ECDC roadmap for integration of molecular and genomic typing into European-level surveillance and epidemic preparedness : Version 1.2, 2013.
Date: 2016-09-15
Institutions: European Centre for Disease Prevention and Control
Subjects: disease prevention, disease vector, epidemiology, health control, medical research, public health, report

TECHNICAL REPORT

ECDC roadmap for integration of 
molecular typing into European-
level surveillance and epidemic 
preparedness 

            Version 1.2, 2013

www.ecdc.europa.eu

 
ECDC TECHNICAL REPORT 

ECDC roadmap for integration of 
molecular typing into European-level 
surveillance and epidemic preparedness – 
Version 1.2, 2013 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This report of the European Centre for Disease Prevention and Control (ECDC) was coordinated by the 
Microbiology Coordination Section 

Contributing authors 
Daniel Palm, Karin Johansson and Marc Struelens. 

Acknowledgements  

Experts from the ECDC Disease Programmes contributed to the disease-specific proposals for integration of molecular 
typing into EU surveillance and outbreak investigations.  

Experts contributing to the systematic literature reviews and expert guidance on the public health effectiveness of 
molecular typing of viral and bacterial pathogens: Richard Myers, Catherine Arnold, Ian Fisher, David Brown, Neil 
Woodford  and  Jonathan  Green,  Health  Protection  Agency,  Microbiology  Services  Colindale,  61  Colindale  Avenue, 
London NW9 5EQ; Noel McCarthy, HPA HPS Local Services, South East, Thames Valley Health Protection Unit; Maria 
Rizzo, Matrix Knowledge, Epworth House, 25 City Road, London, EC1Y 1AA, UK; Alison Martin, Matrix Knowledge, 
Epworth House, 25 City Road, London, EC1Y 1AA, UK; Julian Parkhill, The Sanger Institute, Wellcome Trust Genome 
Campus,  Hinxton,  Cambridge,  CB10  1SA,  UK,  Jan  Albert  Dept  of  Microbiology,  Tumor  and  Cell  Biology  (MTC), 
Karolinska Institutet, Sweden, Harry Vennema, The National Institute for Public Health and the Environment (RIVM), 
Netherlands;  Olav  Hungnes,  Division  of  Infectious  Disease  Control,  Norway;  Mia  Brytting,  Swedish  Institute  for 
Infectious Disease Control, Solna, Sweden; Noel Tordo, Pasteur Institute, France; Gloria Sanchez Moragas, Instituto 
De Agroquímica Y Tecnología De Alimento, Spain; Livia Di Trani, Instituto Superiore di Sanita, Roma, Italia; Matthias 
Niedrig,  Robert  Koch  Institute,  Germany;  Noel  Gill,  Health  Protection  Agency,  United  Kingdom;  Anne-Mieke 
Vandamme,  Laboratory  of  Clinical  and  Epidemiological  Virology,  KU  Leuven;  Jurijs  Perevošcikovs,  Latvia.  Public 
Health Agency Department of Epidemiological Surveillance of Infectious Diseases; Mika Salminen, Virology Unit at 
National Institute for Health and Welfare Finland; Rod Daniels, WHO Collaborating Centre for Reference and Research 
on Influenza UK; Annika Linde, Swedish Institute for Infectious Disease Control, Solna, Sweden; Martin Meike, Robert 
Koch  Institute,  Germany;  Kristin  Kremer,  Antimicrobial  Resistance  and  TB  Laboratory  Network  Tuberculosis  and 
M/XDR-TB Programme, WHO regional Office for Europe, Copenhagen, Denmark; Derek Brown, Scottish Salmonella, 
Shigella  and  Clostridium  difficile  Reference  Laboratory,  Scotland;  Christophe  Sola,  Professeur  des  Universités  at 
IGEPE,Université  Paris-Sud,  Paris,  France;  Raquel  Sá-Leão,  Instituto  de  Tecnologia  Quimica  e  Biologica,  Lisboa, 
Portugal; Mario Ramirez, Molecular Microbiology and Infection Unit, Instituto de Microbiologia, Faculdade de Medicina 
de  Lisboa,  Lisboa,  Portugal;  Mia  Torpdahl,  Statens  Serum  Institut,  Copenhagen,  Denmark;  Rosangela  Tozzoli, 
Instituto Superiore di Sanita, Roma, Italia; Panayotis Tassios, Department of Microbiology Medical  School, National  
& Kapodistrian University of Athens, Greece; Carmen Pelaz, Instituto de Salud Carlos III, Madrid, Spain; Ed Feil, Dept 
of  Biology  and  Biochemistry,  University  of  Bath,  UK;  Dominique  Caugant,  Norwegian  Institute  of  Public  Health, 
Norway;  Jordi  Vila  Estapé,  Instituto  de  Salud  Carlos  III,  Madrid,  Spain;  Tim  Harrison,  Respiratory  and  Systemic 
infection Laboratory, Health Protection Agency UK; Alex Leclerc, Institut Pasteur, Paris; Ed Kuijper, Leiden University 
Medical Center, The Netherlands; Saara Salmenlinna, National Institute for Health and Welfare, Helsinki, Finland; 
Flemming  Scheutz,  Department  of  Microbiology  and  Infection  Control,  Statens  Serum  Institut,  Copenhagen, 
Denmark; Steen Ethelberg, Department of Infectious Disease Epidemiology, Statens Serum Institut, Copenhagen, 
Denmark;  Jørgen  Schlundt,  Technical  University  of  Denmark,  Lyngby,  Denmark;  Rafael  Canton,  Servicio  de 
Microbiología and CIBER en Epidemiología y Salud Pública and Instituto Ramón y Cajal de Investigación Sanitaria, 
Madrid, Spain; Klaus Stark, Robert Koch Institute, Berlin, Germany; Javier Garaizar, Departamento de Inmunología, 
Microbiología y Parasitología, Universidad del País Vasco, Campus de A´ lava, Vitoria-Gasteiz, andCampus de Bizkaia, 
Leioa, Spain; Dominique Blanc, Service of  Hospital Preventive Medicine, Lausanne University Hospital,  Lausanne, 
Switzerland;  Henrik  Westh,  Department  of  Clinical  Microbiology,  Copenhagen  University  Hospital,  Hvidovre, 
Kettegaard Alle 30, DK-2650 Hvidovre, Denmark, members of the ECDC National Microbiology Focal Points, ECDC 
Advisory Forum, the ESCMID Study Group for Epidemiological Markers (ESGEM) and the European Society for Clinical 
Virology participating in the ranking exercises. 

Suggested citation: European Centre for Disease Prevention and Control. Roadmap for integration of molecular 
typing into European-level surveillance and epidemic preparedness – Version 1.2, 2013. Stockholm: ECDC; 2016. 

Stockholm, August 2016 

ISBN 978-92-9193-887-2 

doi 10.2900/481821 

Catalogue number TQ-01-16-575-EN-N 

© European Centre for Disease Prevention and Control, 2016 

Reproduction is authorised, provided the source is acknowledged 

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TECHNICAL REPORT 

Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

Contents 

Abbreviations ............................................................................................................................................... iv 
Executive summary ........................................................................................................................................ 1 
Roadmap priorities for disease specific genomic typing development and implementation, 2012-2015 .............. 4 
Roadmap implementation and evaluation ....................................................................................................... 16 
Evaluation and revision ........................................................................................................................... 17 
General considerations - development of disease-specific molecular surveillance strategies and business cases .... 19 
Molecular typing data collation at the EU level ........................................................................................... 19 
Molecular typing data sharing at the EU and global level ............................................................................ 20 
Staying current – how to support and harmonise the use of new (state-of-the art) typing technologies .......... 21 
Coordination with typing activities in food, feed and animal sectors ............................................................. 22 
Molecular surveillance of antimicrobial resistance ....................................................................................... 23 
References .................................................................................................................................................. 24 

Tables 

Table 1.  Summary of evidence supporting implementation of EU molecular surveillance per disease and health 
issue ............................................................................................................................................................. 8 
Table 2.  Proposed priority pathogen, public health objectives and expected EU-level risk assessment actions and 
risk management implications ....................................................................................................................... 14 
Table 3.  Roadmap for 2012-2015 implementation of EU molecular surveillance per pathogen/antimicrobial 
resistance  .................................................................................................................................................. 15 

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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

TECHNICAL REPORT 

Abbreviations 

Community Network of Reference Laboratories for Human Influenza 
European Commission 
European Food Safety Authority 
Epidemic Intelligence Information System  
External Quality Assessment 
ESCMID Study Group for Epidemiological Markers 
European Union 
ECDC Food- and Waterborne Diseases 
Hepatitis A virus 
Hepatitis B virus 
Hepatitis C virus 
Human Immunodeficiency Virus  
Invasive Bacterial Diseases Network 
Multidrug resistant 
Mycobacterial Interspersed Repetitive Units 
Multi-Locus Sequence Typing 
Multiple Loci VNTR Analysis 
Meticillin-resistant Staphylococcus aureus 
Next Generation Sequencing 
Pulsed Field Gel Electrophoresis 
Public Health England 
 Rijksinstituut voor Volksgezondheid en Milieu (The National Institute for Public Health and the 
Environment), The Netherlands 
Robert Koch-Institut, Germany 
Shiga toxin-producing E. coli  
The European Surveillance system  
Variable Number Tandem Repeat 
Vancomycin-resistant Enterococcus faecium 
Whole Genome Sequencing 
World Health Organisation 
Extensively drug-resistant 

CNRL 
EC 
EFSA 
EPIS 
EQA 
ESGEM 
EU 
FWD 
HAV 
HBV 
HCV 
HIV 
IBD 
MDR 
MIRU 
MLST 
MLVA 
MRSA 
NGS 
PFGE  
PHE 
RIVM 

RKI 
STEC 
TESSy 
VNTR 
VRE 
WGS 
WHO 
XDR 

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TECHNICAL REPORT 

Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

Executive summary 

This document presents the recommended priority options and implementation processes for the medium-term 
integration of molecular typing into EU-level surveillance and epidemic preparedness.  

This roadmap Version 1.2, 2013 is meant to complement ECDC’s Long-Term Surveillance Strategy [1] and guide 
the ECDC molecular typing activities over the next five years is based on the following inputs:  

 
 

 

 

 

 
 

ECDC concept paper on molecular surveillance and long-term surveillance strategy [1,7] 
Retrospective evidence of public health effectiveness and benefits of molecular typing for viral and bacterial 
pathogens identified in two commissioned systematic reviews  
Information on current molecular typing public health practices in the EU/EEA countries, EU disease 
networks and ECDC disease-specific surveillance strategies  
Capabilities and practical constraints identified from typing experiences in Member States and EU network 
capacity assessment projects  
Appraisal of technological advancements in comparative genomics likely to have an impact on future 
molecular epidemiological typing practices  
Expert guidance after two expert consultations and one on-line priority ranking exercise 
Experience from the ECDC-supported ongoing multistate typing pilot project.  

