professor martin maiden @ mrf's meningitis & septicaemia in children & adults 2015
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UKMenCar4: carriage studies, high-resolution genomics, and disease control
Martin Maiden,UKMenCar4 Consortium
Meningococcal structure and characterisation
Jolley, K. A., Brehony, C. & Maiden, M. C. (2007). Molecular typing of meningococci: recommendations for target choice and nomenclature. FEMS Microbiol Rev 31, 89-96.
Component Phenotypic Genotypic
Capsule Serogroup cps region
OMPS Serotype,Subtype, etc.
porA, porB, fetA, etc.
Housekeeping genes
MLEE MLST
Ribosomes MALDITOF 16s rRNA,rMLST
Neisseria meningitidis B: P1.7,16: F3-3: ST-32 (cc32)
Meningococcal disease, England & Wales: the long view
1912 1916 1920 1924 1928 1932 1936 1940 1944 1948 1952 1956 1960 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 -
5.00
10.00
15.00
20.00
25.00
30.00
35.00
Year
Incid
ence
rate
/100
,000
The Big Questions: (i) Why was there such high
disease incidence mid-1980s – mid-2000s?;
(ii) Why has it reduced?; and, (iii) What is likely to happen next?
Cerebrospinal Fever Meningococcal: infection meningitis & septicaemia
Data: courtesy Mary Ramsay Shamaz Ladhani, Public Health England
Meningococcal disease epidemics England & Wales 1984-2013
Data: Meningococcal Reference Unit, Public Health England
1982-1990StonehouseOutbreakGroup B
1993-1999Group C Outbreaks
2001 -Group BIncidencedeclines
Late 1999Group C Conjugate Meningococcal (MCC) Vaccinesintroduced
Meningitis Research Foundation Meningococcus Genome Library
• Charity funded.• Open access.• All available England
and Wales, Scotland (and Ireland, WT funded) meningococcal isolates.
• Assembled & annotated contiguous sequence data.
http://www.meningitis.org/current-projects/genome
Diversity of disease causing meningococciMRF-MGL isolates 2010-2012
Hill, D.M.C., Lucidarme, J., Gray S.J., Newbold , L.S., Ure, R., Brehony, C., Harrison, O.B., Bray, J.E., Jolley, K.A., Bratcher H.B.,, Parkhill, J., Tang, C.M., Borrow, R., and Maiden, M.C.J. Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study. Lancet Infectious diseases, DOI: http://dx.doi.org/10.1016/S1473-3099(15)00267-4.
• A total of 923 isolates from England, Wales and Northern Ireland.
• 899 from England and Wales:• Scanned at >2000 loci;• 2-313 alleles/locus;• 219 STs, 22 clonal
complexes;• 496 rSTs (ribosomal
sequence types);• Most isolates (78%)
belonged to 6 clonal complexes.
1975 ~ 1985 ~ 1995 ~ 1999 2000 2001 ~ 2005 2006 2007 2008 2009 2010 2011 20120
500
1000
1500
2000
2500
3000
41/44 269 11 32 8 213 23 167 174 22 Other UA NT
Epidemics are dominated by particular meningococci
Hill, D.M.C., Lucidarme, J., Gray S.J., Newbold , L.S., Ure, R., Brehony, C., Harrison, O.B., Bray, J.E., Jolley, K.A., Bratcher H.B.,, Parkhill, J., Tang, C.M., Borrow, R., and Maiden, M.C.J. Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study. Lancet Infectious diseases, DOI: http://dx.doi.org/10.1016/S1473-3099(15)00267-4.
Age association of meningococcal genotypes (MRF-MGL 2010-2012)
<1 1-4 5-9 10-14 15-19 20-24 25-29 30-39 40-49 50-69 >700%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Minor clonal complexesNDST-174 complexST-461 complexST-162 complexST-22 complexST-23 complex/Cluster A3ST-213 complexST-60 complexST-41/44 complex/Lineage 3ST-269 complexST-32 complex/ET-5 complexST-11 complex/ET-37 complex
Age category
Prop
ortio
n of
case
s
Hill, D.M.C., Lucidarme, J., Gray S.J., Newbold , L.S., Ure, R., Brehony, C., Harrison, O.B., Bray, J.E., Jolley, K.A., Bratcher H.B.,, Parkhill, J., Tang, C.M., Borrow, R., and Maiden, M.C.J. Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study. Lancet Infectious diseases, DOI: http://dx.doi.org/10.1016/S1473-3099(15)00267-4.
