menb vaccines: pre and post implementation issues by dr matthew snape
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Dr Matthew Snape
Consultant in Paediatrics and Vaccinology
Honorary Senior Clinical Lecturer
Oxford Radcliffe Hospitals NHS Trust
Oxford Vaccine Group, University of Oxford Department of Paediatrics
MenB vaccines: pre and post implementation issues
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Disclosures
• Principal investigator or co-investigator for clinical trials conducted on behalf of University of Oxford with manufacturers of vaccines, including Novartis Vaccine and Diagnostics and Pfizer
• Fees from consultancy work and presentations from vaccine manufacturers paid to seminar fund administered by University of Oxford Department of Paediatrics
• Travel and accommodation expenses for attendance at immunisation conferences paid by vaccine manufacturers to University of Oxford Department of Paediatrics
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Bivalent rLP2086/fHbp based vaccine
• Produced by Pfizer
• Contains lipidated, recombinant, versions of
– rLP2086/fHbp subfamily A (A05)
– rLP2086/fHbp subfamily B (B01)
Marshall et al PIDJ 2012
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Investigational MenB vaccine: 4CMenB
NHBA GNA1030
GNA2091 fHbp
NadA
N
N
N
C
C
+
C
Key antigens
• 50µg Factor H Binding Protein (fHbp)
• 50µg Neisserial adhesin A (NadA)
• 50µg Neisseria Heparin Binding Antigen (NHBA)
• 25µg OMV (New Zealand strain)
• PorA 1.7-2,4 (1.4)
Submitted for licensure in EU in 2010
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
• How well tolerated is the vaccine?
• What is the likely breadth of protection against serogroup B meningococcal disease?
• If introduced, how will we tell if the vaccines are:– Safe?– Working?
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
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Testing immunogenicity of MenB vaccines
Add human complement
X
• For MenB, need to test against a range of meningococcal strains to assess breadth of coverage
• Lack of serum (especially in paediatric studies) limits numbers of strains that can be tested
• MenB test strains used aim to show immunogenicity of vaccine antigens
Serum bactericidal assay (SBA)
SBA ≥ 1:4 used as correlate of protection
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Bivalent rLP2086/fHbp based vaccine
• Produced by Pfizer
• Contains lipidated, recombinant, versions of
– rLP2086/fHbp subfamily A (A05)
– rLP2086/fHbp subfamily B (B01)
Marshall et al PIDJ 2012
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Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccine
Marshall et al PIDJ 2012
Phase II study of ninety 18 to 36 month olds
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Investigational MenB vaccine: 4CMenB
NHBA GNA1030
GNA2091 fHbp
NadA
N
N
N
C
C
+
C
Key antigens
• 50µg Factor H Binding Protein (FHbp)
• 50µg Neisserial adhesin A (NadA)
• 50µg Neisseria Heparin Binding Antigen (NHBA)
• 25µg OMV (New Zealand strain)
• PorA 1.7-2,4 (1.4)
Submitted for licensure in EU in 2010
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Are these proteins immunogenic?• Need to assess response against SBA strains that:
– contain the target antigen being assessed– are ‘mis-matched’ for the other target antigens
Strain ST fHBP NadA NHBA PorA
44/76-SL 32 1.1 - (3) P1.16
5/99 8 2.8 2 20 P1.2
M10713 136 2.9 - 10 P1.3
NZ 98/254 41/44 1.14 - 2 P1.4
4CMenB containsfHBP 1.1NadA 2NHBA
PorA P1.4(OMV)
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44/76-SL 5/99NZ98/254 UKP1.4 GB101 GB355 GB364
Immunisation with 4CMenB at 2, 4, 6 and 12 months: % Participants with hSBA Titres ≥1:4
Baseline Post 3rd dose Pre 12 month dose Post 12 month dose
Adapted from Findlow, Borrow et al CID 2010
fHbp PorA (OMV) NadA
Assessing the bactericidal activity of post-immunisation serum against strains with differing antigen sub-variants or levels of expression
n = 30 - 45
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
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Phase IIb study
• 1885 enrolled
Gossger, Snape et al JAMA 2012
Group2 month
of age
3 month
of age
4 month
of age
5 month
of age
6 month
of age
7 month
of age
B+R246(n= 622)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
B246_R357(n=632)
Blood drawRoutine Routine
Blood draw
Routine
MenC
4CMenB 4CMenB 4CMenB
B+R234(n=317)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
R234(n=314)
Blood draw Blood draw
Routine Routine Routine Men C
*Routine vaccines: Infanrix-Hexa and Prevenar
Incorporating 4CMenB into immunisation
