preventing meningitis: new vaccines and forthcoming changes to the immunisation programme by jamie...

Preventing meningitis: new vaccines and

forthcoming changes to the immunisation programme Jamie Findlow

Vaccine Evaluation Unit, Health Protection Agency, Manchester, UK.

[email protected]

Overview

Neisseria meningitidis. Recent epidemiology. Vaccines and protection strategies. MenB vaccines. Forthcoming schedule changes.

Streptococcus pneumoniae. Recent epidemiology. Vaccine use update.

Summary.

Neisseria meningitidis- groups

Neisseria meningitidis strains are classified into 12 groups.

The polysaccharide capsule is used to identify the different groups.

B

Polysaccharide Capsule

A

W Y

C Five main groups cause the majority (95%) of all meningococcal disease around the world – A, B, C, W and Y.

Canada

USA

Columbia

Argentina

Brazil

Europe

Saudi Arabia

AfricanMeningitis

Belt

SouthAfrica

Australia

NewZealand

Taiwan

Japan

B53%C

21%

B25%

C29%

Y37%

Y50%

B40%

B67%

B22%

B41%

B90%

B82%

B50%

B57%

B80%C

20%

C71%

C11%

W17%

W84%

W35%

Y21%

A78%

A23%

A12%

Meningococcal disease- global epidemiology

Laboratory confirmed cases of MenC disease in England and Wales 1995 to 2012 (calendar year)

Health Protection Agency Meningococcal Reference Unit- Unpublished data

Vaccine driven decline

Clonal exp

ansion (S

T-11)

Public health impact since 1999

Prevention of > 12,000 casesPrevention of > 1200 deaths

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)

0

100

200

300

400

500

600

700

800

900

1000

No

of

con

firm

ed c

ases

Laboratory confirmed cases of MenB disease in England and Wales 1995 to 2012 (calendar year)


Natural fluctuation?

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)

0

200

400

600

800

1000

1200

1400

1600

1800

No

of

con

firm

ed c

ases

Laboratory confirmed cases of MenW disease in England and Wales 1995 to 2012 (calendar year)


Outbreak

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)

0

20

40

60

80

100

120

140

No

of

con

firm

ed c

ases

France: 21

Finland: 2

S. Arabia: 241

Singapore: 4USA: 4

Indonesia: 14

Morocco: 3

Sweden: 2

Norway: 1

Germany: 10

Denmark: 1

Netherlands: 9Scotland: 1

Belgium: 1

England & Wales: 50

Kuwait: 3

Oman: 18

International Hajj associated MenW outbreak 2000*

*cases Apr to Dec 2000, WHO

Burkina Faso (2002), 13,000

Laboratory confirmed cases of MenY disease in England and Wales 1995 to 2012 (calendar year)


Clonal exp

ansion ?

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)

0

10

20

30

40

50

60

70

80

90

100

No

of

con

firm

ed c

ases

Emergence of MenY in Europe

Increases in disease due to MenY has been observed in a number of Countries

across Europe

Reference: EMGM May 2011

France

Sweden

Germany

Switzerland

Finland

Norway

England and Wales

Czech Republic

Gray SJ, et al. Presented at: EMGM . Ljubljana, Slovenia. May 18–20, 2011.

Laboratory confirmed cases of MenY disease in England and Wales by age group and year

Ladhani et al., Emerg Infect Dis 2012;18:63-70

Laboratory confirmed cases of meningococcaldisease in England and Wales in2012 (calendar year)


B82%

C3%

W3%

Y10%

other2%

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 (to Aug 25th)

0

500

1000

1500

2000

2500

3000

No

of

con

firm

ed c

ases

Laboratory confirmed cases of meningococcal disease (all groups) in England and Wales 1995 to 2012 (calendar year)


Average annual number of laboratory confirmed cases of meningococcal disease in children <2 years of age by capsular group and age (2006/2007 to 2009/2010)

