Professor Martin Maiden @ MRF's Meningitis & Septicaemia in Children & Adults 2015
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The UKMenCar4 study: carriage studies, high-resolution genomics and disease control http://www.meningitis.org/conference2015
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Professor Martin Maiden @ MRF's Meningitis & Septicaemia in Children & Adults 2015
- 1. ! ! UKMenCar4: carriage studies, high-resolution genomics, and disease control Martin Maiden, UKMenCar4 Consortium
- 2. 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)
- 3. Meningococcal disease, England & Wales: the long view - 5.00 10.00 15.00 20.00 25.00 30.00 35.00 Incidencerate/100,000 Year 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
- 4. Meningococcal disease epidemics England & Wales 1984-2013 Data: Meningococcal Reference Unit, Public Health England 1982-1990 Stonehouse Outbreak Group B 1993-1999 Group C Outbreaks 2001 - Group B Incidence declines Late 1999 Group C Conjugate Meningococcal (MCC) Vaccines introduced
- 5. 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
- 6. Diversity of disease causing meningococci MRF-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.
- 7. 0 500 1000 1500 2000 2500 3000 1975 ~ 1985 ~ 1995 ~ 1999 2000 2001 ~ 2005 2006 2007 2008 2009 2010 2011 2012 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
- 8. Age association of meningococcal genotypes (MRF-MGL 2010-2012) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% <1 1-4 5-9 10-14 15-19 20-24 25-29 30-39 40-49 50-69 >70 Proportionofcases Age category Minor clonal complexes ND ST-174 complex ST-461 complex ST-162 complex ST-22 complex ST-23 complex/Cluster A3 ST-213 complex ST-60 complex ST-41/44 complex/Lineage 3 ST-269 complex ST-32 complex/ET-5 complex ST-11 complex/ET-37 complex 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
- 9. 0 5 10 15 20 25 <1 1 2 3 4-6 7-9 10-12 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 >97 NK ProportionofIMDCasesEpidemiologicalYear(%) Patient Age (Years) 2010/11 2011/12 0 1 2 3 4 5 6 7 8 9 <1 1-3 4-6 7-9 10-11 ProportionofCases EpidemiologicalYear(%) Patient Age (Months) Age distribution of isolates in meningococcal genome library
- 10. 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.
- 11. 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.
- 12. Meningococcal disease England & Wales Data: Meningococcal Reference Unit, Public Health England Late 1999 Group C Conjugate Meningococcal (MCC) Vaccines introduced
- 13. 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
- 14. UKMenCar 1-3: 8,000 carried meningococci, a diverse population 0 2 4 6 8 10 12 14 16 1999 2000 2001 Proportionofmeningococci(%) Year ST-11 complex ST-865 complex ST-8 complex ST-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 complex ST-60 complex ST-282 complex ST-364 complex ST-35 complex ST-22 complex ST-198 complex ST-103 complex ST-23 complex ST-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 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.
- 15. UKMenCar1-3: major disease associated lineages 0 2 4 6 8 10 12 14 16 1999 2000 2001 Proportionofmeningococci(%) Year ST-11 complex ST-8 complex ST-41/44 complex ST-32 complex ST-269 complex Clonal complex 1998/9 n 1998/9 % 2000/1 n 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.
- 16. UKMenCar 1-3: Carriage of ST-11 genogroup C isolates 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 1999 2000 2001 %Carriage Year NG C Maiden, M. C., et al. (2008). Impact of Meningococcal Serogroup C Conjugate Vaccines on Carriage and Herd Immunity. J Infect Dis 197, 737-743.
- 17. 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.
- 18. 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.
- 19. 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.
- 20. Meningococcal disease England & Wales Data: Meningococcal Reference Unit, Public Health England 1982-1990 Stonehouse Outbreak Group B 1993-1999 Group C Outbreaks 2001 - Group B Incidence Declines Late 1999 Group C Conjugate Meningococcal (MCC) Vaccine introduced
- 21. UKMenCar4: Initial aims 1) 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) ✔ ✔
- 22. UK Meningococcal carriage study, UKMenCar4: 2014-5 Glasgow Stockport Manchester Oxford London Plymouth Cardiff MaidstoneBristol Wigan Preston • 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.
