Dr Matthew Snape's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

1. Non-routine use of meningococcal vaccines
‘At-risk’ groups
Outbreak settings
Dr Matthew Snape
Consultant in General Paediatrics and Vaccinology
Oxford Vaccine Group
Oxford University Hospitals NHS Trust

2. Disclosures
• Investigator for Clinical Trials funded by Novartis
Vaccines, Pfizer, Sanofi-Pasteur MSD, GSK
• Participated in industry sponsored symposium and
advisory panels
• Travel and accommodation costs paid by
pharmaceutical companies to attend international
conferences
• No personal financial benefit - all payments to
University of Oxford Department of Paediatrics

4. JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once Bexsero® is available it should be
offered selectively to the same high risk groups for IMD that are
offered meningococcal ACWY conjugate vaccine currently
(excluding where used as a travel vaccine).Since there are no data
on the cost effectiveness of these immunisations, this advice is
based on clinical judgement.
• Bexsero® could also be offered to laboratory workers who are at
high risk of occupational exposure to meningococcal serogroup B.
• JCVI also supports plans for Public Health England to produce
guidance on the use of Bexsero® for close contacts of cases in
outbreaks of IMD associated with meningococcal serogroup B.

5. Who is considered
as ‘at risk’?
•
Complement deficiency
•
Eculizumab therapy
•
Asplenia
•
Splenic dysfunction
•
Immunosuppressed, HIV infection

6. Immunity against invasive meningococcal
disease in the healthy host
Complement mediated lysis: Membrane attack complex
Janeway et al, 2005
Crucial role of complement mediated lysis in protection against invasive
meningococcal disease recognised by use of complement dependent bactericidal
assays as correlate of protection, rather than quantitative IgG measurement

7. The complement system and
meningococcal disease
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

8. Complement deficiencies and risk of meningococcal
infection: Classical pathway
Inherited deficiencies in CP
(C2, C4) more commonly
associated with autoimmunity, pneumococcal
infections
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

9. Complement Deficiencies and risk of
meningococcal infection: Lectin pathway
?MBL variant
alleles associated
with ↑ risk IMD
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

10. Complement Deficiencies and risk of
Meningococcal Infection: Alternative pathway
Factor H and factor I deficiencies lead to
unregulated activation AP and consequent
complement depletion and ↑ IMD risk
70 cases of properidon deficiency described
(required to stabilise C3, C5 convertase
molecules). ↑ risk and severity IMD
Primary C3 deficiency rare (20 reported cases)
Experience severe, recurrent infections with S.
pneumo, Hib, meningococcus.
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

11. Complement Deficiencies and risk of
Meningococcal Infection:
terminal complement deficiencies
•
Terminal complement deficiencies C6, C7, C8, (C9) →7000 – 10 000 fold higher risk of IMD
•
IMD observed in 40 – 50%
•
Episode of IMD provides no protection against subsequent IMD, despite antibody response
•
Lower mortality from IMD (Reduced endotoxin release due to lack of MAC?)
•
Appears to specifically ↑ IMD risk
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

12. Acquired Complement Deficiencies
1. SLE/ membranoproliferative glomerulonephritis
2. Eculizumab:
•
•
•
Humanised Monoclonal antibody
High affinity binding of C5
Prevents cleavage to
• C5a (anaphylatoxin)
• C5b (initiates membrane attack complex formation)
X
Membrane Attack Complex
Lewis and Ram, Virulence, 2013

13. Eculizumab and meningococcal disease
•
•
•
•
•
195 patients over 66 months
4.2 episodes IMD per 1000 patient years
One case serogroup B (immunised against ACWY)
One case W or Y (immunised against A and C)
Both treated successfully
Hillmen et al Br J Haem. 2013

14. Immunising those with
complement deficiency
Is there any point in the
absence of ability to
generate complement
mediated lysis?
Membrane Attack Complex

15. Immunity against invasive meningococcal
disease in the healthy host
Complement mediated lysis:
Membrane attack complex
Opsonophagocytosis
Phagocyte
Janeway et al, 2005
Criss et al Nature Reviews Microbiology 2012

16. Polysaccharide MenACWY vaccines: immunogenicity
in complement deficiency vs controls (IgG)
Serogroup
specific IgG
concentrations
Fijen et al 1998

17. 45 patients with terminal complement deficiencies
previously experiencing 1 to 5 cases of IMD +/immunisation with MenACWY polysaccharide vaccine
6 episodes out of 31 patients
• 3B, 1C, 2 unknown
N = 31
N = 14
6 episodes out of 14 patients
• 1B, 2A, 1C, 2 unknown
Protection against subsequent invasive meningococcal disease over 2 years
Platanov et al Vaccine 2003

18. Newer generation
vaccines?
MenC/ MenACWY
• No data on glyco-conjugate vaccines in individuals with
complement deficiency
• Likely to be at least as effective as plain polysaccharide
vaccines
MenB
• No data in individuals with complement deficiency
• Will antibodies against sub-capsular antigens be as effective
for opsonophagocytosis?

