Evaluating the impact of a new MenB vaccine and use of MRF genome library

Evaluating the impact of a new meningococcal B vaccine and use of the

MRF Meningococcal genome library.

[email protected]

Vaccine Evaluation Unit, Public Health England, Manchester, UK.

Ray Borrow

2 Monitoring MenB vaccines following implementation

Background information Bexsero and epidemiology Calculation of vaccine strain coverage

Monitoring of Meningococcal vaccines Meningococcal group C (MenC) vaccines Meningococcal group B (MenB) subcapsular vaccine/Bexsero

Summary and conclusions.

Presentation overview

4

Novartis MenB vaccine (Bexsero®)1

NadAfHbp NHBA

OMVs from the New Zealand outbreak strain (NZ 98/254).

Three recombinant proteins discovered by reverse vaccinology.

+

PorA (P1.4)

1http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero

Monitoring MenB vaccines following implementation10

Variant 1

Variants 2 & 3

Variants 1-3

Variants 4-6

249 VR1 variants3

649 VR2 variants4

2 2 2

2Vogel U et al., Lancet Infect Dis 2013;13:416-25.

3Pubmlst.org- last updated 05/07/2013 (accessed 15/08/13).

4Pubmlst.org- last updated 26/07/2013 (accessed 15/08/13).

Variant contained within vaccine.

Expression of proteins is variable

Meningococcal polysaccharide based vaccines

Simply calculated as the proportion of isolates with given polysaccharide.

Genotypic typing information alone is insufficient to calculate coverage.

Novartis have developed an assay to determine strain coverage of Bexsero.

Subcapsular vaccines

More complicated due to:

• Multiple protein variants (vaccine induced antibody is not equally cross-reactive against all variants).

• Protein expression differs between isolates.• Not all isolates harbor genes.

How to predict vaccine strain coverage?


Meningococcal Antigen Typing System (MATS)

Are any of the Bexsero components in the test strain:

(i) Expressed to a sufficient degree? and

(ii) Similar enough to the antigens in the vaccine such that the antibodies generated by Bexsero will kill the bacteria?

MATS ELISA determines the minimum amount of recognisable antigen needed to result in bacterial killing for each of fHbp, Nad A and NHBA (PorA characterised by

sero/genotyping).

For a strain to be ‘covered’, at least one antigen must be greater than the positive bactericidal threshold (PBT) or possess homologous PorA (P1.4).



188

794

P1.4 other

Use of the MRF whole genome library to determine PorA strain coverage:

PorA vs cc among MenB (2010/11 to 2012/13)

19%


Use of the MRF whole genome library to determine PorA strain coverage

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cc103 cc11 cc1157 cc162 cc167 cc18 cc213 cc22 cc254 cc269 cc282 cc32 cc35 cc41/44

cc461 cc60 cc865 UA

0

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40

60

80

100

120

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160 PorA vs cc vs year among MenB (2010/11 to 2012/13) other

P1.4

MATS relative potency (RP) distribution for NHBA, among European MenB strains from

2007/8, by NHBA peptide

PBT with 95% CI

Box and whiskers denote quartile ranges for each distribution.

10 Monitoring MenB vaccines following implementation Vogel U et al., Lancet Infect Dis 2013;13:416-25.

Within each variant, MATS RP varied over a 5-10 fold range, indicating significant differences in expression.

Genotypic information alone (including ST/CC) is insufficient to determine if a strain will be “covered”.


England and Wales

France Germany Italy Norway Combined0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

4Ag>PBT*

3Ag>PBT*

2Ag>PBT*

1Ag>PBT*

Vogel U et al., Lancet Infect Dis 2013;13:416-25.

*> MATS PBT for fHBP, NadA and NHBA/homologous PorA serotype.

MATS predicted coverage of European MenB isolates from 2007/08

MATS concept is to predict strain coverage and is “conservative”- does not

account for any antibody synergy, differences in age-related responses to

Bexsero or responses to minor OMV components.

Donnelly J et al., Proc Natl Acad Sci USA 2010;107:19490-5. Frosi G et al., Vaccine 2013: in press

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MenC disease confirmation and monitoring of MenC vaccines in the UK

1) Confirmation of invasive

meningococcal disease MenCOther Other

3) Monitoring vaccine

effectiveness Vaccine Failure - Fully vaccinated

Non-vaccine failure - Partially vaccinated - Not vaccinated - Insufficient time for immunity

Molecular-Group-MLST-PorA-WGS

Serological-Group-PorA-PorB

2) Additional typing and

monitoring of epidemiology

Determine vaccine history

Culture (+ PCR)PCR (only)

Further typing

Reliance on three key principals

1) Grouping target (MenC capsule) is the vaccine antigen.

2) MenC capsule expression is required for invasive disease.

3) MenC vaccination provides immunity against most MenC strains.

Monitoring MenB vaccines following implementation

MenC


Laboratory Confirmed Cases of Meningococcal Disease (All serogroups) England and Wales

1998/99

1999/2000

2000/2001

2001/2002

2002/2003

2003/2004

2004/20052005/2006

2006/2007

2007/2008

2008/20092009/2010

2010/20112011/2012

2012/2013

2013/2014 (to May 12)

0

500

1000

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1017 990778

639474 432 388 356 327 322 253 223 287 240 260 236

742 712

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463

325 402323 304

237 259 292185

218161 184

104

1044 1110

1089

870

678 655708

608580

672632

504560

397 364

252

PCR only

Culture and PCR

Culture only

no

of

case

s

16

Non-B capsular groups

- Should they be considered in MATS and if positive as a vaccine failure?

