Recent advances and remaining challenges in control of meningococcal disease. Key points: 1) Introduction of meningococcal conjugate vaccines against serogroups A, C, W, and Y have led to declines in disease globally but gaps in vaccine coverage remain, especially for serogroup B. 2) Meningococcal disease epidemiology is changing with the emergence of new serogroups, clonal complexes, and non-groupable strains. 3) Remaining challenges include short duration of vaccine protection, cost of vaccination programs, and development of a vaccine against the evolving pathogen to achieve global control of meningococcal disease.

1. Recent Advances and Remaining
Global Challenges in Control of
Meningococcal Disease
David S Stephens, MD
Emory University, Atlanta, USA

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. 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. 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. 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. 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. 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. 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. 21st Century Vaccinology: Different Human
Transcriptomic Responses to MPSV4 and MCV4
Nature Immunol 2014; 15:195-204

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. 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. 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. 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. Meningococcal Disease Africa
Borrow, R et al. Expert
Review of Vaccines, 16:4, 313-328

15. No lumbar puncture
MenAfriNet 2017 Weeks 1 – 26, 2017

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. 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. Australia Incidence
http://www.health.gov.au

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. 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. 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. 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. 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. Meningococcal Evolution
• Cyclic Changes in Incidence
• Y, W, X emergence; new B, C genotypes
• Emergence of nongroupables:
• cnl strains
• meningococcal urethritis

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. 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. 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. 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. (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. 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. Boosters for MenB Vaccines
Lancet Infectious Diseases (2017) 17:58-67

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. 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. 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. 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