Average annual number of laboratory confirmed cases of all Meningococcal disease in under-2s by serogroup and month of age (2006-07 to 2009-10)

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23Age (months)

Nu

mb

er o

f re

po

rts

Other groups

Ungrouped

ACWY

B

~54% of disease <1 year of age is within the first 6 months

Ladhani et al., Vaccine 2012;30:3710-6

0

50

100

150

200

250

300

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24Age (years)

Nu

mb

er o

f re

po

rts

ACWY

Ungrouped

Other groups

B

Average annual number of invasive meningococcal disease cases by capsular group in children and young adults in England and Wales (2006/07 to 2009/10)

Ladhani et al., Vaccine 2012;30:3710-6

Overview



Summary.

Meningococcal conjugate vaccine production

Vaccine

IsolationPurified polysaccharide Carrier protein

Conjugation

Polysaccharide capsule

B

A WYC

C

A

1999

2010

2010

?

Infants

How do we use meningococcal vaccines to achieve optimal protection?

Adolescents

Immunise

(direct protection)

Immunise

(direct protection)

Indirect protection

Meningococcal conjugate vaccines

Vaccine Active constituents

Manufacturer Carrier protein

Mengitec C Pfizer CRM197

Menjugate C Novartis CRM197

NeisVac-C C Baxter Tetanus toxoid

Menactra A, C, W + Y Sanofi Pasteur Diphtheria toxoid

Menveo A, C, W + Y Novartis CRM197

Nimenrix A, C, W + Y GSK Tetanus toxoid

Menitorix C + Hib GSK Tetanus toxoid

MenHibrix C + Y + Hib GSK Tetanus toxoid

MenAfriVax A Serum Institute of India

Tetanus toxoid

No licensed MenB vaccine available

Overview



Summary.

Why is there currently no MenB vaccine available?

MenB polysaccharide is polysialic acid, a compound identical to that found on the surface of human neuronal cells.

Consequently;

(i) Poorly immunogenic.

(ii) Potential to induce an autoimmune response.

Downside of approach = Diversity

Use subcapsular antigens, which are;

(i) Surface exposed.

(ii) Conserved.

(iii) Induce bactericidal activity.

Development of subcapsular antigen vaccines has broadly followed two pathways-

Subcapsular approaches

Purified OMVs Blebbing

Purified or recombinant outer membrane proteins

Used successfully to combat single clone epidemics of MenB disease.

Immune response is primarily directed against the PorA protein, resulting in limited cross-protection.

(i) Outer membrane vesicles (OMVs)

(ii) Individual proteins

The Pfizer Investigational MenB vaccine rLP2086

Investigational vaccine based upon rLP2086, a surface-exposed lipoprotein of N. meningitidis.

Discovered by traditional vaccine development procedure (fractionation, protein purification and proteomic steps).

LP2086 has since been renamed as factor H binding protein (fHBP).

fHBP is important for survival of the organism in vivo.

The gene is present in all meningococcal MenB disease isolates examined.

fHBP also a component of the Novartis vaccine.

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

Variant 2

Variant 3

Family A

Family B

The vaccine is composed of two recombinant LP2086/fHBP proteins, one from each family.

Promising results have been achieved in three phase I/II trials in young adults and adolescents, and support continued development:

(i) Acceptable safety profile.(ii) Robust serum bactericidal antibody (SBA) response rates.

Clinical development of the Pfizer investigational MenB vaccine

Anderson AS, Jansen KU & Eiden J. Expert Rev Vaccines 2010;10:617-34.

Current situation

Evaluation continuing through later phase trials.

Will be targeted for an adolescent indication.

