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Meningococcal VaccinesThe Journey Continues

Bryna Warshawsky, Associate Medical Officer of Health519-663-5317 ext. 2427; bryna.warshawsky@mlhu.on.ca

Canadian Public Health Association Conference

June 19, 2011

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Outline• Background • Epidemiology• Journey

– Polysaccharide vaccines– Conjugate C vaccines– Conjugate quadrivalent vaccines– Meningococcal A vaccine– Meningococcal B vaccines

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Background

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Meningococcal Disease

• Neisseria meningitidis• Gram negative diplococci• Thirteen different serogroups,

classified by their polysaccharide (sugar) capsule

• Most common A, B, C, Y, W135 and X

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Meningococcal Disease• Causes:

– meningitis - inflammation of the lining brain– meningococcemia - in the blood– Disseminated intravascular coagulation (DIC)

• Presents as fever, headache, vomiting, stiff neck, photophobia and petechial rash

• Fatal in approximately 10%• Long term sequelae 10 - 20% such as hearing

loss, amputation or neurologic

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Immunogenicity• Vaccines authorized based on

immunogenicity, not efficacy• Correlate of protection• Serum bactericidal antibody (SBA) titre

– Dilution of serum able to kill meningococcal bacteria in vitro; requires the addition of complement

– Using human complement correlate is ≥1:4

– Measure: • Percent achieving titre• Geometric mean titre

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Protection

• Circulating antibody titre

• Immune memory– May be too slow for post-exposure

protection

• Herd immunity

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Epidemiology

Meningococcal by Year and Serogroup

Source: NACI Statement, August 2009

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Meningococcal Epidemiology

• 2006:– 210 cases in Canada– Serogroup C 43 cases 0.13/100,000– Serogroup B 113 cases

0.34/100,000– Serogroup Y 27 cases 0.08/100,000– Serogroup W135 6 cases

0.02/100,000– Serogroup A 2 cases 0.01/100,000– Other 19 casesNACI Statement, CCDR, Volume 35 • ACS-3 April 2009

Serogroup B Meningococcal Disease by Age, Canada, 2006Source: NACI Statement, April 2009

0

1

2

3

4

5

6

7

<1 1-4 5-9 10-14 15-19 20-24 25-64 65+

Age

Rate

per

100

,000

Serogroup C Meningococcal Disease By Age, Canada, 2006Source: NACI Statement, April, 2009

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

<1 1-4 5-9 10-14 15-19 20-24 25-64 65+Age

Rat

e p

er 1

00,0

00

Serogroup Y Meningococcal Disease by Age, Canada, 2006Source: NACI Statement, April 2009

0

0.05

0.1

0.15

0.2

0.25

<1 1-4 5-9 10-14 15-19 20-24 25-64 65+Age

Rat

e pe

r 10

0,00

0

Serogroups C, B and Y Meningococcal Disease by Age Canada, 2006

Source: NACI Statement, April 2009

0

1

2

3

4

5

6

7

<1 1-4 5-9 10-14 15-19 20-24 25-64 65+

Age

Rat

e p

er 1

00,0

00

Serogroup C

Serogroup B

Serogroup Y

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The Journey

1960 - 1980

2001 20062010

PolysaccharideA, C

A, C, Y, W135

Conjugate C

Quadrivalent conjugate

A, C, Y and W135 Meningococcal B

Meningococcal A

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Polysaccharide Vaccines

Hyporesponsiveness-Polysaccharide Vaccines

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8 9 10 11

Time

GM

T

First dose

Booster dose Boosting

Hyporesponsive

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NACI Recommendation – Polysaccharide Vaccine

– asplenic patients, sickle cell disease– complement deficient, properdin or factor D

deficiency– travellers e.g. Hajj, Mecca, Saudi Arabia– laboratory workers who handle meningococcal

specimens– military– close contacts of serogroups A, C, Y, W135– outbreaks of serogroups A, C, Y, W135