schedule
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Immunogenicity of 4CMenB
(fHbp) (NadA 2) (PorA P1.4)
Adapted from Gossger, Snape et al JAMA 2012
Minimal reduction in immunogenicity with concomitant routine
immunisation administration
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Group2 month
of age
3 month
of age
4 month
of age
5 month
of age
6 month
of age
7 month
of age
B+R246(n= 622)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
B246_R357(n=632)
Blood drawRoutine Routine
Blood draw
Routine
MenC
4CMenB 4CMenB 4CMenB
B+R234(n=317)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
R234(n=314)
Blood draw Blood draw
Routine Routine Routine Men C
Phase IIb study
• 1885 enrolled
*Routine vaccines: Infanrix-Hexa and Prevenar
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Immunogenicity of 4CMenB
(fHbp) (NadA 2) (PorA P1.4)
Adapted from Gossger, Snape et al JAMA 2012
No reduction in immunogenicity with an
accelerated (2, 3, 4, month) schedule
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Phase IIb study
• 1885 enrolled
Group2 month
of age
3 month
of age
4 month
of age
5 month
of age
6 month
of age
7 month
of age
B+R246(n= 622)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
B246_R357(n=632)
Blood drawRoutine Routine
Blood draw
Routine
MenC
4CMenB 4CMenB 4CMenB
B+R234(n=317)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
R234(n=314)
Blood draw Blood draw
Routine Routine Routine Men C
*Routine vaccines: Infanrix-Hexa and Prevenar
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Minimal interference with routine vaccines
Adapted from Gossger, Snape et al JAMA 2012
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MenB vaccines in adolescents
Lancet 2012
Lancet 2012
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
• How well tolerated is the vaccine?
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Reactogenicity of bivalent fHbp vaccine: 18 to 36 month olds
Marshall et al PIDJ 2012
20µg 60µg 200µg Hep A Vaccine/ Placebo
0102030405060708090
100
Dose 1
Dose 2
Dose 3
Fever
20µg 60µg 200µg Hep A Vaccine/ Placebo
0102030405060708090
100
Dose 1
Dose 2
Dose 3
Irritability
20µg 60µg 200µg Hep A Vaccine/ Placebo
0102030405060708090
100
Dose 1
Dose 2
Dose 3
Local Tendernessn = 19 - 32
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Group2 month
of age
3 month
of age
4 month
of age
5 month
of age
6 month
of age
7 month
of age
B+R246(n= 622)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
B246_R357(n=632)
Blood drawRoutine Routine
Blood draw
Routine
MenC
4CMenB 4CMenB 4CMenB
B+R234(n=317)
Blood draw Blood draw
4CMenB 4CMenB 4CMenB
Routine Routine Routine MenC
R234(n=314)
Blood draw Blood draw
Routine Routine Routine Men C
*Routine vaccines: Infanrix-Hexa and Prevenar
Reactogenicity of 4CMenB
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1 2 3
≥40°C
39-<40°C
38-<39°C
4CMenB + Routine2-4-6 mo
N = 605-624
4CMenB Alone2-4-6 mo
N = 592-612
Dose
0
10
20
30
40
50
60
70
80
90
100
1 2 3
% o
f Sub
ject
s
Routine3-5-7 mo
N = 602-627
4CMenB + Routine2-3-4 mo
N = 310-317
Routine2-3-4 mo
N = 304-311
0
10
20
30
40
50
60
70
80
90
100
1 2 3
0
10
20
30
40
50
60
70
80
90
100
1 2 3 1 2 3
Routine vaccines: Infanrix-hexa, Prevenar
Safety Profile of 4CMenB Vaccine in InfantsFever Rates After First, Second and Third Doses Study V72P12
Adapted from Gossger, Snape et al JAMA 2012
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Local Reactions to 4CMenB and Routine Vaccines
B+R246: 4CMenB + routine infant vaccines at 2, 4, 6 monthsB246_R357: 4CMenB at 2, 4, 6 months, routine infant vaccines at 3, 5, 7 monthsB+R234: 4CMenB+ routine infant vaccines at 2, 3, 4 monthsR234: routine infant vaccines at 2, 3, 4 months
R357
R357
R357
R357
R357
R357
Adapted from Gossger, Snape et al JAMA 2012
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Safety: 4CMenB
• 1882 participants immunised– 1570 received 4CMenB +/- routine immunisations– 312 received routine immunisations alone
• 7365 immunisation episodes– 2787 4CMenB + routine – 1838 4CMenB alone
• 4625 4CMenB episodes
– 2740 routine imms alone
• 20 serious adverse events possibly related to immunisation
Gossger, Snape et al JAMA 2012
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Safety: 4CMenB• 20 SAEs possibly related to
imms…
• 3 hypotonic +/-hyporesponsiveness:– 2 days following 4CMenB and
routine immunisation– Same day as 4CMenB and
routine immunisation – Same day as routine
immunisations
• 6 hospitalisations for fever within 2 days of 4CMenB receipt +/- routine vaccines
• 1 hospitalisation for fever after routine imms alone.
