Effectiveness and safety of seasonal and pandemic influenza vaccines: European Perspectives

Angus Nicoll for the European Centre for Disease Prevention and Control

and the European Medicines Agency

1

Declaration of Interest StatementI have no relevant commercial interests www.europa.eu/transparency

The most entrenched conflict of interest in medicine is a

disinclination to reverse a previous opinion

John Yudkin , Bernd Richter & Edwin Gale Lancet 2011 doi:10.1016/S0140-

6736(10)61112-9

Acknowledgements European Medicines Agency

European Centre for Disease Prevention and Control

European Commission DG Health & Consumers Health Threats Unit and the Pharmaceutical Legislation Unit

Epiconcept and I-MOVE Collaboration

VAESCO & the Brighton Collaboration

National Collaborators and Regulatory Agencies

World Health Organization Europe and HQ

The VENICE-II Collaboration

Many many people in each of these 4

Background • Potentially a new seasonal influenza in Europe –

A(H1N1)2009 based

– ? Affecting younger people

– ? Clinical risk group more important

– ? Significant numbers of severe cases in healthy people

• Flu vaccine used to varying degrees routinely in Europe

• Political commitment – since 2009

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0

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40

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60

70

80

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Data available in 2009. No data available from: Austria, Cyprus, Czech Republic, Greece, Latvia

Data from VENICE survey and other sources, version November 2010. Available from http://venice.cineca.org/Final_2009_Seasonal_Influenza_Vaccination_Survey_in_Europe_1.0.pdf and http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19700

Vaccination coverage for seasonal influenza vaccine in older

people (65 years & older) in EU and EEA countries

Latest seasonal data available in spring 2009 - For season 2007/8

Background • Potentially a new seasonal influenza in Europe –

A(H1N1)2009 based

– ? Affecting younger people

– ? Clinical risk group more important

– ? Significant numbers of severe cases in healthy people

• Flu vaccine used to varying degrees routinely in Europe

• Political commitment since 2009

• Mixed experience in Europe in the pandemic - but things that worked well outside the pandemic functioned in the pandemic - conversely …….

7

Pandemic Vaccination coverage in the population (n=21 countries)

Preliminary results http://ecdc.europa.eu/en/ESCAIDE/ESCAIDE%20Presentations%20lib

rary/ESCAIDE2010_Late_Breakers_Mereckiene.pdf

Vaccine Effectiveness

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Efficacy and Effectiveness of Vaccines – both important

Efficacy • Seen in trials – but

usually optimal subjects

• Can study mild infection only

• Simple

• Through serology – a correlate of protection

• Key in Regulation and annual licensing

Effectiveness• Observed in the field

• Estimates subject to various biases

• Estimates less stable

• Complex - Varying methods

• Can study severe disease and death

• Closer to the individual experience

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Monitoring influenza vaccine effectiveness in EU: why?

Not the most effective vaccine but recommended in all EU MS

Evaluate influenza vaccination programme

Maintain confidence in vaccination programmes

Influenza VE (IVE) varies from year to year

• clinical IVE cannot be predicted based on antigenic distance

• IVE can vary by age, subgroups and virus suptype

Detect variations in effectiveness due to

• changes in the target population

• changes in the epidemiology of disease

• poor virus-vaccine match

• special field conditions

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Monitoring influenza vaccine effectiveness in EU: why?

Trigger other public health measures• use of antivirals

For new vaccines IVE could be incorporated as component of post-licensure surveillance

ILI /ARI incidence does not predictably decrease with increased vaccination coverage

• VE cannot be inferred from surveillance data

Trigger research on more effective vaccines

• mode of administration

• adjuvanted vs non-adjuvanted vaccines

• dosages

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I-MOVE Collaboration (Influenza monitoring VE in Europe)

Objectives

To identify and pilot test methods to measure seasonal and pandemic IVE in EU and EEA

To develop a system to monitor on a routine and real-time basis IVE in EU and EEA– have early estimates during the influenza season

– have a system ready to assess and monitor IVE in a pandemic

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ECDC

EISN

Health Protection Agency, UK

Health Protection Surveillance Centre, Dublin, Ireland

Instituto de Salud Carlos III, Madrid, Spain

Institut de Veille Sanitaire, Paris, France

National Center for Epidemiology, Budapest, Hungary

National Institute of Research –Development for Microbiological and Immunology, Bucharest, Romania