In a meeting organised by ECDC in September 2012, essential feedback on the outline of this document was given 
by ECDC stakeholders. This feedback included the following key points:  

 

 

 

 

Rather than recommending a static list of pathogens for implementation over the next five years, the 
roadmap should propose a stepwise approach starting with a small number of priority pathogens with a 
plan for gradual expansion.  
The roadmap should focus on pathogens for which EU-integrated molecular typing data are absolutely 
needed for informed public health policies and interventions.  
The roadmap should build upon typing programmes that are already operational in Member States with 
minimal additional effort to achieve meaningful EU data sharing and analysis. This would allow for flexibility 
depending on shifting priorities in terms of emerging and resurgent diseases, drawing lessons from the 
experiences gained from the ongoing pilot projects, and allowing in-depth investigations of resources and 
capacities in Member States.  
Molecular typing data collection supported by ECDC should be well integrated with existing typing initiatives 
on an EU and/or global level. 

A four-step development and implementation process is proposed for each new disease to be incorporated in the 
European Surveillance System (TESSy) molecular surveillance system. For pathogens shortlisted for potential 
implementation, there will first be development of a disease specific molecular surveillance and/or epidemic 
preparedness strategy followed by the preparation of a technical business case. The disease specific molecular 
surveillance and/or epidemic preparedness strategy must clearly describe the specific public health questions to be 
addressed through the typing data collection and analysis, and linked actions expected at the European level. For 
pathogens whose business cases are endorsed, an implementation phase will be followed by routine use of the 
system.  

The molecular typing strategy and business case will be produced by ECDC in collaboration with a designated 
Disease Network Typing Reference Group. The main objectives of the molecular typing strategy and business case 
will be to validate findings and elaborate on the conclusions of the roadmap, and to make the necessary 
clarifications to permit practical implementation both from the Member State and ECDC perspective. Components 
to be addressed in the disease specific molecular surveillance business case include:  

 

 
 
 

 

 

refinement of public health objectives and benefits of molecular typing data integration into EU level 
surveillance and/or epidemic investigation 
definition of short, medium and long-term success indicators 
proposed sampling strategy suitable to the public health objectives 
verification of the molecular typing method(s) applied, including current capacities in  Member States, need 
for standardisation, external quality assessments, standard operational procedures, training and other 
support 
data analysis and reporting aspects, including the need for advanced bioinformatics, and expert resources 
for data validation, management, and interpretation support  
data privacy, ethical or legal issues. 

Advice will be sought from stakeholders and discussions with partner organisations will be needed to determine if 
molecular typing data should be stored and analysed within TESSy or within some other (pre-existing) external 
database whenever available.  

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TECHNICAL REPORT 

The roadmap will be updated on an annual basis proposing molecular typing integration for additional pathogens. 
There will also be a bi-annual review and evaluation of performance and public health usefulness of all ongoing 
molecular surveillance components implemented. The purpose of this bi-annual review is to ensure that the 
ongoing data collection and analysis processes for each pathogen continue to meet their designated public health 
objectives. 

Based on collected information presented in this report, ECDC proposes to start practical implementation of tools to 
support collection of molecular typing data for human influenza virus, with the aim to have a functional system to 
support the influenza community by the start of the 2014–2015 season. Molecular typing to support influenza 
surveillance was ranked as a top priority in two of the consultations executed. Characterisation of influenza viruses 
using standardised methods is well-established in nearly all Member States. A dedicated working group in the 
influenza network is in the process of producing a business case describing the background and needs for 
implementation, and describing how interactions with existing global influenza sequence initiatives should be 
conducted [3]. Implementation of this solution would significantly reduce the double reporting of sequence data 
for the users, and would lead to enhanced virological surveillance reporting in TESSy with a minimum of additional 
resources required from both ECDC and Member States.  

Collection of sequence-based molecular typing data on human immunodeficiency virus for surveillance to support 
early detection and monitoring transmission of primary antiviral resistance, identification of transmission routes, 
and informing therapeutic guidance was identified by several expert consultations as being of public health 
importance and was considered timely for EU level surveillance to build upon systems piloted as research projects. 
HIV resistance testing through antiretroviral drug target regions sequence analysis typing is well-standardised, 
highly comparable across countries and performed in 14 Member States as part of standard clinical practice and 
resistance surveillance schemes, using various sampling strategies. Centralised collection and analysis of HIV 
sequence typing data was identified as having potential for public health benefit, but definition of sampling 
strategies and solutions to complex data privacy and confidentiality issues are needed before any such scheme can 
be implemented on a European level. ECDC concludes that development of a strategy and business case for HIV 
antiretroviral resistance surveillance could be explored in 2015.  

The expert panels both gave high priority to Neisseria meningitidis typing, and the ECDC Vaccine-Preventable 
Diseases Programme has indicated a need for centralised data collection for surveillance purposes. The systematic 
review identified multilocus sequence typing (MLST) and porA:fetA sequence analysis as being the most useful 
methods for monitoring the genetic diversity of disease-causing strains, as was recommended by an expert panel 
commissioned in 2009 within the invasive bacterial disease (IBD) network for monitoring the reduction in invasive 
strains following introduction of new vaccine programmes. Building a molecular surveillance strategy to elaborate 
on the specific public health objectives that a system should support is therefore recommended in 2013. This 
would be followed by a business case in 2014 to analyse the resources available in Member States and draft the 
pilot testing phase methods and procedures for launch in 2015. There are already databases which collect MLST 
and porA:fetA data on N. meningitidis, which are managed and funded by the University of Oxford, UK and the 
University of Wurzburg, Germany. The business case needs to take into account interaction with the resources 
invested by these data managers, and their plans for how the database should be supported in the future. 

Typing of Legionella pneumophila for outbreak studies and source attribution was ranked as a top priority both in 
the June consultation and in the discussions with Member States during the Joint Strategy Meeting in September 
2012. The main method for Legionella typing is Sequence Based Typing (SBT, 7 loci MLST), for which there are 
agreed standards and protocols which are broadly applied at the European level. Typing of L. pneumophila has the 
potential to greatly enhance the resolution of cluster analysis and source identification as part of outbreak 
investigation and response. ECDC currently manages the epidemic intelligence information system - European 
surveillance network for travel-associated Legionnaires’ disease- (EPIS-ELDSNet) for reporting and rapid 
communication of travel-associated Legionella cases, and has already supported capacity building for molecular 
typing of Legionella through numerous external quality assessments (EQAs) and training activities. Sequence-based 
typing (SBT) data is currently submitted, stored and analysed in a database managed and funded by Public Health 
England (PHE), UK. There are unresolved issues related to L. pneumophila typing that needs to be addressed in 
the Legionella specific roadmap and business case, such as the current infrequent use and application of existing 
resources for cross-border outbreak investigations.  

Beyond the above listed diseases for which continuous molecular surveillance as performed across Member States 
is proposed for TESSy-based EU integration, there is an unmet public health need for molecular surveillance of 
transmissible clones and mobile genetic determinants of antimicrobial resistance of major epidemiologic 
significance. This includes epidemic/pandemic clones and plasmids harbouring drug resistance determinants 
encoding extensive resistance phenotypes and thereby associated with high risk of treatment and transmission 
control failures. These high risk resistant pathogens include cephalosporin resistant Neisseria gonorrhoeae, 
extensively-drug resistant (XDR) and carbapenem-resistant Enterobacteriaceae, and Acinetobacter baumannii and 
meticillin-resistant Staphylococcus aureus (MRSA). Both of the roadmap expert consultations highlighted the public 
health added value of molecular typing of both strains and antibiotic resistance genetic determinants for 
monitoring prevalence and risk factors associated with infections by multi-drug resistant (MDR)/XDR pathogens 

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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

and delineating cross-border and animal-to-human spread of epidemic strains and genes. Recent ECDC disease 
specific pilot projects on MDR N. gonorrhoeae [4] and MRSA [5] demonstrated the feasibility of pan-EU/EEA 
structured molecular epidemiology surveys of prevalence of MDR pathogens that provide new information for 
control strategies. Concordant expert consultations recommended that ECDC consider supporting the long-term 
surveillance of these issues through planning periodically repeated molecular prevalence surveys including also 
pathogens that are not typed as part of routine surveillance. Whereas these surveys have so far been performed 
using molecular databases hosted by national public health institutes and research laboratories, there is an 
opportunity to explore the pros and cons of their integration into a bioinformatics enabled TESSy platform to 
ensure integration with core surveillance, and provide data security and system sustainability. 

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TECHNICAL REPORT 

Introduction 

The inclusion of molecular typing into European level surveillance and epidemic preparedness has been debated 
among ECDC stakeholders since 2007. Based on these discussions, a concept paper for integration of EU level 
surveillance was developed in 2008 and was further updated in 2011 after internal consultation at ECDC [7]. This 
paper concluded that by combining molecular typing- and epidemiological data there is a potential to improve 
surveillance and epidemic preparedness, and that specific criteria should be fulfilled before implementing a typing 
scheme on a European level. Basic criteria for developing European or broader international collection of molecular 
typing are that there is a practical need for molecular typing data as information for public health action, the data 
meets specific surveillance and outbreak investigation objectives, the resources needed for implementation and 
management are proportional to the expected benefits and there are capacities in Member States for integrating 
molecular surveillance and epidemiological data for meaningful analysis at the EU level. On the technical side, 
methods need to be discriminatory in a meaningful way; data should be comparable between laboratories and the 
interpretation and assessments of the results done by experts with method and pathogen experience, including the 
involvement of specialists from Member States. 

ECDC has a mandate to foster the development of sufficient capacity for diagnosis, detection, identification and 
characterisation of infectious agents which may threaten public health in the EU. To achieve this, ECDC collects, 
collates, evaluates and disseminates relevant scientific and technical data [14]. In its current long-term surveillance 
strategy, ECDC together with Member States has defined the principles of basic and enhanced surveillance 
components at the EU level [1]. The term ‘basic surveillance’ describes the common set of variables collected for 
all of the diseases under the remit of ECDC. In ‘enhanced surveillance’, the basic metadata set can be 
complemented with an additional set of disease-specific variables aligned with specific surveillance objectives. 
Here, detailed laboratory information can be included in the characterisation of disease agents. ECDC has 
supported a significant number of projects with molecular typing components. These projects have included setting 
up EQAs for specific typing methods, supporting the standardising of typing protocols, assessing the benefits of 
molecular typing for public health purposes and running transnational molecular typing projects. The experiences 
in terms of capability across the EU for a specific typing method, cost-benefit analysis and future expectations from 
the ECDC Disease Programmes and the disease networks is an important piece of information in the creation of 
this roadmap.  