Novel antigens discovered by reverse vaccinology

expressionand

purification

purified proteins

immunisations

~350 proteins successfully expressed in E.coli, purified, and used to immunise mice

Based on the genome sequence of MC58, 570 ORFs that potentially encoded novel surface

exposed or exported proteins were identified

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

900,000

1,000,0001,100,0001,200,000

1,300,000

1,400,000

1,500,000

1,600,000

1,700,000

1,800,000

1,900,000

2,000,000

2,100,000

2,200,000IHT-A

IHT-B

IHT-C

1

28 novel protein

antigens identified

Sera used to confirm surface exposure of

novel proteins

Slide provided by Novartis Vaccines

Bexsero®

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

Bexsero (previously known as 4CMenB or rMenB+OMV) contains 4 main antigens.

Novartis investigational MenB 4CMenB vaccine(Bexsero®)

PorA (presented as

part of an OMV)

NadAfHBP (Variant 1)

NHBA

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

Three recombinant proteins discovered by reverse vaccinology.

Bexsero (Novartis Vaccines)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.

Co-administered infant vaccines elicit expected immune responses when given with Bexsero.

Bai X, Findlow J & Borrow R. Expert Opin Biol Ther 2011;11:969-85.

Current situation

Novartis has submitted for marketing approval (licensure) to European regulators (EMA).

Decision is predicted during 2012.

Ongoing trial in English University students to investigate any impact on carriage (herd protection).

Alternative MenB vaccine approaches

Pre-clinical

Numerous approaches using other surface exposed antigens mostly in the form of OMVs.

Walter Reed Army Institute of Research (WRAIR)

Three genetically modified strains used to produce native OMVs.

Genes responsible for three reactogenic components have been “knocked out”. Each OMV has an extra gene for a different PorA inserted (therefore each OMV has two

different PorA proteins). Increased expression of selected proteins including fHBP (Family A and B), OpcA, and

NadA.

Early phase trials have been successfully undertaken which have demonstrated good immunogenicity with a good safety profile.

Novartis Vaccines

Combined vaccine of Bexsero and Menveo (ClinicalTrials.gov Identifier: NCT01210885).

Overview



Summary.

<6

mth

s

6-1

1 m

ths

1-4

yrs

5-9

yrs

10

-14

yrs

15

-19

yrs

20

-24

yrs

25

-34

yrs

35

-44

yrs

45

-54

yrs

55

-64

yrs

65

+ y

rs

0

10

20

30

40

50

60

70

80

90

100

1996-99

% w

ith S

BA

titr

e >

=8

2009

Proportions of sera with MenC SBA titres ≥8 by age in England & Wales, pre and post-introduction of MCC vaccines

1996-9 data: Trotter CL et al., Clin Vaccine Immunol 2008;15:1694-8. 2009 data: Ishola D et al., Clin Vaccine Immunol 2012;19:1126-30

Consequently, need to introduce a booster dose for MenC to

(i) Provide direct protection

(ii) Maintain herd protection

“The committee noted that clinical trial data shows that a single dose of meningococcal C vaccines (NeisvacC® or Menjugate®) provided sufficient immunity in infancy until the booster dose of Hib/MenC at 12 months of age. Given this evidence and the advice from the sub-committee that a dose of meningococcal C should be considered in adolescence to maintain individual and herd protection, the committee advised that a cost-neutral approach could be to remove a dose from the infant schedule and replace it with an adolescent dose of meningococcal C vaccine.JCVI asked that its adolescent sub-committee look at options for the timing of an adolescent dose of meningococcal C vaccine.

Action: committee and sub-committee to consider the timing of an adolescent dose of meningococcal C vaccine.”

“the meningococcal C immune response of quadrivalent meningococcal ACWY vaccine was uncertain and may be inferior to the monovalent vaccine. In the absence of carriage data the impact of use of quadrivalent vaccine on meningococcal Y carriage is also uncertain. For these reasons the sub-committee agreed with the advice of the JCVI meningococcal sub-committee that the monovalent meningococcal C vaccine should be used as a booster dose”

“noting that there is uncertainty about when the expected increase in meningococcal C disease may arise, considered that a booster dose should be introduced as soon as practicable on precautionary grounds. It was noted that the suggested use was outside of the current market authorisations for the vaccines.”

