European Measles and Rubella Laboratory Network :
Accreditation programme and regional verification process requirements
Myriam Ben Mamou, MD - Regional Laboratory Coordinator
Vaccine-preventable Diseases and Immunization Programme
WHO Regional Office for Europe
Copenhagen, Denmark
Meeting of the Italian National Network of Measles and Rubella Laboratories
Rome, 20 March 2017
1
Outline
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•
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•
•
Background
WHO Measles and Rubella Laboratory Network (MR LabNet)
MR LabNet Accreditation programme
Regional verification process : outcomes and requirements
Summary
2
All six WHO Regions have measles elimination goals
3
Laboratory confirmation is key for MR surveillance
Global and Regional Strategies : rapid and accurate diagnosis of measles and
rubella is essential for monitoring progress and detecting outbreaks
4
Measles and Rubella Global Strategic Plan 2012-2020
Mid-term Review (MTR), Sept 2016
“Measuring coverage with measles and rubella containing
vaccines, while important, is not the best indicator of progress
towards measles/rubella control/elimination. Disease incidence,
in the presence of an effective surveillance system, is the most
important indicator of progress. ”
“A top priority for achieving the goals of the Measles Rubella
Strategic Plan is to enhance case-based, laboratory-supported
surveillance for measles and rubella.”
“There is an urgent need to strengthen the collection and use of
surveillance data to better guide program strategy and
implementation.”
http://measlesrubellainitiative.org/wpcontent/uploads/2016/07/MTR-Report-Final-Color-Sept20_v2.pdf
5
SAGE endorsed MTR key findings and recommendations
Weekly Epidemiological Report , Dec 2016
“The basic strategies in the strategic plan are sound, and failure to
reach global targets is mainly due to lack of country ownership
and global political will, as reflected in insufficient resources.”
“SAGE supported the key recommendations from the MTR for
strengthening disease surveillance as disease incidence is the
most important indicator of programmatic success.”
“SAGE stressed the critical role of high quality measles and
rubella case-based surveillance and recommended that, as
countries approach elimination, they should intensify surveillance
and move towards weekly reporting to the Regions .”
Weekly Epidemiological Report Dec 2016, 91, No. 48, 561–584
http://apps.who.int/iris/bitstream/10665/251810/1/WER9
148.pdf?ua=1
6
Number of measles in the WHO European Region, 20072016*
5099 cases
in
34 countries
35,000
30,000
25,000
20,000
Bulgaria
24 410
15,000
France
19 997
10,000
5,000
Ukraine
14 079
Georgia
11 060
Kyrgyzstan
18 097
0
2007
2008
2009
2010
Data source CISID, extracted 17 February 2017
2011
2012
2013
2014
*Provisional data
2015
Romania
2435
2016*
7
Top 10 countries with measles cases,
WHO European Region, 2016*
0
500
1000
1500
2000
Romania
2500
2435
Italy
843
UK
571
Germany
323
Poland
131
Belgium
119
Kazakhstan
106
Ukraine
90
France
79
Switzerland
65
ZERO
measles cases in 16
countries
Data source CISID, as of 1 February 2017
3000
83% of cases in the
Region were reported
from 4 countries
(n=4172)
17 deaths:
16 in Romania
1 in United Kingdom
7 infants (ineligible for vaccination)
7 children
2 teenagers
1 adult
* Provisional data
8
Rubella in the WHO European Region, 2000 & 2010-2016*
99.8%
REDUCTION
2000-2016
Number of reported rubella cases
40,000
35,000
30,000
86%
reported by
Poland
Other
POLAND
ROMANIA
25,000
20,000
15,000
10,000
5,000
0
2010
Data source CISID, as of 1 February 2017
2011
2012
2013
2014
* Provisional data
2015
2016
9
Countries with most rubella cases,
WHO European Region, 2016*
0
200
400
600
800
Poland
935
Germany
Italy
76
27
Georgia
10
Portugal
9
12 other countries
1000
ZERO
33
Data source CISID, as of 1 February 2017
rubella cases in 7 countries
* Provisional data
10
Measles virus genotypes reported to MeaNS,
WHO European Region, 2010-2016
Source : MeaNS, January 2017
11
Number of sequences
reported to MeaNS
Measles virus genotype D8 and B3 named strains reported to
MeaNS, WHO European Region, 2014-2017
Number of sequences
reported to MeaNS
D8 Named
strains
B3 Named strains
Source : MeaNS, March 2017
D8
B3
12
How does genotyping data relate to real life ?