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Conjugate C Vaccines

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Conjugate Vaccines• Sugar linked to a protein

– diphtheria toxoid– diphtheria toxoid mutant – CRM 197 – tetanus toxoid

• T cell dependent• Works in young children• Decreases carriage leading to herd immunity• Boostable response

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NACI RecommendationsMeningococcal C conjugate

• Routine program:– 2 months to 4 year olds– adolescents– young adults– consider for 5-10 year olds

• Post exposure for serogroup C • Outbreaks serogroup C

NACI; CCDR, 2001; 27:2-36

Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3

Geometric Mean Titres Vaccinating 12-18 month olds

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100

200

300

400

500

600

Menjugate Meningitec NeisVacC

GM

Ts

4-6 weeks post-vaccination6 months post-vaccination

Titres >1:8 Vaccinating 12-18 month olds

0

20

40

60

80

100

120

Menjugate Meningitec NeisVacC

Pe

rce

nt

4-6 weeks post-vaccination

6 months post-vaccination

Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3

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Quadrivalent ConjugateA, C, Y, W135

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Conjugate A, C, Y, W135• MenactraTM (sanofi pasteur) – diphtheria

toxoid– Authorized for use May 2006– Authorized for ages 2 – 55 years – Not very immunogenic in infants

• MenveoTM (Novartis ) - mutant diphtheria toxoid CRM197

– Authorized for use May 2010– Mix lyophilized A with liquid C, Y, W135– Authorized for ages 11-55 years– Has been shown to be immunogenic in infants

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NACI Recommendation• asplenic patients, sickle cell disease• complement deficient, properdin or factor D deficiency• travellers e.g. Hajj, Mecca, Saudi Arabia• laboratory workers who handle meningococcal

specimens• military• close contacts of serogroups A, Y, W135• outbreaks of serogroups A, Y, W135• primary antibody deficiencies• HIV positive - consider

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NACI RecommendationAdolescent Vaccination

• Meningococcal C conjugate or quadrivalent conjugate vaccines can be used depending on epidemiology and other considerations

• Give an adolescent doses even if vaccinated at young age

NACI, CCDR, May 2007;33(ACS-3):1-23 NACI, CCDR, April 2009;36(ACS-3):1-40.

Adolescents achieving titre of >=1:8

0

20

40

60

80

100

120

A C Y W135

Per

cen

t

MenveoMenactra

Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10 C non-inferior; others Menveo superior

Adolescents Geometric Mean Titres

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10

20

30

40

50

60

70

80

90

100

A C Y W135

Geo

met

ric

Mea

n T

itre

s (G

MT

)

Menveo

Menactra

Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10 All Menveo superior

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Effectiveness Data from US MenactraTM

• 14 vaccine failures in the US – 8 serogroup C; 6 serogroup Y– Median age at vaccination 18 years (12-20

years)– Mean time from vaccination to disease 395

days (43-1021 day)– 3 underlying conditions– 3 fatal (21% case fatality)

• Vaccine effectiveness estimated at 80-85% within 2 – 3 years after vaccination

MacNeil et al. Pediatric Infectious Disease Journal, June 2011;30(6):451-455

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Effectiveness Data from US MenactraTM

• Case control study – 108 cases; 158 controls

• 78% effectiveness over 5 years of vaccination

(95% CI: 29-93%)

– Vaccinated < 1 year ago 95% (95% CI:10-100%)

– Vaccinated 1 year ago 91% (95% CI:10-101% ??)

– Vaccinated 2-5 years ago 58% (95% CI: -72% - 89%)

• Waning protection over timeACIP; MMWR; January 8, 2011;60(3):72-76.

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US Vaccination Recommendation

• Adolescents – 11-12 year of age and booster at 16 years

• High risk conditions – 2-dose primary schedule – 2 months apart– Booster every five year

• Exposure risk (microbiologist, travelers to endemic countries) – 1-dose primary schedule– Booster 3 years later (2-6 years of age)– Booster 5 years later (7 years of age or

older)ACIP; MMWR; January 8, 2011;60(3):72-76.

