Multicomponent MenB Vaccine (4CMenB): An Innovative Step In the Global Fight Against Serogroup B Meningococcal Disease

Jeffrey J. Stoddard, MD, FAAP

Head, Global Medical Affairs

Novartis Vaccines and Diagnostics

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At-Risk Groups and Established Risk Factors

Infants1-2

Population with highest incidence (17.4-fold increase over average in Europe3)

Adolescents4-6

Population with highest carriage (1.8–5.3-fold increase over other age groups7)

Immature immune system

Reduction of protective maternal antibody levels

Close contact with a case

Respiratory tract infection

Smoking

Crowding

Dormitory

Travel

Concerts

Most cases of meningococcal disease occur in previously healthy persons.

1. Rosenstein NE, et al. N Eng J Med. 2001;344:1378-1388; 2. Figueroa JE, et al. Clin Microbiol Rev. 1991;4:359-395; 3. European Centre

for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe 2008/2009. Stockholm: ECDC; 2011; 4. Bilukha

OO, et al. MMWR Recomm Rep. 2005;54:1-21; 5. Imrey PB, et al. J Clin Microbiol. 1995;33:3133-3137; 6. Neal KR, et al. BMJ.

2000;320:846-849; 7. Christiansen H, et al. Lancet Infect Dis. 2010;10:853–61.

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Conjugate Vaccines Against Meningitis-Causing Pathogens Have Been Successful Using the Polysaccharide Capsule

B A C W

-135 Y

H. influenzae (1 pathogenic type)

S. pneumoniae (25 pathogenic serotypes)

N. meningiditis (5 pathogenic serogroups)

INVASIVE DISEASE INVASIVE DISEASE FULMINANT INVASIVE DISEASE

Hib glycoconjugate

vaccine

Pneumococcal

glycoconjugate

vaccine

Meningococcal

glycoconjugate vaccine

No effective broadly,

protective capsular

vaccine

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The polysaccharide

capsule?

Poorly immunogenic

A single subcapsular

protein component?

Susceptible to antigenic

variability

Multiple subcapsular

components?

Enables broad coverage

across a number of strains

A Multicomponent Approach to MenB Vaccination

N. meningitidis

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Antigenic Components of the 4CMenB

NadA: neisserial adhesin A

– Promotes adherence to and invasion

of human epithelial cells1-3

– Possible importance in carriage

fHbp: factor H binding protein

– Primary function: Binds the bacterial

siderophore enterobactin (in vitro)4

– Secondary function: Binds factor H,

which enables bacterial survival5,6

NHBA: Neisseria heparin-binding antigen

– Present in virtually all strains

– Binds heparin, which may increase

the serum resistance of bacteria7-9

NZ PorA 1.4: porin A

– Major outer membrane vesicles

protein – produces robust antibody

response

4CMenB antigens are important for meningococcal survival,

function, or virulence

1. Comanducci M, et al. J Exp Med. 2002;195:1445-1454; 2. Capecchi B, et al. Mol Microbiol. 2005;55:687-698; 3. Mazzon C, et al. J Immunol. 2007;179:3904-3916; 4. Veggi D, et al. Presented at IPNC. Banff, Canada. September 11-16, 2010; 5. Madico G, et al. J Immunol. 2006;177:501-510; 6. Schneider MC, et al. J Immunol. 2006;176:7566-7575; 7. Serruto D, et al. Proc Natl Acad Sci U S A. 2010;107:3770-3775; 8. Welsch JA, et al. J Infect Dis. 2003;188:1730-1740; 9. Plested, et al. Clin Vaccine Immunol. 2008;15:799-804.

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4CMenB: Vaccine Composition V

accin

e c

om

po

sit

ion

Antigenic Component Amount

Recombinant Neisseria meningitidis serogroup B NHBA fusion protein 50 μg

Recombinant Neisseria meningitidis serogroup B NadA protein 50 μg

Recombinant Neisseria meningitidis serogroup B fHbp fusion protein 50 μg

Outer membrane vesicles (OMV) from Neisseria meningitidis serogroup B strain

NZ98/254 measured as amount of total protein containing the PorA 1.4 25 μg

Each component is adsorbed on aluminum hydroxide adjuvant 0.5 mg of Al+3

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Rate per 100 000 population

0.8 - 3.0

3.1 - 15.0 15.1 - 30.0

Auckland

Proof of principle that MenB

vaccines can work and can be

safely used

OMV Vaccination Eliminated the epidemic in New Zealand

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4CMenB Clinical Development Program

8 studies were conducted

– 6 studies in infants from 2 months of age and toddlers

– 3 studies in adolescents ≥11 years of age and adults

– 7,938 total subjects

• 6,354 infants and toddlers

– 1,630 received a booster dose in the second year of life

• 1,584 adolescents and adults

Geographically diverse (EU, North and South America)

– 4CMenB has been studied in the Northern and Southern

Hemispheres

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4CMenB: Clinical Trial data

Gossger N, Snape MD, Yu LM, et al. Immunogenicity and tolerability of recombinant

serogroup B meningococcal vaccine administered with or without routine infant

vaccinations according to different immunization schedules: a randomized controlled trial.