MeaNS database
Surveillance system
“Real life”
A
B
D8 Rostov
D8 Rep. Komi
D8 Villupuram
B3 Harare
D4 Manchester
Genotyped /epi linked
Lab confirmed  epi linked
Clinically compatible
Not detected

 rates : Laboratory investigation
Viral detection
Cases & chains of transmission
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WHO Global Measles and Rubella Laboratory Network : 2016
2012
N= 690 labs
31 Prov. Labs
+ 331 Prefect. Labs
National Laboratories
Regional Reference Labs
Global Specialised Labs
Provincial Labs China
Sub-National Labs
Slide courtesy of M. Mulders, WHO HQ
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WHO Measles & Rubella Laboratory Network
Global
Specialized
Labs
Regional
Reference
Labs
National
Reference
Labs
Subnational
Labs
 Technical support / training
 Research
 Quality Assurance
 Genotyping, viral characterization
 Reference Testing
Including Genotyping of samples referred by NRLs
 Quality assurance
 Technical support / training
 Testing:
• Case classification for clinically suspected measles and rubella:
IgM detection by EIA.
• Virus isolation or direct RT-PCR or both with samples collected for
genotyping.
• If facilities and capacity do not support molecular testing,
NRL forwards samples to the designated RRL
 Quality assurance (annual accreditation)
 Monitoring of SNLs
 Testing: case classification for clinically suspected measles and rubella
using IgM detection by EIA
 Referral of samples to NRL
 Quality assurance (annual accreditation)
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WHO European Measles & Rubella Laboratory Network
71
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•
•
•
laboratories
1Global Specialized Lab (GSL)
3 Regional Reference Labs (RRLs)
48 National Reference Labs (NRLs)
19 Subnational Labs (SNLs)
100% laboratories accredited
for 2016 and 2017
32174
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Measles Rubella LabNet accreditation programme
8 essential criteria : annually, desk review
Reporting
External QA
Internal QC procedures
 IgM :  4 days
 Sequences : 2 months  IgM detection accuracy
 Lab reporting to WHO
 IgM Proficiency testing
Workload
 Number of specimens
(Measles/ Rubella IgM)
 Internal quality control
 Molecular EQA
Periodically
 On-site review
• Laboratory operating
procedures
• Working practices
• Lab/epi collaboration,
contribution to the
verification
17
Measles Rubella LabNet accreditation programme
Measles and Rubella
Laboratory Check-list
for annual WHO
accreditation
http://mrldms.euro.who.int/Content/download_public/National_MeaslesRubella_Checklist_EURO_2016_EN.docx
Measles and Rubella
Laboratory Manual
Currently under revision, 2017
www.who.int/ihr/elibrary/manual_diagn_lab_mea_rub_en.pdf
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MR Labnet performance: 2017 accreditation
Accreditation criteria
% of participating labs meeting the criteria
≥ 50 specimens annually
Measles
Accuracy of IgM ≥ 90%
Rubella
Measles
Serology PT ≥90%
Rubella
Molecular EQA passed
Measles
Rubella
96 %
100 %
98 %
98 %
98 %
Detection 100%
Genotyping 93%
Detection 97%
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MR Labnet performance: 2017 accreditation
Accreditation criteria
IgM result reporting  4 days
Complete IQC procedures
Molecular EQA - Rubella
Timely genotype reporting
Reporting to CISID / MRLDMS
% of participating labs meeting the criteria
19 %
53 %
Genotyping 63%
30 %
88 % (compl. 74 %, timel. 53 %)
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Laboratory contribution to the verification process
Essential criteria for documenting
the verification
1.
endemic measles and rubella cases have not
occurred for 3 consecutive years,
2.
the disease surveillance system is sufficiently
sensitive, specific, timely and complete to detect
cases if they occurred, and
3.
the absence of endemic cases is supported by
genotyping evidence.
Performance of measles and rubella
surveillance
3 essential standard indicators rely on
laboratory :
1. Rate of laboratory investigations
2. Rate of viral detection
3. Rate of discarded cases
21
Role of NRLs in the verification process
To be considered adequate, laboratories should be able to demonstrate the following characteristics:
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•
•
•
•
•
Fully accredited national reference laboratory according to current WHO laboratory
network standards;
A highly collaborative relationship with the national surveillance and immunization
systems and the medical community;
The ability to report case-based laboratory information linking laboratory data to
clinical and epidemiological data to facilitate reporting and epidemiological
classification of measles and rubella cases;
Develop and maintain a genotype map of the viruses
The means to support CRS identification and monitoring of virus shedding by CRS
cases established by the national laboratory.
