Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:Novel generation influenza vaccines:

AdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvants

for for for for for for for for increasingincreasingincreasingincreasingincreasingincreasingincreasingincreasing

pandemic vaccine supplypandemic vaccine supplypandemic vaccine supplypandemic vaccine supplypandemic vaccine supplypandemic vaccine supplypandemic vaccine supplypandemic vaccine supply

Albert Albert Albert Albert Albert Albert Albert Albert OsterhausOsterhausOsterhausOsterhausOsterhausOsterhausOsterhausOsterhaus

Head Department of VirologyHead Department of VirologyHead Department of VirologyHead Department of VirologyHead Department of VirologyHead Department of VirologyHead Department of VirologyHead Department of Virology

CSO CSO CSO CSO CSO CSO CSO CSO ViroclinicsViroclinicsViroclinicsViroclinicsViroclinicsViroclinicsViroclinicsViroclinics--------Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)Biosciences BV (Erasmus MC)

2222ndndndnd

WHO Consultation on a Global Action Plan WHO Consultation on a Global Action Plan WHO Consultation on a Global Action Plan WHO Consultation on a Global Action Plan

for pandemic Influenza vaccinesfor pandemic Influenza vaccinesfor pandemic Influenza vaccinesfor pandemic Influenza vaccines

Geneva 13Geneva 13Geneva 13Geneva 13thththth

July 2011July 2011July 2011July 2011

Pandemic influenza vaccinesPandemic influenza vaccinesPandemic influenza vaccinesPandemic influenza vaccines

---- Key issues Key issues Key issues Key issues ----

� Response timeResponse timeResponse timeResponse time

((((currentlycurrentlycurrentlycurrently ~6 ~6 ~6 ~6 monthsmonthsmonthsmonths))))

� ProductionProductionProductionProduction capacitycapacitycapacitycapacity

((((currentlycurrentlycurrentlycurrently ~1000 ~1000 ~1000 ~1000 millionmillionmillionmillion doses doses doses doses trivalenttrivalenttrivalenttrivalent vaccine vaccine vaccine vaccine worldworldworldworld----widewidewidewide) ) ) )

� EfficacyEfficacyEfficacyEfficacy////SafetySafetySafetySafety

((((humanhumanhumanhuman trials trials trials trials withwithwithwith prototype H5, H9 vaccines)prototype H5, H9 vaccines)prototype H5, H9 vaccines)prototype H5, H9 vaccines)

NB: NB: NB: NB: RegulatoryRegulatoryRegulatoryRegulatory issuesissuesissuesissues

Bodewes et al, Expert Rev Vaccines. 2010 Jan;9(1):59-72

Bodewes et al, Expert Rev Vaccines. 2010 Jan;9(1):59-72

Seasonal H1N1 pH1N1 2009 HPAI H5N1

Temperature Virus Load

DIAGNOSTIC READ-OUTS

Clinical & Virological Parameters

Lung Weight

Munster et al., Science 2009

Del Giudice et al., Science TM 2009

Chutinimitkul et al., J.Virol 2010

Herfst et al., Vet.Pathol. 2010

Bosch et al., J.Virol. 2010

Kreijtz et al., J.Gen.Virol. 2010

v.d.Brand et al., JID 2010

v.d.Brand et al., J.Virol 2010

Strain selection

Production systems

Seed-strain preparation

Improve efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systemsImprove efficacy; adjuvants & delivery systems

New targets; identify correlates of protectionNew targets; identify correlates of protectionNew targets; identify correlates of protectionNew targets; identify correlates of protection

Pandemic influenza vaccinesPandemic influenza vaccinesPandemic influenza vaccinesPandemic influenza vaccines

- Room for improvement -

““““““““smallsmallsmallsmallsmallsmallsmallsmall”””””””” changes; easy to incorporatechanges; easy to incorporatechanges; easy to incorporatechanges; easy to incorporatechanges; easy to incorporatechanges; easy to incorporatechanges; easy to incorporatechanges; easy to incorporate

larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?larger changes; long path before implementation?

