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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
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
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
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
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?
MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
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
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
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
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
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)
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
MenB vaccines: what do we need to know?
• Are the vaccine components immunogenic?
• Can this vaccine be incorporated into routine immunisation schedules?
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
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
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
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
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
Minimal interference with routine vaccines
Adapted from Gossger, Snape et al JAMA 2012
MenB vaccines in adolescents
Lancet 2012
Lancet 2012
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?
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
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
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
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
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
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
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
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?
• Through the looking glass……..
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
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
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)
Predicting susceptibility of 4CMenB induced bactericidal antibodies
Vaccine
Vaccine
YY
YY
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY Y
YY
Vaccine
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY
YY
YYY
YY
Vaccine
Predicting susceptibility of 4CMenB induced bactericidal antibodies
YY
YY
YY
YY Y
YY
?
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
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
Predicting breadth of coverage of 4CMenB
Vaccine Y YY
Y
XXXX
?
? ??
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
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
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
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
‘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
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
Bivalent fHbp vaccine
• Meningococcal Antigen Surface Expression (MEASURE) Assay
• FACS based analysis to determine expression of fHBP, to predict killing on SBA
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
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?
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)
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
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?
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
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
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
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
Strain replacement?
• Can only be determined by large scale oropharyngeal carriage studies evaluating strains for vaccine target phenotype– e.g. by MATS
• 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
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