laiv for increasing pandemic vaccine supply · (n=2,170) % tiv (n=2,165) % runny nose/nasal...
TRANSCRIPT
LAIV For Increasing Pandemic Vaccine Supply
Kathleen Coelingh
WHO Global Action Plan II Meeting
July 13, 2011
Geneva
2
� This presentation contains discussion of MedImmune’s proprietary live attenuated influenza virus vaccine
� LAIV has been approved by the United States Food and Drug Administration for seasonal influenza since 2003 and is also approved in several other countries globally for use in eligible individuals 2-49 years of age (In the EU, for 2-17 years and in Canada, 2-59 years)
� LAIV is not approved in Switzerland
Disclaimer
3
Licensed Influenza Vaccines
M1, M2=matrix proteins.
*Image adapted from: Clinical Virology. 6th ed. 1997:911-942.
1. Prescribing information. Swiftwater, PA: Sanofi-Pasteur, Inc.
2. Prescribing information. Emeryville, CA: Novartis Vaccines and Diagnostics, Inc.
3. Prescribing information. Gaithersburg, MD: MedImmune, LLC.
4. Hayden FG, et al. Clinical Virology. 6th ed. 1997;911-942.
Live Attenuated Influenza Vaccine, Intranasal
Attenuated vaccine with multiple antigens3,4*
LAIV
Trivalent Inactivated Influenza Vaccine, Intramuscular or Intradermal
HA is the only standardized component; other antigens
may be present1,2*
TIV
Please refer to the specific prescribing information for each manufacturer’s
influenza vaccine as not all influenza vaccines are indicated for all ages.
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Manufacturing
Seasonal and 2009 H1N1 Pandemic LAIV
5
LAIV Production in Eggs
Egg
Vaccine
SeedAllantoic
Fluid
Harvest
Clarification
Centrifugation
Sterile Filtration
Accuspray
(Fill/Finish)
6
LAIV Yield in Eggs
94Average Number of Monovalent Doses Per Egg
487.459.8B/Brisbane/60/2008
857.29.8A/Perth/16/2009
H3N2
7.36
Formulation Target (Log10 FFU/Dose)
10.2
Average Potency (Log10FFU/ml)
148A/California/07/2009*
H1N1
Dose Per Egg2011/12 Formulation
Strains
* A/California/07/2009 was the 2009 Pandemic vaccine strain.
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Production of 2009 H1N1 Pandemic LAIV Seed
May June
Phase 1
•Cloned Swine Flu HA & NA•Constructed 6 vaccines •Preliminary characterization
• Growth about 10X too low• Poor filtration
Received 2 Swine
Flu Isolates
Phase 2
•Modify HA•••• Passage (cells & eggs)•••• Sequence•••• Construct derivatives
• Better growth, but still too low• Better filtration• Some variants not antigenically correct
Phase 3
• Combine most promising changes• Characterize & SelectSeed: A/CA/09 V5 119E/186D
• Grows well in eggs• Filters well• Characteristic traits: ca, ts, att• Antigenically accurate • Immunogenic in animals
Begin BulkManufacturing
April July
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2009 H1N1 Pandemic LAIV Timeline
�LAIV was first pandemic vaccine shipped to the US government
� Provided ~25% of US doses
� Significant use by children
Clinical Trials Start
October
FDA Approval Shipping Starts
NovemberSeptemberAugust
Vaccination Starts
LAIV Vaccine Seed PreparedReceived 2 Swine Flu Isolates
May June
Begin Bulk Manufacturing (90 doses per egg)
April July
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LAIV is Adaptable to Cell Culture Production
� Of 13 cell substrates assessed, only MDCK cells had all the requisite characteristics for manufacturing LAIV.� MRC-5, WI-38; human diploid cells used for other vaccines� 293, CHO, FRhL-2, MDCK, NIH 3T3, Vero and other mammalian continuous cell lines� CEF, CEK, DF-1 and other avian cell lines
� A limited number of MDCK cell clones supported higher levels of virus productivity
0