 

 

 

ECDC has developed a communication platform tool, the Epidemic Intelligence Information System (EPIS) 
which allows Member State bodies to exchange information regarding current or emerging public health 
threats with a potential impact in the EU. This system is not a molecular typing platform per se, but has 
been used as a tool for sharing molecular typing information in outbreak situations.  
The current version of the European Surveillance system (TESSy) has been set up to accept inclusion of 
limited typing information as part of the case-based reporting. This information does not require any 
analytical functionality within TESSy to support interpretation and is submitted to TESSy as supplementary 
information rather than requested typing data. However, the data is not provided in a sufficiently routine or 
timely manner to be useful in for example outbreak investigations or cluster detection.  
TESSy v3 (launched for pilot testing in 2012) provides dedicated bioinformatic tools to support molecular 
typing data input, validation, normalisation, analysis and graphical report generation. This new data 
management module is suitable to molecular epidemiologic studies such as cluster detection and pattern 
matching search algorithms based on either sequence or fingerprint based analysis. 

To get practical experience in setting up and administering molecular typing networks at a European level, 
including the routine use of the TESSy v3 technical platform for analysing the data, ECDC has initiated a molecular 
typing pilot study. A pilot project was limited to covers four different pathogens; Salmonella enterica, Listeria 
monocytogenes and Shiga toxin- producing E. coli (STEC) under ECDC’s Food- and Waterborne Diseases (FWD) 
Programme and multidrug resistant Mycobacterium tuberculosis (MDR-TB). The experiences from the molecular 
typing pilot project was planned to feed into the further development of the molecular surveillance roadmap even 
more in the future 

Introduction to molecular typing 

Molecular typing refers to the application of laboratory methods capable of characterising, discriminating and 
indexing subtypes of microorganisms. Typing methods themselves can be classified into two main groups 
according to the basic principles of characterisation;  

phenotypic methods, including serological methods, focusing on observable or measurable morphological or 
biochemical properties of an organism 
genotypic methods strictly applying different methods for investigating the genetic code of the organism for 
characterisation purposes. 

 

 

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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

For the scope of this roadmap only genotypic typing methods are considered.  

Molecular typing exploits the fact that due to imperfect replication of ribonucleic acid/deoxyribonucleic acid 
(DNA/RNA) or horizontal gene transfer, there is variation in the genome composition that accumulates and brings 
about diversity between different generations of microorganisms [7] [8]. By measuring this genomic divergence, 
there is an opportunity to conclude relatedness between individuals within a species. The speed of differentiation, 
sometimes referred to as the ‘molecular clock’ is different between different species and between different parts of 
the genome within a species. Molecular markers are well characterised areas within the genome of a species that 
can be targeted for molecular typing purposes. Different ‘molecular clock rates’ of these markers make them 
applicable for different purposes. For example, rapidly evolving markers where recent evolutionary events can 
separate two closely related samples from the rest of the population can be useful for investigating transmission 
within a hospital or source attribution in a food outbreak. Slowly evolving markers can on the other hand be useful 
for surveillance purposes when investigating long-term trends and transmission of strains.  

There are multiple typing methods developed for most organisms. A simplified explanation for this observation is 
that advances in technology have allowed the development of faster and cheaper methods with higher resolution, 
and that these continuously replace older methods. This is only partly true and the reason for choosing a specific 
typing method is often multifactorial.  

First, the choice of typing method is linked to the resolution needed to fulfil the objective of the investigation. The 
primary molecular typing objectives in the scope of this report are epidemiological objectives related to infectious 
disease surveillance and outbreak investigation. Both the molecular marker and the typing method itself need to be 
sufficiently validated in terms of reproducibility epidemiological concordance, typeability, etc. [8] 

Second, the choice of typing method needs to be practically feasible for the intended use. Cost, ease of use, 
accessibility, and for the discussion of introducing molecular typing in the EU, capacity and capabilities across 
Member States to perform a specific method need to be acceptable given the objectives and potential benefits.  

In recent years, nucleic acid sequencing using ‘next generation’ methods (also known as ‘next generation 
sequencing’ [NGS]) has emerged as a major tool for studying genetic diversity, short term evolution and 
characteristics of pathogenic microorganisms. This development has dramatically increased the amount of genetic 
information available for the human pathogens under the ECDC remit and is likely to directly or indirectly affect the 
use and rationale for typing, the targets for molecular typing and the laboratory method used.  

Using molecular typing for public health 

As was already described in the molecular surveillance concept paper [7], there are a number of potential public 
health objectives that molecular typing may contribute towards, but all these objectives are not relevant for all 
pathogens. One of the key aspects that need to be clarified before setting up any centralised collection of 
molecular typing for any pathogen is to define the set of specific public health objectives that the typing data 
collection will help to meet. Three main categories for achieving the potential objectives where molecular typing 
data may be beneficial can be discerned. However, the use of other types of sampling models or a combination of 
two or more sampling models should also be considered where appropriate, and will be defined in the disease 
specific molecular surveillance and/or epidemic preparedness strategies. 

Benefits of molecular typing data for surveillance 

Inclusion of molecular typing information into epidemiological surveillance has the potential to improve 
understanding of the mechanisms of disease transmission, and can be applied towards improving and better 
targeting infectious disease prevention and control measures. Some concrete benefits of molecular typing that may 
provide clear added public health value if applied to disease surveillance at an international level include: 

 
 
 
 
 
 

rapid detection of dispersed international outbreaks 
delineation of outbreaks, risk factors and epidemic source  
investigation of transmission chains across EU and globally 
detection of emergence and spread of new virulent types or drug resistant strains of human pathogens 
monitoring emergence of vaccine escape variants 
source attribution by linking to molecular monitoring of pathogen in animals, food and environment 
reservoirs. 

Benefits of molecular typing data for outbreak detection and 
investigation 

Molecular typing has become a standard part of laboratory investigations of outbreaks and epidemics of infectious 
diseases of all scales. It is required to identify and characterise epidemic strains, to refine the definition of 
confirmed epidemic cases based on identification of the epidemic strain(s), and therefore to delineate the exact 
magnitude of an outbreak. Furthermore, molecular typing is used to either generate or verify hypotheses 

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TECHNICAL REPORT 

pertaining to probable modes of transmission and infection source of an outbreak. This is achieved by comparison 
of clonal relatedness between isolates from infected or colonised individuals over time and place and with isolates 
from the environment, animals, food and other contaminated products.  

In addition, molecular typing can provide a powerful and sensitive tool for early outbreak detection [9,10]. To this 
end, it should be applied routinely as part of molecular surveillance of incident cases to continuously analyse 
cumulative data in real time for the early detection of single clone clusters of infected patients linked in time and/or 
place. This finding of molecular clusters generates the hypothesis that an outbreak is occurring, triggering 
verification by an epidemiological investigation. Because of the high resolution provided by this approach, many 
small clusters can be detected that would otherwise be masked by background ‘noise’ of endemic infection caused 
by multiple strains from independent sources.  

Benefits of molecular typing data from structured surveys and point 
prevalence studies 

A third identified area where there can be potential public health benefits and where ECDC frequently invest 
resources, are structured surveys and point prevalence studies with molecular typing components. The intention of 
these studies are not to reach implementation of comprehensive routine systems combining molecular typing and 
epidemiological data, but rather to do distinct efforts to get a snapshot of currently circulating strains of a 
pathogen in the population. Structured prevalence surveys are often conducted repeatedly to assess the impact of 
public health actions aimed at controlling transmission in a target population. Depending on the study, data from 
point prevalence studies have either been submitted through TESSy, or databases for collection of data from 
structured molecular epidemiology population surveys have been funded by ECDC and set up disconnected from 
TESSy as ad hoc microbiological database platforms hosted in Member States [11,12,13]. Potential benefits from 
the collection of molecular typing data in structured surveys and point prevalence studies include:  

 

 
 

 
 

Monitoring secular trends in pathogen type distribution causing disease over time and place within a 
population 
Identifying and delineate geographic extension of widespread epidemic/pandemic types 
Identifying high risk clones with particular public health importance, for example clones with particular 
virulence, antibiotic resistance profile etc.  
Distinguishing between recurrence and recrudescence within a population in an outbreak situation.  
Identifying shifts in strain distribution in target populations, altered by public health interventions aimed at 
controlling or eliminating disease transmission.  

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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

Roadmap methodology 

ECDC’s Microbiology Coordination Section drafted the ECDC roadmap - Version 1.2, 2013 taking into account the 
recommendations from stakeholders, ECDC Disease networks and Diseases programmes and was based on the 
following inputs: 

  Two systematic reviews and an expert guidance on the public health effectiveness of molecular typing 

of viral and bacterial pathogens;  

  The two expert consultations: The first consultation was during a face-to face meeting held on 14–15 
June 2012, while the second was an online consultation. The experts independently ranked the expected 
disease specific impact of typing with regard to the public health objectives “Surveillance” and Outbreak 
detection”.  The  ranking  methodology  applied  the  following  criteria  (weights  of  individual  criteria  in 
brackets):  

need for EU surveillance to improve public health (15)  
importance of EU-wide data collection and analysis for outbreak investigation purposes (15) 

o 
o 
o  method sustainability for surveillance/outbreak investigation application (5) 
o 
o  Obstacles (legal, ethical, data protection) related to collection of data for surveillance/outbreak 

affordability and accessibility of resources for surveillance/outbreak investigation (5) 

investigation purposes (5).  

  A  survey  of  current  typing  activities  in  the  ECDC  disease  networks  through  the  ECDC  Disease 
Programmes: In May 2012, the ECDC Microbiology section conducted an internal survey among members 
of  the  ECDC  Disease  Programmes  to  investigate  the  current  practices  of  molecular  typing  as  applied  to 
surveillance and outbreak investigation for 28 human pathogens. The survey covered five main areas:  

o 

o 
o 

o 
o 

public health objectives for molecular typing activities at national or higher level within the 
EU/EEA 
sampling frames for molecular typing  
current typing activities in Member States, European disease-specific networks, or other 
European wide projects  
ECDC funded external quality assessment or training  activities for molecular typing 
expectations from the disease programmes for the future application of molecular typing.   

  A summary of supported ECDC activities: Additional information on molecular typing activities within the 
ECDC disease networks was extracted from the ECDC Annual Microbiology Activity Reports (2010 and 2011) 
[28-29]. These reports summarise projects with microbiology components that have been outsourced by 
ECDC.  The  microbiology  projects  can  span  over  multiple  areas  such  as  EQA,  training,  typing,  capacity 
assessment, technical guidance. For the purpose of this roadmap we have extracted all information relevant 
for molecular typing. Reports or publications resulting from these outsourced projects were also analysed, 
if available.  

