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. ”

http://measlesrubellainitiative.org/wp-

content/uploads/2016/07/MTR-Report-Final-Color-Sept-

20_v2.pdf

5

“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

http://apps.who.int/iris/bitstream/10665/251810/1/WER9

148.pdf?ua=1

6

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

2007 2008 2009 2010 2011 2012 2013 2014 2015 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)

WHO Measles & Rubella Laboratory Network

15

32174

16

WHO European Measles & Rubella Laboratory Network

71 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

Measles Rubella LabNet accreditation programme

Workload

Number of specimens(Measles/ Rubella IgM)

External QA

Internal QC procedures

IgM detection accuracy

IgM Proficiency testing

Internal quality control

Molecular EQA

IgM : 4 days

Sequences : 2 months

Lab reporting to WHO

Reporting

On-site review

• Laboratory operating

procedures

• Working practices

• Lab/epi collaboration,

contribution to the

verification

8 essential criteria : annually, desk review Periodically

17

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 ManualCurrently under revision, 2017

www.who.int/ihr/elibrary/manual_diagn_lab_mea_rub_en.pdf

Measles Rubella LabNet accreditation programme

18

MR Labnet performance: 2017 accreditation

19

≥ 50 specimens annually 96 %

Accuracy of IgM ≥ 90%Measles 100 %

Rubella 98 %

Serology PT ≥90%Measles 98 %

Rubella 98 %

Molecular EQA passedMeasles

Detection 100%

Genotyping 93%

Rubella Detection 97%

% of participating labs meeting the criteriaAccreditation criteria

MR Labnet performance: 2017 accreditation

20

IgM result reporting 4 days 19 %

Complete IQC procedures 53 %

Molecular EQA - Rubella Genotyping 63%

Timely genotype reporting 30 %

Reporting to CISID / MRLDMS 88 % (compl. 74 %, timel. 53 %)

% 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

30

Acknowledgements

WHO/EURO & HQDragan JankovicMark MuscatSergei DeshevoiShahin HuseynovSiddhartha DattaRobert JensenMalika AbdusalyamovaCatharina de KatTheo KaloumenosSimarjit SinghPatrick O’ConnorRobb ButlerMick Mulders

GI – Moscow Sergey Shulga

Nina Tikhonova

Tamara Mamaeva

LIH – LuxembourgClaude Muller

Judith Hübschen

RKI – BerlinAnnette Mankertz

Sabine Santibanez

Regional Laboratories

All National and Subnational laboratories

CDC, Atlanta, GSLPaul Rota team – measles

Joe Icenogle team – rubella

GID: funding EUR MR lab

GSL, PHE, LondonKevin Brown

David Williams

Armin Peymann

Richard Myers

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

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

39

0

1

2

3

4

5

6

7

8

4 7 101145 1 131819273339444648 3 5 6 7 8 1213151618192223414647495051 1 7 25273235 3 1016172327285310121317243653 4 12141723

2010 2011 2012 2013 2014 2015 2016

?

2B

1G

1E

1a

Rubella genotypes reported to RubeNS, WHO European Region, 2010-2016

Source : RubeNS

14.06.2016

Num

ber

of s

eque

nces

rep

orte

d to

Rub

eNS

39

21

24

2

9

9

4

18

14

3

2

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

20

15

20

16

Eliminated Interrupted 24 months Interrupted 12 months and Interrupted* Endemic No reports

Number of countries and their measles elimination status based on data for 2012-2014 (n=50) and 2015 (n=51)

40

* Interrupted transmission in 2015

Conclusions of the 4th (2015) and 5th (2016) Meetings of the European Regional Verification Commission for measles and rubella elimination.

41

Number of countries and their rubella elimination status based on data for 2012-2014 (n=50) and 2015 (n=51)

20

24

3

9

9

2

18

16

3

2

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

20

15

20

16

Eliminated Interrupted 24 months Interrupted 12 months Endemic No reports

Conclusions of the 4th (2015) and 5th (2016) Meetings of the European Regional Verification Commission for measles and rubella elimination.

42

• 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

Summary of 2016 achievements, EUR MR LabNet