19. Bactericidal activity underestimates killing in passive
protection model, and opsonophagocytic activity
•
Immunisation with 3 doses of rMenB
– MenB vaccine with fHbp, NadA, NHBA vaccine (no OMV)
•
Proportions of immunized subjects with titres of ≥1:4 in
SBA, opsonophacoytic (OPA) or passive protection (PP) assays.
Plested et al Clin Vacc Immunol 2009

20. Proportion of IMD patients with
complement deficiency
•
Inherited deficiencies of complement in ~ 0.03% of Caucasian population
–
C2 def 0.01%
In UK:
• 297 children with serogroup B or C IMD
screened for complement deficiency
• 1 case of C2 deficiency
• 4 yr old, previous pneumococcal
infection
Hoare et al ADC 2002
Figueroa et al Clin Microbiol Rev 1991

21. Spleen function and
meningococcal disease
• Important site for filtering and
phagocytosis of opsonised
organisms
• Functional/anatomical asplenia
associated with impaired
opsonophagocytosis
• Pneumococcus accounts for 80 –
90% of invasive disease postsplenectomy
• Numerous case reports of
overwhelming meningococcal sepsis
post splenectomy
• No formal calculations of incidence
of mortality

22. Response to meningococcal vaccines
in individuals with apslenia
• 130 asplenics
– Immunised with monovalent MenC vaccine
• mostly MenC-CRM
– 17 to 86 year olds (median 54)
• Median age at splenectomy 29 years
• Time from splenectomy to immunisation -0.19 to 53 years
(median 18, 2 received MenC prior to splenectomy)
– 41 to 64 year olds controls (median 47)
Balmer et al Inf and Imm 2004

23. Response to meningococcal vaccines
in individuals with apslenia
% with rSBA ≥ 8
PrePost dose 1
immunisation
Asplenics
Control
rSBA GMT
Post dose 1
26%
80%
48%
98%
157.8
(94.5 – 263.3)
rSBA GMT by
asplenia aetiology
Medical
Trauma
92.1
354.1
1448.2
(751.1 – 2792.0)
• 23 asplenics with post dose 1 SBA < 16 had serum available post 2nd dose MenC
• 16 MenC-CRM, 7 MenC-TT
• 14 (61%) SBA ≥ 8 post 2nd dose.
• 9 (39%) with SBA < 8
Balmer et al Inf and Imm 2004

24. Meningococcal immunisation in HIV
• New York database study of 265 cases meningococcal
disease between 2000 and 2011
• The relative risk for IMD in HIV +ve individuals was 10.0
(95% CI, 7.2 to 14.1).
• The average annual incidence rate of IMD was 0.39
cases per 100 000 persons.
• Among HIV +ve, patients with IMD were 5.3 times
(CI, 1.4 to 20.4 times) as likely as age-matched control
patients to have CD4+ counts < 0.200 × 109 cells/L.
Miller et al Ann Intern Med Oct 2013

25. Meningococcal disease in other
immunocompromised patients
• No formal analysis of increased risk of
meningococcal disease
– Post BMT
– Chemotherapy
– Other immunosuppressive medication

26. Immunisation post BMT
46 patients post allogenic BMT
•
•
•
Immunised with MenACWY-Dip
vaccine at 9 to 25 years
0.6 to 5.2 years post BMT
6 on ritixumab
Response to single dose
MenACWY-Dip in 46
patients:
•
16 failed to respond to any
serogroup
Serogroup
specific IgG
For non-responders, 2nd dose
1.6 to 28 months following first
(n = 16)
Mahler et al Biol Blood Marrow Transp 2012

