the issue of narcolepsy after the 2009 h1n1 pandemic ... · development of narcolepsy’; •...
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The issue of narcolepsy after the 2009 H1N1 pandemic vaccination
European Centre for Disease Prevention and Control
Kari Johansen, Influenza and other respiratory viruses programme
Luxembourg 29-30 April, 2015
Product Adjuvant§ emulsion
Thiomersal Number
of doses
Celvapan®, Baxter
Inactivated, whole
natural virus A/California/7/2009 (H1N1)v
None None All > 6 mo
2 x 0.5 mL
Pandemrix®, GSK
Inactivated,
purified split-influenza, reassortant, A/California/7/2009 (H1N1)v like strain
AS03§
(Squalene + α-tocoferol)
5 µg (per adult dose)
2.5 µg (per pediatric dose)
>10 yrs
1 x 0.5 mL
50 µg 6 mo – 9 yrs
2 x 0.25 mL
Focetria®, Novartis
Inactivated, surface-antigen (haemagglutinin and
neuraminidase),
reassortant, A/California/7/2009 (H1N1)v like strain
MF59§
(Squalene)
50 µg (per adult dose) 25 µg (per pediatric dose)
All > 9 years 1 x 0.5 mL
>6 mo – 8 years 2 x 0.5 mL
Celtura®
Novartis
Inactivated, surface-antigen (haemagglutinin and
neuraminidase), reassortant, A/California/7/2009
(H1N1)v like strain
MF59
(Squalene)
None
Adults 18 – 40 years, children 3 – 17 years
1 x 0.25 mL
Adults > 40 years 2 x 0.25 mL
Fluval P®, Omninvest
Inactivated, whole
reassortant virus A/California/7/2009 (H1N1)v
Aluminium phosphate§
50 µg (per adult dose) 25 µg (per pediatric dose)
Adults and adolescents > 12 years 1 x 0.5 mL
Children 3-12 years 1 x 0.25 mL
Children 12 months-3 years
1 x 0.25 mL*
Panenza®
SanofiPasteur
Inactivated,
purified split-influenza, reassortant, A/California/7/2009 (H1N1)v like strain
None None in single doses
Adults and adolescents >12 years 1 x 1 x 0.5 mL
Elderly >60 years and children 3-8 years 2 x 0.5 mL
PanvaxH1N1® Inactivated,
purified split-influenza, reassortant, A/California/7/2009 (H1N1)v like strain
None None in single doses All > 18 years
1 x 0.5 mL
Cantgrip® Cantacuzino
Inactivated,
purified split-influenza, reassortant, A/California/7/2009 (H1N1)v like strain
None None in single doses All > 18 years
1 x 0.5 mL
Eight pandemic vaccines available in 2009 for use in large vaccination campaigns…
2
Why adjuvants?
• to spare antigen to allow protection of the maximum number of individuals should a severe pandemic occur;
• to stimulate a stronger and broader immune response;
• for some influenza strains (e.g. H5N1, H7N9), unadjuvanted vaccines are insufficiently immunogenic to provide protection in most healthy individuals;
• to support an immune response in persons who are least able to mount an effective immune response to standard influenza vaccines (e.g., very young children, elderly, immunocompromised).
Pandemrix – the vaccine mostly used
• At least 38.6 million individuals were vaccinated with one of the three centrally authorised vaccines*
• In addition, at least 7.6 million individuals were vaccinated with one of the nationally authorised vaccines
Centrally authorised vaccines/Manufacturer
Estimated number of doses administered
Celvapan, Baxter 566, 000
Focetria, Novartis 6.5 million
Pandemrix, GSK 30.8 million
*22nd EMA pandemic pharmacovigilance update published 19 August, 2010
Among many activities EMA and ECDC did in advance of vaccination campaigns …
• EMA defined adverse events of special interest (AESI):
– neuritis, convulsions, anaphylaxis, encephalitis, vasculitis, Guillain-Barré syndrome, Bell’s palsy, demyelinating disorders, laboratory-confirmed vaccination failure
• ECDC requested their newly formed vaccine safety network VAESCO able to conduct studies to investigate
– Background incidence for the possible AESIs including Guillain-Barré syndrome
The unexpected ….
August, 2010 - narcolepsy reported in vaccinated children in Sweden and Finland – ECDC contacts VAESCO September, 2010 - EMA reviews data and concludes "available evidence insufficient …further studies necessary" – VAESCO develops case definition & submits study protocol, national initiatives start in parallel February, 2011 – Finland reports 9-fold increased risk March, 2011 - Sweden reports 4-fold increased risk July 2011 – VAESCO confirms signal in Finland and Sweden July 2011 – EMA recommends restricted use of Pandemrix in persons under 20 years of age. However, overall benefit-risk remains positive.