“The vaccine could be given concomitantly with the current tetanus, diphtheria and polio (Td/IPV) booster. Evidence that would be discussed later in the agenda suggested that the booster would probably most effectively be delivered in schools. Whilst a booster dose at age 15 years (school year 11) may be optimal given that it may have a larger immediate impact on carriage, issues around implementation of a booster dose at that age need to be considered and would be discussed later in the agenda. An alternative strategy that would have a similar impact on carriage would be to introduce routine vaccination in younger adolescents with a time limited catch-up campaign for older ages, although this option would be more costly overall. It would also be important to review new carriage data that may be available later in the year, which may inform scheduling considerations.”

MenC booster

“The committee noted the recent market authorisation of a new quadrivalent meningococcal ACWY conjugate vaccine (Nimenrix® produced by GSK) for children from one year of age and adults. Current Green Book guidance covers use of another quadrivalent meningococcal ACWY conjugate vaccine (Menveo® produced by Novartis) in certain risk groups and as a travel vaccine. The current market authorisation for Menveo® is for use in children from 11 years of age and adults. However, JCVI had advised that it should be used in certain younger children outside of its market authorisation. It was noted that the market authorisation for Menveo® may change in relation to use in younger children.

31. The committee agreed that Green Book guidance should be changed to specify that either Menveo® or Nimenrix® may be used in certain risk groups and as a travel vaccine in individuals from one year of age. Only Menveo® should be used in children under one year of age as there are some data on its use in that age group (there are no data on use of Nimenrix® in this age group) and the amount of tetanus toxoid in Nimenrix® could potentially give rise to greater reactogenicity in infants.

32. The committee also noted that the summary of product characteristics of both vaccines suggested a booster dose of vaccine after one year in individuals that remain at risk of exposure to serogroup A meningococci bacteria because of evidence of waning immunity against this strain. However, it was considered that the data on waning meningococcal A immunity may be unreliable due to the type of assay (human complement serum bactericidal assay) used in clinical trials. It was agreed that a booster dose after five years may be more appropriate for individuals at continued risk from serogroup A meningococci, in line with that5 of the meningococcal ACWY polysaccharide vaccines.”

Quadrivalent meningococcal vaccines

Overview



Summary.

Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the six serotypes IN Prevenar13™ but not in PCV7 : Children aged < 2 years in England and Wales by Epidemiological Year: July-June (2006- To Date)

0

50

100

150

200

250 06-07 07-08 08-09 09-10 10-11 11-12

Week

Nu

mb

er

of R

ep

ort

s

Introduction of Prevenar™ BLUE LINE Week 36 2006

PCV13 introduced WHITE LINE Week 13 2010

Vaccine effectiveness of additional 6

serotypes = 80%

Unclear whether there is an increase in non PCV13 serotypes as yet in children

Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes NOT IN Prevenar13™ : Children aged < 2 Years in England and Wales by Epidemiological Year: July-June (2006- To Date)

26 28 30 32 34 36 38 40 42 44 46 48 50 52 1 3 5 7 9 11 13 15 17 19 21 23 250

20

40

60

80

100

120

14006-07 07-08 08-09 09-10 10-11 11-12

Week

Nu

mb

er

of R

ep

ort

s



Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the six serotypes IN Prevenar13™ but not in PCV7 : Persons aged >5 Years in England and Wales by Epidemiological Year: July-June (2006- To Date)

26 28 30 32 34 36 38 40 42 44 46 48 50 52 1 3 5 7 9 11 13 15 17 19 21 23 250

500

1000

1500

2000

2500 06-07 07-08 08-09 09-10 10-11 11-12

Week

Nu

mb

er

of R

ep

ort

s



Early evidence of herd protection

(within 18 months of implementation)

Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes NOT IN Prevenar13™ : Persons aged >5 Years in England and Wales by Epidemiological Year: July-June (2006- To Date)

26 28 30 32 34 36 38 40 42 44 46 48 50 52 1 3 5 7 9 11 13 15 17 19 21 23 250

500

1000

1500

2000

2500

3000 06-07 07-08 08-09 09-10 10-11 11-12

Week

Nu

mb

er

of R

ep

ort

s



Unclear whether there is an increase in non PCV13 serotypes as yet in >5 year olds

Overview



Summary.