Improve efficacy:Improve efficacy:Improve efficacy:Improve efficacy: adjuvants adjuvants adjuvants adjuvants adjuvants adjuvants adjuvants adjuvants & delivery systems& delivery systems& delivery systems& delivery systems

Adjuvants and antigen presentation systems for viral vaccines tested in humans (1/2)(an arbritary selection)

Adjuvant Viral antigen

Mineral saltsAluminium salts numerousAlum + MPL HBsAg, HSV (gD)

EmulsionsMF 59 / ASOx Flu

HBV (rPreS2-S)

HSV2 (rgB + rgD)HIV1 (gp 120)

CMV (rgB)HPV

MF59 + MTP-PE Flu (split)

HIV1QS21 HIV1 (gp120)

Incomplete Freund (IFA) HIV1 (gp120 depleted)Montamide ISA51 HIV1 (Tat toxoid)

Adjuvants and antigen presentation systems for viral vaccines tested in humans (2/2)(an arbritary selection)

Emulsions (cont.)QS21 HIV1 (gp120)Incomplete Freund (IFA) HIV1 (gp120 depleted)

Montamide ISA51 HIV1 (Tat toxoid)

Bacterial productsMPL (like) numerousHolotoxins (CT, PT, LT) Flu

ImmunoadjuvantsCytokines numerous

Particulate formulationsLiposomes Flu

Virosomes Flu, HAVISCOMS numerous

Pandemic influenza vaccines- Improve efficacy; adjuvants & delivery systems -

- Adjuvants & antigen delivery systems Aluminum saltsMF59ASO3VirosomesISCOMsOthers….

-Variety of presentationsSubunitsSplit vaccinesWhole inactivated virusLive-attenuated virusVirus-like particlesRecombinant proteinsDNA vaccinesOthers….

New New New New adjuvantedadjuvantedadjuvantedadjuvanted influenza vaccines / candidates influenza vaccines / candidates influenza vaccines / candidates influenza vaccines / candidates

(an (an (an (an arbritaryarbritaryarbritaryarbritary selection)selection)selection)selection)

� Approved:Approved:Approved:Approved:

� MF59 (MF59 (MF59 (MF59 (squalenesqualenesqualenesqualene emulsion)emulsion)emulsion)emulsion) seasonal / pandemicseasonal / pandemicseasonal / pandemicseasonal / pandemic

� AS03 (AS03 (AS03 (AS03 (squalene/tocopherolsqualene/tocopherolsqualene/tocopherolsqualene/tocopherol emulsion)emulsion)emulsion)emulsion) pandemicpandemicpandemicpandemic

� Alum Alum Alum Alum pandemicpandemicpandemicpandemic

� VirosomesVirosomesVirosomesVirosomes ((((liposomesliposomesliposomesliposomes)))) seasonalseasonalseasonalseasonal

� PolyoxidoniumPolyoxidoniumPolyoxidoniumPolyoxidonium (poly(poly(poly(poly----electrolyte)electrolyte)electrolyte)electrolyte) seasonalseasonalseasonalseasonal

� Clinical studies (phase 1, 2)Clinical studies (phase 1, 2)Clinical studies (phase 1, 2)Clinical studies (phase 1, 2)

� IscomIscomIscomIscom / / / / IscomIscomIscomIscom Matrix )Matrix )Matrix )Matrix )

� AF3 AF3 AF3 AF3 ((((squalenesqualenesqualenesqualene o/wo/wo/wo/w emulsions)emulsions)emulsions)emulsions)

� SE SE SE SE ((((squalenesqualenesqualenesqualene o/wo/wo/wo/w emulsions)emulsions)emulsions)emulsions)

� GLA GLA GLA GLA (TLR 4 agonist)(TLR 4 agonist)(TLR 4 agonist)(TLR 4 agonist)

� CovaccineCovaccineCovaccineCovaccine (TLR 4 agonist)(TLR 4 agonist)(TLR 4 agonist)(TLR 4 agonist)

� FlagellinFlagellinFlagellinFlagellin (TLR 5 agonist)(TLR 5 agonist)(TLR 5 agonist)(TLR 5 agonist)

� IC31 IC31 IC31 IC31 ((((dI:dCdI:dCdI:dCdI:dC –––– TLR9 agonist)TLR9 agonist)TLR9 agonist)TLR9 agonist)

� InulinInulinInulinInulin (complement activator)(complement activator)(complement activator)(complement activator)

� JVRSJVRSJVRSJVRS----100 (cationic liposome)100 (cationic liposome)100 (cationic liposome)100 (cationic liposome)

Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted Formalin inactivated alum adjuvanted

vaccines:vaccines:vaccines:vaccines:vaccines:vaccines:vaccines:vaccines:

an additional risk?an additional risk?an additional risk?an additional risk?