National Institute for Pubic Health and the Environment (RIVM), Bilthoven, The Nertherlands

Norvegian Institute of Public Health, Oslo, Norway

National Public Health Institute, Helsinki, Finland

National Institute of Public Health, Poland

Publich Health Institute Navarra, Spain

Robert Koch Institute, Berlin, Germany

Scientific Institute of Public Health, Brussels, Belgium

Smittskiddsinstitutet, Stockholm, Sweden

Statens Serum Institut, Copenhagen, Denmark

Scottish Centre for Infection and Environmental Health (CIEH)

Istituto Superiore Di Sanita, Rome, Italy

Greece, National Institute of Health

Royal College of General practitioners Brimingham Research Unit, UK

Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal.

I-MOVE

ECDC

20 EU & EEA Member States

Coordination, EpiConcept

Collaboration with

Australia

Canada

USA

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Three Methodolgies – all based on laboratory confirmed end-points

Case control

Cohort studies and nested case controls

Screening method

See Valenciano M, Kissling E, Ciancio BC, Moren A. Study designs for timely estimation of influenza vaccine effectiveness using European sentinel practitioner networks. Vaccine. 2010 Oct 8;28(46):7381-8. Epub 2010 Sep 17.

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Published Results

2008/9 Pre pandemic elderly – seasonal vaccine

2009 Pandemic vaccines – predominately adjuvanted

2010-2011 Post pandemic seasonal vaccine

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Seasonal vaccine effectiveness 2008-9pooled analysis pilot season (older people) – 5 sites

55.159.1

65.4 59,657.4 56.4

0

20

40

60

80

100

65 - 74 75+

Crude Full model Age Influenza A onlyInfluenza AH3

Vac

cin

e e

ffe

ctiv

en

ess

(%

)

Overall sample size N = 327 Kissling E, Valenciano M, Falcão JM, Larrauri A, Widgren K, Pitigoi D, Oroszi B, Nunes B, Savulescu C, Mazick A, LupulescuE, Ciancio B, Moren A. “I-MOVE” towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe, 2008-9. Euro Surveill. 2009;14(44):pii=19388. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19388

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* Study site in model as a fixed effect

‡ adjusted for sex, chronic diseases and related hospitalisations, smoking, previous seasonal influenza vaccination, functional status,

Pandemic vaccine effectiveness 2009-10, imputed dataset, pooled analysis – 7 study sites

83

72

87

78 8173

94

85 85

73

0

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50

60

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90

100

Crude* Adj ‡ Crude* Adj ‡ Crude* Adj ‡ Crude* Adj ‡ Crude* Adj ‡

All < 65 years 15-64 years < 15 years No chronic disease

PIV

E %

* Study site in model as a fixed effect

‡ adjusted for age-group, sex, month of onset, chronic diseases and related hospitalisations, smoking, seasonal influenza vaccinations and number of practitioner visits in the previous year

Overall sample size N = 2902 Valenciano M Kissling E, Cohen J-M, Oroszi B, Barret AS, Rizzo C et al Estimates of Pandemic Influenza Vaccine Effectiveness in

Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study. Plos Medicine PLoS Med 8(1): e1000388.

doi:10.1371/ journal.pmed.1000388 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000388

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Seasonal vaccine 2010-11 effectivenessby influenza subtype, imputed dataset, pooled

analysis – 8 study sites

Overall sample size N = 4410 : Kissling E, Valenciano M, I-MOVE case–control studies team. Early estimates of seasonal influenza vaccine effectiveness in Europe, 2010/11: I-MOVE, a multicentre case–control study. Euro Surveill. 2011;16(11):pii=19818. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19818

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64

52

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56

66

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Crude* Adjusted‡ Crude* Adjusted‡ Crude* Adjusted‡

All influenza (N=4410) H1N1 (N=3344) B (N=2944)

VE

%

* Study site included in the model as fixed effect‡ Model adjusted for 2009-10 seasonal and pandemic influenza vaccination, least one chronic disease, sex, at least one hospitalisation in previous 12 months, current smoker, age group practitioner visits in previous 12 months, week of symptom onset

Importance of Laboratory Confirmed End-points

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Cohort study to evaluate the

IVE in preventing MA-ILI

Test negative case-control study

to evaluate the IVE in preventing

laboratory-confirmed influenza

IVE 2010-11 against MA-ILI and lab confirmed influenza in pop with chronic conditions, Navarra

* Euro Surveill 2011;16(7):pii=19799.

