Vaccine against meningitis, current issues, what’s new &

what are the future possibilities?

Ray Borrow

Professor of Vaccine Preventable Diseases, Vaccine Evaluation Unit, Health Protection Agency North West, Manchester Royal Infirmary, Manchester, M13 9WZ, UK

ray.borrow@hpa.org.uk

16th June 2011

Advances in

meningococcal

serogroup B vaccines

The Independent

(20p version)

Friday 10th June 2011

Laboratory confirmed cases of meningococcal disease, E&W, Five Weekly

Moving Averages: 1997 - 2011 (week 13)

Percentage of capsular groups of laboratory confirmed cases of meningococcal disease,

E & W, 1999 to 2011 (May 14th)

Increase in serogroup Y disease in England & Wales, 2007 to 2009

Meningococcal Y Strain 2007 2008 2009 All cases

Y:P1.5-1, 10-1: F4-1: ST1655 (CC23) 3 3 15 21

Y:P1.5-1, 10-4: F4-1: ST1655 (CC23) 0 1 5 6

Y:P1.5-1, 10-10: F4-1: ST1655 (CC23) 1 0 1 2

Y:P1.5-1, 10-12: F4-1: ST1655 (CC23) 0 0 1 1

Total 4 4 22 30

Meningococcal ‘serogroup B’ vaccines

• MenB capsule poorly immunogenic

• Main approach in past was outer membrane vesicle vaccines

• Efficacy shown in older trials in South America and Norway

• Poor protection in younger children

• Recent use in New Zealand epidemic

• Short term effectiveness of 73% (95% CI 52 to 85)

• No evidence of major impact on carriage

• Subcapsular, surface exposed, conserved, induces bactericidal activity.

• Two approaches:

Fractionation, protein purification, and proteomics steps - Pfizer.

Reverse vaccinology – Novartis

•Final candidates have some shared component

• If prevents acquisition of carriage, vaccination strategies including adolescents/young adults have the potential to provide indirect (herd immunity) benefits

The solution

The Pfizer Investigational MenB Vaccine rLP2086

• Investigational vaccine is based upon LP2086, a surface-exposed lipoprotein of N. meningitidis.

• LP2086 was identified as a factor H binding protein (fHBP), important for survival of the organism in vivo.

• The gene is present in all meningococcal serogroup B disease isolates examined.

• fHBP in vitro surface expression has been shown in > 98% of MnB isolates – MEASURE assay.

• fHBP also a component of Novartis vaccine.

Factor H (fH) binding protein (fHBP)

Variant or family groups:

Novartis Pfizer

Variant 1 Family B

Variants 2 & 3 Family A

Intra-family cross-reactivity good.

Inter-family cross reactivity poor.

10

Variant 1/ Family B

Variant 2

Variant 3

Family A

• The vaccine is composed of two recombinant LP2086 proteins, one from each subfamily.

• Early clinical studies demonstrated excellent safety profile and broad immunological response to clinical isolates representing the two subfamilies.

• Results have been extended in three phase I/II trials in young adults and adolescents, and support continued development:

- Acceptable safety profile

- Robust SBA response rates against a diverse panel of MenB invasive disease isolates

- Variation with fHBP present in strain

Clinical Development of the Pfizer Investigational MenB Vaccine

Immunogenicity of the Pfizer investigational MenB vaccine in adolescents (11 – 18 yrs)

in 0, 2, 6 month schedule

Richmond P, Marshall H et al. 17th IPNC. Banff, Canada. September 11-16, 2010. VW04, page 37.

0

20

40

60

80

100

A04 A05 B02 B03LP2086 variant in SBA test strains

% s

ub

ject

s w

ith

hS

BA

≥

4

Pre dose 1 1 month post dose 2 1 month post dose 3

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

• Novartis has submitted its meningococcal vaccine Bexsero to European regulators for marketing approval.

• If approved Bexsero would be the first broad-coverage vaccine for MenB.

• Novartis 4CMenB (Bexsero®) contains 4 main antigens:

Novartis 4CMenB (Bexsero®)

PorA (presented as

part of an OMV)

NadAfHBP 1.1 NHBA

Novartis 4CMenB (Bexsero®) clinical program

• Phase 3 studies in infant, toddlers and adolescents complete.