  Early experience from the pilot project. 

Table 1 summarises the collected evidence supporting implementation of EU molecular surveillance per disease 
and health issue. 

7 

 
 
 
 
 
 
 
 
 
 
 
Table 1. Summary of evidence supporting implementation of EU molecular surveillance per disease and health issue 

Pathogen 

Outbreak investigation 

Surveillance 

,

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SR / DP  SR / DP  SR 
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SR / DP  SR / DP  SR / DP  SR 

SR / DP  SR / DP 

Multidrug resistant Acinetobacter baumannii 
Bacillus anthracis*  
Bordetella pertussis 
Clostridium botulinum* 
Clostridium difficile 
Corynebacterium diptheriae 
Coxiella burnetii 
Vancomycin-resistant Enterococcus faecium (VRE)  DP 
Shiga-Toxin producing E. coli  
Hepatitis A virus 
Hepatitis B virus 
Hepatitis C virus 
Human Immunodeficiency Virus (HIV) 
Influenza virus 
Multidrug resistant Klebsiella pneumoniae 
Legionella pneumophila 
Listeria monocytogenes 
Measles virus* 
Mumps virus* 
Multidrug resistant Mycobacterium tuberculosis 
(MDR-TB) 
Neisseria gonorrhoeae 
Neisseria meningitidis 
Norovirus 
Salmonella enterica 
SARS virus* 
Meticillin-resistant Staphylococcus aureus 
Streptococcus pneumoniae 
West Nile virus 

DP 

SR 

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SR / DP  Medium  Medium 
Medium  Medium 
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High 
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Medium  High 
Low 
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Medium  High 
Low 
Medium  High 
High 
Low 
Medium  Medium 
High 
Medium  Medium 
High 

SR / DP  High 
SR 

High 

High 

SR 
SR 
DP 
SR 

DP 
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Low 
Low 
High 
High 
Medium 
Low 
High 
High 
Medium 
Low 
High 
High 
Medium  Low 
High 
High 

SR (blue) indicates molecular typing objective identified as documented in the systematic reviews, DP (yellow) indicates molecular typing objective identified as applied in the EU by the survey of ECDC Disease 
Programmes, SR/DP (green) indicates molecular typing objective both identified in the systematic reviews and in the survey. 
* indicates that no information was provided by the ECDC Disease Programmes about current application of typing of this pathogen for the public health sub-objective. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TECHNICAL REPORT 

Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

Roadmap priorities for disease specific genomic typing 
development and implementation, 2012-2015 

Based on all the evidence, consultations and recommendations received, ECDC proposes the following roadmap 
V1.2 priorities for pathogen/disease specific genomic typing development and implementation, 2012-15. The next 
revision of the roadmap V1.2 implementation and priorities will take place in 2015-2016. 

Pathogens already undergoing molecular typing data integration into 
TESSy (pilot project, 2012–2014) 

Salmonella enterica 
For Salmonella enterica, integration of molecular typing data collection using PFGE and MLVA (for S. Typhimurium 
only) has been implemented in TESSy as part of the molecular surveillance pilot project. The project will continue 
until May 2014, at which point it will be evaluated and a decision will be made about its future. The molecular 
surveillance pilot project is described in more detail in the molecular surveillance project description document 
[15].  

Listeria monocytogenes 
For Listeria monocytogenes, integration of molecular typing data collection using PFGE has been implemented in 
TESSy as part of the molecular surveillance pilot project. The project will continue until May 2014, at which point it 
will be evaluated and a decision will be made about its future. The molecular surveillance pilot project is described 
in more detail in the molecular surveillance project description document [15]. 

Shiga-Toxin producing E. coli  
For STEC, integration of molecular typing data collection using PFGE has been implemented in TESSy as part of the 
molecular surveillance pilot project. The project will continue until May 2014, at which point it will be evaluated and 
a decision will be made about its future. The molecular surveillance pilot project is described in more detail in the 
molecular surveillance project description document [15]. 

Multidrug-resistant Mycobacterium tuberculosis  
For MDR-TB, integration of molecular typing data collection using MIRU-VNTR and spoligotyping has been 
implemented in TESSy as part of the molecular surveillance pilot project. The project will continue until May 2014, 
at which point it will be evaluated and a decision will be made about its future. The molecular surveillance pilot 
project is described in more detail in the molecular surveillance project description document [15]. 

Pathogens proposed for strategic development and potential 
implementation in 2013–2015 

The pathogens and health issues described in this section are those for which ECDC recommends the 
corresponding Disease Programmes and networks to develop disease-specific molecular surveillance strategies and 
business cases for, to be able to make a proposal for EU integration of molecular typing data into surveillance 
programmes in 2015–2016. The completion of a business case is in itself not a commitment that implementation 
will actually be performed, but sets the scene for subsequent informed decisions. 

Influenza virus 
Virological characterisation of influenza viruses using standardised methods (sequencing, antiviral susceptibility 
testing etc) is well-established in nearly all Member States. The influenza molecular surveillance roadmap, which 
was produced by ECDC and commented on by an expert group in 2011 [3], clearly describes the public health 
benefits of having access to sequence information of individual strains. The influenza roadmap also expresses a 
very clear wish that any actions taken on the European level shall be well integrated with the existing global 
influenza sequence initiatives. ECDC has therefore discussed a solution through which EU/EEA Member State 
virologists that are also nominated TESSy users can submit their data in an external database and flag it also for 
reporting to TESSy or vice versa. This data would then become available in TESSy and could be linked to the full 
epidemiological case data records that are submitted separately. Implementation of such a solution would reduce 
the double reporting of sequence data for the users, and would lead to increased virological reporting in TESSy 
with a minimum of additional resources required from both ECDC and the Member States. 

For the 2013–2014 influenza season, ECDC and Member States are already planning to move from the existing 
reporting scheme of aggregated reporting to strain-based reporting. If the business case is then endorsed in 2013, 
a system for simplified molecular typing data handling including sequence data could be available by the start of 
the 2014–2015 influenza season. 

9 

 
 
 
 
 
 
 
 
 
 
 
 
Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

TECHNICAL REPORT 

Human immunodeficiency virus  
The systematic review identified clear public health benefits from using sequence-based molecular typing on HIV 
for surveillance of transmitted drug resistance, transmission routes, and informing treatment guidance. A recent 
report (unpublished) made by a consortium of HIV antiviral drug resistance experts identified the potential for early 
detection and characterisation of antiviral resistance as the main public health benefit of HIV molecular typing. The 
report also concluded that HIV typing and sequence-based resistance monitoring are based on well standardised 
methods, provide comparable data across countries and were performed in 14 Member States as part of standard 
clinical practice and national surveillance programmes. There were previous EU research-sponsored projects 
dedicated to the collection and analysis of HIV typing data for resistance monitoring (SPREAD [FP5] and EuResist 
[FP6] projects) but since 2010 funding for these projects is no longer active. Although both the generic and HIV 
expert panels identified the centralised collection and analysis of HIV typing data as important, they also identified 
the need to agree representative sampling approaches and resolve the issue of data protection and access before 
any such scheme can be implemented. 

As EU-wide collection and continuing analysis of HIV typing and drug resistance data was identified as technically 
mature and having potential for public health benefits, we recommend that development of a EU molecular 
surveillance HIV strategy and business case be considered in 2015, including solutions to data privacy and 
confidentiality issues. 

Neisseria meningitidis 
For Neisseria meningitidis, the systematic review identified MLST and surface protein gene porA:fetA sequencing 
schemes as being the most useful methods for identifying the genetic diversity of disease-causing strains as was 
recommended by an expert panel commissioned in 2009 within the IBD network. The expert panels both gave high 
priority to typing at the EU level and ECDC has indicated a need for centralised data collection for surveillance 
purposes, and in particular for monitoring the reduction in vaccine targeted invasive strains following introduction 
of new vaccine programmes. A molecular surveillance strategy to elaborate on the specific public health objectives 
that a system should support is therefore recommended in 2013. This would be followed by a business case in 
2014 to analyse the resources available in Member States and draft the pilot testing phase methods and 
procedures for launch in 2015.  

There are already databases which collects MLST and porA:fetA data on N. meningitidis, which are managed and 
funded by the University of Oxford, UK and University of Wurzburg, Germany. The business case needs to take into 
account interaction with the resources invested by these data managers, and their plans for how the database 
should be supported in the future. 

Legionella pneumophila 
The original systematic review did not identify any publications demonstrating public health utility of legionella 
typing. This was most likely due to the exclusion of local studies applied as part of the selection criteria of the 
systematic review. The May and June expert panels provided a number of relevant publications demonstrating the 
public health use of L. pneumophila typing for outbreak studies and source attribution. Molecular typing of 
L. pneumophila greatly enhances the resolution of cluster analysis and source identification as part of outbreak 
investigation and response. ECDC currently manages EPIS-ELDSNet for reporting and rapid communication of 
travel-associated legionella cases, and has actively supported capacity building for molecular typing of legionella 
through numerous EQAs and training activities, and will continue to do so through a new call for tender soon to be 
published. The main method for legionella typing is Sequence Based Typing (SBT; 7 loci MLST) for which there are 
agreed standards and protocols which are broadly applied on the European level. SBT data is currently submitted, 
stored and analysed in a database managed and funded by PHE, UK. In addition to SBT, PFGE is also commonly 
used for legionella typing.  

Legionella surveillance was ranked as a top priority both in the June consultation and in discussions with Member 
States. However, there are unresolved issues related to L. pneumophila typing, such as infrequent use and 
application of existing resources for cross border outbreak investigations. The results from the activities included in 
the upcoming tender should form the basis for a disease-specific roadmap in 2014 and business case in 2015, 
where the public health objectives and practical challenges of using molecular typing data in L. pneumophila 
outbreak investigation are clearly described.  