Courtesy Jesús Castilla

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I-MOVE future

To monitor influenza VE against severe outcomes

Network of EU hospitals

– similar protocol pooling

– can be used for other diseases

ECDC EVER programme

– collect, analyse, communicate data and information on immunisation programmes in EU

– bring under same umbrella activities previously covered by different projects

– integrate the elements of vaccine preventable disease surveillance programme: disease surveillance, vaccine effectiveness, vaccination safety and vaccination coverage

Effectiveness Acknowledgements Sentinel networks

Partners conducting studies in 2010/11

– England and Wales, RCGP: Douglas Fleming, Haylay Durnall,

– France, OpenRome / GROG: Jean-Marie Cohen, Anne Mosnier, Isabelle Daviaud

– Hungary, NCE, : Beatrix Oroszi, Krisztina Horvath, Marta Melles, Agnes Csohan

– Ireland, HSE: Anne-Sophie Barret , Joan O'Donnell, Darina O’Flanagan, Aidan O´Hora,

– Italy, ISS: Caterina Rizzo, Paolo Dancona, Antonino Bella , Maria Cristina Rota

– Portugal, Inst Nac Saude Dr Ricardo Jorge: Baltazar Nunes, José Marinho Falcão, Raquel Guiomar

– Romania, Cantacuzino Institut: Viorel Alexandrescu, Daniela Pitigoiti, Emilia Lupulescu,

– Scotland, HPS: Jim McMenamin, Chris Robertson, Arlene Reynolds

– Spain, ISCIII: Amparo Larrauri, Silvia Jiménez, Salvador De Mateo

– Spain, Navarra Public Health Institute: Jesús Castilla , Iván Martínez

– Poland, National Institute of Public Health: Iwona Paradowska-Stankeiwicz, Malgosia Fluchowska, Pawel Stefanoff

– UK, HPA: Richard Pebody, Nick Andrews, Pia Hardelid

ECDC: Bruno Ciancio, Piotr Kramarz, Angus Nicoll

EpiConcept: A Moren, M Valenciano, E Kissling, C Savulescu, T Seyler, A Halm, V Nancey, N Colombo, G Jeannerod

Other Partner Institutes

– Belgium, IPH– Denmark, SSI– Finland, THL– France, InVS– France, Sentinelles– Italy, Campobasso, Catholic University– Greece, KEEPNO – Norway, FHI– Spain, Valencia CSISP– Sweden, SMI– The Netherlands, RIVM– The Netherlands, Erasmus University,

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An agency of the European Union

Vaccine Safety Monitoring and investigating in Europe

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Content

2525

• Methods of safety monitoring

• General Safety

• Investigating Adverse Events Following

Immunisations

• Guillain-Barré syndrome

• Narcolepsy

Methods of safety monitoring and

investigation Spontaneous Reporting by Clinicians and (increasingly) the public

National Systems

Feed into EMA System Eudravigilance

Special Systems and outputs in the Pandemic (EMA Pandemic

Pharmacovigilance Summaries http://www.ema.europa.eu/influenza/updates.html )

EU Vaccine Task Force

http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/04/WC500105820.pdf

Rapid Evaluation Group – (PREG) -

Review by Committee on Human Medical Products

Formal requests for special studies when signal appears 26

ADJUVANTED pandemic

influenza vaccines “

NON-ADJUVANTED

pandemic influenza vaccines

**

Number ADRs with

Autoimmune Disorders 126 12

Number ADRs total 49,236 4,048

% 0.26 0.30

CI 95 % [0.21 - 0.30] [0.13 - 0.46]

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* Arepanrix™, Celtura™, Fluval P™, Focetria™, Pandemrix™, Humenza™

** Cantgrip™, Celvapan™, Panenza™

Preliminary analyses from EudraVigilance: reporting proportion of Autoimmune

disorders (MedDRA HLGT ‘Autoimmune disorders’) amongst all ADR reports, 1st

October 2009 to 31st December 2010

2. Analysis restricted to Autoimmune Disorders with causality related (certain,

probable, possible), time to onset 1→42 days for GBS and 1→30 days for

other reactions and BC 1-3 (GBS), 1-2 (ITP), 1-3 (ADEM)

Vaccine Safety Signal detection and assessment in Europe

Routine reporting of adverse events following immunization

Validation of safety concerns – case ascertainment

Causal association studies

Benefit/risk evaluations

Risk communication

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Post-licensure monitoring for AEFIs shared responsibility between manufacturers, Public Health Institutes/ECDC and National Regulatory Agencies/EMA

