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 1 Meeting of the Italian National Network of Measles and Rubella Laboratories Rome, 20 March 2017
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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
1
Meeting of the Italian National Network of Measles and Rubella LaboratoriesRome, 20 March 2017
2
• Background
• WHO Measles and Rubella Laboratory Network (MR LabNet)
• MR LabNet Accreditation programme
• Regional verification process : outcomes and requirements
• Summary
Outline
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
“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.”
“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. ”
“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 .”
“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.”
Weekly Epidemiological Report Dec 2016, 91, No. 48, 561–584
SAGE endorsed MTR key findings and recommendations Weekly Epidemiological Report , Dec 2016
Number of measles in the WHO European Region, 2007-2016*
Data source CISID, extracted 17 February 2017 *Provisional data7
Bulgaria
24 410
France
19 997Ukraine
14 079
Kyrgyzstan
18 097
*
Georgia
11 060Romania
2435
5099 cases in
34 countries
2435
843
571
323
131
119
106
90
79
65
0 500 1000 1500 2000 2500 3000
Romania
Italy
UK
Germany
Poland
Belgium
Kazakhstan
Ukraine
France
Switzerland
Top 10 countries with measles cases, WHO European Region, 2016*
83% of cases in the
Region were reported
from 4 countries
(n=4172)
* Provisional data
ZERO measles cases in 16 countries
8
17 deaths: 16 in Romania 1 in United Kingdom
7 infants (ineligible for vaccination)7 children2 teenagers 1 adult
Data source CISID, as of 1 February 2017
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
2010 2011 2012 2013 2014 2015 2016
Nu
mb
er o
f re
po
rted
ru
bel
la c
ases
Other
POLAND
ROMANIA
Rubella in the WHO European Region, 2000 & 2010-2016*
99.8%REDUCTION
2000-2016
9Data source CISID, as of 1 February 2017 * Provisional data
86% reported by Poland
Countries with most rubella cases, WHO European Region, 2016*
10
935
76
27
10
9
33
0 200 400 600 800 1000
Poland
Germany
Italy
Georgia
Portugal
12 other countries
ZERO rubella cases in 7 countries
* Provisional dataData source CISID, as of 1 February 2017
11
Measles virus genotypes reported to MeaNS,WHO European Region, 2010-2016
Source : MeaNS, January 2017
12
Num
ber
of s
eque
nces
repo
rted
to M
eaN
SMeasles virus genotype D8 and B3 named strains reported to
MeaNS, WHO European Region, 2014-2017
Source : MeaNS, March 2017
B3B3 Named strains
D8D8 Named
strains
Num
ber
of s
eque
nces
repo
rted
to M
eaN
S
A
B
How does genotyping data relate to real life ?MeaNS database
D8 Rostov
D8 Rep. Komi
D8 Villupuram
B3 Harare
D4 Manchester
“Real life”
Cases & chains of transmission
13
Surveillance system
Genotyped /epi linkedLab confirmed epi linked
Clinically compatible
Not detected
rates : Laboratory investigation
Viral detection
Global Specialised Labs
National LaboratoriesRegional Reference Labs
N= 690 labs
+ 331 Prefect. Labs
2012
Provincial Labs ChinaSub-National Labs
31 Prov. Labs
WHO Global Measles and Rubella Laboratory Network : 2016
Slide courtesy of M. Mulders, WHO HQ14
Global Specialized
Labs
Technical support / training Research Quality Assurance Genotyping, viral characterization
Regional Reference
Labs
Reference Testing Including Genotyping of samples referred by NRLs Quality assurance Technical support / training
National Reference
Labs
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
Subnational Labs
Testing: case classification for clinically suspected measles and rubella using IgM detection by EIA Referral of samples to NRL Quality assurance (annual accreditation)
% of participating labs meeting the criteriaAccreditation criteria
Laboratory contribution to the verification process
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.
3 essential standard indicators rely on
laboratory :
1. Rate of laboratory investigations
2. Rate of viral detection
3. Rate of discarded cases
Essential criteria for documenting
the verification
Performance of measles and rubella
surveillance
21
Role of NRLs in the verification process
To be considered adequate, laboratories should be able to demonstrate the following characteristics:
• 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
23
Rate of measles laboratory investigations, 2015
24
Rate
of la
bo
rato
ry inve
stiga
tio
n
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
Rate of rubella laboratory investigations, 2015
25
Rate
of la
bo
rato
ry inve
stiga
tio
n
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
ITALY
Laboratory confirmation : Are specimens tested in proficient labs ?