– Over 5000 infants/toddlers and 2000 adolescents/adults vaccinated.

• Acceptable safety and tolerability profile in all age groups.

– Short-lived fever in infants without medical consequences.

– No excess fever in adolescents/adults.

• Co-administered infant vaccines elicit expected immune responses when given with 4CMenB.

• Additional studies are ongoing (i.e., 2, 3, 4 month primary vaccination, long-term persistence, carriage study in adolescents).

Novartis 4CMenB Phase III study in infants% of subjects with hSBA ≥ 1:5 one month

after dose 3 (2, 4, 6 month schedule)

Vesikari T, Esposito S, Kimura A et al. Presented at the 17 th IPNC. Banff, Canada. September 11-16, 2010. P180, page 167.

0

20

40

60

80

100

fHBP NadA PorA 1.4

Baseline

Post-primary

N = 1149 to 1152

% S

ub

ject

s w

ith

bac

teri

cid

al t

iter

s ≥1

:5

Antigen

NHBA

Findlow J, Borrow R, Snape MD et al. Clin Infect Dis 2010;51:1127-37.

% S

ub

ject

s w

ith

SB

A t

itre

s ≥1

:4

fHBP NadA PorA

Baseline Post 3rd dose Pre booster Post booster

UK infant trial: proportion of subjects with hSBA titres ≥ 4 before & after Novartis

4CMenB vaccine

Strains

Summary of systemic reactogenicity after receipt of Novartis 4CMenB vaccine

Findlow J, Borrow R, Snape MD et al. Clin Infect Dis 2010;51:1127-37.

Potential coverage of the

investigational 4CMenB

vaccine

against group B isolates from

England and Wales

Isolates

All invasive MenB isolates received at the Health Protection Agency Meningococcal Reference Unit from a single epidemiological year were selected.

Epidemiological year was from July 2007 to June 2008.

Total of 535 MenB isolates.

Methods - Genotypic coverage

All MenB isolates were genetically characterised with respect to:

MLST

fHBP

NHBA

NadA

PorA

Clonal complex of MenB isolates from 2007/2008

N = 535

PorA genotype of MenB isolates from 2007/2008

N = 535

Cumulative percentage (from n=535)

20 36 50 58 62 64 67 68 70 71

Top ten PorA genotypes of MenB isolates from 2007/2008

Calculation of coverage by genotypic methods does not account for,

Any differences in expression (or accessibility) of protein by each isolate.

Any differences in cross-reactivity of vaccine induced antibody to protein variants.

Any potential synergy between different antibody populations induced by the different components of 4CMenB.

Discussion - genotypic coverage

Complications: Variants of the proteins exist (vaccine induced antibody is not equally cross-reactive against all protein variants). Protein expression differs between isolates.

Meningococcal protein vaccines- evaluation of immunogenicity and

coverage

Immunogenicity Multiple (representative) strains with different antigenic repertoires are required to evaluate the breadth of protection in the SBA assay.

This is impractical due to the low volumes of sera gained from infant trials. CoverageDifferences in expression and cross-reactivity of induced antibody, mean that typing information (genotypic) alone is insufficient.

Methodological issues- to determine expression and/or cross-reactivity?

Antigen expression

Cross-reactivity

Combination of expression and cross-reactivity

Mathematically calculated threshold of being killed by post-vaccination

sera (i.e. being covered or not covered)

Meningococcal Antigen Typing System (MATS)

Donnelly J et al. PNAS 2010;107:19490-19495

Each isolate is compared to a reference strain to give a relative potency (per recombinant protein).

For each recombinant protein a positive bactericidal threshold (PBT) which predicts SBA activity has been established.

Determined using serum pools from 13 month toddlers immunised with four doses of 4CMenB.

The PBT is the value above which >80% of strains are killed in the SBA assay.

This gives a binary outcome of either covered/not covered by the vaccine (per recombinant protein).

Coverage by the PorA (OMV) component of the vaccine is determined genotypically.

Analysis of MATS data

Methods - MATS

The same 535 invasive MenB isolates were characterised:

Phenotypically using MATS for recombinant antigens (fHBP, NHBA, NadA).

