a120426t1541-79501-swe-5a. fluenz a live attenuated influenza vaccine (laiv)
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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
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