200
400
600
800
1000
1200
< 7.6 7.6-7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6-8.8
Range of Virus Titer (log FFU/mL)
Nu
mb
er
of
Clo
ne
s
Productivity stable
over 25 passages
10
Estimated Production Times in Eggs or Cell Culture
0
100
200
300
400
500
600
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Weeks in Production
Cu
mu
lati
ve B
ulk
Do
ses (
X1,0
00)
Bioreactors Eggs
• Time from strain ID to seed generation unchanged
• Time to produce bulk vaccine reduced by 2 or more months
Cell Production
Egg Production
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Plasmid Rescue Eliminates AVA Risks
� LAIV vaccines are 6:2 reassortants� The internal genes of cell and egg produced vaccines are
genetically identical
� Plasmid rescue of 6:2 vaccine strains is part of the current eggproduced LAIV product
Plasmid rescue eliminates the risk from any potential contaminants in the wild type (human) isolate
WILD TYPE VACCINE PURIFIED PLASMID DNAs
HA
NA
Transfect
CellsHA
NA
HA
NA
NANA
HAHA
PB1PB1
PB2PB2
PAPA
NPNP
MM
NSNS
Recombinant
DNA ca, ts, att
MDV
WT
12
Intranasal Administration of Large Particle Mist
13
Manufacturing Summary
� Produced in specific pathogen-free eggs
� High yields per egg
� Relatively simple production process
� Relatively complex testing
� Could be adapted to cell culture production
> Cell culture could shorten the total production time, but not the time to production of the first doses
> Reverse genetics engineering of vaccine seed reduces risk of anyadventitious agent present in original isolate
� Needle-free administration
� Storage at refrigeration temperatures
� Shelf life of 18 weeks
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Safety, Efficacy and Immunogenicity
Seasonal LAIV
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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.
4. Prescribing information. Gaithersburg, MD: MedImmune LLC
Placebo-controlled studies2 to 6 years of age1-2
TIV-controlled study2 to 6 years of age3
Event
LAIV(N=876-1,759)
%
Placebo(N=424-1,034)
%
LAIV (N=2,170)
%
TIV (N=2,165)
%
Runny nose/nasal congestion* 58 50 51 42
Decreased appetite 21 17 13 12
Irritability 21 19 12 11
Decreased activity (lethargy) 14 11 7 6
Sore throat 11 9 5 6
Headache 9 7 3 3
Muscle aches 6 3 2 2
Chills 4 3 2 2
Fever*
100º-101ºF Oral 9 6 6 4
101º-102ºF Oral 4 3 4 3
Solicited events within 10 days after Dose 1Data from 2 pooled placebo-controlled studies and 1 TIV-controlled study4
Summary of Solicited Events in Children
1616
LAIV Safety in Children <2 YearsFindings from the MI-CP111 Study
� In children 6-11 months, hospitalizations through 180 days were increased in LAIV recipients
� 6.1% LAIV vs. 2.6% TIV (P=0.002)
� Among children 6-23 months of age, LAIV was associated with increased rates of wheezing through 42 days
� 6-11 months: 6.9% LAIV vs. 4.2% TIV (P=0.03)
� 12-23 months: 5.4% LAIV vs. 3.6% TIV (P=0.03)
� Among children 24-59 months, neither wheezing nor hospitalizations were increased among LAIV recipients
� Wheezing: 2.1% LAIV vs. 2.5% TIV
� Hospitalization: 2.1% LAIV vs. 2.5% TIV
Belshe et al., N Eng J Med, 356:685–696, 2007; Belshe et al., Vaccine, 26S:D10–D16, 2008.
1717
Summary of solicited adverse events in healthy adults aged 18 years to 49 years
Event
LAIV(n=2,458)
%
Placebo(n=1,290)
%
Runny nose* 44 27
Headache* 40 38
Sore throat* 28 17
Tiredness/weakness 26 22
Muscle aches 17 15
Cough 14 11
Chills 9 6
Summary of solicited events reported within 7 days of either vaccine or placebo (normal egg allantoic fluid) administration in healthy adults 18 years to 49 years of age.