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Guillain Barré Syndrome (GBS)

• Passive surveillance suggested a possible association between GBS and MenactraTM

• Two large studies in US using managed care organization data have not found any association

• Past GBS no longer needs to be considered a precaution for MenactraTM

Presentations by Velentgas and Weintraub to ACIP; June 2010.

Provincial SchedulesProvince

Infant / ToddlerMen C Conjugate

Adolescent Timing

Adolescent Product

BC 2, 12 months Grade 6 Men C

Alberta 2, 4, 12 months

Grade 9 Quadrivalent

SK 12 months, 4-6 years

Grade 6 Men C Quadrivalent

Manitoba 12 months Grade 4 Men C

Ontario 12 months Grade 7 Quadrivalent

Quebec 12 months Catch-up < 18 years

Men C

NB 12 months Grade 9 Quadrivalent

Provincial SchedulesProvince

Infant / ToddlerMen C Conjugate

Adolescent Timing

Adolescent Product

NS 12 months Grade 7 Men C

PEI 12 months Grade 9 Quadrivalent

NF 12 months Grade 4 Quadrivalent

NWT 2, 12 months; < 5 years

Grade 9 Men CQuadrivalent if going to school outside

Yukon 2, 12 months Grade 6University students if not previously vaccinated

Men C

Nunavut 12 months Grade 9 Men C

Canadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011

http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php

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Meningococcal A

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MenAfriVacTM

• Conjugate meningococcal A vaccine for Sub-Saharan Africa meningitis belt

• Meningitis Vaccine Project• Introduced into Burkina Faso, Mali and Niger

in December 2010 with dramatic effects • Plans for Cameroon, Chad and Nigeria, then

other countries• Given to 1-29 year olds• Cost less than 50 cents per dose• Estimated to prevent 1 million cases and save

$300 million over the next decadehttp://www.meningvax.org/

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Meningococcal B

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Difficulties with Development

• Capsule structurally identical to fetal brain cell adhesion molecules– Induce a weak immune response– Could involve production of

autoantibodies• Outer-membrane-vesicle vaccine

– Strain specific PorA, highly variable across strains

– Each outbreak needs its own vaccine– Vaccines incorporate multiple PorAs

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Reverse Vaccinology• Take the genetic composition of the

bacteria• Look for genes that may represent surface

exposed proteins• Put into Escherichia coli expression system

to make proteins• Mice immunized and antibodies assessed

by serum bactericidal antibody (SBA) assay• Best candidate antigens made into vaccine

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Novartis Vaccine – Bexsero

• Factor H binding protein (fHbp) – fusion protein

• Neisserial heparin-binding antigen (NHBA) - fusion protein

• Neisserial adhesin A (NadA) • Outer-membrane-vesicle New Zealand

(OMVnz)• Aluminum adjuvant

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Immunogenicity

• Needs to be assessed using serum bactericidal antibody (SBA) assays against various strains that express the target antigens

• Evidence showing it is immunogenic at various ages and has an acceptable safety profile

Bai et al. Expert Opin Biol Ther 2011

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Coverage of Strains• Because of the antigenic variation and

different levels of expression of the proteins, need to assess how well the vaccine will protect against circulating strains

• Meningococcal antigen typing assay (MATS)• ELISA measures cross-reactivity and

quantity of the antigen• Correlates with serum bactericidal antibody

(SBA) assay

Donnelly J et al. PNAS Early Edition

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Coverage of Strains

• Strains exceeded the threshold value for any of the three antigens had a ≥ 80% chance of being killed by SBA

• MATS will allow for assessing expected strain coverage in various countries

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Pfizer Vaccine

• Contains two factor H binding proteins, to cover various strains

• In Phase II trials

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The Journey Continues

?? Questions ??

Thank You