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Prof David Stephens @ Meningitis & Septicaemia in Children & Adults

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Recent advances and remaining global challenges in control of meningococcal disease.
https://www.meningitis.org/mrf-conference-2017

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Prof David Stephens @ Meningitis & Septicaemia in Children & Adults

  1. 1. Recent Advances and Remaining Global Challenges in Control of Meningococcal Disease David S Stephens, MD Emory University, Atlanta, USA
  2. 2. Advances and Challenges • Neisseria meningitidis • Changing Global Epidemiology • Vaccine Impact • Overall global declines in incidence but….. • Meningococcal Evolution • Challenges with 21ST Century Meningococcal Vaccines “It's tough to make predictions, especially about the future” (and especially about the meningococcus)
  3. 3. Neisseria meningitidis • Ancient Human Commensal • ~300 million->1 billion meningococcal carriers worldwide • 5%-25% of population • Protective immunity- antibody mediated serum bactericidal activity • “Recent” Human Pathogen • Historically ~550,000 – 1 million cases of invasive disease (meningitis, meningococcemia) worldwide annually • High mortality and morbidity • Epidemics
  4. 4. Geneva - 1805 • Outbreak • Rapid onset (hrs) • Hemorrhagic eruption* • Febrile course • High mortality • Gross inflammation of the central nervous system - Vieusseux, Matthey J. de Chirurgerie et Pharmacie 11:243, 1806 Epidemic Meningitis
  5. 5. Genomic Era- Clonal Complexes and Fine Typing of N. meningitidis • Genetic typing: multi-locus sequence type (MLST) and now whole genome sequencing (http://pubmlst.org/neisseria/ based at the University of Oxford, UK). • 12 MLST clonal complexes cause almost all epidemic and endemic invasive meningococcal disease: • ST-5, ST-7 (serogroup A); ST-41/44, ST-32, ST-18, ST-8, ST-269, ST-35 (serogroup B); ST-11 (serogroup C or W); ST-23, ST-167 (serogroup Y); ST-181 (serogroup X). • Large genetic islands, 8-32 kb: bacteriophage elements, restriction enzymes, virulence proteins, potential toxins; CRISPR • Genomic population of colonizing meningococci (MLST) considerably more diverse • Fine typing: fetA, porA, porB, fHbp • Transformation: major mechanism of genetic exchange and evolution, highly recombinogenic (>80:1 recombination:mutation) Tettelin et al., Science 287: 1809, 10 March 2000
  6. 6. DynamicBiology of N. meningitidisLifeCycle • Waves of introduction, carriage and transmission of clonal strains in populations- emergence of new and disappearance of strains- immunity following carriage • Changes in nasopharyngeal carriage of Neisseria meningitidis: • Age- Adolescents • Crowding (military recruits, Hajj, college dorms) • Social Behavior (smoking, intimate kissing, pubs) • Transformation/Recombination as the major mechanism meningococcal evolution • “Capsule switching” • Microbiome effects • Neisseria lactamica • Carriage Density • Environmental effects: • Harmattan, humidity Prevalence of Meningococcal Carriage Christensen et al. Lancet ID 10:853, 2010
  7. 7. Changing Global Epidemiology • Impact of New Meningococcal Vaccines- Importance of Herd Protection • Targeted and “Widespread” Chemoprophylaxis • Reduction of Risk Factors: Crowding, Smoke, Microbiome Changes
  8. 8. 21st Century-MeningococcalVaccines • Serogroup C polysaccharide protein conjugates* • Introduced 1999-2000 (Protein: CRM197 or Tetanus Toxoid) • Serogroup ACYW polysaccharide protein conjugates* • Introduced 2005-2010 • Men ACYW Polysaccharide Diphtheria Toxoid Conjugate Vaccine • Men ACYW Oligosaccharide Conjugate CRM197 • Serogroup A polysaccharide protein conjugate* • Introduced 2010 • PsA–TT-serogroup A tetanus toxoid conjugate vaccine • In Development- ACYWX conjugate (NmCV-5) 2020–2022 *Effect biology by prevention of new acquisitions at mucosal surfaces : Herd or community protection • Serogroup B outer membrane protein based vaccines • Introduced 2013, 2014-2015 • fHBP, NadA , NHBA, outer membrane vesicles containing PorA P1.4 • Bivalent fHBp
