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Public Health England – Unpublished data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epidemiological yearPHE – unpublished data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