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Pandemic flu and the anti-H1N1 vaccine:

a retrospective view.

Albert OsterhausHead Dept Virology

Chairman ESWICSO Viroclinics-Biosciences BV

ESCMID conference on the impact of vaccines on

Public HealthPrague, 2nd April 2011

ESCMID Online Lecture Library

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Human influenza: three appearances

Seasonal influenza(A: H3N2, H1N1; B)

Avian influenza(A: H7N7, H5N1…)

Pandemic influenza(A: H1N1, H2N2, H3N2, H1N1…?)ESCMID Online Lectu

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INFLUENZA A VIRUS

Subtype

H7N7H5N1H9N2H5N1H7N7H7N2H7N3H5N1

Country

UKHongkongSE-AsiaHongkongNetherlandsUSACanadaSE-Asia/M-East/Europe/W-Africa

Year

1996199719992003200320032004

2003-11

# Cases

118>22?8912

.>500

# Deaths

0601100

>300*

Recent zoonotic transmissions

*CFR ~ 60%


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Confirmed H5N1 avian influenza virus endemic areas (poultry and wild birds) since 2003


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Avian influenza A H5N1 virus- HA: Receptor specificity -

Shinya et al., Nature 440, 2006

Van Riel et al.,Science 2006

Van Riel et al., Am J Pathol 2007

Van Riel et al., Am J Pathol 2009

Van Riel et al., Am J Pathol 2010ESCMID Online Lectu

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Pandemic H1N1Seasonal H3N2

HPAIV H5N1

Introduction- Attachment to the upper respiratory tract -


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Last four pandemics

A(H1N1) A(H2N2) A(H3N2)

1918

“Spanish Flu”

1957

“Asian Flu”1968

“Hong Kong Flu”

>40 million deaths 1-4 million deaths 1-4million deaths

Credit: US National Museum of Health and Medicine

2009

”Swine Flu”

???

A(H1N1)ESCMID Online Lecture Library

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Air traffic from Mexico


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PB2,PA:

PB1:

~ 1998

~ 1968 ~ 1998

HA, NP, NS:~ 1918

NA, MA:~ 1979

PB2PB1PAHANPNAMANS

N-America

Eurasia

Classical swine

Eurasian swine

Triple reassortant

A/California/4/2009

The H1N1v flu virusCourtesy: Ron FouchierESCMID Online Lectu

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The Mexican flu virus... ...where did it come from?


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11

The Flu OrphansChildren in the Alaskan village of Nushagak survived

the Spanish flu of 1918

Alaska State Library

7

48

124

71

26 26

0

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120

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Mor

talit

ite

0-4 Yrs 5-24 Yrs 25-49 Yrs 50-64 Yrs ≥65 Yrs UnknownAge Groups

2%

16%

9% 9%

41%

24%

`2009 pandemic


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Avian influenza A virus- Adaptation -

E. De Wit & R.A.M. Fouchier, J Clin Virol (2008)E. De Wit, Y. Kawaoka, M.D. De Jong & R.A.M. Fouchier, Vaccine (2008)E. De Wit E, Munster VJ, van Riel D, et al., J.Virol 2010 HA

NA

NS1

PB1, PB2, PA, NP


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2009 influenza A (H1N1) virus:relevant mutations

Virulence associated substitution in HA: D222G(Herfst et al., J.Virol. 2010)

Oseltamivir resistance substitution in NA: H275Y(de Vries et al., J.Clin Microbiol. 2010)

Zanamivir resistance substitution in NA: I223R(de Vries et al NEJM 2010)


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2009 pandemic Influenza associated ARDS

Despite the relative mildness of this pandemic, severe illness and death did occur.After the first influenza wave countries reported frequent ICU admissions, often in younger individuals.Most of the admitted individuals had serious underlying medical conditions, about 30% did not.ARDS was often associated with shock and DIC.

In USA 300,000 – 2,000,000 years lost (vaccination!!!)

Davies A et al JAMA, Dominguez-Cheritet et al JAMA, Jain S et al N Engl J Med 2009


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INFLUENZA: are we prepared?- medical interventions –

SurveillanceHumans and animals: “early warning” en “rapid response”

Antiviral therapypreventive and therapeutic…resistance development ???

VaccinationCornerstone of prevention !!!