• FormalinFormalinFormalinFormalin----inactivated paramyxovirus vaccines adjuvanted with alum inactivated paramyxovirus vaccines adjuvanted with alum inactivated paramyxovirus vaccines adjuvanted with alum inactivated paramyxovirus vaccines adjuvanted with alum

can predispose to hypersensitivity responses (sixties!!!)can predispose to hypersensitivity responses (sixties!!!)can predispose to hypersensitivity responses (sixties!!!)can predispose to hypersensitivity responses (sixties!!!)

• Similar pathology seen for FISimilar pathology seen for FISimilar pathology seen for FISimilar pathology seen for FI----RSV, FIRSV, FIRSV, FIRSV, FI----MV, FIMV, FIMV, FIMV, FI----hMPVhMPVhMPVhMPV, SARS, SARS, SARS, SARS----CoVCoVCoVCoV

•• How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?How about formalin inactivated Flu alum vaccines?

ImmunopathologyImmunopathologyImmunopathologyImmunopathology study in monkey: study in monkey: study in monkey: study in monkey:

General conclusion about safetyGeneral conclusion about safetyGeneral conclusion about safetyGeneral conclusion about safety

� Protection against homologous challenge

�� NoNoNoNoNoNoNoNo pneumonia exacerbationpneumonia exacerbationpneumonia exacerbationpneumonia exacerbationpneumonia exacerbationpneumonia exacerbationpneumonia exacerbationpneumonia exacerbation observed when monkeys

vaccinated with an inactivated split-virion influenza

A/H5N1 adjuvanted with aluminum hydroxide were

challenged with a parental wild type strain

RuatRuatRuatRuat et alet alet alet al., ., ., ., J.VirolJ.VirolJ.VirolJ.Virol., 2008., 2008., 2008., 2008

Protective immunity

(Rimmelzwaan et al., Vaccine 1998)

0

2

4

6

0

2

4

6

log T

CID

50/m

l

0

2

4

0 1 2 3 4 6 8 11

0

2

4

log T

CID

50/m

l

0

2

4

0 1 2 3 4 6 8 11

0

2

4

days post challenge infectiondays post challenge infection

A/NL/18/94 iscoms SIV-iscoms controls

NDNDND ND NDND

log T

CID

50/m

l

0

2

4

0

2

4

6

days post challenge infection0 1 2 3 4 6 8 11

0

2

4

LLF

PS

NSlo

g T

CID

50/m

l

0

2

4

0

2

4

6

days post challenge infection0 1 2 3 4 6 8 11

0

2

4

log T

CID

50/m

l

0

2

4

0

2

4

6

days post challenge infection

0 1 2 3 4 6 8 11

0

2

4

log T

CID

50/m

l

0

2

4

0

2

4

6

days post challenge infection0 1 2 3 4 6 8 11

0

2

4

A/NL/18/94 glycoproteinpreparation I

A/NL/18/94 glycoproteinpreparation II

primary infection with A/NL/18/94

ND NDNDNDND ND

LLF

PS

NS

Nature 308:457Nature 308:457Nature 308:457Nature 308:457---- 460, 1984460, 1984460, 1984460, 1984

Lung damage: HPAI H5N1 virus challenge in ferretsLung damage: HPAI H5N1 virus challenge in ferretsLung damage: HPAI H5N1 virus challenge in ferretsLung damage: HPAI H5N1 virus challenge in ferrets

---- response to NA important response to NA important response to NA important response to NA important ----

Bosch B.J. Bosch B.J. Bosch B.J. Bosch B.J. et al., et al., et al., et al., J.VirolJ.VirolJ.VirolJ.Virol.... 2010201020102010

Assessment of preAssessment of preAssessment of preAssessment of preAssessment of preAssessment of preAssessment of preAssessment of pre--------pandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trialspandemic H5N1 clinical trials

Need two doses of 3.8 Need two doses of 3.8 Need two doses of 3.8 Need two doses of 3.8 µµµµggggSplit vaccine with AS adjuvantSplit vaccine with AS adjuvantSplit vaccine with AS adjuvantSplit vaccine with AS adjuvant

Need two doses of 7.5 Need two doses of 7.5 Need two doses of 7.5 Need two doses of 7.5 µµµµggggWhole virus Vero cell culture, no adjuvant Whole virus Vero cell culture, no adjuvant Whole virus Vero cell culture, no adjuvant Whole virus Vero cell culture, no adjuvant

