1. Preventing meningitis:
new vaccines and forthcoming
changes to the
immunisation programme
Jamie Findlow
Vaccine Evaluation Unit, Health Protection Agency, Manchester, UK.
jamie.findlow@hpa.org.uk

2. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

3. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

4. Neisseria meningitidis-
groups
 Neisseria meningitidis strains are
classified into 12 groups.
 The polysaccharide capsule is used
to identify the different groups.
B
A C  Five main groups cause the majority
(95%) of all meningococcal disease
Polysaccharide Capsule around the world – A, B, C, W and Y.
W Y

5. Meningococcal disease-
global epidemiology
Canada
B Europe
C 53%
21%
Japan
B
90%
B
B Y 57%
USA Y 25% 21%
37% A
C W 12%
29% African 17% B
Meningitis W 50%
Belt A W Taiwan
78% 35%
84%
Saudi Arabia
B Y
Columbia 50% Brazil
40%
Australia
B
22%
C A
71% 23%
B
C 80%
Argentina 20% B B
67% 41%
C
11%
South New
Africa Zealand B
82%

6. Laboratory confirmed cases of MenC
disease in England and Wales
1995 to 2012 (calendar year)
1000
900
800
700
No of confirmed cases
600
500
Public health impact since 1999
400
300
Prevention of > 12,000 cases
Prevention of > 1200 deaths
200
100
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
(to Aug
25th)
Health Protection Agency Meningococcal Reference Unit- Unpublished data

7. Laboratory confirmed cases of MenB
disease in England and Wales
1995 to 2012 (calendar year)
1800
1600 Natural fluctuation?
1400
No of confirmed cases
1200
1000
800
600
400
200
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
(to Aug
25th)
Health Protection Agency Meningococcal Reference Unit- Unpublished data

8. Laboratory confirmed cases of MenW
disease in England and Wales
1995 to 2012 (calendar year)
140
Outbreak
120
100
No of confirmed cases
80
60
40
20
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
(to Aug
25th)
Health Protection Agency Meningococcal Reference Unit- Unpublished data

9. International Hajj associated
MenW outbreak 2000*
Netherlands: 9
Scotland: 1
Norway: 1
England & Wales: 50 Sweden: 2
Finland: 2
Belgium: 1 Denmark: 1
Germany: 10
France: 21 Kuwait: 3
USA: 4 Morocco: 3
Singapore: 4
Indonesia: 14
Burkina Faso
(2002), 13,000 S. Arabia: 241
*cases Apr to Dec 2000, WHO Oman: 18

10. Laboratory confirmed cases of MenY
disease in England and Wales
1995 to 2012 (calendar year)
100
90
80
70
No of confirmed cases
60
50
40
30
20
10
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
(to Aug
25th)
Health Protection Agency Meningococcal Reference Unit- Unpublished data

11. Emergence of MenY
in Europe
Increases in disease due to MenY has
been observed in a number of Countries
across Europe
France
Sweden
Germany
Switzerland
Finland
Norway
Reference: EMGM May 2011
England and Wales
Czech Republic
Gray SJ, et al. Presented at: EMGM . Ljubljana, Slovenia. May 18–20, 2011.

12. 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

13. Laboratory confirmed cases of meningococcal
disease in England and Wales in
2012 (calendar year)
Y other
W 10% 2%
3%
C
3%
B
82%
Health Protection Agency Meningococcal Reference Unit- Unpublished data

14. Laboratory confirmed cases of meningococcal
disease (all groups) in England and Wales
1995 to 2012 (calendar year)
3000
2500
2000
No of confirmed cases
1500
1000
500
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
(to Aug
25th)
Health Protection Agency Meningococcal Reference Unit- Unpublished data

15. 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)
~54% of disease <1 year annualis within the first 6 months
Average of age number of laboratory confirmed cases of all Meningococcal
disease in under-2s by serogroup and month of age (2006-07 to 2009-10)
40.0
35.0 Other groups
Ungrouped
30.0 ACWY
Number of reports
B
25.0
20.0
15.0
10.0
5.0
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age (months)
Ladhani et al., Vaccine 2012;30:3710-6

16. 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)
300
ACWY
250 Ungrouped
Other groups
B
Number of reports
200
150
100
50
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Age (years)
Ladhani et al., Vaccine 2012;30:3710-6

17. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

18. Meningococcal conjugate vaccine
production
Polysaccharide capsule
C 1999
Vaccine
A C Y W 2010
A 2010
B ?

19. How do we use meningococcal
vaccines to achieve optimal
protection?
Infants
Indirect
protection
Adolescents

20. Meningococcal conjugate
vaccines
Vaccine Active Manufacturer Carrier protein
constituents
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 Tetanus toxoid
India
No licensed MenB vaccine available

21. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

22. 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.
 Use subcapsular antigens, which are;
(i) Surface exposed.
(ii) Conserved.
(iii) Induce bactericidal activity.
Downside of approach = Diversity

23. Subcapsular approaches
 Development of subcapsular antigen vaccines has broadly followed
two pathways-
(i) Outer membrane vesicles (OMVs) (ii) Individual proteins
 Used successfully to combat single
clone epidemics of MenB disease.
 Immune response is primarily Purified or recombinant outer
directed against the PorA membrane proteins
Blebbing Purified OMVs
protein, resulting in limited cross-

24. 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.

