MenB vaccines: pre and post implementation issues by Dr Matthew Snape

MenB vaccines: pre and post
implementation issues

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

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

N NHBA GNA1030 C

N GNA2091 fHbp C +
N NadA 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?

Testing immunogenicity of MenB vaccines
Serum bactericidal assay (SBA)

Add human
complement

X
SBA ≥ 1:4 used as
correlate of protection

• 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

Testing immunogenicty of fHbp proteins in bivalent
fHbp MenB vaccine
Phase II study of ninety 18 to 36 month olds



N NHBA GNA1030 C

N GNA2091 fHbp C +
N NadA C

Key antigens
• 50µg Factor H Binding Protein (FHbp)
• 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
4CMenB
contains
44/76-SL 32 1.1 - (3) P1.16
fHBP 1.1
NadA 2 5/99 8 2.8 2 20 P1.2
NHBA
PorA P1.4 M10713 136 2.9 - 10 P1.3
(OMV)
NZ 98/254 41/44 1.14 - 2 P1.4

Immunisation with 4CMenB at 2, 4, 6 and 12 months:
% Participants with hSBA Titres ≥1:4

44/76-SL NZ98/254 5/99 UKP1.4 GB101 GB355 GB364
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

Baseline Post 3rd dose Pre 12 month dose Post 12 month dose

Adapted from Findlow, Borrow et al CID 2010


schedules?

Incorporating
2 month 3 month 4 month 5 month 6 month 7 month
4CMenB into Group
of age of age of age of age of age of age
immunisation
Blood draw Blood draw
schedule
B+R246 4CMenB 4CMenB 4CMenB
(n= 622)
Routine Routine Routine MenC

Phase IIb study Blood draw Blood draw

B246_R357 4CMenB Routine 4CMenB Routine 4CMenB Routine
(n=632)
• 1885 enrolled MenC

(n=317)

R234
(n=314) Routine Routine Routine Men C

*Routine vaccines: Infanrix-Hexa and Prevenar

Gossger, Snape et al JAMA 2012

Immunogenicity of 4CMenB

Minimal reduction in
immunogenicity with
concomitant routine
immunisation
administration

(fHbp) (NadA 2) (PorA P1.4)

Adapted from Gossger, Snape et al JAMA 2012

Phase IIb study Group

• 1885 enrolled Blood draw Blood draw
(n= 622)


(n=632)
MenC

(n=317)

R234


Immunogenicity of 4CMenB

No reduction in
immunogenicity with an
accelerated (2, 3, 4, month)
schedule

(fHbp) (NadA 2) (PorA P1.4)


Minimal interference
with routine vaccines


MenB vaccines in adolescents

Lancet 2012

Lancet 2012


• Can this vaccine be incorporated into routine
immunisation schedules?


Reactogenicity of bivalent fHbp vaccine: 18 to 36 month olds
100
90 Fever 100 Irritability
80 90
70 80
60 70
50 60
Dose 1 50
40 Dose 1
30 Dose 2 40
30 Dose 2
20 Dose 3
20 Dose 3
10
0 10
0
20µg 60µg 200µg Hep A
Vaccine/ 20µg 60µg 200µg Hep A
Placebo Vaccine/
Placebo

100 Local Tenderness
90
80 n = 19 - 32
70
60
50 Dose 1
40
30 Dose 2
20 Dose 3
10
0
20µg 60µg 200µg Hep A
Vaccine/
Placebo


Reactogenicity
of 4CMenB Group

(n= 622)


(n=632)
MenC

(n=317)

R234


Safety Profile of 4CMenB Vaccine in Infants
Fever Rates After First, Second and Third Doses Study V72P12

≥40°C
100 100 100 39-<40°C
90 90 90 38-<39°C
80 80 80
% of Subjects

70 70 70
60 60 60
50 50 50
40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
Dose 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

4CMenB + Routine 4CMenB Alone Routine Routine 4CMenB + Routine
2-4-6 mo 2-4-6 mo 3-5-7 mo 2-3-4 mo 2-3-4 mo
N = 605-624 N = 592-612 N = 602-627 N = 304-311 N = 310-317

Routine vaccines: Infanrix-hexa, Prevenar

Local Reactions to 4CMenB and Routine Vaccines

R357
R357

R357
R357

R357
B+R246: 4CMenB + routine infant vaccines at 2, 4, 6 months R357
B246_R357: 4CMenB at 2, 4, 6 months, routine infant vaccines at 3, 5, 7 months
B+R234: 4CMenB+ routine infant vaccines at 2, 3, 4 months Adapted from Gossger, Snape et al JAMA 2012
R234: routine infant vaccines at 2, 3, 4 months

