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Meningococcal VaccinesThe Journey Continues
Bryna Warshawsky, Associate Medical Officer of Health519-663-5317 ext. 2427; [email protected]
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
0
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
0
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