non-routine use of meningococcal vaccines in outbreaks and for individuals with clinical risk...

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Non-routine use of meningococcal vaccines

Dr Matthew SnapeConsultant in General Paediatrics and VaccinologyOxford Vaccine GroupOxford University Hospitals NHS Trust

‘At-risk’ groups

Outbreak settings

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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

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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.

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Who is considered as

‘at risk’?• Complement deficiency

• Eculizumab therapy

• Asplenia

• Splenic dysfunction

• Immunosuppressed, HIV infection

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Immunity against invasive meningococcal disease in the healthy

host

Janeway et al, 2005

Complement mediated lysis: Membrane attack complex

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

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The complement system and meningococcal disease

Membrane Attack Complex

Lewis and Ram, Virulence, 2013

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Complement deficiencies and risk of meningococcal infection: Classical pathway



Inherited deficiencies in CP (C2, C4) more commonly associated

with auto-immunity, pneumococcal infections

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Complement Deficiencies and risk of meningococcal infection: Lectin

pathway


?MBL variant alleles associated

with ↑ risk IMD


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Complement Deficiencies and risk of Meningococcal Infection: Alternative

pathway


Primary C3 deficiency rare (20 reported cases)Experience severe, recurrent infections with S. pneumo, Hib, meningococcus.

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


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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


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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


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Eculizumab and meningococcal disease

Hillmen et al Br J Haem. 2013

• 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

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Immunising those with complement deficiency


Is there any point in the absence of ability to

generate complement mediated lysis?

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Immunity against invasive meningococcal disease in the healthy

hostOpsonophagocytosis

Criss et al Nature Reviews Microbiology 2012Janeway et al, 2005

Complement mediated lysis: Membrane attack complex

Phagocyte

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Polysaccharide MenACWY vaccines: immunogenicity in complement deficiency

vs controls (IgG)

Fijen et al 1998

Serogroup specific IgG

concentrations

www.ovg.ox.ac.uk Platanov et al Vaccine 2003

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

6 episodes out of 14 patients• 1B, 2A, 1C, 2 unknown

Protection against subsequent invasive meningococcal disease over 2 years

N = 31

N = 14

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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?

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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

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Proportion of IMD patients with complement deficiency

Figueroa et al Clin Microbiol Rev 1991

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

• Inherited deficiencies of complement in ~ 0.03% of Caucasian population

– C2 def 0.01%

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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 post-splenectomy

• Numerous case reports of overwhelming meningococcal sepsis post splenectomy

• No formal calculations of incidence of mortality

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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

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% with rSBA ≥ 8 rSBA GMT

Pre-immunisatio

n

Post dose 1

Post dose 1 rSBA GMT by asplenia aetiology

Asplenics 26% 80% 157.8(94.5 – 263.3)

Medical Trauma

92.1 354.1

Control 48% 98% 1448.2(751.1 – 2792.0)

Response to meningococcal vaccines in individuals with

apslenia

• 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

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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

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Meningococcal disease in other immunocompromised patients

• No formal analysis of increased risk of meningococcal disease – Post BMT– Chemotherapy– Other immunosuppressive medication

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Immunisation post BMT

Mahler et al Biol Blood Marrow Transp 2012

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)

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MenACWY-Dip in HIVImmunogenicity post first and second dose MenACWY-Dip given 6 months apart to 2 – 10 year olds (all CD4% ≥ 15)

Siberry et al PIDJ 2012

Post dose 1 Post dose 2

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

Lujan-Zilbermann J Peds 2012

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MenB immunisation

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

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Current UK recommendations:

Meningococcus

Immunisation against infectious disease: The Green Book. Public Health England

• MenACWY-TT licensed from one year

• MenACWY-CRM licensed from 2 years of age in Europe (from 2 months of age in USA)

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

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Current UK recommendations:

Meningococcus

Immunisation against infectious disease: The Green Book. Public Health England

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.’

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Licensed posology for 4CMenB

Bexsero SPC

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Laboratory workers and meningococcal disease:

USA

Sejvar et al J Clin. Microbiol. 2005

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

www.ovg.ox.ac.uk Boutet et al J Hosp Inf 2001

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

Laboratory workers and meningococcal disease:

UK

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Immunisation of laboratory workers

Kimura et al Clin Vacc Immunol 2011

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• 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.

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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

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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

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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

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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

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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...

Health & Medicine