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

Safety: 4CMenB
• 20 SAEs possibly related to • 6 hospitalisations for fever within
imms… 2 days of 4CMenB receipt +/-
routine vaccines
• 3 hypotonic +/- • 1 hospitalisation for fever after
hyporesponsiveness: routine imms alone.
– 2 days following 4CMenB and
routine immunisation • 2 episodes of reported Kawasaki
– Same day as 4CMenB and disease, reviewed by
routine immunisation independent expert panel
– Same day as routine – 1 ‘unlikely’ Kawasaki’s disease,
immunisations symptom onset prior to 4CMenB
– 1 ‘complete’ Kawasaki disease,
onset 23 days after 4CMenB:
‘possibly related’


Convulsions in Phase IIb study of 4CMenB

Participants With Febrile Seizures
Days 1-2+ Days 3-14 Days >14 Total
4CMenB +/- routine 0 1 1 2
Control* 0 0 2 2

Participants With Afebrile Seizures
Days 1-2+ Days 3-14 Days >14 Total
4CMenB +/- routine 2 0 1 3
Control* 2 0 1 3

*Routine vaccines: Infanrix-Hexa and Prevenar Gossger, Snape et al JAMA 2012


schedules?


• What is the likely breadth of protection against serogroup B
meningococcal disease?

• Through the
looking
glass……..

Immunisation with 4CMenB at 2, 4, 6 and 12 months:
% Participants with hSBA Titres ≥1:4

44/76-SL NZ98/254 5/99 UKP1.4 GB101 GB355 GB364
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
Baseline Post 3rd dose Pre 12 month dose Post 12 month dose

Adapted from Findlow, Borrow et al CID 2010


N NHBA GNA1030 C

N GNA2091 fHBP C +
N NadA C

Key antigens
• 50µg Factor H Binding Protein (FHbp)
• PorA 1.7-2,4 (1.4)

Predicting susceptibility of 4CMenB induced
bactericidal antibodies

Vaccine

Predicting susceptibility of 4CMenB induced
bactericidal antibodies

Vaccine

?

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 …….

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


Vaccine
X X X X


Vaccine
X X X X
X X
X X
Would predict 16/24 strains
X X
likely to be killed by vaccine
induced antibodies X X
X X

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

Y Y Y Y

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
4CMenB European coverage estimates†

Norway: 85% [95% CI: 76%, 98%]
n=41
England & Wales: 73% [59%, 88%]
n=535
Germany: 82% [69%, 92%]
n=222
France: 85% [70%, 93%]
n=200
Italy: 87% [70%, 93%]
n=54

 Based on MATS, 4CMenB is predicted to cover 78% of strains isolated during 2007 - 2008
Slide provided by Novartis Vaccines

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.

Half of All European Strains Tested Were Covered by More
Than One Antigen Contained in 4CMenB
Percent of strains predicted covered by number of
4CMenB antigens above Positive Bactericidal Threshold

Percent (%)
4CMenB coverage estimates†

28% 5 European Countries:
1Ag>Threshold 78% [66%, 92%]

22% 34%
2Ag>Threshold
• 4CMenB may still be effective
0Ag>Threshold
if one antigen is down
16% regulated or mutated
3Ag>Threshold

0.1%
4Ag>Threshold Slide provided by Novartis Vaccines

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.

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
• Would require deployment of vaccine in
adolescence/ young adulthood

Christensen et al Lancet ID 2010

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)

MenB vaccines: post implementation surveillance

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

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’?
Oropharyngeal carriage strains
• If the MenB vaccines can in a population

influence oropharyngeal
carriage of meningococcus….

• Potential for ‘selection’ for
strains either
– Lacking the genes for the target
antigens
– Low expressors of the target
antigens

Will we see ‘strain replacement’?
• If the MenB vaccines can Oropharyngeal carriage strains
in a population
influence oropharyngeal
carriage of meningococcus….

• Potential for ‘selection’ for
strains either
– Lacking the genes for the target
antigens
– Low expressors of the target
antigens

Strain replacement?
• Can only be determined by large scale
oropharyngeal carriage studies evaluating
strains for vaccine target phenotype
– e.g. by MATS

Summary: 4CMenB
• 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

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

MenB vaccines: pre and post implementation issues by Dr Matthew Snape

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