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.

4

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.

7

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

8

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

9

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

11

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

15

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

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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!