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Meningococcal Vaccines
The Journey Continues
Canadian Public Health
Association Conference
June 19, 2011
Bryna Warshawsky, Associate Medical Officer of Health
519-663-5317 ext. 2427; bryna.warshawsky@mlhu.on.ca
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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
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Meningococcal by Year and Serogroup
Source: NACI Statement, August 2009
Meningococcal Epidemiology
• 2006:
– 210 cases in Canada
– Serogroup C
43 cases
– Serogroup B
113 cases
– Serogroup Y
27 cases
– Serogroup W135 6 cases
– Serogroup A
2 cases
– Other
19 cases
0.13/100,000
0.34/100,000
0.08/100,000
0.02/100,000
0.01/100,000
NACI Statement, CCDR, Volume 35 • ACS-3 April 2009
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Serogroup B Meningococcal Disease by Age, Canada, 2006
Source: NACI Statement, April 2009
7
6
Rate per 100,000
5
4
3
2
1
0
<1
1-4
5-9
10-14
15-19
Age
20-24
25-64
65+
Serogroup C Meningococcal Disease By Age, Canada, 2006
Source: NACI Statement, April, 2009
0.7
0.6
Rate per 100,000
0.5
0.4
0.3
0.2
0.1
0
<1
1-4
5-9
10-14
15-19
Age
20-24
25-64
65+
Serogroup Y Meningococcal Disease by Age, Canada, 2006
Source: NACI Statement, April 2009
0.25
Rate per 100,000
0.2
0.15
0.1
0.05
0
<1
1-4
5-9
10-14
15-19
Age
20-24
25-64
65+
Serogroups C, B and Y Meningococcal Disease by Age
Canada, 2006
Source: NACI Statement, April 2009
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6
Serogroup C
Serogroup B
Serogroup Y
Rate per 100,000
5
4
3
2
1
0
<1
1-4
5-9
10-14
15-19
Age
20-24
25-64
65+
The Journey
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Meningococcal A
Quadrivalent
conjugate
A, C, Y and W135
Conjugate C
Polysaccharide
A, C
A, C, Y, W135
1960 1980
2001
2006
2010
Meningococcal B
Polysaccharide Vaccines
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Hyporesponsiveness-Polysaccharide
Vaccines
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First dose
30
Booster dose
25
Boosting
GMT
20
15
10
Hyporesponsive
5
0
1
2
3
4
5
6
Time
7
8
9
10
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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 Recommendations
Meningococcal 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
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Geometric Mean Titres
Vaccinating 12-18 month olds
600
500
GMTs
400
4-6 weeks postvaccination
6 months postvaccination
300
200
100
0
Menjugate
Meningitec
NeisVacC
Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3
Titres >1:8 Vaccinating 12-18 month olds
120
100
4-6 weeks postvaccination
6 months postvaccination
Percent
80
60
40
20
0
Menjugate
Meningitec
Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3
NeisVacC
Quadrivalent Conjugate
A, 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
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• HIV positive - consider
NACI Recommendation
Adolescent 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
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NACI, CCDR, May 2007;33(ACS-3):1-23
NACI, CCDR, April 2009;36(ACS-3):1-40.
Adolescents achieving titre of >=1:8
120
100
Menveo
Menactra
Percent
80
60
40
20
0
A
C
Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10
Y
W135
C non-inferior; others Menveo superior
Adolescents Geometric Mean Titres
100
Menveo
Menactra
Geometric Mean Titres (GMT)
90
80
70
60
50
40
30
20
10
0
A
C
Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10
Y
W135
All Menveo superior
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 time
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ACIP; MMWR; January 8, 2011;60(3):72-76.
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.
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Provincial Schedules
Province Infant / Toddler Adolescent Adolescent
Product
Men C Conjugate Timing
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
Ontario
12 months
12 months
Grade 4
Grade 7
Men C
Quadrivalent
Quebec
12 months
Catch-up <
18 years
Men C
NB
12 months
Grade 9
Quadrivalent
Provincial Schedules
Province Infant / Toddler Adolescent Adolescent
Product
Men C Conjugate Timing
NS
PEI
NF
NWT
Yukon
12 months
12 months
12 months
2, 12 months;
< 5 years
Grade 7
Grade 9
Grade 4
Grade 9
2, 12 months
Grade 6
Men C
Quadrivalent
Quadrivalent
Men C
Quadrivalent if going to
school outside
Men C
University students
if not previously
vaccinated
Nunavut
12 months
Grade 9
Canadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011
http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php
Men C
Meningococcal A
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MenAfriVacTM
• Conjugate meningococcal A vaccine for SubSaharan 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 decade
http://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
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