Need two doses of 7.5 Need two doses of 7.5 Need two doses of 7.5 Need two doses of 7.5 µµµµggggSubunit with MF59 adjuvantSubunit with MF59 adjuvantSubunit with MF59 adjuvantSubunit with MF59 adjuvant

Need two doses of 10Need two doses of 10Need two doses of 10Need two doses of 10----15 15 15 15 µµµµggggWhole virus (egg) with alumWhole virus (egg) with alumWhole virus (egg) with alumWhole virus (egg) with alum

Need two doses of 30Need two doses of 30Need two doses of 30Need two doses of 30----45 45 45 45 µµµµggggSplit/subunit vaccine with alumSplit/subunit vaccine with alumSplit/subunit vaccine with alumSplit/subunit vaccine with alum

Need two doses of 90 Need two doses of 90 Need two doses of 90 Need two doses of 90 µµµµggggSplit vaccine no adjuvantSplit vaccine no adjuvantSplit vaccine no adjuvantSplit vaccine no adjuvant

Compliance with EU licensing Compliance with EU licensing Compliance with EU licensing Compliance with EU licensing

criteriacriteriacriteriacriteria

Type of vaccineType of vaccineType of vaccineType of vaccine

Data presented at WHO meeting, February 2007Data presented at WHO meeting, February 2007Data presented at WHO meeting, February 2007Data presented at WHO meeting, February 2007

(Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK,(Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK,(Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK,(Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK, Novartis,BaxterNovartis,BaxterNovartis,BaxterNovartis,Baxter))))

(Courtesy: John Wood)(Courtesy: John Wood)(Courtesy: John Wood)(Courtesy: John Wood)

CHMP CHMP CHMP CHMP CHMP CHMP CHMP CHMP

criteriacriteriacriteriacriteriacriteriacriteriacriteriacriteria

40404040

IX International Symposium on Respiratory Viral Infections ; March 3 – 6, 2007, Hong Kong

0000

25252525

50505050

75757575

100100100100

Post first dosePost first dosePost first dosePost first dose Post second dosePost second dosePost second dosePost second dose

Seroconversion

Seroconversion

Seroconversion

Seroconversion

rate (%)

rate (%)

rate (%)

rate (%)

3.8µg H5

7.5µg H5

15µg H5

30µg H5

3.8µg H5 AS

7.5µg H5 AS

15µg H5 AS

30µg H5 AS

The three CHMP criteria are exceeded by The three CHMP criteria are exceeded by The three CHMP criteria are exceeded by The three CHMP criteria are exceeded by

all the adjuvanted doses: all the adjuvanted doses: all the adjuvanted doses: all the adjuvanted doses: seroconversionseroconversionseroconversionseroconversionseroconversionseroconversionseroconversionseroconversion ratesratesratesratesratesratesratesrates

Reactogenicity data are consistent with results obtained in H5N1/AS03A pandemic vaccine:general adverse events

Devaster JM. et al. Immunogenicity and safety of an A/H1N1v AS03A-adjuvanted pandemic influenza vaccine candidate: Preliminary results

from a randomized, controlled trial in adults. Vaccine Congress 2009, Singapore.

% s

ub

jec

ts

Arthralgia Fatigue Fever Headache Myalgia Shivering Sweating

0

10

20

30

40

50

60

70

80

90

100

H1N1 (5.25µg) + AS03A

H1N1 (21µg)

H5N1 (3.75µg) + AS03A*

Grade 3All grades

20 subjects per group

H5N1/AS03A pandemic vaccine has shown a broad and persistent immune response

Two immunisations at day 1 and day 21 with H5N1 A/Vietnam/1194/04 split virus, AS03A

Leroux-Roels et al. Broad clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza

vaccine. PLoS ONE 2008; 3 (2): e1665.

20

40

60

80

A/Indonesia/5/05Clade 2.1

Day 21

Day 42

Day 180

3.8 µg 3.8 µg + AS03A 3.8 µg 3.8 µg + AS03A3.8 µg 3.8 µg + AS03A

A/turkey/Turkey/1/05Clade 2.2

A/Anhui/1/05Clade 2.3

Sero

convers

ion

rate

(%

)

0

100

MF59-ADJUVANTED H5N1-VIETNAM VACCINE GENERATED BROADER ANTIBODY PROFILE COMPARED TO

UNADJUVANTED VACCINE (phage-display library)STUDY-1:

NIAID (HAI-80)

Correlates of broadprotection?