<1 1 2 3 4-6 7-910-12
13-15
16-18
19-21
22-24
25-27
28-30
31-33
34-36
37-39
40-43
44-46
47-49
50-52
53-55
56-58
59-61
62-64
65-67
68-70
71-73
74-76
77-79
80-82
83-85
86-88
89-91
92-94
95-97 >9
7 NK0
5
10
15
20
25
2010/112011/12
Patient Age (Years)
Prop
ortio
n of
IMD
Case
s Epi
dem
iolo
gica
l Yea
r (%
)
<1 1-3 4-6 7-9 10-110123456789
Patient Age (Months)Pr
opor
tion
of C
ases
Epi
dem
iolo
gica
l Ye
ar (%
)
Age distribution of isolates in meningococcal genome library
Meningococcal carriage by age
Christensen, H., May, M., Bowen, L., Hickman, M. & Trotter, C. L. (2010). Meningococcal carriage by age: a systematic review and meta-analysis. The Lancet Infectious Diseases 10, 853-861.
100 years of disease and carriage studies
Glover, J. A. (1918). "Spacing out" in the Prevention of Military Epidemics of Cerebro-Spinal Fever. Br Med J 2, 509-512.
Glover, J. A. (1918). Observations on the Meningococcus Carrier-Rate in relation to density of population in Sleeping Quarters. J Hyg (Lond) 17, 367-379.
Glover, J. A. (1918). The Cerebro-Spinal Fever Epidemic of 1917 at X Depot. J Hyg (Lond) 17, 350-365.
Meningococcal disease England & Wales
Data: Meningococcal Reference Unit, Public Health England
Late 1999Group C Conjugate Meningococcal (MCC) Vaccinesintroduced
UK Meningococcal carriage study: UKMenCar1-3, 1999-2001
Ibarz-Pavon, A. B., et al. (2011). Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation. J Infect Dis 204, 1046-1053.Maiden, M. C., et al. (2008). Impact of Meningococcal Serogroup C Conjugate Vaccines on Carriage and Herd Immunity. J Infect Dis 197, 737-743.Maiden, M. C., Stuart, J. M. & Group, U. M. C. (2002). Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 359, 1829-1831.
Glasgow
Stockport
Nottingham Oxford
London
Plymouth
Wales
MRU/SMPRL Phenotype
16,700 X 3
Sequence type siaD/cnl
Questionnaire Risk factors for carriage
2,500 X 3
UKMenCar 1-3: 8,000 carried meningococci, a diverse population
1999 2000 20010
2
4
6
8
10
12
14
16ST-11 complex ST-865 complex ST-8 complexST-254 complex ST-212 complex ST-162 complex ST-92 complex ST-18 complex ST-178 complex ST-1136 complex ST-750 complex ST-41/44 complex ST-167 complex ST-32 complexST-60 complex ST-282 complex ST-364 complex ST-35 complex ST-22 complex ST-198 complex ST-103 complex ST-23 complexST-53 complex ST-1157 complex ST-269 complex ST-1117 complex ST-213 complex ST-461 complex ST-174 complex ST-106 complex ST-116 complex ST-334 complex ST-37 complex ST-376 complex
Year
Prop
ortio
n of
men
ingo
cocc
i (%
)
Ibarz-Pavon, A. B., Maclennan, J., Andrews, N. J., Urwin, R., Gray, S. J., Clarke, S. C., Walker, A. M., Evans, M. R., Kroll, J. S., Neal, K. R., Ala'aldeen, D. A., Crook, D. W., Cann, K., Harrison, S., Cunningham, R., Baxter, D., Kaczmarski, E., Cameron, J. C. & Stuart, J. M., & Maiden, M. C. (In press). Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation. J Infect Dis.