6
Narcolepsy disease*
Disabling chronic sleep disorder
Excessive daytime sleepiness
Cataplexy
Sleep paralysis
Hypnagogic hallucinations
Disrupted nocturnal sleep
Insidious onset
Commonly long time between onset and diagnosis
Diagnosis includes
- multi sleep latency test
- assessment of hypocretin-1 in CSF
Genetically susceptible individuals - strong association with HLA haplotype DQB1*0602
*Common with parents delay, patient delay, & doctors delay
Video
https://bi.ema.europa.eu/analyticsSOAP/saw.dll?PortalPages
n=1,379
Onset in Finland MPA Sweden press release
on possible association
EDS 1st contact
Referral G47.4
Incidence of narcolepsy before, during and after vaccination
11 *Denmark, Netherlands, Sweden, Italy, UK (data missing for Finland from 2010), Vaccine 2012
Assessed in databases in six European countries 2000 – 2010*
Association between Pandemrix and narcolepsy assessed in PE studies…
Country Age in years
Study design
Definition of onset
Follow-up period
Risk RR/OR
95% CI
Finland 4-19 Cohort 1st contact to HC 1 Jan 2009 – 15 Aug 2010
12.7 6.1 – 30.8
France <19
≥19
Case-control
Date for referral to MSLT
1 April 2009 – 30 April,
2011
5.1
3.9
2.11 – 2.3
1.4 – 11.0
Ireland 5-19 Cohort 1st contact to HC 1 Apr 2009 -31 Dec 2010
13.0 4.6 – 34.7
Norway 4-19 Cohort Date of EDS recorded by
patient/family
1 Oct 2009 – 30 June 2010
14.5* Not reported
Sweden
≤19
21-30 31+
Cohort
Cohort Cohort
Date of diagnosis G47.4
1 Oct 2009 – 31 Dec 2010 1 Oct 2009 – 31 Dec 2011
4.06
2.18 1.58
2.87 – 5.58
1.00-4.75 0.68-3.44
United Kingdom
4-19 Case-Cohort SCCS
Date of EDS recorded by GP
6 months post-
vaccination
16.2 9.9
3.1 – 84.5 2.1 – 47.9
12 *Reported as at least 10-fold increase in final scientific publication
Uncertain association between Arepanrix and narcolepsy determined in PE studies…
Country Age in years
Study design
Definition of
onset
Follow-up
period
Risk RR/OR
95% CI
Canada
<20 years >20 years
Cohort
Most probable date for onset of
EDS and/or cataplexy symptoms
using questionnai
re
1 Jan 2009 – Dec 31
2010
6.39 2.44
1.60-23.38 0.26-11.80
<20 years >20 years
SCCS
2.96 1.18
0.71-12.39 0.20-7.09
<20 years >20 years
Case-control
3.21 0.73
0.37-90.37 0.06-6.70
13
Pathogenesis still unknown – does the manufacturing process matter?
Downstream Process *
Arepanrix produced by the Quebec method
Pandemrix produced by the Dresden method
Virus inactivated by UV light followed by formaldehyde
Virus concentrated and purified by zonal centrifugation using a linear sucrose density gradient solution containing detergent to split the virus
Purified by centrifugation and disrupted by deoxycholate
Further purified by diafiltration
Virus inactivated by consecutive effect of deoxycholate and formaldehyde
* In correspondance with GSK
No difference in upstream process
Pathogenesis cont…
• US Patent Application by Novartis AG – Nov 13, 2014 ‘Avoiding narcolepsy risk in influenza vaccines’;
• ..’The fact that Pandemrix and Focetria have different oil-in-water emulsion adjuvants led to the wide-spread assumption that the adjuvant might be implicated in the development of narcolepsy’;
• ‘The inventors have surprisingly discovered, however, that the causative factor is likely instead to be the different influenza nucleoproteins in the two vaccines which in Pandemrix can mimic the orexin (hypocretin) receptor. Narcolepsy has been associated with loss of neurons that produce orexin’…
15 *http://www.freepatentsonline.com/y2014/0335116.htm Publication date: 11/13/2014l
Lessons learned • Unexpected events occur – were we/are we prepared?
• Routine monitoring of vaccine programmes and the products used is needed – exposure in immunization registries is key
• Should an unexpected safety signal arise several stakeholders are needed, some of these are:
– Manufacturers responsible for respective product
– Regulatory agencies responsible for authorisation
– Public health responsible for the programmes
• However, important to distinguish and agree on roles and responsibilities, have proper SOPs in place for signal detection / signal verification for hypothesis generation / epidemiologic study for hypothesis testing / funding
• Liability/compensation (compensation for narcolepsy varies significantly from countries with organised schemes to countries where each family has to file complaint in court*)
16 *The risk window for compensation is still under discussion
