0
Non-routine use of meningococcal vaccines
‘At-risk’ groups

Outbreak settings
Dr Matthew Snape
Consultant in General Paedi...
Disclosures
• Investigator for Clinical Trials funded by Novartis
Vaccines, Pfizer, Sanofi-Pasteur MSD, GSK
• Participated...
JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once ...
Who is considered
as ‘at risk’?
•

Complement deficiency
•

Eculizumab therapy

•

Asplenia

•

Splenic dysfunction

•

Im...
Immunity against invasive meningococcal
disease in the healthy host
Complement mediated lysis: Membrane attack complex

Ja...
The complement system and
meningococcal disease

Membrane Attack Complex

Lewis and Ram, Virulence, 2013
Complement deficiencies and risk of meningococcal
infection: Classical pathway

Inherited deficiencies in CP
(C2, C4) more...
Complement Deficiencies and risk of
meningococcal infection: Lectin pathway
?MBL variant
alleles associated
with ↑ risk IM...
Complement Deficiencies and risk of
Meningococcal Infection: Alternative pathway

Factor H and factor I deficiencies lead ...
Complement Deficiencies and risk of
Meningococcal Infection:
terminal complement deficiencies

•

Terminal complement defi...
Acquired Complement Deficiencies

1. SLE/ membranoproliferative glomerulonephritis
2. Eculizumab:
•
•
•

Humanised Monoclo...
Eculizumab and meningococcal disease

•
•
•
•
•

195 patients over 66 months
4.2 episodes IMD per 1000 patient years
One c...
Immunising those with
complement deficiency
Is there any point in the
absence of ability to
generate complement
mediated l...
Immunity against invasive meningococcal
disease in the healthy host
Complement mediated lysis:
Membrane attack complex

Op...
Polysaccharide MenACWY vaccines: immunogenicity
in complement deficiency vs controls (IgG)

Serogroup
specific IgG
concent...
45 patients with terminal complement deficiencies
previously experiencing 1 to 5 cases of IMD +/immunisation with MenACWY ...
Newer generation
vaccines?
MenC/ MenACWY
• No data on glyco-conjugate vaccines in individuals with
complement deficiency
•...
Bactericidal activity underestimates killing in passive
protection model, and opsonophagocytic activity
•

Immunisation wi...
Proportion of IMD patients with
complement deficiency
•

Inherited deficiencies of complement in ~ 0.03% of Caucasian popu...
Spleen function and
meningococcal disease
• Important site for filtering and
phagocytosis of opsonised
organisms
• Functio...
Response to meningococcal vaccines
in individuals with apslenia

• 130 asplenics
– Immunised with monovalent MenC vaccine
...
Response to meningococcal vaccines
in individuals with apslenia
% with rSBA ≥ 8
PrePost dose 1
immunisation
Asplenics
Cont...
Meningococcal immunisation in HIV
• New York database study of 265 cases meningococcal
disease between 2000 and 2011
• The...
Meningococcal disease in other
immunocompromised patients

• No formal analysis of increased risk of
meningococcal disease...
Immunisation post BMT
46 patients post allogenic BMT
•
•
•

Immunised with MenACWY-Dip
vaccine at 9 to 25 years
0.6 to 5.2...
MenACWY-Dip in HIV
Immunogenicity post first and second dose MenACWY-Dip given 6
months apart to 2 – 10 year olds (all CD4...
MenB immunisation
• No reports of immunogenicity of recently
licensed MenB vaccine in
apslenics, HIV, immunosuppressed
Current UK recommendations:
Meningococcus

First presenting
under two years

Complete
according to
routine
schedule

MenAC...
Current UK recommendations:
Meningococcus

Over two years

Hib-MenC booster

MenACWY

‘Individuals with immunosuppression ...
Licensed posology for 4CMenB

Bexsero SPC
JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once ...
Laboratory workers and
meningococcal disease: USA
Suggested annual incidence of
20/100000.
(Compared with 0.3/100000 for U...
Laboratory workers and
meningococcal disease: UK

All 5 cases prepared N.meningitidis
outside safety cabinet

Annual incid...
Immunisation of
laboratory workers

Kimura et al Clin Vacc Immunol 2011
JCVI interim position statement on
use of Bexsero® meningococcal B
vaccine in UK: July 2013
• JCVI …. concluded that once ...
Risk in month from
meningococcal disease
• 97% cases sporadic
• Background 1/250,000/month
• After a household contact?

H...
Risk in month from
meningococcal disease
• 97% cases sporadic
• Background 1/250,000/month
• After a household contact? – ...
Management of case
clusters
•

Individuals who were identified as close
prolonged contacts of cases due to
vaccine prevent...
Summary
• Groups at increased risk for meningococcal disease
– Immunodeficiency
• Inherited
• Acquired, including iatrogen...
Acknowledgments
• Noel McCarthy
– Public Health England

• Dominic Kelly, Fiona McQuiad
– Oxford Vaccine Group
Non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk factors
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Non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk factors

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

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Transcript of "Non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk factors"

  1. 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. 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
  3. 3. 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.
  4. 4. Who is considered as ‘at risk’? • Complement deficiency • Eculizumab therapy • Asplenia • Splenic dysfunction • Immunosuppressed, HIV infection
  5. 5. 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
  6. 6. The complement system and meningococcal disease Membrane Attack Complex Lewis and Ram, Virulence, 2013
  7. 7. 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
  8. 8. Complement Deficiencies and risk of meningococcal infection: Lectin pathway ?MBL variant alleles associated with ↑ risk IMD Membrane Attack Complex Lewis and Ram, Virulence, 2013
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. Immunising those with complement deficiency Is there any point in the absence of ability to generate complement mediated lysis? Membrane Attack Complex
  14. 14. 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
  15. 15. Polysaccharide MenACWY vaccines: immunogenicity in complement deficiency vs controls (IgG) Serogroup specific IgG concentrations Fijen et al 1998
  16. 16. 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
  17. 17. 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?
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. Meningococcal disease in other immunocompromised patients • No formal analysis of increased risk of meningococcal disease – Post BMT – Chemotherapy – Other immunosuppressive medication
  25. 25. 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
  26. 26. 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
  27. 27. MenB immunisation • No reports of immunogenicity of recently licensed MenB vaccine in apslenics, HIV, immunosuppressed
  28. 28. 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
  29. 29. 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
  30. 30. Licensed posology for 4CMenB Bexsero SPC
  31. 31. 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.
  32. 32. 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
  33. 33. 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
  34. 34. Immunisation of laboratory workers Kimura et al Clin Vacc Immunol 2011
  35. 35. 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.
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. Acknowledgments • Noel McCarthy – Public Health England • Dominic Kelly, Fiona McQuiad – Oxford Vaccine Group
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