How could we monitor the impact of Bexsero® (1)


meningococcal disease Other


Molecular -Group -MLST -PorA -fHbp -WGS

Serological -Group -PorA -PorB



OtherMenB

Further typing



Non-vaccine failure - Partially vaccinated - Not vaccinated - Insufficient time for immunity


MATS -fHbp -NadA -NHBA -PorA

“Covered”

MenB

“Covered” includes genotyped PorA P1.4.

“Not Covered”

- PBT may not be applicable to non-MenB strains. Evaluation of PBT’s is ongoing.

- Non-culture PorA and fHbp sequencing implemented at PHE MRU.- Possibility of non-culture WGS?


PCR confirmed only

- Do we ignore these cases?

- Not covered by vaccine

All covered by MRF

WGS library

Early penicillin treatment- Good for patients, bad for epidemiologists?


Cartwright KA, Jones DM. Value of throat swabs from index cases of meningococcal meningitis. J Clin Pathol 1990;43:438.

Early penicillin treatment- Good for patients, bad for epidemiologists? (2)


Nasopharyngeal isolates from meningococcal cases

* HPZone is a web based support tool designed to provide local Health Protection Units with timely & comprehensive information on cases, outbreaks, incidents and threats.

UK NICE guidelines do not stipulate submission of nasopharyngeal isolates from cases.

However, HPZone* prompts for collection in suspected meningococcal cases.

Feasible to use throat swabs/carriage isolates from cases in MATS to determine if “covered”/vaccine failure (where no invasive isolate available).

Prudent to cross-check any typing data between isolate and clinical sample (e.g. group, PorA and fHbp).

Need to evaluate if PBTs apply to carriage isolates (including comparison of expression between matched invasive and carriage isolates).


20

How could we monitor the impact of Bexsero® (2)


meningococcal disease


Molecular -Group -MLST -PorA -FetA -WGS

Serological -Group -PorA -PorB



OtherMenB

Further typing



Non-vaccine failure - Partially vaccinated - Not vaccinated - Insufficient time for immunity - Not covered by vaccine


MATS -fHbp -NadA -NHBA -PorA

“Covered”

MenB

“Not Covered”


No

Unknown (of if not fully

vaccinated, non-vaccine failure)

Other

PorA P1.4 Not PorA P1.4

Genotype PorA

Carriage isolate

Yes


Considerations for monitoring the impact of Bexsero®

MATS

“Conservative” results not accounting for any antibody synergy, age related-responses or responses against minor OMV components.1,2

Currently un-validated for carriage isolates or non-MenB strains.

MATS may underestimate NadA expression due NadR repression during the in-vitro assay growth conditions.1,3

“Unknowns” (vaccine failure or non-vaccine failure)

If you are unable to determine a case as a vaccine failure or not, how do you accurately calculate vaccine efficacy?

Educated guesses

In some cases you will have partial genotypic information.

e.g. Non-culture PorA genotype indicative of a lineage which has thus far always been “non-covered”. Assume it is not a vaccine failure?

1Donnelly J et al., Proc Natl Acad Sci USA 2010;107:19490-5.2Frosi G et al., Vaccine 2013: in press3Vogel U et al., Lancet Infect Dis 2013;13:416-25.

Descriptive and effectiveness studies

Descriptive studies

Summary of epidemiology of meningococcal disease by vaccination status, age, etc.

Focus on both MenB and non-MenB cases to evaluate cross-protection and any replacement.

Effectiveness studies

Prospectively determined using the screening method as successfully undertaken in the UK for MenC1, Haemophilus influenzae type b2, and influenza vaccines3.

Screening method is based on the proportion of vaccinated among cases and the population and control achieved by using vaccine coverage estimates.

If the screening method is inapplicable then a case control method could be utilised.


1Trotter CL et al., Lancet 2004;364:365-7.2Ramsay ME et al., J Infect Dis 2003;188:481-5.3Fleming DM et al., J Epidemiol Community Health 2010;64:1062-7.

Summary and conclusions (1)

The key issue regarding monitoring of Bexsero is how to categorise each case as either a vaccine failure or non-vaccine failure.

Whole genome sequencing provides all necessary molecular typing. However, methods previously undertaken for MenC (or MenAWY) and genotypic information alone are insufficient for monitoring subcapsular vaccines such as Bexsero®.

Based on protein expression and accounting for any variation in the protein, MATS is currently the only way to predict if a strain is likely to be “covered” by Bexsero® and hence a vaccine failure. Although MATS is currently only validated for MenB invasive isolates, its use on non-MenB isolates and matched carriage isolates seems a sensible adaptation.


Summary and conclusions (2)

Monitoring will be difficult in PCR confirmed cases where no invasive isolate has been cultured.

MATS on nasopharyngeal isolates from the case is one way to address this issue.

Other methods to determine protein expression in non-culture cases would be beneficial.

There is likely to be a considerable number of cases in vaccinated individuals which would fit into an “unknown” category.

Other considerations are important when monitoring impact, such as waning immunity and any underlying conditions such as complement deficiencies.


Acknowledgements


Vaccine Evaluation Unit, Public Health England, Manchester

Jamie Findlow, Jay Lucidarme, Stephen Clark.

Meningococcal Reference Unit, Public Health England, Manchester

Lynne Newbold, Steve Gray and Tony Carr.

Immunisation Department,Public Health England, Colindale, London

Mary Ramsay, Shamez Ladhani.

Evaluating the impact of a new MenB vaccine and use of MRF genome library

Health & Medicine

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