High-risk multidrug and extensively-drug resistant (MDR/XDR) pathogens 
In Table 2 and 3 are listed the two pathogens and one health issue for which EU level molecular surveillance is 
recommended to monitor the cross- border dissemination of MDR and XDR strains of high public health risk, due to 
treatment failures and potentially untreatable infections [16]. Beyond the diseases for which continuous molecular 
surveillance as performed across Member States would permit integration in continuous EU-level surveillance, there 
is an unmet public health need for molecular surveillance of these transmissible antimicrobial resistant pathogens 
of major epidemiologic significance, caused by epidemic/pandemic clones and plasmids. These difficult-to-control 
resistant pathogens include MDR/cephalosporin resistant Neisseria gonorrhoeae, extensively-drug resistant (XDR) 
and carbapenem resistant Enterobacteriaceae and Acinetobacter baumannii as well as MRSA [17]. Both of the 

10 

 
 
 
 
 
 
 
 
 
 
TECHNICAL REPORT 

Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

roadmap expert consultations highlighted the public health added value of molecular typing of both strains (clonal strain 
typing methods) and antibiotic resistance genetic determinants (resistance gene profiling) for monitoring prevalence and 
risk factors associated with infections by MDR/XDR pathogens, and delineating cross-border and animal-to-human 
spread of epidemic resistant strains and epidemic resistance genes.  

Recent ECDC disease specific pilot projects on MDR N. gonorrhoeae [4] and MRSA [5] demonstrated the feasibility of 
pan-EU/EEA structured molecular epidemiology surveys of prevalence of MDR pathogens that provided new information 
for control strategies. Concordant expert consultations recommended to ECDC to consider supporting the long-term 
surveillance of these issues through planning periodically repeated prevalence molecular surveys. Whereas these surveys 
have so far been performed using molecular databases hosted by national public health institutes and expert research 
laboratories, there is now an opportunity to explore the pros and cons of their integration into a bioinformatics-enabled 
TESSy platform to ensure integration with core surveillance, data security and system sustainability. 

Neisseria gonorrhoeae  
For Neisseria gonorrhoeae, there is recent evidence that supports public health benefits for molecular typing using 
the NG-MAST method, specifically identification and confirmation of outbreaks, transmission chains and monitoring 
emergence of antimicrobial resistance across Europe and globally. Although both expert panels have assigned a 
low priority to gonorrhoea typing, the 2011 ECDC-supported study of an EU-wide dataset revealed the emergence 
of multidrug resistant strains in Europe that may over time become a larger public health threat [4]. If European 
level collection of molecular typing data for gonorrhoea is to be implemented, it will most likely be to support 
investigations of the circulating multidrug resistant strains only. In addition, a number of areas (sampling strategy, 
period intervals, quality of epidemiological information, additional NG-MAST and other genetic markers evaluation, 
stability of associations between sequence type and antimicrobial resistance) require further investigation before 
implementation of molecular surveillance based on periodic prevalence surveys of (multidrug resistant) gonorrhoea 
can be established at the European level. 

Extensively drug-resistant/carbapenem-resistant Enterobacteriacaeae (including Klebsiella 
pneumoniae) and Acinetobacter baumannii  
For monitoring the XDR/carbapenem-resistant Enterobacteriacaeae (K. pneumoniae, E. coli, etc.) and A. 
baumannii, there are a number of strain typing methods available for outbreak and prevalence studies, including 
internationally validated, sequence based methods like the MLST schemes. In addition, there are established 
schemes for PCR or micro-array based profiling of XDR and carbapenemase encoding genes. However, definition of 
molecular antimicrobial resistance surveillance strategy and completion of pilot prevalence studies, as planned for 
2013 [18], are still needed to identify which strain and drug resistance molecular markers could be monitored 
before a business case for EU molecular antimicrobial resistance surveillance scheme can be developed in 2014. 
Furthermore, discussion on joint molecular database management will be required with research groups and public 
health organisations currently administering global reference MLST databases and providing expert characterisation 
of carbapenemase/XDR genetic determinants. 

Meticillin-resistant Staphylococcus aureus 
For MRSA, the main public health objectives for typing are linked to monitoring the emergence and geographical 
spread of multiresistant clones in the community as spill-over from hospital sources or animal husbandry as well as 
a tool for targeting and evaluating control measures at Member State level. The systematic review identified many 
methods that have been used for S. aureus typing for public health purposes. These include PFGE, spa sequence 
based typing, MLVA and a combined MLST and SSC-mec analysis. Whole genome sequencing WGS is being 
developed for molecular typing of this pathogen. spa sequence based typing is currently recommended as the 
primary typing system that is fully operational across the EU, complemented by subset typing of resistance genes 
and SCCmec cassette.  

Pathogens not proposed for molecular surveillance implementation by 2015 

The summaries of collected evidence described in this section are for those pathogens for which ECDC does not 
currently see a need for implementation into an EU level molecular typing system within the next five years. This is 
however subject to change if public health priorities shift. 

Bacillus anthracis 
The systematic review did not identify any relevant studies for this pathogen. Two papers were subsequently 
added by the expert panels, and there are some data supporting the use of WGS for outbreak investigation. 
However, due to the low priority given by the two expert panels and the lack of requests for inclusion by ECDC 
anthrax is not considered for further studies by 2016. 

Bordetella pertussis 
The systematic review and June expert panel identified molecular typing as useful for identifying circulating strains 
and changing profiles over time, including before and after the introduction of the vaccine. At present, novel typing 
methods (MLVA, SNP typing) are emerging. Currently, the priority for European-wide molecular typing for this 
pathogen is low; however, this may change as a result of the increased prevalence observed in Europe.  

11 

 
 
 
 
 
 
 
 
 
 
Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

TECHNICAL REPORT 

Clostridium botulinum 
The systematic review identified very few relevant studies for this pathogen, and the June expert panel concluded 
that further evidence for public health use and method standardisation efforts are required before application of 
molecular typing on the European level. 

Clostridium difficile 
The systematic review and the June expert panel identified a number of papers documenting well PCR ribotyping 
as useful for outbreak investigation as well as surveillance at the national level. MLVA is emerging as a useful and 
more discriminatory method that can be used to resolve common ribotypes during an outbreak investigation. 
Harmonisation between Member States of these typing methods and protocols is however needed. Provided that 
methods and protocols are agreed on within the network, ECDC foresees that collection of molecular typing data 
could be of value for surveillance purposes. The decision to implement a centralised data collection will depend on 
the national typing strategies and availability of resources within Member States. This will need to be further 
reviewed once agreement on methods and protocols has been reached. 

Corynebacterium diptheriae 
Evidence collected showed a link between molecular typing and public health intervention, especially for outbreak 
investigation purposes. At present, ribotyping (widely viewed as the gold standard) is being 
complemented/replaced by newer methods (MLVA, MLST) that are in a developmental and validation phase. Both 
expert panels assigned medium priority to the EU integration of typing data for this pathogen. Future steps for 
integration of this pathogen into an EU level molecular typing system need to include validation and 
standardisation of new typing methods as well as plans for interactions with existing databases for storing 
ribotyping data (currently hosted by PHE, UK) and MLST data (currently hosted by University of Oxford, UK). Due 
to the low annual case incidence and the small number of Member States currently able to perform diphtheria 
typing, a centralised typing service option could also be considered. 

Coxiella burnetii 
The evidence for public health usefulness for Coxiella burnetii molecular typing is limited. It was not deemed a high 
priority by any of the expert panels, and ECDC does not foresee any European-level molecular typing scheme by 
2016.  

Vancomycin-resistant Enterococcus faecium (VRE) 
Both expert consultations (June and September) deemed the inclusion of typing data for VRE to be of low priority. 
ECDC also does not foresee any need for centralised collection of molecular typing data by 2016. However, if in the 
future TESSy will support the inclusion of data from point prevalence studies, this position should be reassessed. 

Hepatitis A virus  
The systematic review and June expert panel identified public health benefits from using sequencing (sub-genomic 
fragments and/or WGS) to trace HAV infection through risk groups, to link HAV outbreaks to food and 
environmental sources, and to monitor potential vaccine escape strains. The June expert panel recognised the 
need for a transnational sequence data sharing facility, and the September consultation also confirmed the 
importance of using molecular typing data in public health analyses. ECDC foresees the need to collect sequence 
data for outbreak investigation purposes; however, integration of HAV molecular typing data is not considered a 
priority in this version of the roadmap. Annual updates of the roadmap can however give HAV typing future 
priority. In addition, ECDC foresees the need to have a future network for foodborne viruses in place to provide 
information on Member State activities and feasibility aspects. 

Hepatitis B virus  
The systematic review and June expert panel identified public health benefits from using molecular typing (mainly 
sequencing) to track HBV transmission and for monitoring drug resistance and vaccine escape. In addition, there is 
good evidence in the literature for linking HBV genotyping to clinical presentation and disease progression 
monitoring.  

The June expert panel recognised the need for a transnational sequence data sharing facility, such as The 
International Repository for Hepatitis B Virus Strain Data managed by PHE, UK [19]. However, due to the low 
priority given by the two expert panels it is not considered a priority for further studies until 2016. 

Hepatitis C virus  
The systematic review identified the potential use of HCV molecular typing data (mainly sequencing) for public 
health purposes such as surveillance of genetic diversity, drug resistance, treatment outcomes and disease 
severity, although much of the work done is still at a research stage and currently not directly applicable. Due to 
the relatively low priority given by the two expert panels and the lack of request for inclusion by ECDC, HCV is not 
considered a priority for further studies by 2016. However, there is a new, promising HCV vaccine currently under 
development; should that vaccine be routinely used in Member States then molecular typing to support monitoring 
of circulating strains etc. may be of higher priority.  

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Measles virus 
The public health usefulness of measles molecular typing is well established, and both expert panels considered 
the sharing of measles typing data to be of high priority. However, there is no need for any additional efforts on 
the European level as this need is already met by the World Health Organization (WHO) global typing surveillance 
system. 

Mumps virus 
The evidence for public health usefulness of mumps molecular typing is limited. Mumps is part of the vaccine-
preventable diseases monitored globally by WHO, and no additional action at the European level is needed. 

Norovirus 
The systematic review identified evidence for public health usefulness of typing of norovirus for outbreak 
investigation and source attribution purposes. In addition, monitoring of emerging strains is important for 
predicting population impact. The main method used is sequencing, and a global database for collection of 
norovirus sequences is managed and funded by RIVM, Netherlands [20]. 

Due to the relatively low priority given by the two expert panels and the existence of a global database norovirus is 
not considered a priority for further studies by 2016. 

SARS virus 
The evidence for public health usefulness for SARS molecular typing is limited and not seen as a priority by neither 
the expert panels nor ECDC. However, it should be acknowledged that molecular characterisation may play an 
important role when dealing with emerging pathogens. 

Streptococcus pneumoniae 
The systematic review and June expert panel identified molecular typing as useful for this pathogen, especially in 
relation to surveillance activities to support monitoring of vaccine programmes. However, it was not deemed a high 
priority by any of the expert panels, and ECDC does not foresee any European-level molecular typing scheme by 
2016.  

West Nile virus 
The evidence identified in the systematic review for public health usefulness for West Nile virus molecular typing is 
limited, and ECDC does not foresee any European-level molecular typing scheme. The virus was however deemed 
a high priority by both expert panels, and given the emergence of disease in southern Europe and potential public 
health impact, European-level collection of molecular typing may need to be further investigated within the next 
few years. 