LAIV Safety and Tolerability in Adults
� 21 studies support the safety and tolerability of LAIV in adults:
� Solicited events and adverse events were mostly mild and transient upper respiratory and systemic symptoms
� SAE rates were low (≤1.5% in the largest studies) and balanced between treatment groups
Prescribing information. Gaithersburg, MD: MedImmune LLC
18
Meta-Analysis of LAIV Pediatric Efficacy Studies
� 9 randomized, controlled trials between 1997 and 2005
� 6 placebo-controlled
� 3 TIV-controlled
� Mostly healthy children previously unvaccinated against influenza
� 25,000 children aged 6 to 71 months
� 2,000 children aged 6 to 17 years with asthma
� Primary endpoint: rates of culture-confirmed influenza illness associated with vaccine-similar strains
Rhorer et al., Vaccine, 27:1101-1110, 2009.
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High Efficacy Relative to Placebo6 Randomized Studies; Matched Strains
14,000 Children 6–71 Months of Age
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 infirst season(previously
unvaccinated)
Two doses in first season
(previouslyunvaccinated)
Revaccinationwith one dose
in second season(previouslyvaccinated)
Incid
en
ce o
f In
flu
en
za
(Ma
tch
ed
Str
ain
s)
UnvaccinatedLAIV
Rhorer et al., Vaccine, 27:1101-1110, 2009.
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Higher Efficacy Relative to TIV3 Randomized Studies
13,000 Children 6 Months to <18 Years of Age
� Children 6 – 59 months of age2
� 249 study sites in 16 countries (40% in USA); 8,475 children randomized 1:1
� 2004-05 season: Matched H1N1, mismatched H3N2, matched/mismatched B
� Children 6 – 71 months of age1
� 114 study sites in 9 EU countries; 2,187 children randomized 1:1
� 2002 – 03 season: Matched H1N1 and B strains, matched/mismatched H3N2
� Children 6 – 17 years of age with asthma history3
� 145 study sites in 13 EU countries; 2,229 children randomized 1:1
� 2002-03 season: Matched H1N1 and B strains, matched/mismatched H3N2
� Primary efficacy endpoint in each study was culture-confirmed influenza illness associated with vaccine-similar strains
1.Ashkenazi et al., Pediatr Infect Dis J, 25:870-879, 2006; 2. Belshe et al., N Engl J Med, 356:685-696,
2007; 3. Fleming et al., Pediatr Infect Dis J, 25:860-869, 2006.
2121
Higher Efficacy Relative to TIV3 Randomized Studies; Matched Strains
13,000 Children 6 Months – <18 Years of Age
1. Belshe et al., NEJM, 356:685-696, 2007
2. Ashkenazi et al., Pediatr Infect Dis J, 25:870-879, 2006
3. Fleming et al., Pediatr Infect Dis J, 25:860-869, 2006
0%
1%
2%
3%
4%
5%
6%
7%
53% reduction(95% CI: 22, 72)
2.3%
4.8%
6–71 mo2
Incid
en
ce o
f In
flu
en
za
(Ma
tch
ed
Str
ain
s)
TIVLAIV
44% reduction(95% CI: 22, 61)
1.4%
2.4%
6–59 mo1
35% reduction(95% CI: 4, 56)
4.1%
6.4%
6–17 ywith asthma3
Age
2222
LAIV Efficacy Against Mismatched StrainsTwo Studies
9,833 Children 6 – 85 Months of Age
1. Belshe et al., J Pediatr, 136:168–175, 2000
2. Belshe et al., N Eng J Med, 356:685–696, 2007
86% reduction(95% CI: 75, 92)
79% reduction(95% CI: 71, 86)
6% reduction(95% CI: –32, 33)
1.6%0.9%
1.7%
11.6%
4.5%
1.8%
0%
2%
4%
6%
8%
10%
12%
14%
MismatchedA/H3N2 (1997–98)
MismatchedA/H3N2 (2004–05)
Mismatched B(2004–05)
Incid
en
ce o
f
Cu
ltu
re-C
on
firm
ed
In
flu
en
za
Placebo RecipientsLAIV RecipientsTIV Recipients
26–85 months1 6–59 months2 6–59 months2
2323
Relative Efficacy of LAIV and TIVEfficacy Against All Strains Regardless of Match
Children and Adults
Ambrose et al., Influenza Other Respi Viruses, 5:67-75, 2011
*Non-randomized study design; non-laboratory confirmed endpoint†Challenge study
1 100.1
LAIV more efficacious
Children, 6 months -<18 years
Adults, 17–49 years
Adults, >60 years
Ashkenazi
Belshe
Fleming
Piedra/Halloran*
Ohmit 2006
Ohmit 2008
Monto
Wang, all*
Wang, recently unvaccinated*
Eick, recruits*
Eick, non-recruits*
Treanor†
Forrest
Incidence rate ratio
TIV more efficacious
24
Ambrose et al., Pediatr Infect Dis J, 27:744-748, 2008; Ambrose et al., Pediatr Infect Dis J, 29: 806-811, 2010
Bracco et al., Pediatr Infect Dis J, 28:365-371, 2008.