H1-98%

Khurana S, et al.(2010) Science Transl Med 20 2010 2:15ra5

19

Composition MF59:Composition MF59:Composition MF59:Composition MF59:

0.5% 0.5% 0.5% 0.5% PolysorbatePolysorbatePolysorbatePolysorbate 80 80 80 80

(water(water(water(water----soluble surfactant)soluble surfactant)soluble surfactant)soluble surfactant)

0.5% 0.5% 0.5% 0.5% SorbitanSorbitanSorbitanSorbitan TriolateTriolateTriolateTriolate

(oil(oil(oil(oil----soluble surfactant)soluble surfactant)soluble surfactant)soluble surfactant)

4.3% 4.3% 4.3% 4.3% SqualeneSqualeneSqualeneSqualene ----oiloiloiloil

Water for injectionWater for injectionWater for injectionWater for injection

10 10 10 10 nMnMnMnM NaNaNaNa----citrate buffercitrate buffercitrate buffercitrate buffer

H2O

H2O

OIL

H2OH2OH2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

H2O

The response in adultsThe response in adultsThe response in adultsThe response in adults

Y YY

Y

Y Y YY

Y Y Y YY

Y

Y Y YY

Y Y Y YY

Y

Y Y

YY

Y

Y

In adults, already primed by natural infection ( ), vaccination with plain influenza vaccine essentially expands pre-existing memory B cells directed against the HA2 region, with little effect on priming naive B cells against the HA1 region ( ). Vaccination with MF59-adjuvanted vaccine, dramatically primes

naive B cells that now produce antibodies against the HA1 region ( )

In adults, already primed by natural infection ( ), vaccination with plain influenza vaccine essentially expands pre-existing memory B cells directed against the HA2 region, with little effect on priming naive B cells against the HA1 region ( ). Vaccination with MF59-adjuvanted vaccine, dramatically primes

naive B cells that now produce antibodies against the HA1 region ( )

1

2

3

1

2

3

HA1 HA2

Khurana et al, Science Transl Med 2011

20 | Briefing Dutch Health Council | June 29, 2011 | Response to Questions on (Pre)pandemic Influenza Vaccines | Confidential

• 2 immunisations of ferrets at D0 and D21 (H5N1 A/Vietnam/1194/04 split virus /

AS)

• Heterologous challenge (wild-type virus A/Indonesia/5/05, 105 TCID50) at D49

• Post challenge results at D5

Dead Alive % Survival

Pooled controls

(15 µg Antigenonly or AS only)

12 0 0

1.7 µg H5N1 – AS 1 5 833.8 µg H5N1 – AS 0 6 1007.5 µg H5N1 – AS 0 5 10015 µg H5N1 – AS 0 6 100

Ferrets Ferrets Ferrets Ferrets Ferrets Ferrets Ferrets Ferrets vaccinatedvaccinatedvaccinatedvaccinatedvaccinatedvaccinatedvaccinatedvaccinated withwithwithwithwithwithwithwith ASASASASASASASAS--------adjuvantedadjuvantedadjuvantedadjuvantedadjuvantedadjuvantedadjuvantedadjuvanted

H5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccineH5N1 split candidate vaccine

Baras et al., PLoS One 2008

16-10-2001

Influenza pandemic virus 2009- New H1N1 -

New pandemic

- First animal models

testing vaccines

testing antivirals

studying pathogenesis

- First genetic and antigenic data

- Clinical network

antiviral therapy

(IV / ICU / ECMO)

antiviral resistance

Key publications:J. v.d. Brand et al, EID 2011J. v.d. Brand et al, JID 2010S. Herfst et al J.Virol. 2010F. Wildschut et al. Plos One 2010G. Del Giudice et al. Science TM 2009S. Herfst et al, Vet Pathol. 2009. J. Van den Brand et al, EID 2009. V. Munster et al, Science. 2009 A. Meijer et al, J Clin Virol. 2009

23

Ne

utr

ali

zin

g a

nti

bo

dy t

iters

(GM

T w

ith

95%

CI)

0

200

400

600

800

1000150020002500

Day 0

Day 21

Day 42

Day 48

15 µgno adj

(2x)

15 µg+ AS03A

(2x)

3.75 µg+ AS03A

(1x)

3.75 µg+ AS03A

(2x)

1.9 µg+ AS03A

(1x)

1.9 µg+ AS03A

(2x)

1.9 µg+ AS03B

(2x)

PBS

(2x)

Neutralization assay (Challenge strain)

Anti-The Netherlands/602/09 neutralizing titers

0/6

6/6

4/6

5/5

3/5

6/6

6/6

0/6

Neutralizing antibodies observed in all groups immunized with AS03-split H1N1 vaccines���� 88% response rate (100% with two doses, 64% with a single dose).