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Rappuoli et al. 2009, Science

SCIENCE 2009


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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


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Whole virus Split virus`

Subunit(surface antigen)

Live attenuated

Baxter (Austria)Omnivest (Hungary)

8 manufacturers in ChinaCSL (Australia)Sanofi Pasteur (France)Green Cross (Korea)GSK Biologicals

Novartis (US) MedImmune (US)Microgen (Russia)

Examples of licensed monovalent pandemic influenza H1N1v vaccines

WHO. Marie-Paule Kieny. Update of the development of A(H1N1) pandemic influenza vaccines. November 9, 2009


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Future generations:avian and pandemic influenza vaccines

Several novel generations of influenza vaccines are being developed(adjuvanted, DNA, LAIV, vectored, VLP, and protein / peptide-based …vaccines)

Novel adjuvants have led to flu vaccine candidates against avian influenza (H5,H9…)and pandemic flu that are Ag-sparing and broadly active

Vectored vaccines are promising next generation flu vaccine candidates

LAIV is used for seasonal vaccination and is a promising pandemic vaccine candidate


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HLA-A1, A2, B8, B35

HLA-A1, A3, B8, B35

HLA-A1, A2, B8, B27

In vitro expanded T lymphocytes (influenza virus A/Ned/18/94 (H3N2))

BLCL infected with influenza H3N2 or H5N1 virus

IFNγ ELISPOT assay

Kreijtz et al. J Virol 2008, 82(11):5161-5166

Cross reactivity of human virus specific CTL

-Virus infected cells-


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Vaccination against H3N2 prevents induction of heterosubtypic immunity by H3N2 infection

against fatal H5N1 infection

Kreijtz et al., Hum Vaccin. 2009 Bodewes et al ., Plos One 2009Bodewes et al ., Lancet 2010Bodewes et al ., J.Virol 2011


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Vaccination against H3N2 prevents induction of heterosubtypic immunity by H3N2 infection

against fatal H5N1 infection

Kreijtz et al., Hum Vaccin. 2009 Bodewes et al ., Plos One 2009Bodewes et al ., Lancet 2010Bodewes et al ., J.Virol 2011

Q: universal flu vaccination of children?


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Adjuvanted influenza vaccines / candidates

Approved:MF59 (squalene emulsion) seasonalAS03 (squalene/tocopherol emulsion) pandemic Virosomes (liposomes) seasonalPolyoxidonium (poly-electrolyte)seasonal

Clinical studies (phase 1, 2)Iscoms (with virosomes)AF3 (squalene o/w emulsions)SE (squalene o/w emulsions)GLA (TLR 4 agonist)Covaccine (TLR 4 agonist)Flagellin (TLR 5 agonist)IC31 (dI:dC – TLR9 agonist)Inulin (complement activator)JVRS-100 (cationic liposome)


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Assessment of pre-pandemic H5N1 clinical trials

Type of vaccine Compliance with EU licensing criteria

Split vaccine no adjuvant Need two doses of 90 µg

Split/subunit vaccine with alum Need two doses of 30-45 µg

Whole virus (egg) with alum Need two doses of 10-15 µg

Subunit with MF59 adjuvant Need two doses of 7.5 µg

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

Split vaccine with AS adjuvant Need two doses of 3.8 µg

Data presented at WHO meeting, February 2007(Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK, Novartis,Baxter)


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CHMP criteria

40

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

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25

50

75

100

Post first dose Post second dose

Sero

conv

ersi

on ra

te (%

)3.8µg H5 7.5µg H5 15µg H530µg H5

3.8µg H5 AS7.5µg H5 AS15µg H5 AS30µg H5 AS

The three CHMP criteria are exceeded by all the adjuvanted doses: seroconversion rates


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• 2 immunisations of ferrets at D0 and D21 (H5N1 A/Vietnam/1194/04 split / AS)• Heterologous challenge (wild-type virus A/Indonesia/5/05, 105 TCID50) at D49• Post challenge results at D5

Dead Alive % SurvivalPooled controls(15 µg Antigen

only 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 vaccinated with AS-adjuvanted H5N1 split candidate vaccine

Baras et al., PLoS One 2008 NB: similar data with clade 2.2 and 2.3 viruses


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Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets B. Baras et al., Vaccine. 2011


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Del Guidice et al. Science TM 2009

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

Seasonal vaccine provides priming against A/H1N1 pandemic influenza

- = PBSA = seasonal H1N1F = seasonal H1N1 + MF59C = pdm H1N1C+ = pdm H1N1 + MF59

Vaccines


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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.

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ubje

cts

H1N1 (21µg)H1N1 (5.25µg)+

AS03A

D21 D211

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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.