Accountability to ensure the proficiency of other labs performing MR testing
22
Collaboration between laboratory, epidemiologists
and NVC is essential to the verification process
1. Laboratory confirmation of suspected cases
(ELISA, RT-PCR)
2. If cases are confirmed  Characterization
of viruses by genotyping (nucleotide sequencing):
Genotypes / Variants / Named strains
3. Submission to MeaNS and RubeNS (WHO sequence
surveillance databases)
• Sensitivity of surveillance
• Specimens for genotyping
• Linkage of genetic and
epidemiological data
• Annual Status Update :
laboratory sections, MeaNS
and RubeNS data
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Rate of laboratory investigation
Rate of measles laboratory investigations, 2015
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
24
Rate of laboratory investigation
Rate of rubella laboratory investigations, 2015
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
25
Laboratory confirmation :
Are specimens tested in proficient labs ?
ITA GRE, MNE
CRO, FRA, GEO, DEU,
27%
ISR, NET, NOR,
0%
POL, SWE
Unknown
AND, MON, SMR No testing
BIH
Measles
100%
(37 MS)
BEL, CRO, GEO, DEU,
ISR, NET, NOR, POL,
SRB, SWE
EST
GRE
ITA
POR
MNE
32%
80% 0%
Unknown
AND, CZH,
No testing
DEN, LUX,
MON, SMR, SVK
Rubella
100%
(30 MS)
BIH
Laboratory that is WHO accredited and/or has an established quality assurance programme with oversight by a WHO-accredited laboratory
Data source : 2015 Country Annual Status Updates, as of October 2016
26
Availability of genotype information in 2015 ASUs
Measles Genotyping Sequences in
cases info in ASU
MeaNS
Number of Member States
Y
Y
Y
31/37
N
N
N
14
N
16% (6/37) did not provide
measles genotyping data
Y
N
Rubella Genotyping Sequences in
cases info in ASU
RubeNS
Y
N
Y
Y
N
N
Number of Member States
Y
N
7/24
25
N
71% (17/24) did not provide
rubella genotyping data
Data source : 2015 Country Annual Status Updates, as of October 2016
27
Rate of measles viral detection, 2015
ITALY
Rate of viral detection
(clin +epi + lab), log scale
- 2
number of reported cases
- 50
Total
- 20 000
- 4 000
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
28
Rate of rubella viral detection, 2015
- 250
- 8
- 1
(clin +epi + lab), log scale
Rate of viral detection
- 100
 Total number of reported cases
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
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Acknowledgements
WHO/EURO & HQ
Dragan Jankovic
Mark Muscat
Sergei Deshevoi
Shahin Huseynov
Siddhartha Datta
Robert Jensen
Malika Abdusalyamova
Catharina de Kat
Theo Kaloumenos
Simarjit Singh
Patrick O’Connor
Robb Butler
Mick Mulders
CDC, Atlanta, GSL
Paul Rota team – measles
Joe Icenogle team – rubella
GID: funding EUR MR lab
GSL, PHE, London
Kevin Brown
David Williams
Armin Peymann
Richard Myers
Regional Laboratories
GI – Moscow
Sergey Shulga
Nina Tikhonova
Tamara Mamaeva
LIH – Luxembourg
Claude Muller
Judith Hübschen
RKI – Berlin
Annette Mankertz
Sabine Santibanez
All National and Subnational laboratories
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Summary : essential for successful verification
1. WHO-Accredited NRLs : pre-requisite
2. 80% laboratory data should originate from proficient
laboratories (Regional Framework’s definition) : WHO-accredited
national laboratories’ accountability to ensure the proficiency of
other labs performing MR testing
31
Summary : essential for successful verification
3. Renewed focus on high-quality (elimination-standard) surveillance
4. Strengthened collaboration between laboratories, epidemiologists,
NVC
• Optimize the characterization of measles chains of transmission (rates of viral
detection  80%)
•  specimen collection from rubella suspected cases   rates of lab
investigation and viral detection
• Timely reporting to MeaNS/ RubeNS and use of NL listing
32
Supplementary slides
33
Genotyping data: D8 most dominant in 2015
34
Measles genotypes and sequence variants
Genotypes :
Sequence variants
If genetically diverse genotype
Large numbers
Large geographical region,
Long period of time
 Utility of genotype-only
within genotypes (lineages)
Identical sequences
Finer resolution
Dynamic
Named strains / Distinct Sequence
ID in MeaNS
http://www.who.int/wer/2012/wer8709.pdf
35
Interpretation of sequence data
needs epidemiological information
Small outbreaks, low incidence countries
different genotypes / different variants
Large number of cases
 identical sequences
over one year
likely to be importation
?
