Transcript FLUENZ A Live Attenuated Influenza Vaccine (LAIV)

A120426T1541-79501-SWE-5A
FLUENZ
A Live Attenuated Influenza Vaccine
(LAIV)
Agenda
FLUENZ
Product characteristics
Indication
Mode of Action
Others
Efficacy
Safety
Practical information.
Product characteristics
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FLUENZ
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FLUENZ nasal spray, suspension
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Storage at 2-8 ºC
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FLUENZ /FluMist has been used in the US since 2003.
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)
Approved in U.S., Hong Kong, South Korea, Israel, UAE, Macau for 249 years, Canada for 2-59 years, Europe for 2-17 years.
Ref. SmPC FLUENZ
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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
Ref. SmPC FLUENZ
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FLUENZ SmPC
Contraindications
Children and adolescents:
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Special warnings & precautions
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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
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Should not be administered to children
with severe asthma or active
wheezing as not adequately
studied
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Vaccine recipients should attempt to
avoid close association with severely
immunocompromised individuals
For additional information, see SmPC
Ref. SmPC FLUENZ
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Extensive documentation behind EMA approval
Clinical efficacy or immunogenicity data from 43 studies
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> 64.000 subjects
31 studies included paediatric subjects
Efficacy in paediatric subjects were assessed in 9 studies:
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> 20.000 children
6 placebo-controlled
3 TIV (trivalent inactivated influenza vaccine) controlled
Safety data
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> 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, 2011-03-17
Assessment report Fluenz, 2011-09-26
http://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/sniffing
not 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
1. FLUENZ SmPC
2. Tosh P et al. Mayo Clin Proc 2008; 83: 77–84.
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Types of influenza vaccine approved in the EU
TIV
LAIV
Trivalent inactivated influenza
vaccine, intramuscular
Live attenuated influenza
vaccine, intranasal
HA is the only standardised
component; other antigens
may be present1,2*
Attenuated vaccine with
multiple antigens3,4*
NA
HA
HA
HA
HA
NP
HA: haemagglutinin; M1, M2: matrix proteins; NA: neuraminidase; NP: nucleoprotein.
*Image adapted from: Clinical Virology. 6th ed. 1997:911–942.4
Please refer to the specific prescribing information for each manufacturer’s
influenza vaccine as not all influenza vaccines are indicated for all ages
1. Fluarix [Summary of Product Characteristics]. GlaxoSmithKline plc.
2. Fluvirin [Summary of Product Characteristics]. Novartis Vaccines and Diagnostics Ltd.
3. FLUENZ SmPC
4. Hayden FG et al. Clinical Virology. 6th ed. 1997;911–942.
CONFIDENTIAL – For Internal Use Only
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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
1. Cox RJ, et al. Scand J Immunol. 2004;59:1-15
2. SmPC FLUENZ
3. Assessment report Fluenz, 2011-09-26
4. Maassab HF, DeBorde DC. Vaccine. 1985b;3(5):355-369
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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
1. Cox RJ, et al. Scand J Immunol 2004;59:1-15.
2. Tam JS, et al. Pediatr Infect Dis J 2007;26(7):619-628
3. Ambrose C, et al. Pediatri Infect Dis J 2008; 27:744-8.
4. Honolulo HI, Halloran ME, et al. Am J Epidemiol. 2003;158:305-311
5. Gaglani M, et al. Pediatr Infect Dis J 2001;20:1155-1160
6. Fluenz: EPAR – Public assessment report. Published: 17/03/2011
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Efficacy
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Key studies conducted in children* –
Placebo-controlled trials
Study
Region
Age range
N
Influenza season
D153-P502
Europe
6–35 months
1,616
2000/2001
2001/2002
D153-P504
Africa, Latin America
6–35 months
1,886
2001
2002
D153-P513
Asia/Oceania
6–35 months
2,107
2002
D153-P522
Europe, Asia/Oceania, Latin
America
11–24 months
1,150
2002/2003
D153-P501
Asia/Oceania
12–35 months
2,764
2000/2001
2001/2002
AV006
USA
15–71 months
1,259
1996/1997
1997/1998
*LAIV is not approved for children under 24 months of age
Ref. FLUENZ SmPC
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Summary of 6 randomized studies:
High FLUENZ efficacy in pediatric population.