JAMA. 2012;307:573-582.

Santolaya ME, O'Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a

multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in

Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet.

2012;379:617-624.

Vesikari T, Esposito S, Kimura A, et al. Immunogenicity of an investigational,

multicomponent, meningococcal serogroup B vaccine in healthy infants at 2, 4, and 6

months of age. Presented at: International Pathogenic Neisseria Conference; Sept 11-16,

2010; Banff, Canada.

Esposito S, Vesikari T, Kimura A, et al. Tolerability of a three-dose schedule of an

investigational, multicomponent, meningococcal serogroup B vaccine and routine infant

vaccines in a lot consistency trial. Presented at: International Pathogenic Neisseria

Conference; Sept 11-16, 2010; Banff, Canada.

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MATS The Meningococcal Antigen Typing System

MATS is based on a ELISA that measures the 3 recombinant protein antigens

(fHbp, NadA, and NHBA) of 4CMenB against:

– Antigen quantity

– Similarity of strain antigens to vaccine antigens

MATS links ELISA scores to hSBA killing

– Developed using adult sera against a panel of 124 strains expressing a broad range

of antigen variants; a subset of 57 strains were further tested using infant sera

This allowed for the determination of the minimum amount of antigen measured

by MATS needed to result in killing in the hSBA assay

– Positive Bactericidal Threshold (PBT)

– PBT is established for the three recombinant protein antigens

For PorA, conventional PCR genotyping is used to determine the similarity of

the PorA gene sequence in the test strains to that in 4CMenB

ELISA, enzyme-linked immunosorbent assay; fHbp, factor H-binding protein; hSBA, human complement serum bactericidal assay;

NadA, Neisserial adhesin protein A; NHBA, Neisseria Heparin Binding Protein; PorA, Porin A.

Donnelly J, et al. PNAS. 2010;107:19490-19495.

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Infant pooled sera (13 months)

Adult pooled sera

# of strains tested 57 124

Estimated killed

in MATS 77% 72%

Actual killed in

hSBA ≥1:8 74% 85%

MATS Results Correlate With hSBA

hSBA, human complement serum bactericidal assay.

Donnelly J, et al. PNAS. 2010;107:19490-19495.

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MATS Allows for Systematic Estimation of 4CMenB Coverage for Any Given Region

MATS methodology: – Standardized and transferred across 5 reference laboratories

• Health Protection Agency, Institut Pasteur, Norwegian Institute of Public Health,

University of Würzburg, Istituto Superiore di Sanità

– Transferred to 10 countries and transfer is ongoing in several more

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4CMenB Has the Potential to Cover the Majority of MenB Strains in 5 European Countries

Based on MATS, 4CMenB is predicted to cover 78% of strains

†Coverage based on MATS from pooled sera from 13-mo-old infants vaccinated at 2,4, 6, and 12 mo of age tested on

1,052 strains isolated during the 2007-2008 epidemiological year.

Boccadifuoco G, et al. Presented at: Meningitis and Septicaemia in Children and Adults 2011 (Organized by Meningitis Research

Foundation); 8–9 November 2011; London, UK. Poster V36.

Norway: 85% [95% CI: 76%, 98%]

n=41

France: 85% [70%, 93%]

n=200

Germany: 82% [69%, 92%]

n=222

Italy: 87% [70%, 93%]

n=54

England & Wales: 73% [59%, 88%]

n=535

4CMenB European coverage estimates†

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Pro

po

sed

in

dic

ati

on

s

Population Age Dose

series Interval

Booster

recommended

Infants 2 to 5 months 3 1 to 2

months

At 12 to 23

months

Unvaccinated infants 6 to 11 months 2 2 months

At 12 to 23

months;

≥2 months from

primary series

Unvaccinated

toddlers and children

12 months to 10

years 2

≥2

months

Adolescents and

adults 11 years and older* 2

1 to 2

months

4CMenB: Proposed Indications

*The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied.

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Summary Serogroup B meningococcal disease is a feared and often deadly disease, affecting mainly

infants

It is easily misdiagnosed, can kill within 24 hours of onset and may cause serious, life-long

disabilities despite appropriate treatment

4CMenB includes 4 components that are important for the survival, function, and/or

virulence of the meningococci: fHbp, NadA, NHBA, and PorA

– Use of multiple well-chosen antigens is likely to maximize coverage of genetically varied and changing strains

– Of note, 50% of MenB strains tested are covered by more than one 4CMenB antigen

In clinical studies, 4CMenB has demonstrated a protective immune response in infants,

children and adults

In clinical studies, reactions seen after vaccination with 4CMenB were similar to those seen

after vaccination with other routine vaccines

4CMenB is the first vaccine to demonstrate potential coverage of the majority of

meningococcal serogroup B strains hereby helping to predict the public health impact of

vaccination