In 3 TIV-controlled studies, the relative efficacy of LAIV versus TIV for matched strains increased with time in each study

Results are best explained by a decline in TIV efficacy over time

Time from first vaccination to influenza illness (months)0

0

1

2

3

4

Incid

en

ce,

%

1 2 3 4 5 6 7 8

TIVLAIV

0–4 monthsRelative efficacy (95% CI):

34% (3, 55)

>4–8 monthsRelative efficacy (95% CI):

62% (42, 76)

Efficacy by time post-vaccination versus placebo; matched strains

21

Ambrose CS et al. Pediatr Infect Dis J 2010; 29: 806–811.

Adapted from Ambrose CS et al, 2010

Safety

22

Comparable safety to placebo in children aged 2–17 years of age†

23

Adapted from Ambrose CS et al, 2011

Solicited reactogenicity events days 0–10 post-vaccination in year 1 of placebo-controlled

studies

†Data available from 14 placebo-controlled studies.*Statistically significant difference (p<0.05).Ambrose CS et al. Influenza Other Respi Viruses 2011; DOI: 10.1111/j.1750-2659.2011.00243.x.

*

*

0

70

Incid

en

ce,

%

60

50

40

30

20

10* *

Runny

/stu

ffy no

se

Coug

h

Dec

reas

ed a

ppet

ite

Irrita

bilit

y

Abdom

inal

pai

n

Dec

reas

ed a

ctivity

/tired

ness

Hea

dach

e

Vomiti

ng

Sore

thr

oat

Mus

cle

ache

Chill

s

≥38

.0C

≥39

.0C

≥40

.0C

Fever

LAIV dose 1Placebo dose 1LAIV dose 2Placebo dose 2

Comparable safety to TIV in children aged 2–17 years of age†

24

Solicited reactogenicity events days 0–10 post-vaccination in year 1 of TIV studies

*

*

0

70

60

50

40

30

20

10

Runny

/stu

ffy no

se

Coug

h

Dec

reas

ed a

ppet

ite

Irrita

bilit

y

Abdom

inal

pai

n

Hea

dach

e

Vomiti

ng

Sore

thr

oat

Mus

cle

ache

Chill

s

≥38

.0C

≥39

.0C

≥40

.0C

*

LAIV dose 1TIV dose 1LAIV dose 2TIV dose 2

Dec

reas

ed a

ctivity

/tired

ness

Fever

Adapted from Ambrose CS et al, 2011

†Data available from six TIV-controlled studies.*Statistically significant difference (p<0.05).Ambrose CS et al. Influenza Other Respi Viruses 2011; DOI: 10.1111/j.1750-2659.2011.00243.x.

Incid

en

ce,

%

Study P515: asthma exacerbations within 42 days of vaccination with LAIV or TIV

The incidence of asthma exacerbations were comparable between groups

No significant differences were observed between treatment groups in mean PEFR findings, asthma symptoms scores, or night-time awakening scores

25

PEFR: Peak expiratory flow rate.Fleming D et al. Pediatr Infect Dis J 2006; 25: 860–869.

12.0

0.3

8.3

11.411.8

7.7

11.6

0.30

2

4

6

8

10

12

14

Asthma exacerbations

Hospitalisation Unscheduled clinic visits

Increasedmedication

Incid

en

ce (

%)

TIV LAIV

Asthma exacerbations occurring within 42 days of vaccination with LAIV or TIV

Adapted from Fleming D et al, 2006

FLUENZ SmPC Adverse reactions

Adverse reaction frequenciesAdverse reaction frequencies are reported as: Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Very rare (< 1/10,000)

Adverse reaction Frequency

Respiratory, thoracic, and mediastinal disorders:Nasal congestion/rhinorrhoeaEpistaxis

Very commonUncommon

Metabolism and nutrition disorders:Decreased appetite Very common

Nervous system disorders:HeadacheGuillain-Barre syndrome Worsening of Leigh syndrome

Very commonVery rare Very rare

General disorders and administration site conditions:MalaisePyrexia

Very commonCommon

Musculoskeletal and connective tissue disorders:Myalgia Common

Immune system disorders:Hypersensitivity reactions (including facial oedema, urticaria and very rare anaphylactic reactions) Uncommon

Skin and subcutaneous tissue disorders:Rash Uncommon

26

Summary

Offer a novel administration well suited for children

Superior efficacy vs traditional influenza vaccines among pediatric populations.

Both during match and mismatch seasons.

Shown protection over time (12 months).

Protects at the site entry of influenza virus. Designed to trigger a broad immunity: IgA, IgG antibodies and T-cellular immune response.

Well documented with safety aligned with traditional influenza vaccine.

Used in US since 2003 with > 39 million doses distributed.

Experience from seasonal and pandemic setting within pediatric population without safety issues.

27

Practical Information

28

Administration & others

FLUENZ is supplied as a single-use, pre-filled intranasal spray device, containing a 0.2 ml dose. 10-pack.

FLUENZ must be administered by a Healthcare Professional

The patient should breathe normally

There is no need to readminister if:

FLUENZ drips out of the nose

The patient sneezes

The patient blows their nose

Shelf life

18 weeks from distribution date; expiration date is listed on the sprayers

29

Ref. SmPC FLUENZ

Back up

30

FLUENZ SmPC Contraindications

FLUENZ is contraindicated in children and adolescents with hypersensitivity to the active ingredients, any excipients, gentamicin, to eggs or to egg proteins

FLUENZ is contraindicated for children and adolescents who are clinically immunodeficient due to conditions or immunosuppressive therapy such as: acute and chronic leukemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high dose corticosteriods

FLUENZ is not contraindicated for use in individuals with asymptomatic HIV infection; or individuals who are receiving topical/inhaled corticosteroids or low-dose systemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. for adrenal insufficiency

FLUENZ is contraindicated in children and adolescents receiving salicylate (e.g. aspirin) therapy because of the association of Reyes syndrome with salicylates and wild-type influenza infection

31

Ref. SmPC FLUENZ

FLUENZ SmPCSpecial warnings and precautions

32

As with most vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of FLUENZ.