Efficacy of one and two doses of LAIV vs. placebo on
culture-confirmed influenza for antigenically similar subtypes
Incidence of influenza
(matched strains), %
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60% reduction
(95% CI: 51, 68)
77% reduction
(95% CI: 72, 80)
14.6%
14.5%
14
87% reduction
(95% CI: 81, 90)
12.6%
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Placebo
LAIV
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8
5.7%
6
4
3.1%
1.6%
2
0
One dose in first season
(previously unvaccinated)
Two doses in first season
(previously unvaccinated)
Revaccination with one dose
in second season
(previously vaccinated)
*LAIV is not approved for children under 24 months of age
Rhorer J et al. Vaccine 2009; 27: 1101–1110.
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Key studies conducted in children* –
TIV-controlled trials
Study
Region
Age range
N
Influenza 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
Europe
6–17 years with
asthma
2,211
2002/2003
*LAIV is not approved for children under 24 months of age
FLUENZ [Summary of Product Characteristics]. AstraZeneca Ltd.
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Higher efficacy relative to TIV for all strains
regardless of match
Incidence of influenza
(matched strains), %
10
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3 randomised studies: all strains regardless of match
13,000 children 6 months to 17 years*
55% reduction
52% reduction
32% reduction
(95% CI: 45, 63)
(95% CI: 25, 71)
(95% CI: 1, 54)
8.6%
8
7
5.8%
6
5
4
TIV
LAIV
6.6%
4.5%
3.9%
2.8%
3
2
1
0
6–59 months1
6–71 months2
Age
6–17 years3
*LAIV is not approved for children under 24 months of age
1. 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.
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Mismatched strains:
Comparison of LAIV vs. placebo or TIV
Incidence of
culture-confirmed influenza, %
Incidence of culture-confirmed influenza in children aged 6–85 months* in
2 randomised studies
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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)
11.6%
Placebo recipients
LAIV recipients
TIV recipients
10
8
4.5%
6
4
2
0
1.6%
0.9%
1.8%
1.7%
Mismatched
A/H3N2 (1997/1998)
Study AV006
Mismatched
A/H3N2 (2004/2005)
Study CP111
Mismatched B
(2004/2005)
Study CP111
26–85 months1
6–59 months2
6–59 months2
*LAIV is not approved for children under 24 months of age
1.
2.
Belshe RB et al. J Pediatr 2000; 136: 168–175.
Belshe RB et al. N Eng J Med 2007; 356: 685–696.
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Cochrane review
Efficacy LAIV and TIV.
Children > 2 år
Efficacy
LAIV vs placebo
TIV vs placebo
82%
59%
(95% CI: 71%-89%)
(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
1. Ambrose C, et al. Pediatri Infect Dis J 2008;27:744-748
2. Tam J, et al. Pediatr Infect Dis J 2007;26:619-628
3. Fluenz SmPC
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LAIV shows an increase in efficacy over time
relative to TIV
Efficacy by time post-vaccination versus placebo; matched strains
Incidence, %
4
0–4 months
Relative efficacy (95% CI):
34% (3, 55)
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>4–8 months
Relative efficacy (95% CI):
62% (42, 76)
TIV
LAIV
2
1
0
0
1
2
3
4
5
6
7
8
Time from first vaccination to influenza illness (months)
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
Adapted from Ambrose CS et al, 2010
Ambrose CS et al. Pediatr Infect Dis J 2010; 29: 806–811.