• 2 episodes of reported Kawasaki disease, reviewed by independent expert panel– 1 ‘unlikely’ Kawasaki’s disease,
symptom onset prior to 4CMenB – 1 ‘complete’ Kawasaki disease,
onset 23 days after 4CMenB: ‘possibly related’
Gossger, Snape et al JAMA 2012
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Convulsions in Phase IIb study of 4CMenB
*Routine vaccines: Infanrix-Hexa and Prevenar
Participants With Febrile Seizures
Days 1-2+ Days 3-14 Days >14 Total
4CMenB +/- routine 0 1 1 2
Control* 0 0 2 2
Gossger, Snape et al JAMA 2012
Participants With Afebrile Seizures
Days 1-2+ Days 3-14 Days >14 Total
4CMenB +/- routine 2 0 1 3
Control* 2 0 1 3
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
• How well tolerated is the vaccine?
• What is the likely breadth of protection against serogroup B meningococcal disease?
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• Through the looking glass……..
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Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccine
Marshall et al PIDJ 2012
Phase II study of ninety 18 to 36 month olds
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44/76-SL 5/99NZ98/254 UKP1.4 GB101 GB355 GB364
Immunisation with 4CMenB at 2, 4, 6 and 12 months: % Participants with hSBA Titres ≥1:4
Baseline Post 3rd dose Pre 12 month dose Post 12 month dose
Adapted from Findlow, Borrow et al CID 2010
fHbp PorA (OMV) NadA
Assessing the bactericidal activity of post-immunisation serum against strains with differing antigen sub-variants or levels of expression
n = 30 - 45
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Investigational MenB vaccine: 4CMenB
NHBA GNA1030
GNA2091 fHBP
NadA
N
N
N
C
C
+
C
Key antigens
• 50µg Factor H Binding Protein (FHbp)
• 50µg Neisserial adhesin A (NadA)
• 50µg Neisseria Heparin Binding Antigen (NHBA)
• PorA 1.7-2,4 (1.4)
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Predicting susceptibility of 4CMenB induced bactericidal antibodies
Vaccine
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Vaccine
YY
YY
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY Y
YY
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Vaccine
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY
YY
YYY
YY
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Vaccine
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY
YY
YY Y
YY
?
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Susceptibility of meningococcal strains to serum obtained in recipients of 4CMenB can be predicted by:
3. Whether the antibodies induced by the vaccine antigens ‘cross-react’ with the relevant antigen on the target strain
Vaccine
?• PorA• fHbp variant 1.1 and fHbp 1.2, 1.3, 1.4….?• NHBA peptides …….
YY
YY
YY
YY Y
YY
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Predicting breadth of coverage of 4CMenB
• Need to estimate what % of strains will have at least one ‘target’ antigen that is:– Expressed at sufficient quantities– Sufficiently ‘cross-reactive’ with the vaccine antigens
Susceptible to killing by vaccine induced antibodies
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Predicting breadth of coverage of 4CMenB
Vaccine Y YY
Y
XXXX
?
? ??
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Predicting breadth of coverage of 4CMenB
Vaccine Y YY
Y
XXX
X
X XXX
XX
XXXX
Would predict 16/24 strains likely to be killed by vaccine
induced antibodies
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Meningococcal Antigen Typing System: MATS
• Developed by Novartis Vaccines to create a
– reproducible system for assessing panels of region specific meningococcal strains
– assess for presence of at least one expressed antigen sufficiently matched to allow killing by vaccine induced antibodies
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Predicting breadth of coverage of 4CMenB:MATS
Binding of target proteins in MenB strains under assessment to assay antibodies compared to that of ‘reference strains’
• Assessing both expression and cross-protection
• Expressed as a proportion (‘relative potency’)
• Threshold for proportion that predicts killing by pooled post-immunisation infant sera SBA determined for each antigen
• Representative panel of strains assessed to assess proportion of strains with at least one antigen above this threshold
YYYY
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MATS methodology: – Transferred across 8 reference laboratories
• Health Protection Agency, Institut Pasteur, Norwegian Institute of Public Health, University of Würzburg, Istituto Superiore di Sanità, National Center for Microbiology-Institute of Health Carlos III, Centers for Disease Control, Queensland Paediatric Infectious Disease Laboratory
– Ongoing in several more
Slide provided by Novartis Vaccines
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‘Coverage’ of 4CMenB in 5 European countries as predicted by MATS
Based on MATS, 4CMenB is predicted to cover 78% of strains isolated during 2007 - 2008
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†
Slide provided by Novartis Vaccines
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22%
28%
34%
16%
Half of All European Strains Tested Were Covered by More Than One Antigen Contained in 4CMenB
0Ag>Threshold 2Ag>Threshold
3Ag>Threshold
1Ag>Threshold
0.1%4Ag>Threshold
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.