“The committee agreed with the sub-committee that it would not be effective nor cost effective to introduce a programme in the UK to offer PCV13 to those in clinical risk groups or to older adults given the evidence of accumulating indirect protection of the population from the childhood immunisation programme. However, certain groups with a greatly increased risk of death from IPD from PCV13 serotypes would continue to benefit, but only in the short-term, from PCV13 given under the supervision of a secondary care physician. Given the expected disappearance of PCV13 serotypes within a small number of years, use of PCV13 outside of the routine childhood immunisation programme would become ineffective even in these groups. It was noted that several medical professional bodies had recommended use of PCV13 in certain clinical risk groups. Action: the committee and sub-committee to produce a more detailed statement with this advice.

18. In addition, the committee also accepted the advice of the sub-committee: • to revise the definition of chronic kidney disease for the purposes of pneumococcal vaccination; • that there should be no changes currently to guidance on the use of pneumococcal polysaccharide vaccine (PPV23); • the use of PPV23 should be reviewed within two years to determine whether it remains effective and cost effective in light of the changing epidemiology of invasive pneumococcal disease and further analysis of the accumulating UK data on the effectiveness of PPV23.”

Pneumococcal vaccines

Overview



Summary.

Meningococcal epidemiology

In England and Wales we are currently in a period of comparatively lower meningococcal disease incidence.

The number of MenY disease cases has risen over recent years and is associated with pneumonia in older age groups. MenB is currently responsible for ~85% of meningococcal disease in and is currently unpreventable by vaccination.

The peak incidence of MenB disease is at 5 months of age.

Vaccination strategies can be designed to provide indirect protection in addition to direct protection.

Summary (1)

MenB vaccines There are two MenB vaccines in the later stages of development.

Bexsero (Novartis Vaccines) is currently being reviewed by the EMA. If licensed this would result in the first broad coverage vaccine for MenB becoming available.

Licensure of Bexsero does not necessarily equate to recommendation/implementation into the UK schedule which is based upon multiple considerations.

It is probable that other broad coverage MenB vaccines will subsequently become available over the next decade.

Summary (2)

Future schedule changes (meningococcal vaccines)

We will be changing from a two dose MCC priming schedule to a single dose priming schedule in the near future.

In a “cost neutral” approach, this MCC dose will re-scheduled to become an adolescent booster.

A second quadrivalent meningococcal polysaccharide vaccine (Nimenrix, GSK) has been recently licensed by the EMA.

The “Green book” will be updated shortly to include Nimenrix.

Summary (3)

Pneumococcal epidemiology and vaccination

Excellent direct impact of PCV13 in targeted age groups, with overall vaccine effectiveness of the additional 6 serotypes covered by PCV13 ~80%.

Early evidence of rapid herd protection with PCV13 (within 18 months) despite no catch up.

The JCVI have recommended no changes to the use of PPV23 in clinical at-risk groups (except those with a very high risk of contracting disease).

Summary (4)

10th June 2011 or 2013?

What the papers say

30th Sept 20122012

Vaccine Evaluation Unit, HPA, Manchester

Ray Borrow.

Meningococcal Reference Unit, HPA, Manchester

Ed Kaczmarski, Steve Gray and Tony Carr.

Immunisation Department, HPA, Colindale

Liz Miller, Pauline Kaye, Shamez Ladhani and Rashmi Malkani.

Acknowledgements

preventing meningitis: new vaccines and forthcoming changes to the immunisation programme by jamie...

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