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ADJUVANTS AND FLU VACCINES

Seasonal flu-vaccine~ Annual boosting of primed individuals (limited effect)

~ Yearly administration of alum may carry risks~ FLUAD (MF59, Novartis) for elderly: > longevity antibody

Pandemic flu-vaccine does it require adjuvant? ~ Priming of non-exposed individuals~ Without adjuvant larger doses of antigen required (90 ug: H5N1)~ Adjuvant can enhance capacity (5 to 15-fold dose reduction)

~ Little effect in primed individuals (H1N1 vs H5N1)

POINTS TO CONSIDER


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Efficacy of live attenuated vaccines against 2009 pandemic H1N1 influenza in ferrets: WHO initiative

Stittelaar et al. submitted


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New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and TherapeuticEfficacy in Ferrets Friesen R.H. et al, PLoS One. 2010


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Two vaccination effectivenes studies "Mexican flu"

The Scottish VIPER study and a German study

vaccination was effective 97% in 15-65 age group83% in > 65 age group

vaccination reduced risk of Influenza vaccination reduced risk of pneumonia and hospitalisationvaccination reduced mortality

Additional data report that the vaccines were safe!!!ESCMID Online Lectu

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Germany: Effectiveness of GSK’s AS03-adjuvanted pandemic H1N1 2009 vaccine

O. Wichmann, P. Stöcker, G. Poggensee, et al. Pandemic influenza A(H1N1) 2009 breakthrough infections and estimates effectiveness in Germany 2009-2010. Euro Surveillance 2010.

289 H1N1 cases with complete data:- 228 cases were vaccinated < 14 days before onset of symptoms- 61 cases were vaccinated > 14 days before onset of symptoms


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http://en.wikipedia.org/wiki/File:Flag_of_Germany.svg

Direct effectiveness of GSK’s AS03-adjuvanted pandemic H1N1 2009 vaccine

German data:

Persons 14 to 59 years: 96,8%Persons ≥ 60 years: 83,3%

Scottish data:

At risk persons (all ages): 95,0%

Canadian data:

Children 36 months to < 10 years: 100%ESCMID Online Lectu

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Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial

Karl G Nicholson et al., The Lancet Infectious Diseases, 2011

AS03A-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy should be considered for older people.


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

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


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Safety surveillance of influenza A(H1N1)v monovalent vaccines during the 2009-2010 mass vaccination campaign in France

Caillet et al. Eur J Clin Pharmacol, 2010


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Conclusion by the EMA:

“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 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.”ESCMID Online Lectu

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

“As per 17 September 2010, there are 81 reports from healthcare professionals suggestive of narcolepsy, 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.”Recently new data from Finland and other Scandinavian countries emerged(genetic predisposition, latitude association, geographical restriction, 9x increased incidence: report Finland …). EMA and European studies ongoing!

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.


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Pandemic H1N1 virus… …what may happen next?

Co-circulation with other influenza viruses

(e.g. H3N2 and avian H5N1)

Change virulence (re-assortment or mutation)

Acquire antiviral resistance (re-assortment or mutation)

Circulate as seasonal flu virus

THERE WILL BE ANOTHER FLU PANDEMIC: H5N1…?ESCMID Online Lectu

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Influenza research at Erasmus MC- The team leaders -

Prof. Dr. R.A.M. Fouchier Virology

Prof. Dr. T. Kuiken Pathology

Prof. Dr. M. Koopmans Epidemiology

Prof. Dr. C.A.B. Boucher Antiviral research

Dr.A.van der Eijk / Dr.P.Fraaij Clinical research

Prof.Dr. G.F. Rimmelzwaan Immunology

Dr. M. Schutten Diagnostics

Dr. A. Andeweg Genomics


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Influenza research at Erasmus MC

- collaborations -

Erasmus MC VirologyVincent MunsterEmmie de WitDebby van RielTheo BestebroerGer van der WaterGeert van AmerongenRobert Dias d’UlloisMarion KoopmansMartin SchuttenJan de JongCharles BoucherAnnemiek van der EijkPieter FraaijGuus RimmelzwaanBart HaagmansThijs KuikenRon FouchierAb Osterhaus

Viroclinics- Biosciences BVKoert StittelaarRob van LavierenLeon de WaalCarel van BaalenFemkeBerkhoffEdwin Veldhuis-KroezeLeo SprongPaul ZoeteweijJames Simon… many others.Sanofi PasteurGSKRocheNovartisSolvayNobilonCrucellet al.


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