Recent Advances and Remaining Global Challenges in Control of

Meningococcal Disease

David S Stephens, MDEmory University, Atlanta, USA

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)

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

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, 1806Epidemic Meningitis

Genomic Era- Clonal Complexes andFine 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

Dynamic Biology of N. meningitidis Life Cycle

• 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

Changing Global Epidemiology

• Impact of New Meningococcal Vaccines- Importance of Herd Protection

• Targeted and “Widespread” Chemoprophylaxis

• Reduction of Risk Factors: Crowding, Smoke, Microbiome Changes

21st Century-Meningococcal Vaccines

• 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

21st Century Vaccinology: Different Human Transcriptomic Responses to MPSV4 and MCV4

Nature Immunol 2014; 15:195-204

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

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)

Guinea-Bissau

Cameroon

Chad

Ethiopia

GhanaKenya

MauritaniaNiger

Somalia

SudanBurkina

Faso

Mali

Gambia

Senegal

GuineaSierra

Leone Liberia BeninTogo

Djibouti

CentralAfrican Rep.

NigeriaIvoryCoast

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

MVP, MenAfriCar, MenAfriNetMenAfriVac (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

Meningococcal Disease Africa

Borrow, R et al. ExpertReview of Vaccines, 16:4, 313-328

No lumbar puncture

MenAfriNet 2017 Weeks 1 – 26, 2017

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

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

Australia Incidence

http://www.health.gov.au

Meningococcal Disease Incidence and Case-Fatality, U.S., 1920-2002

Disappearance of Serogroup A Meningococcal Outbreaks

0

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8

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12

14

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1924

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1948

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Disappearance of serogroup A carriage and transmission. Antibiotic effects on carriage?Other environmental or ecology (micrbiome) changes?

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

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Serogroup B Serogroup C Serogroup Y

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.

U.S. Antibiotic Prescribing

Antibiotic Agent (top 5): Number ofPrescriptions 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

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

Meningococcal Evolution

• Cyclic Changes in Incidence

• Y, W, X emergence; new B, C genotypes

• Emergence of nongroupables:• cnl strains

• meningococcal urethritis

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

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

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) 65:550-2PNAS (2017) 114:4237-4242CID (2017) 65:92-99

US N. meningitidis urethritis clade isolates distinct with respect to lineage 11.2

Tzeng et al. PNAS 2017;114:4237-4242

US_NmUCClade

(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

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?

Boosters for MenB Vaccines

Lancet Infectious Diseases (2017) 17:58-67

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 eculizumabrecipients

• Daily antibiotic chemoprophylaxis

Summary of Clusters/Outbreaks in the United States

Type NumberMax

Cases

Median Cumulative Attack Rate‡

CommunityMSM# 2 22 12.4Non-MSM# 20 14 1.0

OrganizationUniversity 9 10 47.6Other† 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.

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

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 AddressedGaps in Vaccine Coverage (some B subtypes, X, nongroupable) Duration of Protection/Waning Efficacy and Effectiveness- BoostersInstitutional and Community OutbreaksHigh 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