  9. 9. 21st Century Vaccinology: Different Human Transcriptomic Responses to MPSV4 and MCV4 Nature Immunol 2014; 15:195-204
  10. 10. Herd Protection of Meningococcal Conjugate Vaccines • Accounts for ~one half of their effectiveness at preventing disease, and has significantly enhanced the cost-effectiveness. • Important consideration in strategies for vaccine introduction (mass campaigns and emphasizing need for high vaccination uptake among those with the highest transmission rates), implementation and evaluation, cost-effectiveness • Mucosal immunity-”knowledge gap” • Mucosal immunoglobulins • Transudation of high avidity serum IgG • Th17 Immunity
  11. 11. Invasive Meningococcal Disease Incidence • Africa: Meningitis Belt 2-7.5/100,000 (2017) • South Africa 0.36/100,000 • Europe: 0.3-1.96/100,000 (2016/2017) • Americas • USA: 0.12 cases/100,000 (2016) • Canada: 0.22/100,000 (2016) • Mexico: 0.01-.04/100,000 • South America: 0.4-1/100,000 • Asia • China: 0.2/100,000 (2015) • Japan 0.03/100,000 (2014) • South East Asia 0.1/100,000 • India: 0.32/100,000 (2014) • Singapore O.1/100,000 (2015) • Australia: 1.2/100,000 (2017) • New Zealand: 1.6/100,000 (2017)
  12. 12. Guinea-Bissau Cameroon Chad Ethiopia Ghana Kenya Mauritania Niger Somalia Sudan Burkina Faso Mali Gambia Senegal GuineaSierra Leone Liberia BeninTogo Djibouti Central African Rep. NigeriaIvory Coast Uganda -African meningococcal epidemics Incidence 10-1000 cases/100,000 population- Serogroup A -1996-1997 >300,000 cases, 30,000 deaths - 88,199 meningococcal meningitis cases in Africa in 2009 Harmattan Sub-Saharan African Meningitis Belt ~1900
  13. 13. MVP, MenAfriCar, MenAfriNet MenAfriVac (2000-2017) began Burkina Faso 2010, Mali, Chad, Niger, Benin, Ghana, Senegal, Cameroon, Nigeria, Sudan, Gambia, Ethiopia also have had campaigns. >275 million doses in mass vaccination campaigns (1-29 year olds) that maximized herd protection, Now being introduced in routine childhood vaccine schedules MenAfriCar: Welcome Trust/ Gates Vaccine Effectiveness MenAfriNet: Gates/ CDC Post Vaccine Surveillance Dec 6, 2010
  14. 14. Meningococcal Disease Africa Borrow, R et al. Expert Review of Vaccines, 16:4, 313-328
  15. 15. No lumbar puncture MenAfriNet 2017 Weeks 1 – 26, 2017
  16. 16. EUROPE Whittaker et al. The Epidemiology of Invasive meningococcal Disease in EU/EEA countries, 2004–2014 Vaccine, Volume 35, Issue 16, 2017, 2034–2041 EUROPE
  17. 17. European Incidence- 2016 • England: 1/100,000 B, W, Y, C • Scotland: 1.96/100,000 B, W, C • Ireland: 1.51/100,000 B, C, W, Y • Netherlands: 0.57/100,000 B, W, Y, C • France: 0.78/100,000 B, C, Y, W • Sweden: 0.6/100,000 W-Y, B ,C • Finland: 0.35/100,000 B, Y, C, W • Germany: 0.41/100,000 B, C, Y, W • Portugal: 0.41/100,000 B, Y, W, C • Italy: 0.39/100,000 B, C • Greece: 0.5/100,000 B, Y, W • Czech Republic: 0.4-0.5/100,000 B ,C ,Y, W • Poland: 0.46/100,000 B, C, W, Y • Russia: 0.43/100,000 B, C, A, W, Y
  18. 18. Australia Incidence http://www.health.gov.au
  19. 19. Meningococcal Disease Incidence and Case-Fatality, U.S., 1920-2002 Disappearance of Serogroup A Meningococcal Outbreaks 0 2 4 6 8 10 12 14 1921 1924 1927 1930 1933 1936 1939 1942 1945 1948 1951 1954 1957 1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 Year Rateper100,000 population 0 10 20 30 40 50 60 70 80 Casefatalityratio (%) Incidence Case-fatality ratio * * * Disappearance of serogroup A carriage and transmission. Antibiotic effects on carriage? Other environmental or ecology (micrbiome) changes?