Responders: neutralizing titers > 40

24

Viral load in the lungs by culture

Day 4 post-challenge (A/The Netherlands/602/09)

Lower virus load observed in animals immunized with AS03-adjuvanted vaccines

compared to ferrets receiving the non-adjuvanted vaccine (or PBS).No virus detected with two doses of AS03-adjuvanted vaccine, virus detected in

27% (3/11 ferrets) ferrets receiving a single dose.

6/62/6

0/51/5

0/60/6

6/6

0/61.0

2.0

3.0

4.0

5.0

6.0

7.0

2x 15 µg

Non-adj

2x 15 µg

AS03A

1x 3.75 µg

AS03A

2x 3.75 µg

AS03A

1x 1.9 µg

AS03A

2x 1.9 µg

AS03A

2x 1.9 µg

AS03B

2x PBS

Vir

us t

iter

(Lo

g T

CID

50/g

r w

ith

CI9

5)

Del Guidice et al. Science TM 2009

v.d.Brand et al J.Virol. 2010

Seasonal vaccine provides priming against Seasonal vaccine provides priming against Seasonal vaccine provides priming against Seasonal vaccine provides priming against

A/H1N1 pandemic influenzaA/H1N1 pandemic influenzaA/H1N1 pandemic influenzaA/H1N1 pandemic influenza

- = PBS= PBS= PBS= PBS

A = seasonal H1N1A = seasonal H1N1A = seasonal H1N1A = seasonal H1N1

F = seasonal H1N1 + MF59F = seasonal H1N1 + MF59F = seasonal H1N1 + MF59F = seasonal H1N1 + MF59

C = C = C = C = pdmpdmpdmpdm H1N1H1N1H1N1H1N1

C+ = C+ = C+ = C+ = pdmpdmpdmpdm H1N1 + MF59H1N1 + MF59H1N1 + MF59H1N1 + MF59

VaccinesVaccinesVaccinesVaccines

Preliminary immunogenicity results post-dose one exceed the regulatory threshold

Devaster JM. et al. Immunogenicity and safety of an A/H1N1v AS03A-adjuvanted pandemic influenza vaccine candidate: Preliminary

results from a randomized, controlled trial in adults. Vaccine Congress 2009, Singapore.

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

D0 D21 D0 D21

SCRSPRGMT

% s

ub

jects

% s

ub

jects

H1N1 (21µg)H1N1 (5.25µg)+

AS03A

D21 D21

1

10

100

1000

D0 D21 D0 D21

H1N1 (21µg)H1N1 (5.25µg)

+AS03A

H1N1 (21µg)H1N1 (5.25µg)

+AS03A

Prior to receipt of official regents vaccines were formulated using an alternative assay for HA content. HA potencies were then retested by SRD once calibrated reagents were available.

Vaccination Vaccination Vaccination Vaccination Vaccination Vaccination Vaccination Vaccination effectiveneseffectiveneseffectiveneseffectiveneseffectiveneseffectiveneseffectiveneseffectivenes studiesstudiesstudiesstudiesstudiesstudiesstudiesstudies

""""""""SwineSwineSwineSwineSwineSwineSwineSwine fluflufluflufluflufluflu 2009"2009"2009"2009"2009"2009"2009"2009"

The Scottish VIPER The Scottish VIPER The Scottish VIPER The Scottish VIPER The Scottish VIPER The Scottish VIPER The Scottish VIPER The Scottish VIPER studystudystudystudystudystudystudystudy and a and a and a and a and a and a and a and a GermanGermanGermanGermanGermanGermanGermanGerman studystudystudystudystudystudystudystudy

� vaccination vaccination vaccination vaccination waswaswaswas effective effective effective effective

97% in 1597% in 1597% in 1597% in 15----65 age group65 age group65 age group65 age group

83% in > 65 age group83% in > 65 age group83% in > 65 age group83% in > 65 age group

� vaccination vaccination vaccination vaccination reducedreducedreducedreduced riskriskriskrisk of Influenza of Influenza of Influenza of Influenza

� vaccination vaccination vaccination vaccination reducedreducedreducedreduced riskriskriskrisk of of of of pneumoniapneumoniapneumoniapneumonia and hospitalisationand hospitalisationand hospitalisationand hospitalisation

� vaccination vaccination vaccination vaccination reducedreducedreducedreduced mortalitymortalitymortalitymortality

Available at: http://Available at: http://Available at: http://Available at: http://www.patriotsaints.comwww.patriotsaints.comwww.patriotsaints.comwww.patriotsaints.com. Last accessed 02 November 2010.. Last accessed 02 November 2010.. Last accessed 02 November 2010.. Last accessed 02 November 2010.