However, should a signal arise sustainable European infrastructure only now being built

VAESCO ECDC since 2008 funds and collaborates closely with

a consortium of researchers in Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, and UK:

Vaccine Adverse Event Surveillance & Communication

– Coordination of the VAESCO consortium – Brighton Collaboration

– Central data analyses by Erasmus University

Major component - data linkage of different health registries

Rationale: For rare events populations of one country is too small

Project was accelerated due to use of new pandemic vaccines – unprecedented effort - need for €€€infusion

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EUROPEAN LEVELPooling of national/regional aggregated

data at Erasmus university medical center

Jerboa vaccine

module software

Database in

country 1

…

Jerboa vaccine

module software

Database in

country 2

Jerboa vaccine

module software

Database in

country..n

Country borders

The European Vaccine Safety Data linkage system

*this comes from the drug safety area where it is proven to work well and also in the US CDC Vaccine Safety Datalink system

*

On-going and completed studiesEstablishing Base-line for selected conditions – undergoing validation

Assessment of GBS and pandemic vaccines – € 1,1 million

TP and MMR – proof of

concept, Vaccine 2011

CCS – accepted BMJ

SCCS – in manuscript

Assessment of narcolepsy and pandemic vaccines – € 524,000

Case definition finalized together with European network of narcolepsy experts

Background incidence being developed

Case control study on-going31

Proof of concept – using data linkage in Denmark and England*

Results obtained from data linkage can be pooled from different countries using MMR vaccine and a

known adverse event trombocythopenic purpura

following MMR

Figure1: Timing of ITP around MMR

0

10

20

30

40

50

60

13 to 18 7 to 12 0 to 6 0 to 6 7 to 12 13 to 18 19 to 24 25 to 32 33 to 40

Interval from MMR (weeks)

Count of IT

P

Denmark

England

Post MMRPre MMR

Period after MMR (days)

Analysis 0-13 14-27 28-42 0-42

RI (95% CI) [n] RI (95% CI) [n] RI (95% CI) [n] RI (95% CI) [n]

Pooled data with

common age effect

1.38 (0.76-2.50) 3.09 (2.02-4.73) 1.97 (1.18-3.28) 2.13 (1.55-2.94)

Pooled data with country

specific age effects

1.30 (0.71-2.38) 2.87 (1.85-4.46) 1.81 (1.07-3.05) 1.98 (1.41-2.78)

Meta-analysis 1.30 (0.71-2.38) 2.84 (1.82-4.43) 1.83 (1.08-3.09) 1.98 (1.41-2.78)

Table 3: Relative incidence of ITP after MMR vaccination in children aged 12-23 months using

SCCS analysis of pooled data from Denmark and England and using meta-analysis of each countries individual SCCS RI estimates.

32Andrews N et al Vaccine 2011

Background incidence results pooledimportance of age and sex standardisation *

IR

*Unpublished – validation on-going

Results GBS case control study*

9.6

2.31.85

2.5

0.41

1.3

0.89

2.8

0.62

2.01

0.91

0.03125

0.0625

0.125

0.25

0.5

1

2

4

8

16

32

64

unadj. adj unadj adj unadj adj unadj adj unadj adj unadj adj

DK SW NL UK Pooled UK/NL Pooled UK/SW/NL

We can exclude a relative risk increase beyond 2.7 based on

the 95% confidence interval. Less than 3 attributable cases per

1,000,000 vaccinated persons

*Dieleman et al BMJ 2011 http://www.bmj.com/cgi/doi/10.1136/bmj.d3908

Conclusions

Field vaccine effectiveness system can be established - need infrastructure and some expert capacity

Don’t over-state effectiveness

Vaccine safety again need infrastructure

Simple signal reporting - need independent systems for rapid investigation – but its never fast

Linked data-bases and registries are a way to go

How to make the systems sustainable? 35

Acknowledgements European Medicines Agency

European Centre for Disease Prevention and Control

European Commission DG Health & Consumers Health Threats Unit and the Pharmaceutical Legislation Unit

Epiconcept and I-MOVE Collaboration

VAESCO & the Brighton Collaboration

National Collaborators and Regulatory Agencies

World Health Organization Europe and HQ

The VENICE-II Collaboration

Many many people in each of these 36

Thank you

37