Sustained Duration of ProtectionEfficacy by Time Post-Vaccination; Matched Strains
� In 2 placebo-controlled studies, efficacy following 2 doses of LAIV was
comparable through 9 – 12 months following vaccination.
� In 2 placebo-controlled studies, efficacy persisted throughout the second
season without revaccination.
24 mo
Study 1(12–35 mo)
Study 2(15–71 mo)
Study 3 (6–35 mo)
73% (95% CI:54, 84)
69%(95% CI:48, 81)
56%(95% CI:31, 73)
94%(95% CI:89, 97)
86%(95% CI:59, 95)
57%(95% CI:6, 82)
74%(95% CI:64, 81)
5 mo 9 mo 12 mo
Season 1
7 mo
Season 2
25
2525
Increased Efficacy Over Time Relative to TIVRelative Efficacy by Time Postvaccination
� In 3 TIV-controlled studies, the relative efficacy of LAIV versus TIV for matched strains increased with time in each study� 0 to 4-month period: 34% (95% CI: 3, 55)
� >4 to 8-month period: 62% (95% CI: 42, 76)
� Results are best explained by a decline in TIV efficacy over time
Time From First Vaccination to Influenza Illness, mo
00
1
2
3
4
Incid
en
ce,
%
1 2 3 4 5 6 7 8
TIV
LAIV
Ambrose et al., Pediatr Infect Dis J, 29: 806-811, 2010
26
A/H1N1 responses
Belshe, year 1
A/H3N2 responses
Belshe, year 2
Tam, year 1
Tam, year 2
Vesikari, year 1
Vesikari, year 2
Bracco, year 1
Bracco, year 2
B responses
10
8169
8238
7379
6226
4457
30
9168
Did not circulate
-10214
7380
9025
10060
8632
9061
5
9653
100
4928
Did not circulate56
9050
9247
10028
8160
41
Did not circulate48
Did not circulate
94
Bandell et al., Exp Rev Vaccines, 2011, In Press
Seroconversion and EfficacyAll Children Regardless of Baseline Serostatus
Matched Strains
Efficacy (matched strains), %
Seroresponse (HAI), %
27
LAIV Utilization by American Pediatric Providers
� Use has increased significantly; ~90% of pediatricians stock LAIV� LAIV use varies among providers; lower with family practitioners
*Excludes 2009 H1N1 pandemic vaccinations
8 1025
34 3715
17
16
1820
77 7360
48 43
0%
20%
40%
60%
80%
100%
2006-07 2007-08 2008-09 2009-10* 2010-2011Perc
en
tag
e o
f V
acc
ina
tio
ns (
Cla
ims D
ata
)
LAIV TIV prefilled syringe TIV multi-dose vial
Toback et al., Vaccine, 29:4225-4229, 2011; Toback et al., Annual Conference on Vaccine Research, April 2011
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Thank You!