UKMenCar1-3: major disease associated lineages
1999 2000 20010
2
4
6
8
10
12
14
16
ST-11 complex ST-8 complex ST-41/44 complex
ST-32 complex ST-269 complex
Year
Prop
ortio
n of
men
ingo
cocc
i (%
) Clonal complex
1998/9n
1998/9%
2000/1n
2000/1%
ST-11 complex
553 32.8 264 20.5
ST-41/44 complex
423 25.1 373 28.9
ST-269 complex
253 15.0 275 21.3
ST-32 complex
99 5.9 79 6.1
ST-8 complex
84 5.0 15 1.2
a) Carried meningococcal clonal complexes b) Clonal complexes isolated from disease
Maiden, M. C., Ibarz-Pavon, A. B., Urwin, R., Gray, S. J., Andrews, N. J., Clarke, S. C., Walker, A. M., Evans, M. R., Kroll, J. S., Neal, K. R., Ala'aldeen, D. A., Crook, D. W., Cann, K., Harrison, S., Cunningham, R., Baxter, D., Kaczmarski, E., Maclennan, J., Cameron, J. C. & Stuart, J. M. (2008). Impact of Meningococcal Serogroup C Conjugate Vaccines on Carriage and Herd Immunity. J Infect Dis 197, 737-743.
UKMenCar 1-3: Carriage of ST-11 genogroup C isolates
1999 2000 20010
0.05
0.1
0.15
0.2
0.25
0.3
0.35
NGC
Year
% C
arria
ge
Maiden, M. C., et al. (2008). Impact of Meningococcal Serogroup C Conjugate Vaccines on Carriage and Herd Immunity. J Infect Dis 197, 737-743.
Clonal complex, disease, and serogroup England and Wales, 1999
Clonal complex Disease association OR B C W-135 Y
ST-8 14.7 [6.8 - 31.9] 11 69 0 0
ST-11 28.7 [20.1 - 41.1] 7 525 1 0
ST-22 0.23 [0.17 - 0.32] 5 0 42 1
ST-23 0.14 [0.07 - 0.28] 0 1 0 9
ST-32 2.1 [1.5 - 3.0] 80 1 0 0
ST-35 0.29 [0.16 - 0.53] 13 0 0 0
ST-41/44 1.8 [1.5 - 2.1] 390 7 0 0
ST-213 0.4 [0.28 - 0.57] 39 1 0 0
ST-269 4.4 [3.4 - 5.8] 214 7 0 0
Unassigned 0.28 [0.24 - 0.34] 140 32 2 9
Data: Ure R., Gray S., McCarthy N.D., Pavon A.B., and Maiden, M.C. Unpublished.
Risk factors for carriage
Smoking Kissing
Y Y
Y N
N Y
N N
MacLennan, J., Kafatos, G., Neal, K., Andrews, N., Cameron, J. C., Roberts, R., Evans, M. R., Cann, K., Baxter, D. N., Maiden, M. C. & Stuart, J. M. (2006). Social behavior and meningococcal carriage in British teenagers. Emerg Infect Dis 12, 950-957.
The long-term impact of herd immunity
Trotter, C. L. & Maiden, M. C. (2009). Meningococcal vaccines and herd immunity: lessons learned from serogroup C conjugate vaccination programs. Expert Review Vaccines 8, 851-861.
Meningococcal disease England & Wales
Data: Meningococcal Reference Unit, Public Health England
1982-1990StonehouseOutbreakGroup B
1993-1999Group C Outbreaks
2001 -Group BIncidenceDeclines
Late 1999Group C Conjugate Meningococcal (MCC) Vaccineintroduced
UKMenCar4: Initial aims1) Compare the genotypes of
meningococcal disease and carriage isolates in high and low incidence settings (UK 1999 and UK 2014).
2) Investigate the risk factors for meningococcal carriage and in particular the effect of changes in social behaviour with respect to smoking, kissing, and socialising.
Incidence Carriage Disease
High (1999) ✔ ✔
Low (2014) ✔ ✔
UK Meningococcal carriage study, UKMenCar4: 2014-5
Glasgow
Stockport Manchester
Oxford
London
Plymouth
Cardiff
Maidstone Bristol
WiganPreston
• Multi-centre cross-sectional survey of meningococcal carriage
• 18,000 UK teenagers• Compared to UKmenCAR1-3:
– Similar study sites;– Same age group;– Sampling in schools/colleges;– Similar time of year (but
extended from autumn to spring);
– Similar microbiological methods;
– Same key risk factors.