27. MenACWY-Dip in HIV
Immunogenicity post first and second dose MenACWY-Dip given 6
months apart to 2 – 10 year olds (all CD4% ≥ 15)
Post dose 1
In 11 to 24 year olds
• Poor immunogenicity of single dose MenACWY-Dip for serogroup C
• Good response for all serogroups following 2nd dose
• Reduced immunogenicity if CD4%< 15
Siberry et al PIDJ 2012
Lujan-Zilbermann J Peds 2012
Post dose 2

28. MenB immunisation
• No reports of immunogenicity of recently
licensed MenB vaccine in
apslenics, HIV, immunosuppressed

29. Current UK recommendations:
Meningococcus
First presenting
under two years
Complete
according to
routine
schedule
MenACWY
at least one
month after
Hib-MenC
After 2nd
birthday
one
additional
dose of
Hib-MenC
•
MenACWY-TT licensed from one year
•
MenACWY-CRM licensed from 2 years of age in Europe (from 2 months of age in USA)
Immunisation against infectious disease:
The Green Book. Public Health England

30. Current UK recommendations:
Meningococcus
Over two years
Hib-MenC booster
MenACWY
‘Individuals with immunosuppression and HIV infection …..should be given
meningococcal vaccines in accordance with the routine schedule……Re-immunisation
should be considered after treatment is finished and recovery has occurred.’
Immunisation against infectious disease:
The Green Book. Public Health England

31. Licensed posology for 4CMenB
Bexsero SPC

32. JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once Bexsero® is available it should be
offered selectively to the same high risk groups for IMD that are
offered meningococcal ACWY conjugate vaccine currently
(excluding where used as a travel vaccine).Since there are no data
on the cost effectiveness of these immunisations, this advice is
based on clinical judgement.
• Bexsero® could also be offered to laboratory workers who are at
high risk of occupational exposure to meningococcal serogroup B.

33. Laboratory workers and
meningococcal disease: USA
Suggested annual incidence of
20/100000.
(Compared with 0.3/100000 for US
adult population)
17/18 cases (data available) involved
processing meningococcal isolates
outside of biosafety cabinet
Sejvar et al J Clin. Microbiol. 2005

34. Laboratory workers and
meningococcal disease: UK
All 5 cases prepared N.meningitidis
outside safety cabinet
Annual incidence of 130 per 100 000
RR of 184 (60 – 431) compared with
adult population
Boutet et al J Hosp Inf 2001

35. Immunisation of
laboratory workers
Kimura et al Clin Vacc Immunol 2011

36. JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once Bexsero® is available it should be
offered selectively to the same high risk groups for IMD that are
offered meningococcal ACWY conjugate vaccine currently
(excluding where used as a travel vaccine).Since there are no data
on the cost effectiveness of these immunisations, this advice is
based on clinical judgement.
• Bexsero® could also be offered to laboratory workers who are at
high risk of occupational exposure to meningococcal serogroup B.
• JCVI also supports plans for Public Health England to produce
guidance on the use of Bexsero® for close contacts of cases in
outbreaks of IMD associated with meningococcal serogroup B.

37. Risk in month from
meningococcal disease
• 97% cases sporadic
• Background 1/250,000/month
• After a household contact?
HPA
Davison et al Arch Dis Child 2004

38. Risk in month from
meningococcal disease
• 97% cases sporadic
• Background 1/250,000/month
• After a household contact? – 1/300
• After a case in your school (E and W 1995 to 2001):
– Nursery 1/1500 (age specific background 1/3000)
– Primary 1/18000
– Secondary 1/33000
HPA
Davison et al Arch Dis Child 2004

39. Management of case
clusters
•
Individuals who were identified as close
prolonged contacts of cases due to
vaccine preventable strains of N.
meningitidis who received
chemoprophylaxis should be offered an
appropriate vaccine once diagnosis has
been confirmed and up to four weeks
after illness onset.
•
MenC contacts receive MenC boost if
completed infant prime/boost more
than a year previously
•
MenACWY (conjugate) for any contact
MenA, W or Y disease

40. Summary
• Groups at increased risk for meningococcal disease
– Immunodeficiency
• Inherited
• Acquired, including iatrogenic
– Exposure
• Laboratory workers
• Outbreak settings
• Precedent of MenACWY vaccines shows complement
deficiencies can be overcome by immunisation
• Evidence for MenB immunogenicity in immunodeficient
patients important area for future research

41. Acknowledgments
• Noel McCarthy
– Public Health England
• Dominic Kelly, Fiona McQuiad
– Oxford Vaccine Group