FLUENZ should not be administered to children and adolescents with severe asthma or active wheezing because these individuals have not been adequately studied in clinical studies.

Note: FLUENZ is NOT contraindicated for children mild or moderate asthma

Do not administer FLUENZ to infants and toddlers younger than 12 months. In a clinical study, an increase in hospitalisations was observed in children younger than 12 months after vaccination. It is not recommended to administer FLUENZ to infants and toddlers 12-23 months of age. In a clinical study, an increased rate of wheezing was observed in children 12-23 months of age after vaccination.

Vaccine recipients should be informed that FLUENZ is an attenuated live virus vaccine and has the potential for transmission to immunocompromised contacts. Vaccine recipients should attempt to avoid, whenever possible, close association with severely immunocompromised individuals (e.g. bone marrow transplant recipients requiring isolation) for 1-2 weeks following vaccination.

No data exist regarding the safety of intranasal administration of FLUENZ in children with unrepairedcraniofacial malformations.

FLUENZ should under no circumstances be injected.

Ref. SmPC FLUENZ

Asthma documentation

There are several studies in children with asthma.  

The Fleming study: LAIV vs TIV. N= 2 211 Children (6-17 y) with mild-moderate asthma.

Results: LAIV higher efficacy vs TIV with comparable safety.

The Ashkenazi study: LAIV vs TIV. N= 2187 . Young children (6-71 months) with history of wheezing (46%) and asthma (23%).

Results: LAIV higher efficacy vs TIV with comparable safety.

The Redding study: LAIV vs placebo. N= 48. Children (9 - 17 y) with moderate to severe asthma.

Results: comparable safety.

EMA: safety has been established in children of all ages with mild to moderate asthma.  Not sufficient data on children with sever asthma.

33

Ref: Ashkenazi S et al Pediatr.Infect.Dis.J. 2006 Oct;25(10):870-879. Fleming DM et al. Pediatr.Infect.Dis.J. 2006 Oct;25(10):860-869 Redding et al Pediatr Infect Dis J, 2002;21:44–8. EMA Assessment report FKUENZ

Recommendations in other countries.

34

FLUENZ SmPC Undesirable effects

Not indicated in children < 24 months of age due to increased risk of wheezing post vaccination

Children with Hospitalisations and Wheezing from CP111

Adverse reaction Age group FLUENZ Active Control

Hospitalisation (any cause)From randomisation through 180 days post last vaccination

6–11 months 6.1 % 2.6 %

12+ months No significant difference

WheezingRequiring bronchodilator therapy or with significant respiratory symptoms, from randomisation through 42 days post last vaccination

6–23 months 5.9 % 3.8 %

24+ months No significant difference

35

Summary of adverse events in children aged 2- 6 years

*Most common adverse reactions (≥10% in LAIV and at least 5% greater than in control) are runny nose or nasal congestion and fever >37,8°C in children 2-6 years of age

Placebo studies

D153-P501 and AV0062 years to 6 years of age1-2

Active-controlled study2 years to 5 years of age3

MI-CP111

Event

LAIV(N=876-1,764)

%

Placebo(N=424-1,036)

%

LAIV(N=2,170)

%

TIV(N=2,165)

%

Runny nose/nasal congestion* 58 50 51 42

Decreased appetite 21 17 13 12Irritability 21 19 12 11Decreased activity (lethargy) 14 11 7 6Sore throat 11 9 5 6Headache 9 7 3 3Muscle aches 6 3 2 2Chills 4 3 2 2

Fever*

37,8°C – 38,3°C Oral 9 6 6 438,3°C – 38,9°C Oral 4 3 4 3

Studies reflect the data collected between 2 pooled studies and 1 active-controlled study

1. Belshe, et al. N Engl J Med, 338:1405, 1998. 2. Tam, et al. Pediatr Infect Dis J, 26:619, 2007. 3. Belshe, et al. N Engl J Med, 356:685,2007.

Rates of wheezing in children* through 42 days following vaccination

A small but significant increase in wheezing after LAIV vs. TIV was observed in children aged 6–23 months, but there was no significant difference in children aged ≥2 years

37

Medically significant wheezing rates by age

Perc

en

tag

e o

f su

bje

cts

wit

h m

ed

ically s

ign

ifican

t w

heezi

ng

Adapted from Belshe R et al, 2008

*LAIV is not approved for children under 24 months of age†Age at time of first vaccine dose1. Belshe RB et al. Vaccine 2008; 26S: D10–D16.

Increased hospitalizations observed in children 6-11 months of age through 180 days

Rates of hospitalisation for any cause were only higher amongst LAIV recipients aged 6–11 months*

38

Hospitalisation rates by age

p=0.002

0

1

2

3

4

5

6

7

6–11 12–23 24–35 36–47 48–59

Age (months)

Incid

en

ce (

%)

LAIV

TIV

*LAIV is not approved for children under 24 months of ageBelshe RB et al. N Eng J Med 2007; 356: 685–696.

Adapted from Belshe R et al, 2007