Multiple importations
or
Endemic transmission
36
Standard indicators and targets for measuring performance
of measles and rubella surveillance
•
•
•
Rate of laboratory investigations : Percentage of cases suspected for measles
or rubella with adequate specimens collected and tested in a proficient
laboratory
Rate of discarded cases : The rate of suspected measles or rubella cases
investigated and discarded as non-measles or non-rubella cases using
laboratory testing in a proficient laboratory and/or epidemiological linkage to
another confirmed disease
Viral detection : Percentage of laboratory-confirmed chains of transmission of
measles or rubella with samples adequate for viral detection collected and
tested in an accredited laboratory
A proficient laboratory is WHO accredited and/or has an established quality
assurance programme with oversight by a WHO accredited laboratory
37
Use of MeaNS tools for the verification
MeaNS Distinct Sequence ID :
Specific identifier of each distinct
N-450 sequence in MeaNS
Named strains
NL Listing function
MeaNS ID
WHO name
Country
City
Sample Date Epi week Epi year
Genotype Distinct Seq ID
Named Strain
45607
90635
90636
MVs/Rostov on Don.RUS/47.13/2
MVs/Salzburg.AUT/10.15/
MVs/St Polten.AUT/10.15/
Russian Federation
Austria
Austria
Rostov On Don
Salzburg
St Polten
22/11/2013
12/03/2015
12/03/2015
47
11
11
2013
2015
2015
D8
D8
D8
2987
2987
2987
MVs/Rostov on Don.RUS/47.13/2
MVs/Rostov on Don.RUS/47.13/2
MVs/Rostov on Don.RUS/47.13/2
35186
65282
MVs/Victoria.AUS/6.11/
MVs/Vienna.AUT/02.15/
Australia
Austria
Victoria
Vienna
09/02/2011
07/01/2015
6
2
2011
2015
D8
D8
2279
2279
MVs/Victoria.AUS/6.11/
MVs/Victoria.AUS/6.11/
31946
65874
82459
MVs/Gadag.IND/02.13/
MVs/Vienna.AUT/16.15/
MVs/Korneuburg.AUT/17.15/
India
Austria
Austria
Gadag
Vienna
Korneuburg
07/01/2013
19/04/2015
23/04/2015
2
17
17
2013
2015
2015
D8
D8
D8
2748
2748
2748
60306
65875
MVs/Hawaii.USA/42.14/
MVs/Stein.AUT/16.15/
United States of America Hawaii
Austria
Stein
19/10/2014
13/04/2015
42
16
2014
2015
D8
D8
3268
3268
38
Rubella genotypes reported to RubeNS,
WHO European Region, 2010-2016
8
Number of sequences reported to RubeNS
7
6
?
5
2B
1G
1E
4
1a
3
2
1
0
4 7 10 11 45 1 13 18 19 27 33 39 44 46 48 3 5 6 7 8 12 13 15 16 18 19 22 23 41 46 47 49 50 51 1 7 25 27 32 35 3 10 16 17 23 27 28 53 10 12 13 17 24 36 53 4 12 14 17 23
2010
2011
2012
2013
2014
2015
Source : RubeNS
14.06.2016
2016
39
39
Number of countries and their measles elimination status
based on data for 2012-2014 (n=50) and 2015 (n=51)
Conclusions of the 4th (2015) and 5th (2016) Meetings of the European Regional Verification Commission for
measles and rubella elimination.
Eliminated
2016
2015
0%
Interrupted 24 months
10%
20%
21
24
30%
Interrupted 12 months and Interrupted*
40%
2
50%
60%
70%
9
Endemic
80%
18
9
4
No reports
90%
100%
3
14
2
* Interrupted transmission in 2015
40
Number of countries and their rubella elimination status
based on data for 2012-2014 (n=50) and 2015 (n=51)
Conclusions of the 4th (2015) and 5th (2016) Meetings of the European Regional Verification Commission for
measles and rubella elimination.
Eliminated
2016
2015
0%
10%
Interrupted 24 months
20%
20
30%
Interrupted 12 months
40%
3
24
50%
60%
Endemic
70%
9
80%
18
9
2
No reports
90%
100%
3
16
2
41
Summary of 2016 achievements, EUR MR LabNet
• Well-functioning laboratory network of WHO-accredited labs
• High level of proficiency and capacity: 100% accredited in 2016 and 2017
• 1st molecular EQA successfully rolled-out for 30 NRLs, 3 RRLs, 1 GSL
• Measles RT-PCR capacity increasingly available at national level
• Information on measles molecular epidemiology increasingly available
• Laboratory component fully integrated into the regional verification process
• Implementation of WHO recommendations (accreditation visits):
Improved performance (ITA, SRB, SWE, IRE,..)
• Excellent involvement of RRLs and GSL (visits, trainings, meetings)
collaboration with NRLs strengthened
42