Percent (%)
Percent of strains predicted covered by number of4CMenB antigens above Positive Bactericidal Threshold
5 European Countries: 78% [66%, 92%]
4CMenB coverage estimates†
• 4CMenB may still be effective if one antigen is down regulated or mutated
Slide provided by Novartis Vaccines
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Bivalent fHbp vaccine
• Meningococcal Antigen Surface Expression (MEASURE) Assay
• FACS based analysis to determine expression of fHBP, to predict killing on SBA
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MenB vaccines: potential for herd immunity
• Impact of either vaccine on oro-pharyngeal carriage unknown
• Potential for herd immunity therefore unknown
Christensen et al Lancet ID 2010
• Would require deployment of vaccine in adolescence/ young adulthood
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MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
• How well tolerated is the vaccine?
• What is the likely breadth of protection against serogroup B meningococcal disease?
• If introduced, how will we tell if the vaccines are:– Safe?– Working?
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MenB vaccines: post implementation surveillance
Safety/Reactogenicity• Potential need for active surveillance for
– Kawasaki disease– Febrile convulsions following immunisation– Numbers and management of infants < 3 months
presenting to hospital with fever following immunisation
• Ideally conducted before and after implementation, to determine if any change from baseline
• Precedent of using BPSU (e.g. GBS post H1N1 immunisation)
• Requires agreement of disease definitions (Brighton colloboration)
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Determining vaccine effectiveness requires– Accurate data on vaccine uptake– Robust system of disease notification
Vaccine effectiveness determined by comparing – Rates of immunised/unimmunised in
• child with disease• general population
MenB vaccines: post implementation surveillance
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What would constitute a ‘MenB’ vaccine failure?
• If a child develops serogroup B meningococcal disease due to strain not bearing vaccine targets – is this a failure?
• If a child develops serogroup Y meningococcal disease due to a strain bearing vaccine targets – is this a vaccine failure?
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Determining vaccine effectiveness
• Expression of vaccine target antigens (e.g. by MATS) can only be determined on meningococcal isolates (not PCR)
• Represents a challenge, especially given widespread use of antibiotics prior to hospital
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Will we see ‘strain replacement’?• If the MenB vaccines can
influence oropharyngeal carriage of meningococcus….
• Potential for ‘selection’ for strains either– Lacking the genes for the target
antigens– Low expressors of the target
antigens
Oropharyngeal carriage strains in a population
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Will we see ‘strain replacement’?
• If the MenB vaccines can influence oropharyngeal carriage of meningococcus….
• Potential for ‘selection’ for strains either– Lacking the genes for the target
antigens– Low expressors of the target
antigens
Oropharyngeal carriage strains in a population
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Will we see ‘strain replacement’?
• If the MenB vaccines can influence oropharyngeal carriage of meningococcus….
• Potential for ‘selection’ for strains either– Lacking the genes for the target
antigens– Low expressors of the target
antigens
Oropharyngeal carriage strains in a population
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Strain replacement?
• Can only be determined by large scale oropharyngeal carriage studies evaluating strains for vaccine target phenotype– e.g. by MATS
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• Vaccine prevention of serogroup B meningococcal disease closer than ever before
• Clinical trials have shown immunogenicity of vaccine components
• Immunogenicity demonstrated across a range of immunisation schedules and with routine immunisations
• Implementation of new vaccines will ultimately depend on cost-effectiveness analyses, and local epidemiology
• True effectiveness unlikely to be known until vaccines have been introduced
Summary: 4CMenB
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Acknowledgments
• Jamie Findlow (HPA) for provision of vaccine failure definitions
• Novartis Vaccines for provision of MATS data
• Professor Andrew Pollard and staff of the Oxford Vaccine Group