dr jay lucidarme @ mrf's meningitis & septicaemia in children & adults 2015
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First use of genomics to inform national meningococcal
immunisation policyJay LucidarmePublic Health England, Vaccine Evaluation Unit/Meningococcal Reference Unit Manchester, United Kingdomjay.lucidarme@phe.gov.uk
Meningococcal Reference Unit (MRU)
National reference unit for Neisseria meningitidis
Services include: Confirmation of meningococcal disease Characterisation of specimens/isolates
Meningococcal typing
Meningococcal typing
Multilocus Sequence Typing (MLST – 7 enzymes)
Group
Type
Subtype
Meningococcal typing
Multilocus Sequence Typing (MLST – 7 enzymes)
GroupTypeSubtype
Population biology
Case management
Outbreak detection
MLST - eBURST
MLST - eBURST
MLST - eBURST
cc41/44
cc269
cc32
• Open access online database of whole genome sequences of all invasive disease isolates from:
- England, Wales and Northern Ireland (July 2010 onward; n = 2308)
- Scotland (2009 to 2013; n = 172)• Metadata e.g. Country, year, serogroup• Annotated for all genes and typing loci including:
- vaccine antigen genotypes- genogroup, genosubtype, 7-locus MLST- x-locus MLST!
Meningococcus Genome Library Est. Sep. 2012
Group W disease – England and Wales
Public Health England – Unpublished data
0
20
40
60
80
100
120
140
160
180
2008 2009 2010 2011 2012 2013 2014 2015 (to 19 Oct)
n
year
Group W disease – England and Wales
ST-11 complex (cc11)!
• High morbidity and mortality• Outbreaks and epidemics
The ST-11 complex (cc11)
• High morbidity and mortality• Outbreaks and epidemics
The ST-11 complex (cc11)
1960 1970 1980 1990 2000 2010 2020
Serogroup C cc11 (C:cc11)
MenC disease vs year England and Wales
0
100
200
300
400
500
600
700
800
900
1000
n
epidemiological yearPHE – unpublished data
• High morbidity and mortality• Outbreaks and epidemics
The ST-11 complex (cc11)
1960 1970 1980 1990 2000 2010 2020
Serogroup C cc11 (C:cc11)
• High morbidity and mortality• Outbreaks and epidemics
The ST-11 complex (cc11)
Serogroup B cc11 (B:cc11)
1960 1970 1980 1990 2000 2010 2020
Serogroup C cc11 (C:cc11)
?
• High morbidity and mortality• Outbreaks and epidemics
The ST-11 complex (cc11)
Serogroup W cc11 (W:cc11)
Serogroup B cc11 (B:cc11)
1960 1970 1980 1990 2000 2010 2020
Serogroup C cc11 (C:cc11)
?
?
W:2a:P1.5,2:ST-11
1960 1970 1980 1990 2000 2010 2020
?
1960 1970 1980 1990 2000 2010 2020
?
1960 1970 1980 1990 2000 2010 2020
?
1960 1970 1980 1990 2000 2010 2020
?
W:cc11
?
Experiment 1Hi-res comparison of available genomes
• All W:cc11 genomes on MGL/Pubmlst Neisseria database (n=83; Feb 2014)• Genome comparator tool (1546 genes; PubMLST Neisseria database)
isolate 1 isolate 2 isolate 3 isolate 4isolate 1 0isolate 2 100 0isolate 3 34 95 0isolate 4 56 54 20 0
Distance matrix
Experiment 1Hi-res comparison of available genomes
• All W:cc11 genomes on MGL/Pubmlst Neisseria database (n=83; Feb 2014)• Genome comparator tool (1546 genes; PubMLST Neisseria database) • Distance matrix visualised graphically using SplitsTree v4.12.8
e.g. distance matrix of UK cities visualised using SplitsTree v4.12.8
London Bristol Manchester Oxford CambridgeLondon 0Bristol 106 0
Manchester 163 141 0Oxford 51 61 127 0
Cambridge 50 127 132 67 0
Manchester
London
Cambridge
Bristol
Oxford
Distances in miles
Experiment 1Hi-res comparison of available genomes
• All W:cc11 genomes on MGL/Pubmlst Neisseria database (n=83; Feb 2014)• Genome comparator tool (1546 genes; PubMLST Neisseria database) • Distance matrix visualised using SplitsTree v4.12.8
England & Wales (n=71; Jun 2010 – July 2013)England & Wales (n=1; 2000)Ireland (n=2; 2013)South Africa (n=8; 2003-2011)Burkina Faso (n=1; 2002)
UK Hajj pilgrim (2000)
Ladhani et al., 2015
Experiment 1Hi-res comparison of available genomes
• All W:cc11 genomes on MGL/Pubmlst Neisseria database (n=83; Feb 2014)• Genome comparator tool (1546 genes; PubMLST Neisseria database) • Distance matrix visualised using SplitsTree v4.12.8
England & Wales (n=71; Jun 2010 – July 2013)England & Wales (n=1; 2000)Ireland (n=2; 2013)South Africa (n=8; 2003-2011)Burkina Faso (n=1; 2002)
UK Hajj pilgrim (2000)
Ladhani et al., 2015
Single strain responsible for UK increase Distinct from Hajj and Sth Africa strains?