25. fHBP
Variant or family groups
Variant 1 Family B
Novartis Pfizer
Variant 1 Family B
Variants 2 & 3 Family A
Variant 2
Intra-family cross-reactivity good.
Family A
Inter-family cross reactivity poor.
Variant 3

26. Clinical development of the Pfizer
investigational MenB vaccine
 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.
Current situation
 Evaluation continuing through later phase trials.
 Will be targeted for an adolescent indication.
Anderson AS, Jansen KU & Eiden J. Expert Rev Vaccines 2010;10:617-34.

27. Novel antigens discovered by
reverse vaccinology
Based on the genome sequence of MC58,
~350 proteins successfully expressed in
570 ORFs that potentially encoded novel surface
E.coli, purified, and used to immunise mice
exposed or exported proteins were identified
1 IHT-A
2,200,000 100,000
2,100,000 200,000
2,000,000 300,000
expression
IHT-C 1,900,000
400,000
and
1,800,000
500,000
purification
1,700,000
IHT-B
600,000 purified proteins
1,600,000
700,000
1,500,000
800,000
1,400,000
900,000
1,300,000
1,000,000
1,200,000 1,100,000
Sera used to confirm
surface exposure of immunisations
novel proteins
Bexsero®
28 novel
protein
antigens
identified
Slide provided by Novartis Vaccines

28. Novartis investigational MenB
®
4CMenB vaccine(Bexsero )
 Bexsero (previously known as 4CMenB or rMenB+OMV) contains 4
main antigens.
 Three recombinant proteins discovered by reverse vaccinology.
 OMVs from the New Zealand outbreak strain (NZ 98/254).
fHBP NadA NHBA PorA
(Variant 1) (presented as
part of an OMV)
http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero

29. 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.
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).
Bai X, Findlow J & Borrow R. Expert Opin Biol Ther 2011;11:969-85.

30. 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).

31. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

32. Proportions of sera with MenC SBA titres ≥8 by
age in England & Wales, pre and post-
introduction of MCC vaccines
Consequently, need to introduce a
1996-99 2009 booster dose for MenC to
100
(i) Provide direct protection
90
(ii) Maintain herd protection
80
70
% with SBA titre >=8
60
50
40
30
20
10
0
6-11 mths
<6 mths
10-14 yrs
15-19 yrs
20-24 yrs
35-44 yrs
45-54 yrs
55-64 yrs
65+ yrs
25-34 yrs
1-4 yrs
5-9 yrs
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

33. “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.”

34. MenC booster
“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.”

35. Quadrivalent meningococcal vaccines
“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.”

36. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

37. 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)
250 06-07 07-08 08-09 09-10 10-11 11-12
200
PCV13 introduced WHITE
LINE Week 13 2010
Number of Reports
150
100
Introduction of Prevenar™
BLUE LINE Week 36 2006
50
Vaccine effectiveness
of additional 6
serotypes = 80%
0
Week

38. 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)
06-07 07-08 08-09 09-10 10-11 11-12
140
120 PCV13 introduced WHITE
LINE Week 13 2010
100
Number of Reports
80
60
Introduction of Prevenar™
40 BLUE LINE Week 36 2006
20
0
Week
Unclear whether there is an increase in non PCV13 serotypes as yet in children

39. 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)
2500 06-07 07-08 08-09 09-10 10-11 11-12
PCV13 introduced WHITE
LINE Week 13 2010
2000
Number of Reports
1500
1000
Introduction of Prevenar™
BLUE LINE Week 36 2006
Early evidence of
500 herd protection
(within 18 months of
implementation)
0
Week

40. 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)
3000 06-07 07-08 08-09 09-10 10-11 11-12
2500 PCV13 introduced WHITE
LINE Week 13 2010
2000
Number of Reports
1500
Introduction of Prevenar™
1000 BLUE LINE Week 36 2006
500
0
Week
Unclear whether there is an increase in non PCV13 serotypes as yet in >5 year olds

41. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

42. Pneumococcal vaccines
“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.”

43. Overview
 Neisseria meningitidis.
 Recent epidemiology.
 Vaccines and protection strategies.
 MenB vaccines.
 Forthcoming schedule changes.
 Streptococcus pneumoniae.
 Recent epidemiology.
 Vaccine use update.
 Summary.

44. Summary (1)
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.

45. Summary (2)
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.

46. Summary (3)
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.

47. Summary (4)
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).

48. What the papers say
10th June 2011 or
2012 30th Sept 2012
2013?

49. Acknowledgements
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.