  20. 20. Decline of Meningococcal Disease Incidence United States, 1994-2014 ACYW Conjugate VaccinesY outbreak 1Source: ABCs cases from 1993-2012 estimated to the U.S. population with 18% correction for under reporting 2National Immunization Survey – Teen; 2006-2012 0 20 40 60 80 100 0 0.1 0.2 0.3 0.4 0.5 0.6 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 CoveragewithMenACWYamong13-17year olds2 Incidenceper100,0001 Serogroup B Serogroup C Serogroup Y
  21. 21. Clonal Expansion- Serogroup Y USA • Serogroup Y (CC23) became leading cause of meningococcal disease in US 1997-1999, reached a serogroup incidence of 0.52/100,000. • During this time of increased incidence, CC23 was the predominant carriage isolate found in >40% of carriers, indicating rapid spread in the population. J Infect Dis. (2002) 186:40-48.
  22. 22. U.S. Antibiotic Prescribing Antibiotic Agent (top 5): Number of Prescriptions in Millions (%) and Prescriptions per 1,000 Persons Azithromycin 51.5 166 Amoxicillin 51.4 166 Amoxicillin/clavulanate 21.5 70 Ciprofloxacin 20.4 66 Cephalexin 20.1 65 N Engl J Med 2013; 368:1461-1462 258 M outpatient antibiotic courses in 2010, 833 prescriptions per 1,000 Persons
  23. 23. Microbiome • Neisseria lactamica • Neisseria polysaccharea and Neisseria bergeri • Bacillus pumilus polysaccharide cross-reactive with meningococcal group A polysaccharide • Escherichia coli capsule types K51 or K93 • The decrease in S. pneumoniae PCV7 VT serotypes, increase in H. influenzae, especially NTHi, and S. aureus • Antagonistic relationship between Corynebacterium accolens and S. pneumoniae- microbiota-derived FFAs MenAfriCar Journal of Infection (2016), 72:667-677 mBio. 2016 Jan-Feb
  24. 24. Meningococcal Evolution • Cyclic Changes in Incidence • Y, W, X emergence; new B, C genotypes • Emergence of nongroupables: • cnl strains • meningococcal urethritis
  25. 25. Serogroup X CC (ST)181 • 2000-2010, outbreaks of serogroup X meningitis occurred in Niger, Uganda, Kenya, Ghana, Togo and Burkina Faso • Show pattern of highly localized clonal waves, in affected districts, other meningococcal serogroups are usually absent from disease • Unique genes identified by WGS Emerging Infectious Diseases (2016) 22:698-702
  26. 26. New Serogroup C Clades Africa and China • Niger, Nigeria, CC-10217, PorA type P1.21-15,16 PorB 3–463 and FetA type F1-7. • Sequence type CC-4821 P1.7-2, 14 was first reported in China in 2003, serogroups C and B Emerg Infect Dis (2016) 22:1762-1768 Genomics (2008)91: 78-87
  27. 27. US Nm urethritis clade, US_NmUC • ~300 confirmed cases of meningococcal urethritis since 2014 due to same clade • All US_NmUC isolates belong to the cc11.2/ET-15 lineage (usually serogroup C) • Identical fine type: PorA P1.5-1, 10-8; FetA F3-6; PorB 2-2 and express a unique fHBP allele. • A common molecular fingerprint of the clade is an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. MMWR(2016) 65:550-2 PNAS (2017) 114:4237-4242 CID (2017) 65:92-99
  28. 28. US N. meningitidis urethritis clade isolates distinct with respect to lineage 11.2 Tzeng et al. PNAS 2017;114:4237-4242 US_NmUC Clade