Sampling
Tributyrin Test * Positive reaction: yellow/yellow orange * Negative reaction: red
Results: Moraxella catarrhalis (+) Neisseria spp. (-)
Microbiology testing
Genome sequencing of Neisseria meningitidis isolates
|||||||||||OX40001 |||||||||||
OX40001
|||||||||||OX40001
Sequence read processing
Visualization
Analysis of study data
These are just some of the types of analyses possible …
Cluster 1
Cluster 2
Cluster 3
Genome analysis of disease and carriage isolates from Chad
Reference genome: 2070 genes from ST5 WUE2594 [Schoen, C. et al., 2011]
Genome comparator output: 1542 genes identical in all genomes (1347
share same allele as ref/196 have a different allele);
66 genes missing in all 23 genomes; 221 incomplete genes were excluded; 242 variable genes.
Diallo K, Trotter C, Borrow R, Stuart JM, Greenwood BM, Maiden MCJ, & MenAfriCar consortium. Unpublished.
UKMenCar4 totals by centreCentre Recruitment
targetFinal total
Glasgow 2600 2632
Bristol 2600 1814
London 2600 1933
Oxford 2600 2141
Stockport 2600 2438
Cardiff 2600 3130
Plymouth 1500 2252
Maidstone 1000 1022
Preston 1000 1016
Central Manchester & Wigan
1000 3497
Total 20,100 21,874
UKMenCar4: Meningococcal carriage rates
1999-2000 2000-2001 2001-2002 2014-2015Carriage of Neisseria meningitidis * Putative
meningococciStockport 25.4 % 24.9 % 24.4 % 11.7 %Cardiff 14.4 % 17.6 % 16.7 % 8.6 %Glasgow 11.7 % 16.2 % 17.5 % 7.1 %Oxford 25.2 % 22.6 % 20.3 % 9.3 %Plymouth 8.2 % 15.4 % 19.9 % 5.9 %Bristol N/A N/A N/A 8.4 %North Thames 9.1 % 12.5 % 14.4 % N/ABangor 20.9 % 19.2 % 22.9 % N/ANottingham 19.9 % 19.8 % 16.0 % N/A
Shisha smokingSmoking ban 2006/7
Changes since UKMencar1-3: smoking
Meningococcal disease England & Wales
Data: Meningococcal Reference Unit, Public Health England
1982-1990StonehouseOutbreakGroup B
1993-1999Group C Outbreaks
2001 -Group BIncidencedeclines
Late 1999Group C Conjugate Meningococcal (MCC) Vaccineintroduced
WhatNext?
MRF Genome Library Era:England and Wales 2010-2015
07/2010-06/2011
07/2011-06/2012
07/2012-06/2013
07/2013-06/2014
07/2014-06/2015
0
50
100
150
200
250
300
350
400
450
BCWY
http://www.meningitis.org/current-projects/genome
Lineage 11 (cc11) Group W: UK epidemiology
Current UK
UK Hajj
UK1996 (n=3)1997 (n=2)1998 (n=2)
UK1975 (n=6)1987 (n=1)1989 (n=1)1990 (n=1)
UK1996 (n=2)1998 (n=1)
Argentina 2008-2012
Brazil 2008-2011
Current South Africa
Lucidarme, J., Hill, D. M., Bratcher, H. B., Gray, S. J., du Plessis, M., Tsang, R. S., Vazquez, J. A., Taha, M. K., Ceyhan, M., Efron, A. M., Gorla, M. C., Findlow, J., Jolley, K. A., Maiden, M. C. & Borrow, R. (2015). Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage. J Infect In the press.
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
0
10
20
30
40
50
60
70
80
90
N. meningitidis cases per year among inpatients in Bamako, Mali (2002-2012)
Group A meningococcal cases
Group W135 meningococcal cases
Year
Num
ber o
f Cas
es
Nm W England and Wales
2015 vaccine introductions
UKMenCar5: Evaluation of changes in the UK national meningococcal immunisation programme
UKMenCar4 provides the pre-vaccination baseline for circulating meningococci and will allow full evaluation of the impact of ACWY vaccine on meningococcal populations.
2014 2015 2016 2017 2018
UKMenCar4 ACWY vaccination UKMenCar5 with catch up
UKMenCar4 Team
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