menb vaccines: pre and post implementation issues by dr matthew snape

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?

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)


Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccine


Phase II study of ninety 18 to 36 month olds


NHBA GNA1030

GNA2091 fHbp

NadA

N

N

N

C

C

+

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

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

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


B+R234(n=317)




R234(n=314)


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)




B246_R357(n=632)


Blood draw

Routine

MenC


B+R234(n=317)




R234(n=314)



Phase IIb study

• 1885 enrolled


Immunogenicity of 4CMenB

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


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)




B246_R357(n=632)


Blood draw

Routine

MenC


B+R234(n=317)




R234(n=314)




Minimal interference with routine vaccines


MenB vaccines in adolescents

Lancet 2012

Lancet 2012

Reactogenicity of bivalent fHbp vaccine: 18 to 36 month olds


20µg 60µg 200µg Hep A Vaccine/ Placebo

0102030405060708090

100

Dose 1

Dose 2

Dose 3

Fever


0102030405060708090

100

Dose 1

Dose 2

Dose 3

Irritability


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)




B246_R357(n=632)


Blood draw

Routine

MenC


B+R234(n=317)




R234(n=314)




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


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


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

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’


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

• Through the looking glass……..

Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccine


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


NHBA GNA1030

GNA2091 fHBP

NadA

N

N

N

C

C

+

C

Key antigens

• 50µg Factor H Binding Protein (FHbp)



• PorA 1.7-2,4 (1.4)

Predicting susceptibility of 4CMenB induced bactericidal antibodies

Vaccine

Vaccine

YY

YY


YY

YY Y

YY

Vaccine


YY

YY

YY

YYY

YY

Vaccine


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


Vaccine Y YY

Y

XXXX

?

? ??


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†


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


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






• 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

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

menb vaccines: pre and post implementation issues by dr matthew snape

Health & Medicine