  29. 29. (A) (B) 53-bp aniAnorBgpxANMC1546 NMC1550 aniAnorBNGO1274 NGO1277 FA1090 CNM10 Nitric oxide reductase Nitrite reductase CPH isolates N. gonorrhoeae N. meningitidis CPH isolates N. gonorrhoeae N. meningitidis N. lactamica (C) US_NmUC isolates Have Acquired the Gonococcal aniA/norB locus Tzeng et al. PNAS 2017;114:4237-4242
  30. 30. Challenges with Meningococcal Vaccines • Gaps in Vaccine Coverage (some B subtypes, X, nongroupable) • Duration of Protection/Waning Efficacy and Effectiveness-Boosters • High Risk Populations • Global Vaccine Introduction and Policy Diversity by Country • Cost and Cost-effectiveness • Do we have a Path to a Gonococcal Vaccine?
  31. 31. Boosters for MenB Vaccines Lancet Infectious Diseases (2017) 17:58-67
  32. 32. Eculizamab • Complement component inhibitor licensed for: • Paroxysmal nocturnal hemoglobinuria (PNH) (2007) • Atypical hemolytic uremic syndrome (aHUS) (2011) • Incidence of meningococcal disease 307/100,000 person-years • 8 of 16 cases in US (50%) due to NG strains • Vaccination provides at best incomplete protection to eculizumab recipients • Daily antibiotic chemoprophylaxis
  33. 33. Summary of Clusters/Outbreaks in the United States Type Number Max Cases Median Cumulative Attack Rate‡ Community MSM# 2 22 12.4 Non-MSM# 20 14 1.0 Organization University 9 10 47.6 Other† 10 8 444 Total 41 22 8.3 # MSM = Men who have sex with men ‡ Among clusters with known population size † Includes correctional facility, health-care facility, high-school, sports camp, etc.
  34. 34. Effectiveness of a group B outer membrane vesicle meningococcal vaccine against gonorrhoea in New Zealand: a retrospective case-control study Helen Petousis-Harris PhD , Janine Paynter PhD , Jane Morgan MD, Peter Saxton PhD , Barbara McArdle MCE , Prof Felicity Goodyear-Smith MD , Prof Steven Black MD • Outer membrane vesicle meningococcal B vaccine (MeNZB) used in New Zealand for previous serogroup B outbreak control • Estimate vaccine effectiveness of MeNZB against gonorrhoea in 15-30 year olds after adjustment for ethnicity, deprivation, geographical area, and sex was 31% (95% CI 21–39) • OM vesicle also a component of MenB-4 390: 1603–1610, 30 September 2017
  35. 35. Next 20 years….. • Global Control (<0.1/100,000) of Meningococcal Disease is Achievable with: Timely Global Surveillance Whole Genome Sequencing and Global Databases Coordinated Strategies for Vaccine Introduction Expanded Use of Quadrivalent or Pentavalent Polysaccharide- Protein Conjugate Vaccines combined with B vaccine antigens • Meningococcal Evolution will Continue New Clades, Pathogenesis, Antibiotic Resistance • Vaccine Challenges must be Addressed Gaps in Vaccine Coverage (some B subtypes, X, nongroupable) Duration of Protection/Waning Efficacy and Effectiveness- Boosters Institutional and Community Outbreaks High Risk Populations- Complement Deficiency Global Vaccine Introduction and Policy Diversity by Country Cost and Cost-effectiveness “It's tough to make predictions, especially about the future” “When you get to a fork in the road take it” Yogi Berra

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