26
100% (37 MS)
0%
Unknown
27%
ITACRO, FRA, GEO, DEU,
ISR, NET, NOR,
POL, SWE
No testingAND, MON, SMR
BIH Measles
GRE, MNE
Unknown
No testing
100%(30 MS)
0%
32%
80%
BEL, CRO, GEO, DEU,
ISR, NET, NOR, POL,
SRB, SWE
AND, CZH,
DEN, LUX,
MON, SMR, SVK
BIH
EST
POR
GRE
MNEITA
Rubella
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
Measles
cases
Genotyping
info in ASU
Sequences in
MeaNS
Number of Member States
Y Y Y 31/37
N N N 14
Y N N16% (6/37) did not provide
measles genotyping data
Availability of genotype information in 2015 ASUs
Rubella
cases
Genotyping
info in ASU
Sequences in
RubeNS
Number of Member States
Y Y Y 7/24
N N N 25
Y N N71% (17/24) did not provide
rubella genotyping data
27Data source : 2015 Country Annual Status Updates, as of October 2016
Rate of measles viral detection, 2015
28
To
tal n
um
ber o
f rep
orte
d c
ase
s
(clin
+epi +
lab), lo
g s
caleR
ate
of vira
l d
ete
ctio
n
- 4 000
- 20 000
- 50
- 2
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
29
Rate of rubella viral detection, 2015 R
ate
of vira
l d
ete
ctio
n
- 100
- 250
- 8
- 1
To
tal n
um
ber o
f rep
orte
d c
ase
s
(clin
+epi +
lab), lo
g s
cale
ITALY
Member States
Data source : 2015 Country Annual Status Updates, as of October 2016
national laboratories’ accountability to ensure the proficiency of
other labs performing MR testing
31
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
Summary : essential for successful verification
Supplementary slides
33
Genotyping data: D8 most dominant in 2015
34
Measles genotypes and sequence variants
Genotypes :If genetically diverse genotypeLarge numbersLarge geographical region,Long period of time Utility of genotype-only
http://www.who.int/wer/2012/wer8709.pdf
Sequence variants within genotypes (lineages)
Identical sequences
Finer resolution
Dynamic
Named strains / Distinct Sequence
ID in MeaNS
35
Interpretation of sequence data needs epidemiological information
Small outbreaks, low incidence countries
different genotypes / different variantslikely to be importation
Endemic transmission
Multiple importationsLarge number of cases
identical sequences
over one year? or
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 MVs/Rostov on Don.RUS/47.13/2 Russian Federation Rostov On Don 22/11/2013 47 2013 D8 2987 MVs/Rostov on Don.RUS/47.13/2
90635 MVs/Salzburg.AUT/10.15/ Austria Salzburg 12/03/2015 11 2015 D8 2987 MVs/Rostov on Don.RUS/47.13/2
90636 MVs/St Polten.AUT/10.15/ Austria St Polten 12/03/2015 11 2015 D8 2987 MVs/Rostov on Don.RUS/47.13/2
35186 MVs/Victoria.AUS/6.11/ Australia Victoria 09/02/2011 6 2011 D8 2279 MVs/Victoria.AUS/6.11/
65282 MVs/Vienna.AUT/02.15/ Austria Vienna 07/01/2015 2 2015 D8 2279 MVs/Victoria.AUS/6.11/
31946 MVs/Gadag.IND/02.13/ India Gadag 07/01/2013 2 2013 D8 2748
65874 MVs/Vienna.AUT/16.15/ Austria Vienna 19/04/2015 17 2015 D8 2748
82459 MVs/Korneuburg.AUT/17.15/ Austria Korneuburg 23/04/2015 17 2015 D8 2748
60306 MVs/Hawaii.USA/42.14/ United States of America Hawaii 19/10/2014 42 2014 D8 3268
65875 MVs/Stein.AUT/16.15/ Austria Stein 13/04/2015 16 2015 D8 3268
MeaNS ID WHO name Country City Sample Date Epi week Epi year Genotype Distinct Seq ID Named Strain
45607 MVs/Rostov on Don.RUS/47.13/2 Russian Federation Rostov On Don 22/11/2013 47 2013 D8 2987 MVs/Rostov on Don.RUS/47.13/2
90635 MVs/Salzburg.AUT/10.15/ Austria Salzburg 12/03/2015 11 2015 D8 2987 MVs/Rostov on Don.RUS/47.13/2
90636 MVs/St Polten.AUT/10.15/ Austria St Polten 12/03/2015 11 2015 D8 2987 MVs/Rostov on Don.RUS/47.13/2
35186 MVs/Victoria.AUS/6.11/ Australia Victoria 09/02/2011 6 2011 D8 2279 MVs/Victoria.AUS/6.11/
65282 MVs/Vienna.AUT/02.15/ Austria Vienna 07/01/2015 2 2015 D8 2279 MVs/Victoria.AUS/6.11/
31946 MVs/Gadag.IND/02.13/ India Gadag 07/01/2013 2 2013 D8 2748
65874 MVs/Vienna.AUT/16.15/ Austria Vienna 19/04/2015 17 2015 D8 2748
82459 MVs/Korneuburg.AUT/17.15/ Austria Korneuburg 23/04/2015 17 2015 D8 2748
60306 MVs/Hawaii.USA/42.14/ United States of America Hawaii 19/10/2014 42 2014 D8 3268
65875 MVs/Stein.AUT/16.15/ Austria Stein 13/04/2015 16 2015 D8 3268 38