Genotypic data for PorA was combined with MATS data to give an overall coverage prediction.

fHBP All (34/34) isolates with the vaccine homologous fHBP 1.1 had positive MATS phenotype.

Of the fHBP 1.1 variants, there were up to a 6 fold difference in MATS RP.

Of the 63% of strains with fHBP positive phenotype, 6% were variant 1.1. 57% were fHBP variants other than 1.1.

NadAOnly three isolates had positive MATS phenotype.

All were ST-11 isolates harbouring variant 2 proteins.

Results - MATS

NHBA131/133 (98%) of isolates with vaccine homologous P0002 NHBA had positive MATS phenotype.

MATS RP ranged from <1% to ~200%.

Of the 55% of isolates with positive NHBA phenotype, 25% were variant P0002. 30% were variants other than the vaccine homologous variant.

Results - MATS

• Overall coverage estimates are heavily influenced by the proportion of isolates with variant 1 fHBP and low numbers with cross-reactive NadAs.

• As 50% and 16% of isolates are covered by 2 and 3 antigens, respectively, this has the potential to reduce the likelihood of vaccine escape mutants.

• The MATS PBT and hence subsequent coverage estimates are based upon immunological cross-reactivity in 13-month olds following a 3 + 1 schedule.

• Immunogenicity data have demonstrated that cross-reactivity of induced antibody to fHBP increases with age.

•Therefore, it is likely that the coverage estimate will overestimate coverage in infants and underestimate that of adults.

• Antibody populations induced by the OMV may act synergistically making coverage potentially higher.

Discussion - MATS results

Using MenB isolates from the epidemiological year 2007/2008, we predict that 4CMenB would have a coverage of 72.9 % (95% CI 59.8-89.6) in England and Wales.

Coverage of 50% of isolates would be afforded by at least two antigens in 4CMenB decreases the likelihood of vaccine escape mutants occurring.

We conclude that 4CMenB has the potential to protect against a significant proportion of MenB disease in England and Wales.

MenB coverage conclusion

www.clinicaltrials.gov ClinicalTrials.gov Identifier: NCT01214850

A phase 3 to evaluate the effect of Novartis vaccine's 4CMenB and Menveo on pharyngeal carriage of N.

meningitidis in young adults, n = 3,000.

Group 1: Subjects in this arm will receive 2 doses of Novartis 4CMenB vaccine.

Group 2: Subjects in this arm will receive one dose of Menveo.

Group 3: Control arm-subjects in this arm will receive 2 doses of IXIARO (Japanese encephalitis).

Sheffield, Manchester, Liverpool, Nottingham, Bristol, Middlesbrough, Oxford, Southampton, London

Pneumo

Incidence of Invasive pneumococcal disease per 100,000 population by age

England & Wales 1998-2006

Pneumococcal vaccination programme in England and Wales

Pneumococcal 23-valent polysaccharide vaccine (PPV23)

Pre-2003: PPV23 only used in at risk groups.

2003 to date: PPV23 recommended for all elderly:

– From August 2003: ≥ 80 yr olds

– From April 2004: 75 to 79 yr olds

– From April 2005: 65 to 74 yr olds

Pneumococcal conjugate vaccines (PCV)

From 2002, PCV7 for at risk children under 2 years of age.

September 2006: PCV7 introduced for all infants + catch-up up to 2 years of age.

April 2010: PCV13 replaced PCV7 for all infants.

Pneumococcal Vaccines

PCV7, 7-valent conjugate vaccine (Prevenar™ ) contains serotypes

14 18C 19F 23F 4 6B 9V

There are over 90 serotypes of Streptococcus pneumoniae

PPV23, the 23- valent polysaccharide vaccine (Pneumovax™ ) contains

14 18C 19F 23F 4 6B 9V 7F 5 1 3 19A 9N 8 33F 22F

20 2 17F 15B 12F 11A 10A

Six additional serotypes added for Prevenar13TM, PCV13

7F 5 1 3 19A 6A

Vaccine efficacy estimates for each age cohort , 62 to 80+ years, are being determined.