- 23. Sampling
- 24. Tributyrin Test * Positive reaction: yellow/yellow orange * Negative reaction: red Results: Moraxella catarrhalis (+) Neisseria spp. (-) Microbiology testing
- 25. Genome sequencing of Neisseria meningitidis isolates ||||||||||| OX40001 ||||||||||| OX40001 ||||||||||| OX40001 Sequence read processing Visualization
- 26. Analysis of study data These are just some of the types of analyses possible …
- 27. 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.
- 28. UKMenCar4 totals by centre Centre Recruitment target Final 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
- 29. UKMenCar4: Meningococcal carriage rates 1999-2000 2000-2001 2001-2002 2014-2015 Carriage of Neisseria meningitidis * Putative meningococci Stockport 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/A Bangor 20.9 % 19.2 % 22.9 % N/A Nottingham 19.9 % 19.8 % 16.0 % N/A
- 30. Shisha smokingSmoking ban 2006/7 Changes since UKMencar1-3: smoking
- 31. Meningococcal disease England & Wales Data: Meningococcal Reference Unit, Public Health England 1982-1990 Stonehouse Outbreak Group B 1993-1999 Group C Outbreaks 2001 - Group B Incidence declines Late 1999 Group C Conjugate Meningococcal (MCC) Vaccine introduced What Next?
- 32. MRF Genome Library Era: England and Wales 2010-2015 0 50 100 150 200 250 300 350 400 450 B C W Y http://www.meningitis.org/current-projects/genome
- 33. Lineage 11 (cc11) Group W: UK epidemiology Current UK UK Hajj UK 1996 (n=3) 1997 (n=2) 1998 (n=2) UK 1975 (n=6) 1987 (n=1) 1989 (n=1) 1990 (n=1) UK 1996 (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. 0 10 20 30 40 50 60 70 80 90 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 NumberofCases Year N. meningitidis cases per year among inpatients in Bamako, Mali (2002-2012) Group A meningococcal cases Group W135 meningococcal cases Nm W England and Wales
- 35. 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
- 36. UKMenCar4 Team
Editor's Notes
- This is shown in this slide of the odds ratio of carriage using a baseline of the youngest participants who were 15 years o age. The odds of carriage increases more than two fold between 15 and 19 years of age. The graph on the right shows how the carriage prevalence changes according to specific risk factors, namely smoking, kissing and attendance at pubs and clubs. The x axis shows how carriage of meningococci increases as attendance at pubs and clubs in the previous week increases in the absence of other risk factors. If you add in other risk factors of smoking and intimite kissing, the carriage rates increase such that these ones, the party animals, who are smoking, kissing and found out on the town most nights, have rates of carriage four times higher than these ones, the party poopers who don’t have any of these risk factors. And once you adjust for these risk factors, you can see that age no longer has an effect. And so it is not age per se that is responsible for the observed increase in meningococcal carriage, but their behaviour.
- Oxidase Test: Positive for the enzyme cytochrome c oxidase (a large transmembrane protein complex found in bacteria - It is the last enzyme in the respiratory electron transport chain of the bacterial membrane. Grams Stain: Gm(-) diplococci Tributyrin Test: hydrolysis enzyme
- Second generation sequencing does not produce ‘trace files’ like Sanger sequencing, electronic reads are processed directly using Velvet (algorithm based de novo genomic assembler) Additional programs are needed if the sequence files need to be viewed – something like Bowtie (an ultrafast memory-efficient short read aligner from Johns Hopkins Univ.) + Tablet (high-performance graphical viewer from The James Hutton Inst.)
- Antigen distribution (pie charts from Ellie’s paper) Comparison to disease in the UK (graph from Dot’s paper)
- Full characterisation of isolates has not yet been undertaken, and these are the rates of putative meningococci that hae been identified to the level of oxidase positive, gram negative meningococci, and we know we will find some commensals and some moraxella amongst them. Despite this, I think it is clear that the overall carriage rates have dropped by at least 50%. Consistently seen across the centres. Previously carriage rates were around 17-18%, now they are more like 8% and bearing in mind these are putative meningoccocci these rates are likely to drop.
- We were particularly interested in changes in smoking habits over the past 15 years, most notably the smoking ban in 2006 in Scotland and 2007 in the UK would have on meningococcal carriage, possibly counteracted in part by an increase in shisha smoking which was almost non-existent fifteen years ago amongst teenagers and becoming more popular now. There are few data available on how much teenagers are currently shisha, and we thought that potentially it provided a warm moist environment in the presence of tobacco smoke and a shared mouthpiece which might facilitate transmission of meningococci.