C33%
W63%
B4%
C
W
B
Methods - Repeat experiment 1 on:- Geo-temporally diverse cc11 isolates (n=750)
- 25 countries- 6 continents- 6 decades
- inc. representatives of major cc11 outbreaks- non-cc11 reference isolates (n=2, cc41/44 & cc8)
Experiment 2Develop a hi-res cc11 population structure
cc8
cc41/44
Results
100
Subl
inea
ge 1
1.2
Subl
inea
ge 1
1.1 Line
age
11
cc8
cc41/44
MenW (n=470)
MenC (n=246)MenB (n=34)
(b)(a)
Lineage 11.1 Lineage 11.2
cc8
cc41/44
Results
100
Subl
inea
ge 1
1.2
Subl
inea
ge 1
1.1 Line
age
11
cc8
cc41/44
MenW (n=470)
MenC (n=246)MenB (n=34)
(b)(a)
Other clonal complexes
cc11
Lineage 11.1 Lineage 11.2
cc8
cc41/44
Results
100
Subl
inea
ge 1
1.2
Subl
inea
ge 1
1.1 Line
age
11
cc8
cc41/44
MenW (n=470)
MenC (n=246)MenB (n=34)
(b)(a)
MenW
cc11
Other clonal complexes
ResultsMenW
W:cc11England and Wales (2009-)
South America (2003-)
Hajj (2000)
South Africa (2003-)
subSaharan Africa(2000-2004)
Public Health England – Unpublished data
England and Wales (2009-)
South America (2003-)
Hajj (2000)
South Africa (2003-)
Case fatality rate 27% (Chile)
Lucidarme et al. (2015) J infect.
Araya et al. (2015) Emerg Infect Dis.
subSaharan Africa(2000-2004)
W:cc11
Outcome Highly virulent strain Accelerated expansion Public health emergency (JCVI 13th March 2015)
Phased MenACWY vaccination in UK (from Aug 2015)- UK 13 year olds- UK 14-18 year olds- New undergraduates up to 25 years
• Genomics informing national vaccination policy• Predictive vs reactive vaccination
Further work- enhanced surveillance (post vaccine intro)
- ‘real-time’ genome sequencing- ‘acute’ outbreak detection
- healthcare setting- care home- Scout Jamboree
- international cooperation- Scotland, Sweden, Japan- France, Finland, Ireland, - Australia, USA? Others?
Acknowledgements
University of OxfordMartin MaidenHolly Bratcher
James Bray
Dorothea Hill
Keith Jolley
Ray BorrowJamie Findlow
Steve Gray
Tony Carr
Next Generation Sequencing Service
Wellcome Trust Sanger InstituteJulian ParkhillDavid Harris
Health Protection ScotlandAndrew SmithKevin ScottRoisin UreNational Public Health Institute, FinlandMaija ToropainenPublic Health Agency, CanadaRaymond W TsangHacettepe University, TurkeyMehmet CeyhanInstitut Pasteur, FranceMuhamed-Kheir TahaInstituto de Salud Carlos III, SpainJulio A VázquezNational Health Laboratory Service, South AfricaMignon du PlessisInstituto Nacional de Enfermedades Infecciosas, Argentina. Adriana M. EfronAdolfo Lutz Institute, BrazilMaria C. Gorla
Ray BorrowJamie FindlowSteve GrayTony CarrHelen CampbellMary RamsayKazim BeebeejaunShamez ladhani
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