Table 2 provides an overview of the pathogens proposals for implementation in terms of public health objectives 
and expected EU level risk assessment actions and risk management implications per proposed priority pathogen. 

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Table 2. Proposed priority pathogen, public health objectives and expected EU level risk assessment 
actions and risk management implications* 

Potential public health 
objectives* 

Expected EU level risk 
assessment action(s) 

Potential EU level risk 
management implication(s) 

Pathogens/AMR 
issue proposed for 
implementation 

Salmonella enterica, 
Shiga-Toxin 
producing E. coli , 
Listeria 
monocytogenes 

Outbreak investigation 

Control-oriented surveillance 

Strategy-oriented surveillance 

MDR Mycobacterium 
tuberculosis  

Outbreak investigation 

Control-oriented surveillance 

Strategy-oriented surveillance 

Influenza virus 

Outbreak investigation 

ECDC rapid risk assessment, support 
to multicounty outbreak 
investigation and food source trace 
back (both jointly with food safety 
authorities) 

Early detection, verification and 
notification of dispersed cross-border 
clusters, Outbreak investigation 

RASFF notification, Food source 
control and vehicle recall  

Coordinated outbreak control  

Food source attribution of disease, 
Identifying population groups /food 
categories at increased risk of 
infection with specific strains 

Targeted food chain 
decontamination interventions to 
eliminate the source of specific 
endemic strains  

Support to multicounty outbreak 
investigation 

Identify and investigate high-risk 
strains ("super spreaders" and/or 
MDR/XDR-TB), Epidemic 
investigation 

Provide an overview of (MDR)-TB 
clusters and strain diversity in the 
EU, Identify high-risk geographical 
areas and/or population groups 

Detection of potential pandemic 
influenza strains, virological Risk 
Assessment 

Coordinated outbreak control  

Coordinated epidemic control and 
revision of treatment guidance 

Evaluation of TB control programme 

Pandemic notification and public 
health response 

Control-oriented surveillance 

Detection of novel influenza viruses,   Development of diagnostics and 

Strategy-oriented surveillance 

Human 
Immunodeficiency 
Virus (HIV) 

Strategy-oriented surveillance 

Neisseria 
meningitidis 

Outbreak investigation 

Detection of genetic markers 
associated with antiviral resistance, 
Rapid epidemiological investigation 
Detection of genetic change in 
circulating influenza viruses,  

Early detection and characterisation 
of antiretroviral resistant strains, 
Characterisation of transmission 
routes and risk groups 

Support to multicounty outbreak 
investigation 

Control-oriented surveillance 

Identify cross-border epidemic 
strains 

Strategy-oriented surveillance 

Legionella 
pneumophila 

Outbreak investigation 

Neisseria 
gonorrhoeae/MDR 

Strategy-oriented surveillance 

Enterobacteriaceae 
and Acinetobacter 
baumannii 
XDR/carbapenem-R 

Staphylococcus 
aureus 
MDR/meticillin-R 

Strategy-oriented surveillance 

Strategy-oriented surveillance 

Monitoring of vaccine strain 
coverage and vaccine programme 
effectiveness 

Travel-associated cross-border 
outbreak investigation and source 
trace-back 

Monitoring of emergence and cross-
border transmission of MDR strains, 
Identify high-risk geographical areas 
and/or population groups 

Monitoring of emergence and cross-
border transmission of XDR strains, 
Identify high-risk geographical areas 
and/or population groups 

seed viruses for vaccines 

Revision of treatment guidance 
Altering the strain selection for 
current vaccine (when combined 
with antigenic data) 

Revision of clinical treatment 
guidance, Evaluation of HIV 
prevention and control programme 

Coordinated outbreak control 
measures including strain-targeted 
vaccination  

Coordinated epidemic control 
measures including strain-targeted 
vaccination  

Revision of vaccine composition or 
national immunisation programmes 

Outbreak control through source 
elimination 

Revision of clinical treatment 
guidance, Evaluation of gonorrhoea 
prevention and control programme 

Evaluation and revision of healthcare 
infection control and prevention 
programmes including active 
surveillance of cross-border patient 
transfers 

Monitoring of emergence and cross-
border transmission of MDR strains, 
Identify high-risk geographical areas 
and/or population groups (including 
livestock contact) 

Evaluation and revision of healthcare 
infection control and prevention 
programmes including active 
surveillance of cross-border patient 
transfers 

RASFF: Rapid alert system for food and feed; * The public health objectives are categorised as described in Baker et al [6] 

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Table 3 lists the six pathogens/health issues proposed for strategy definition and business case studies in 2013–15, 
in addition to the four pathogens under pilot TESSy testing in 2012–2013. Indicative timelines are given for gradual 
development, testing and implementation. 

The principles guiding the selection of priorities in this table are:  

  disease or health issue for which EU molecular surveillance is necessary to inform public health policies and 

coordinated public health actions of Members States; 

  pathogen with fully validated and portable (sequence-based) typing system in operation in a substantial 

proportion of Member States. 

Table 3. Roadmap for 2012–2015 implementation of EU molecular surveillance per 
pathogen/antimicrobial resistance 

Pathogens/AMR 
issue proposed for 
implementation 

Typing method  EU public health objective/sampling 

Disease specific roadmap step/year 

design 

Surveillance, 
continuous  

Surveillance, 
prevalence 
surveys 

Multi-state 
outbreak 
investigations 

Molecular 
surveillance 
strategy 

Business 
case 

System 
implement
ation  

Routine 
use from 

* 

* 

* 

* 

* 

* 

* 

Salmonella enterica 

PFGE, MLVA 

Shiga-Toxin producing 
E. coli  

PFGE 

Listeria monocytogenes  PFGE 

MDR Mycobacterium 
tuberculosis  

MIRU-VNTR, 
spoligotyping 

Influenza virus 

Human 
Immunodeficiency 
Virus (HIV) 

sequencing 

sequencing 

Neisseria meningitidis 

sequencing 

Legionella pneumophila sequencing 

Neisseria 
gonorrhoeae/MDR 

sequencing 

Enterobacteriaceae and 
Acinetobacter 
baumannii 
XDR/carbapenem-R 

Staphylococcus aureus 
MDR/meticillin-R 

PCR, sequencing 

PCR, sequencing 

* 

* 

* 

* 

* 

* 

* 

* 

* 

2011 

2011 

2011 

2012 

2012 

2014 

2013 

2014 

2013 

2014 

2012 

2012 

2012 

2012 

2013 

2015 

2014 

2015 

2015 

2013 

2013 

2013 

2013 

2014 

2016 

2015 

2016 

2016 

2014 

2014 

2014 

2014 

2015 

2017 

2016 

2017 

2016 

2015 

2016 

2017 

2014 

2015 

2016 

2017 

Pathogens in blue shaded rows are included in the TESSy molecular surveillance pilot project, 2012–2013 

Pathogens in orange shaded rows are proposed as high risk multidrug and extensively-drug resistant (MDR/XDR) pathogens with 
prevalence surveys including molecular typing components planned 

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Roadmap implementation and evaluation 
Roadmap implementation process 

The implementation of molecular surveillance will be a four-step process for each pathogen or health issue 
shortlisted for potential implementation into EU wide molecular surveillance or epidemic preparedness system: 

 

 

 
 

ECDC will consult with disease network representatives to define a disease specific molecular surveillance 
and/or epidemic preparedness strategy. This includes validation and refinement of the public health 
objectives of molecular typing, expected benefits, and process and outcome success indicators. 
The ECDC Disease Programmes and disease networks will prepare a disease-specific business case 
describing the surveillance or outbreak sampling frame and study design, typing methods, data 
management resource and IT requirements, and a draft data collection and management protocol. On the 
basis of this report, ECDC will consult with Member States to get their feedback on the business case and a 
decision about implementation will be made.   
If the business case is endorsed, the implementation phase will take place. 
Following adjustments found necessary during the initial implementation phase, the technical system and 
any associated activities will become part of routine surveillance and epidemic intelligence/outbreak 
response support activities. 

These four phases are described in more detail below: 

The disease specific molecular surveillance and/or epidemic 
preparedness strategy 

The definition of the disease specific molecular surveillance and/or epidemic preparedness strategy will include 
validation and refinement of the public health objectives and expected operational benefits of integrating molecular 
typing data for a particular pathogen and/or antimicrobial resistance issue. It will also propose process and 
outcome indicators of performance. The strategy will be drafted by the ECDC Disease Programmes in collaboration 
with a Disease Network either through an annual network meeting or an ad hoc meeting with a Typing Reference 
or Advisory Group. Some networks already have such groups whereas other networks may need to appoint them.  

The business case  

A template of topics to be covered in the business case report will be provided by ECDC. Key components will be: 

 

 
 

 

 

Strategy: Pathogen-specific public health objectives and benefits of TESSy integration of molecular typing 
data at the EU and Member State level 
Short, medium and long term process and outcome success indicators  
Description of the sampling strategy: 
 

Assessment of whether the current sampling strategies are appropriate to fulfil the EU level public 
health objectives  
Proposal of the sampling strategies and alternative strategies, e.g. repeated prevalence surveys 

 
Description of the molecular typing method(s) and nomenclature:  
 
 
 
 
Description of data management aspects that affect the choice of technical implementation: 
 

Availability of agreed typing method(s)  
Description of the level of standardisation of the typing method(s) 
Status of EQA/certification scheme(s) in EU and/or Member States 
Recent/likely developments in terms of new typing methods  

Description of available EU or global typing databases: 
o  Name, hosting organisation and funding  

 

A description of what kind of collaboration/interaction is needed and/or desirable with 
this database 

 

Data collection and analysis aspects: 
o  Proposed list of variables (metadata) 
o  Molecular data format: ‘raw data’ or ‘normalised data’ 
o  A description of to what extent Member States are able to link their case-based epidemiological 

data to the isolate-based molecular typing data  

o  Analysis plan and geospatial/bioinformatics functionalities: 

  A discussion on how the molecular typing data should be interpreted and used in an 

epidemiological context 

o  A description of any integration needed with other systems and/or tools (i.e. EPIS platform) 

 

A description of the resource needs for molecular typing of this pathogen: 
 

A review of the current practices of Member States in terms of overall availability of resources 

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 

List of twinning arrangements, centralised typing services etc. where relevant 
If known, an indication of future availability of resources on the Member State level 

o 
o 
A description of the resources needed at ECDC for supporting the management of the submitted 
typing data 
o  Technical support 
o  Analysis support 

 

 

Ethical and/or legal issues 
 
 
Plans for technical training and expert meeting(s) 

Data protection and confidentiality aspects 
Data ownership and intellectual property aspects 

System implementation 

If the business case is endorsed, the system implementation phase will commence. Based on the comments 
received during the business case consultation process, ECDC in collaboration with the disease network will define 
a system implementation plan. This plan will cover all technical aspects of and contain a clear timeline for the 
implementation phase. Some important areas that will require Member State involvement include: 

Data curation, analysis and interpretation 
Where appropriate, ECDC will follow up the needs identified in the business case with calls for tender for specific 
support services. One area where this is expected is the validation, analysis and interpretation of typing data, 
which will be of high importance. 