These new data will inform as to the pneumococcal vaccination of those 65 years+.

The use of PPV23 in at risk groups also being looked in to.

PPV23 (Pneumovax™)

PCV7 introduced in England & Wales on September 4th 2006

• Children aged > 13 months & < 2 years, born between 5/9/04 & 3/8/05

1 dose of PCV 7.

• Children aged 8 months to 13 months, born between 4/8/05 & 3/2/06

1 dose PCV7 at routine 13 month visit.

• Children aged > 2 months & < 8 months, born between 4/2/06 & 3/7/06

2 doses of PCV 7 separated by 2 months, with a further dose at routine 13 month visit.

CATCH – UP Campaign

HPA Enhanced Surveillance of IPD

Microbiology Labs in England and Wales

Hospitals in England and Wales

S pneumoniae Isolates sent for serotyping to RSIL

Reports of S. pneumoniae isolates sent to CFI via CoSurv

Electronic data imported into CFI systems

Rapid telephone follow to get PCV vaccination status

Clinical advice sent to GP and paediatrician

sends blood to HPA Manchester

DATA SHARED ON JOINT DATABASE AT CFI

Antibody results

HPA Manchester

Feed back results with further advice

CASES OF IPD FOLLOWED UP to 14th June 2011

• 2254 cases of IPD in children born since 04/09/2004

• 2052 (91%) serotyped – i.e. isolate sent to RSIL

• Remainder are from CoSurv reports to Centre for Infections but no isolate sent to RSIL for serotyping

• Immunisation status obtained for 99%.• 317 of total serotyped (15%) have a PCV7 serotype.• 1105 of total serotyped (53%) have a PCV13 (but not in 7) serotype.• 127 children have died.

• Around (75%) attributable to pneumococcal sepsis. • 503 children (22%) had pneumococcal meningitis.

• Case fatality rate of meningitis was 12%.• 1,424 bloods sent to HPA Manchester for serotype-specific IgG

responses for measurement post-disease or post-completion of PCV immunisation.

The impact on Invasive Pneumococcal Disease

Children Under 5 yrs: Serotypes contained in PCV7

The impact on Invasive Pneumococcal Disease

Children Under 5 yrs: Serotypes NOT contained in PCV7

The impact on Invasive Pneumococcal Disease

Persons ≥ 5 yrs: Serotypes contained in PCV7

The impact on Invasive Pneumococcal Disease

Persons ≥ 5 yrs: Serotypes NOT contained in PCV7

Incidence of invasive pneumococcal disease per 100,000 population by age

England & Wales 1998-2010

Cumulative weekly number of reports of Invasive Pneumococcal Disease

Serotypes in PCV 13 but not in PCV 7Children aged <2 years in England and Wales by Epidemiological Year:

Pneumococcal conclusions

• Little impact seen from PPV23 vaccination programme in the elderly.

• Estimates show excellent vaccine efficacy with PCV7 in the targeted age groups.

• Evidence of a herd immunity effect from PCV7 introduction has been seen.

• Despite replacement disease, the reduction in IPD in children is substantial.

• The phenomenon of replacement needs to be confronted and investigated.

• Evidence of direct impact of PCV13 in under 2 year olds.

• There is a role for higher valency conjugate vaccines.

Acknowledgements

Meningococcal acknowledgementsHPA Manchester

Jamie Findlow, Jay Lucidarme, Xilian Bai, Stefanie Gilchrist, Danielle Thompson, Lynne Newbold, Steve Gray, Ed Kaczmarski

Immunisation Department, HPA Centre for Infections, Colindale

Shamez Ladhani, Mary Ramsay

Pneumococcal acknowledgementsImmunisation Department, HPA Centre for Infections, Colindale

Pauline Kaye, Liz Miller, Rashmi Malkani, Shamez Ladhani, Nick Andrews, Stefan Flasche

Respiratory & Systemic Infection Laboratory, HPA Centre for Infections, Colindale

Robert George, Mary Slack, Androulla Efstratiou, Siobhan Martin, Christine More

HPA Manchester Elaine Stanford

Infectious Diseases and Clinical Microbiology, University of Oxford, UK

David Griffiths, Derrick Crook