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Safety
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Comparable safety to placebo in children
aged 2–17 years of age†
Solicited reactogenicity events days 0–10
post-vaccination in year 1 of placebo-controlled studies
70
Incidence, %
60
*
LAIV dose 1
Placebo dose 1
LAIV dose 2
Placebo dose 2
50
40
30
20
10
*
*
*
0
Fever
Adapted from Ambrose CS et al, 2011
†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.
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Comparable safety to TIV in children
aged 2–17 years of age†
Solicited reactogenicity events days 0–10
post-vaccination in year 1 of TIV studies
70
Incidence, %
60
*
LAIV dose 1
TIV dose 1
LAIV dose 2
TIV dose 2
50
40
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30
20
10
*
0
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.
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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
Incidence (%)
Asthma exacerbations occurring
within 42 days of vaccination with LAIV or TIV
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12
TIV
LAIV
12.0 11.8
11.4 11.6
10
8.3
8
7.7
6
4
2
0
0.3 0.3
Asthma
Hospitalisation
exacerbations
Unscheduled
clinic visits
Increased
medication
Adapted from Fleming D et al, 2006
PEFR: Peak expiratory flow rate.
Fleming D et al. Pediatr Infect Dis J 2006; 25: 860–869.
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FLUENZ SmPC
Adverse reactions
Adverse reaction frequencies
Adverse 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/rhinorrhoea
Epistaxis
Very common
Uncommon
Metabolism and nutrition disorders:
Decreased appetite
Very common
Nervous system disorders:
Headache
Guillain-Barre syndrome
Worsening of Leigh syndrome
Very common
Very rare
Very rare
General disorders and administration site conditions:
Malaise
Pyrexia
Very common
Common
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
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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.
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Practical Information
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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
Ref. SmPC FLUENZ
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Back up
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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
Ref. SmPC FLUENZ
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FLUENZ SmPC
Special warnings and precautions
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 unrepaired
craniofacial malformations.
FLUENZ should under no circumstances be injected.
Ref. SmPC FLUENZ
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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.
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
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Recommendations in other countries.
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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
Hospitalisation (any cause)
From randomisation through 180
days post last vaccination
6–11 months
Wheezing
Requiring bronchodilator therapy or
with significant respiratory
symptoms, from randomisation
through 42 days post last vaccination
6–23 months
12+ months
24+ months
FLUENZ
Active Control
6.1 %
2.6 %
No significant difference
5.9 %
3.8 %
No significant difference
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Summary of adverse events in children aged 2- 6
years
Placebo studies
D153-P501 and AV006
2 years to 6 years of age1-2
Event
Runny nose/nasal congestion*
Decreased appetite
Irritability
Decreased activity (lethargy)
Sore throat
Headache
Muscle aches
Chills
Fever*
37,8°C – 38,3°C Oral
38,3°C – 38,9°C Oral
Active-controlled study
2 years to 5 years of age3
MI-CP111
LAIV
Placebo
LAIV
TIV
(N=876-1,764)
%
(N=424-1,036)
%
(N=2,170)
%
(N=2,165)
%
58
21
21
14
11
9
6
4
50
17
19
11
9
7
3
3
51
13
12
7
5
3
2
2
42
12
11
6
6
3
2
2
9
4
6
3
6
4
4
3
*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
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
Percentage of subjects with
medically significant wheezing
Medically significant wheezing rates by age
Adapted from Belshe R et al, 2008
*LAIV is not approved for children under 24 months of age
†Age at time of first vaccine dose
1. Belshe RB et al. Vaccine 2008; 26S: D10–D16.
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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*
Hospitalisation rates by age
7
TIV
p=0.002
LAIV
Incidence (%)
6
5
4
3
2
1
0
6–11
12–23
24–35
Age (months)
36–47
48–59
Adapted from Belshe R et al, 2007
*LAIV is not approved for children under 24 months of age
Belshe RB et al. N Eng J Med 2007; 356: 685–696.
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