EQA and certification scheme(s) 
High data quality is a prerequisite for analysis and of vital importance for the success of any molecular typing data 
collection. Different typing methodologies will require different levels of EQA and other types of standardisation 
efforts. EQA schemes should also form the basis for certification and approval of direct acceptance of molecular 
typing data uploaded in TESSy where needed. 

Through the ECDC Disease Programmes, EQA rounds covering key aspects of molecular typing capabilities will be 
executed within the relevant laboratories in the disease networks and Member States. The pathogen-specific 
molecular typing coordination group have an important role to play in terms of providing advice on the scope, 
content and frequency of EQA to support molecular typing capacity building within the network and ensure high 
quality outputs of the full system. For the certification process, the pathogen-specific molecular typing coordination 
group should support ECDC in presenting a practical solution that promotes maximum Member State participation 
while still ensuring the required data quality. 

Training 
Based on results from EQA or capacity analysis made as part of the feasibility study, ECDC will direct resources to 
support molecular typing training initiatives.  

Upgrading and testing the system  
If TESSy is proposed to be the system of choice for storing, integrating and analysing molecular typing data, ECDC 
will implement the necessary changes in the system. User acceptance testing and validation of the system, both 
internally and with a subset of Member State laboratories, will be executed as part of the implementation phase.  

Routine molecular typing 
As implementation phase ends, the technical system and any associated activities will become part of routine 
surveillance and epidemic intelligence/outbreak response support activities. All Member States will now be invited 
to contribute with data.  

Timeline 

Table  contains a tentative timetable for the gradual roadmap implementation process. It is however important to 
note that each step may require either more or less time than indicated in the table, depending on disease-specific 
needs and issues. The timetable is of course also subject to revision if public health priorities shift. 

Evaluation and revision 

Revision of the roadmap 

Due to the constantly changing nature of molecular typing for public health, it is anticipated that the roadmap 
document and associated list of priority pathogens is updated annually. This revision should incorporate input from 
the relevant disease networks and ECDC, previous evaluations of the roadmap implementation, as well as any 
strategic discussions on molecular typing held with stakeholder groups.  

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Evaluation of roadmap implementation 

Regular reviews of the public health benefits of enhanced molecular typing data collection are very important, and 
therefore interim evaluations of typing data collection for each new pathogen are foreseen after about one year of 
operation. While this is clearly not enough time to be able to assess the success of any long-term public health 
objectives, a review of the short term public health objectives and success indicators as well as the functionality of 
the system, resource needs and associated activities (training, external quality assessment [EQA] etc.) will enable 
ECDC and Member State users to learn from the first year of operation and agree on minor changes needed to 
make the system more efficient towards reaching its long-term goals. This evaluation should be made by ECDC 
and the disease network with contributions on specific issues from relevant stakeholders, and should cover the 
following areas: 

 

 
 

 

review of how well the short term public health objectives addressed and success indicators have been 
achieved 
evaluation of the performance of the technical system  
summary of the data volume, coverage and quality 
 
follow-up of related activities: 
 
 
 

review of resources used so far, and expected future needs 

curation 
training 
EQA/certification 

In addition, ECDC foresees a bi-annual evaluation of the public health added value from molecular typing data 
collection. This exercise will cover all pathogens for which molecular typing data has been implemented and will be 
led by the ECDC Microbiology Coordination Section and will summarise the ongoing molecular typing data 
collection managed by ECDC, review its short- and long-term public health objectives, evaluate the use of 
molecular typing data in ECDC’s daily work, summarise resource needs (current and future) based on information 
gathered from the disease networks, and assess the ‘value for money’ aspect per pathogen.  

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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

General considerations for the development 
of disease-specific molecular surveillance 
strategies and business cases 

Molecular typing data collation at the EU level  

Need for EU-level data integration and analysis  

The critical precondition for developing an ECDC system is to provide molecular typing analysis output that is 
needed for EU-level public health action and that is not available from any other place. Such information may 
include information regarding incidence and spread on a European level of a specific molecular type found in the 
Member State, and of baseline epidemiological data reported for cases with the specific molecular type. The cluster 
analysis tool included in the molecular typing pilot project is one attempt at providing this kind of information to 
the users, as is the future integration of structured molecular typing data in EPIS FWD v2. It is essential that a 
dialogue between ECDC and the Member States ensures that TESSy is making maximum use of the shared 
molecular typing data submitted and is delivering feedback of practical value for disease prevention and control to 
the users. 

Resources and funding issues 

Although the potential of molecular typing for improving public health is well established, it is clear that this can 
only be realised if adequate resources are available for producing and analysing the data.  

As has already been described in the sections above, it is impossible to separate the discussion of resources from 
the discussion of data generation, analysis, use etc. The issue of resources cuts across all other issues, and must 
be addressed at several different levels and from different angles. 

From the financial perspective, it is clear that any collection of molecular typing data at the European level will rely 
heavily on Member States using their own funds for the actual typing. It is however unrealistic to expect all 
Member States to have funds to type (or have someone else type) all pathogens, as Member States will naturally 
focus their resources for molecular typing on pathogens where typing has a maximum impact on their national 
public health efforts. It is critical that the pathogen-specific situation for each Member State is clear before any 
decision can be made about whether to collect typing data for that pathogen at the EU level.  

Resource management also includes providing the people working in the field with the expertise needed as a result 
of new developments. The expert meeting ‘Molecular epidemiology of human pathogens: how to translate 
breakthroughs into public health practice’ which was organised by ECDC in November 2011 clearly recognised the 
need for advanced training and capacity building, especially in the field of bioinformatics, and for developing cross-
disciplinary competences of public health professionals, as provided by programmes such as the European 
Programme for Public Health Microbiology (EUPHEM). 

Point prevalence studies: alternative sampling design for molecular 
surveillance schemes 

The potential benefits of the collection of molecular typing data through point prevalence studies have been 
described above. There are many potential advantages with also integrating molecular typing data from point 
prevalence studies in TESSy: 

 
 
 

Compliance with the ECDC mandate to manage EU-level surveillance systems for communicable diseases   
Sustainability: Ensures comparability of recurrent prevalence studies in a systematic manner  
Possibility of combining epidemiological and microbiological data. 

When the first pathogen for which molecular typing data is collected through point prevalence studies is proposed 
for implementation, an evaluation of the concept of gathering molecular typing data through point prevalence 
studies in TESSy (or elsewhere) will be carried out. 

Reporting frequency 

The reporting frequencies needed for making efficient use of typing data for public health purposes depend on the 
pathogen investigated and the typing method(s) applied, but most of all on the public health objectives the typing 
data collection seeks to fulfil. Generally, for many surveillance-related objectives less frequent reporting is perfectly 
acceptable, whereas if typing data is to be used for outbreak investigation a near real-time reporting frequency is 

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TECHNICAL REPORT 

needed. In this context, the term real-time is also disease dependent. For example, data needs to be more rapidly 
collected to be useful in an STEC outbreak investigation compared to a tuberculosis investigation. 

It is imperative that the required periodicity of reporting is discussed and described together with the specific 
public health objectives. Before any decision is made to collect the data at the EU level, Member States (and ECDC) 
must assess whether their national systems would allow them to meet those reporting requirements, and what 
kind of resources would be required. Data collection of typing data for a specific pathogen should not be initiated 
unless a majority of Member States agree that the reporting frequency required for the data to be useful at the EU 
level can be upheld. 

Where needed, ECDC should seek to support Member States in meeting these more frequent reporting needs. One 
way of doing this (described in the ECDC molecular surveillance concept paper [7]) would be through supporting 
Member States to establish automated (‘machine-to-machine’) reporting to TESSy, which in the longer term would 
require less resources on the Member State level. In parallel, ECDC should also ensure that other tools (templates, 
scripts etc.) to facilitate easy TESSy reporting are available to Member State users for whom automated reporting 
is not an option.  

Cross-border strategies for generating data  

In ECDC, various initiatives for increasing technical proficiency for or outsourced access to molecular typing are 
supported. These initiatives can include EQA, training, technique assessments etc. However, given the difference in 
Member States’ laboratory systems, financial situation, disease burden and priorities, it is neither realistic nor cost-
effective that all Member States should have the technical capacity to carry out typing for all the different human 
pathogens within their national reference public health laboratories. To increase access to the required typing 
services in a cost-efficient manner, ECDC should focus on establishing alternative ways of making molecular typing 
of relevant pathogens possible for all Member States. 

One model is for ECDC to support and/or actively organise twinning arrangements between Member States. Such 
arrangements, which are currently organised directly by Member States on a bilateral basis, involve two Member 
States agreeing that one of them will process certain samples from the other Member State under some agreed 
terms of collaboration.  

In the food and animal health sector, the European Commission has established a network of EU-wide reference 
laboratories, whose tasks also include typing of relevant samples from National Reference Laboratories in all 
Member States. ECDC and the EC are currently investigating the feasibility of EU-level reference laboratories for 
human samples [21]. 

Molecular typing data sharing at the EU and global level 

It is important that the ECDC initiative to collect molecular typing data at the EU level is not carried out in isolation. 
Many human infectious diseases increasingly have a global reach. In addition to the severe acute respiratory 
syndrome and influenza A(H1N1)pdm09 pandemics, pandemics in poultry of highly-pathogenic avian influenza 
(H5N1) virus, the intercontinental transmission of Vibrio cholerae, and the global spread of emergent antimicrobial 
resistance are exacerbated by global trade and travel. Local infectious disease events have the potential to develop 
rapidly into international public health emergencies. The specific epidemiologic profile of infectious agents varies 
because infectious agents can readily transfer between distinct reservoirs and exchange genetic material. Rapid 
detection, analysis and timely public health response to infectious diseases worldwide are crucial for the prevention 
and global spread of infectious diseases [22].  