In the lay press pandemic vaccines 2009 were said to be unsafe

Europe: Experience with pandemic vaccines in mass vaccination programs

“The CHMP re-assessed the benefit-risk profile of Celvapan [Baxter], Focetria

[Novartis] and Pandemrix [GSK]. Taking into account the comprehensive

information available on the clinical safety and efficacy of these vaccines, the

CHMP concluded that

the benefit-risk profile of these vaccines continues to be positive.

Consequently, the CHMP recommended the further use of the vaccines within

the EU in the authorised indication even after the pandemic was declared

over. ”

Conclusion stated by EMA

European Medicines Agency. Twenty-second pandemic pharmacovigilance update. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Report/2010/08/WC500095870.pdf.

European Medicines AgencyEuropean Medicines Agency updates on the review of Pandemrix and reports of narcolepsynarcolepsy (23 September 2010)

� “As per 17 September 2010, there are 81 reports from healthcare professionals suggestive of narcolepsynarcolepsy, all collected through spontaneous reporting systems.”

� “The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) agreed that at present the benefit-risk balance for Pandemrix continues to be positive, and that while the review is still ongoing there was no need for Europe-wide restrictions on use.”

� “Available evidence does not confirm a link; more research needed.”

European Medicines Agency. Press release 23 September 2010. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC500096998.pdf.

AdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvantsAdjuvants

for pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccinesfor pandemic influenza vaccines

� effectiveness (Ag sparing, breadth/longevity response...)effectiveness (Ag sparing, breadth/longevity response...)effectiveness (Ag sparing, breadth/longevity response...)effectiveness (Ag sparing, breadth/longevity response...)

� nanananaïïïïve versus primed individualsve versus primed individualsve versus primed individualsve versus primed individuals

� also effective and safe for seasonal vaccine usage?also effective and safe for seasonal vaccine usage?also effective and safe for seasonal vaccine usage?also effective and safe for seasonal vaccine usage?

� correlates of protection (HAI/VN antibody, T cells...? regulatorcorrelates of protection (HAI/VN antibody, T cells...? regulatorcorrelates of protection (HAI/VN antibody, T cells...? regulatorcorrelates of protection (HAI/VN antibody, T cells...? regulatory issues!)y issues!)y issues!)y issues!)

� safety issues (also upon challenge; autosafety issues (also upon challenge; autosafety issues (also upon challenge; autosafety issues (also upon challenge; auto----immune, e.g. GBS, narcolepsy.. )immune, e.g. GBS, narcolepsy.. )immune, e.g. GBS, narcolepsy.. )immune, e.g. GBS, narcolepsy.. )

� availability, IP rights, cost... availability, IP rights, cost... availability, IP rights, cost... availability, IP rights, cost...

� ease to manufactureease to manufactureease to manufactureease to manufacture

� ease to formulateease to formulateease to formulateease to formulate

� separate storage possible (emulsions!!)separate storage possible (emulsions!!)separate storage possible (emulsions!!)separate storage possible (emulsions!!)

� …………

POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:POINTS TO CONSIDER:

AcknowledgementsAcknowledgements

Virology, Erasmus MCVirology, Erasmus MCVincent MunsterEmmie de WitDebby van Riel

Theo BestebroerJudith v.d. BrandGeert van AmerongenRobert Dias d’UlloisMartin Schutten

Jan de JongGuus RimmelzwaanBart HaagmansThijs KuikenRon Fouchier

…

ViroclinicsViroclinics Biosciences BVBiosciences BVJames Simon

Koert Stittelaar

GSKGSK

NovartisNovartis

SanofiSanofiSanofiSanofiSanofiSanofiSanofiSanofi PasteurPasteurPasteurPasteurPasteurPasteurPasteurPasteur

Solvay Solvay

IsconovaIsconova

……