Open vs. closed sharing of typing data, data privacy and 
confidentiality aspects 

The sharing of epidemiological data through TESSy has traditionally been restricted to a closed community, where 
access rights are role- and disease-specific and granted by Member States through a formal nomination process. 
The exact rules that control the data access in TESSy are described in the TESSy Data Access policy [23] which is 
periodically revised and approved by Member States. The molecular typing pilot project in 2012–2014 elected to 
follow the TESSy data access policy also for the typing data, and specific nominations have been received from 
Member States to grant specific users specific access to the data.  

As typing data becomes increasingly complex, the data storage and analysis needs are also such that a 
collaborative approach is needed to make best use of the global resources and to get the most use out of the data. 
Next-generation sequencing  techniques, which are expected to replace and/or complement existing molecular 
typing methods within a relatively short time period [24], are a particularly good example of where the 
management and analysis of the data will require such highly specialised and qualified expertise that it is simply 
not feasible that all public health institutions shall have this competence in-house. The expert meeting ‘Molecular 
epidemiology of human pathogens: how to translate breakthroughs into public health practice’ which was 

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organised by ECDC in November 2011 identified the central storage and curation of data is needed for public 
health application of NGS, and proposed that ECDC should (in global collaboration) be involved in setting the 
design and accreditation standards for genome-based surveillance databases.  

An overall goal of the ECDC molecular surveillance initiative should thus be to strive towards maximum openness 
and sharing of molecular typing data while still respecting data privacy and confidentiality regulations. In the long-
term, ECDC should work together with  Member States to identify ways of sharing typing data also with the wider 
scientific community, without compromising  Member States’ data privacy and confidentiality restrictions. In 
addition, the TESSy Data Access Policy needs to better describe some issues where there are specific concerns 
related to the collection of molecular typing data. These include: 

 
 
 
 

data ownership 
user access and nomination 
scientific publication policy 
management of multinational clusters. 

A revised TESSy data access policy document was reviewed and approved by ECDC’s Management Board in 
November 2015. 

Collaboration with existing typing initiatives on an EU or global level 

Molecular typing data collection supported by ECDC should be well integrated with existing typing initiatives on an 
EU and/or global level. There is no added value from the EU side to create a competing molecular surveillance 
system where a functional one already exists, so every effort should be made to link in collaboration with these 
initiatives. However, it is ECDC’s responsibility to ensure that all data collected through these initiatives are 
submitted by a user that has been nominated by an appropriate Competent Body. Specific agreements will need to 
be made between ECDC and each initiative to ensure that Member States’ reporting requirement to ECDC can be 
adequately met by submission through a system external to ECDC. 

Focus should be on simplifying data submission for the Member States, and on minimising reporting to more than 
one system and reporting of the same data in more than one format (‘double reporting’). It may be that some 
double reporting is needed for a limited period of time (for example during a pilot phase where it is tested which is 
the preferred way of the Member States for sending molecular typing data), but then a plan is needed for ensuring 
that this double reporting is monitored and ultimately resolved. 

Staying current – how to support and harmonise the use of 
new (state-of-the art) typing technologies 

In a fast-developing research world, new typing methods for specific pathogens frequently become available. While 
it may be tempting from the scientific perspective to use the most advanced method available for typing, the 
requirements from the public health side are rather more conservative. In public health, molecular typing data, like 
epidemiological data, is primarily important as information for public health action. Therefore there are often high 
requirements that the data has been generated in a standardised and comparable way and that data is robust 
enough to be used for public health action. Data generated using a non-standardised and/or non-validated protocol 
may well be interesting from a research perspective, but usually cannot form the basis of a decision for public 
health action without further verification. Any sharing of molecular typing data at the EU level must therefore 
ensure that standardisation and validation issues are adequately addressed for the pathogens and methods used, 
and that there is a broad consensus amongst the data providers and users on these topics. 

Supporting typing method standardisation and validating public 
health use  

A molecular epidemiology expert consultation held in 2011 identified that ECDC has role in keeping Member States 
informed of developments, and in supporting activities that lead to validation of newer typing methods and 
bioinformatic tools that are customised for public health use [22]. In addition, an expert panel organised by ECDC 
in June 2012 considered that ECDC has a role in supporting international validation studies of new methods, and in 
developing consensus definition and co-ordination of the use of standard methods that have demonstrated 
epidemiological utility.  

There was a strong consensus that clear definitions are lacking for these terms, especially for clinical and public 
health laboratories processing samples from human origin. The concept of standardisation is particularly difficult 
for bacterial pathogens where there is often a wide range of methods available which vary greatly in terms of need 
for standardisation and resources already invested to make data comparable between laboratories. The bacterial 
field cover highly standardised methods (PFGE for Salmonella enterica, Listeria monocytogenes and STEC; MLVA 
for Salmonella Typhimurium; MIRU-VNTR for Mycobacterium tuberculosis etc.) with community-agreed laboratory 

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TECHNICAL REPORT 

protocols and comprehensive EQA schemes in place, to laboratory methods not standardised at all. For the viral 
pathogens, the frequent use of sequence-based methods implies a certain inherent level of standardisation, but 
there are still large differences in the levels of laboratory protocol harmonisation and data sharing. The expert 
panel concluded that the lack of validation studies published is likely due to the difficulty of having articles on this 
topic accepted and published in mainstream peer reviewed journals, and partly due to a lack of resources and/or 
interest at the local/regional/national/EU level to publish results of completed validation studies. 

It is clear that the concepts of standardisation and validation are key issues to review in-depth for each pathogen-
method combination considered for EU-wide data collection. It is also to be expected that additional efforts are 
needed for international validation studies of new methods and/or methods agreed to be applied at the European 
level. 

Transitioning to next generation methods 

Recent technological advances in molecular biology, specifically in sequencing and mass spectrometry, are likely to 
transform detection and typing methodologies applied in clinical and public health microbiology laboratories. The 
use of new mass spectrometry instruments and applications is likely to have the highest impact in clinical 
laboratories, especially as replacement of culture-based bacterial characterisation. This can influence the number 
of samples available for secondary testing that can be used for public health purposes. Next generation sequencing 
applications are predicted to first influence molecular typing as used for surveillance and outbreak investigations 
[22,25]. 

In November 2011, ECDC hosted the meeting ‘Molecular epidemiology of human pathogens: how to translate 
breakthroughs into public health practice’ to discuss with European experts the opportunities and challenges 
related to the introduction of these new methods into laboratory microbiology. Here it was concluded that next 
generation sequencing-based typing technologies represent a window of opportunity for public health application in 
the coming years. However, in spite of its great potential there are a number of hurdles for implementation of NGS 
for public health purposes. Without either well-utilised local instrumentation or contact with larger sequencing 
institutes, many public health institutes are excluded from the possibility of using NGS routinely. The time from 
sampling to results is generally too long and a major unresolved question is how genome data should be best 
analysed for epidemiological application. Harmonisation of quality parameters for NGS data production is needed. 
Routine removal of genetic regions with high variation gave rise to concerns that too much information is left out 
of analyses – a concern for the analysis of mobile genetic elements that are of particular interest for public health. 
To stimulate developments, collaborations in research networks, combining human and veterinary bacteriology, 
virology and epidemiology with genomic bioinformatics, molecular biology and population genetics should be 
facilitated and ECDC has a role to play to as information broker, capacity builder and natural hub for many of the 
involved laboratories [22]. 

In general, the sequencing community advocates for free sharing of genomic data, but it is acknowledged that 
translation into public health practice highlights several issues including ownership of data, confidentiality and 
national policies. During the November meeting, it was proposed that these aspects should be kept in mind when 
developing new bioinformatic tools and systems with adjustable access levels, depending on the users and 
purposes of using the information could be one solution to mitigate these obstacles [22]. ECDC is also participating 
actively in the initiative on use of genomics for global surveillance and outbreak detection and diagnostics, which is 
led jointly by the Danish Technical University (DTU), and the Food and Drug Administration (FDA), US. This 
initiative aims to create a global solution for NGS data sharing and analysis for multiple scientific disciplines, and it 
remains to be seen to what extent its tools and solutions will be suitable from the European public health 
perspective [24].  

To further explore opportunities and address barriers within this field, ECDC will present a separate framework for 
NGS data handling for public health purposes at the European level by 2016. This date may however be brought 
forward if ECDC Disease Programmes or networks decide to support one or more projects where solutions to this 
issue are needed on a disease-specific basis.  

Coordination with typing activities in food, feed and animal 
sectors 

The European Commission in collaboration with ECDC and the European Food Safety Authority (EFSA) are leading 
an initiative to encourage the collation of data on molecular testing so that the linkage of molecular typing data 
from humans to similar types of data from food and animals is possible. Given that the data is provided in a timely 
manner, this would enable rapid detection of clusters and outbreaks, and suggest links with potential sources. 
Such linking would allow the speeding-up of epidemiological investigations, a better evaluation of the importance 
of certain foods and animal populations as sources of food-borne infections and outbreaks through case-by-case 
source attribution studies, and a better understanding of the epidemiology of food-borne infections.  

22 

 
 
 
 
 
 
 
 
 
 
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Roadmap for integration of molecular typing into European-level surveillance and epidemic preparedness V. 1.2, 2013 

Maximum use should be made from the existing networks (EURLs, ECDC FWD network, EFSA Task Force) and data 
collection systems so that any duplication is avoided, and both management and handling of information is under 
mandate of appropriate authorities/institutes. This is part of the EU follow-up/lessons learnt of the E. coli O104:H4 
outbreak. The added value of a centralised molecular typing data sharing and analysis resource was clearly 
illustrated in the recent coordinated cross-border and inter-sectoral investigation of a Salmonella Stanley foodborne 
outbreak affecting ten Member States [26]. 

Due to the potentially very large financial and societal impact of the results of these types of joint analyses, the 
information access must be regulated between and monitored by the involved parties. An agreement on the data 
availability and use must be clearly established before any information is published. 

Molecular surveillance of antimicrobial resistance 

For several bacterial pathogens covered in this review, only multidrug- resistant strains have been included. The 
reason for this is that they have a public health impact related to the increased morbidity, mortality and costs 
associated with difficult to treat infections. In addition, multidrug resistance is amplified in Gram-negative 
pathogens such as Klebsiella pneumoniae, E. coli, A. baumannii both by epidemic dissemination of resistant strains 
but also by horizontal spread of plasmid and other transferable genetic elements between pathogens. During the 
expert consultations and Joint Strategy Meeting workshop, a suggestion was made to consider approaching the 
issue from the resistance marker perspective rather than from an individual pathogen point of view. ECDC has 
followed such an approach in its risk assessment recommendation for enhanced surveillance and early warning of 
extremely resistant pathogens of high public health impact such as carbapenemase-producing/carbapenem-
resistant Enterobacteriaceae and A. baumannii [16]. 

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TECHNICAL REPORT 

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25 

 
 
 
 
 
 
 
 
 
 
 
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