Prospects for preventing bacterial meningitis

Elizabeth Miller

Immunisation Department

Centre for Infections

Health Protection Agency,

Colindale, London

Bacteraemia

Soft Tissue Infection

Arthritis

Sinusitis

Otitis Media

Meningitis

Pneumonia

Peritonitis

The Clinical Spectrum of Pneumococcal Disease

Outcomes of bacterial meningitis by causative organism

Meta-analysis of prospective cohort studies from developed countries: Baraff et al.

0

5

10

15

20

25

30

Mortality Retardation Spasticity/paresis Deafness Seizure Disorder

% o

f C

hild

ren

S.pneumoniae

N.meningitidis

H.influenzae

% o

f ch

ildre

n

Pneumococcal Meningitis - Proportion of cases infected with a conjugate vaccine serotype1998-2004

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

a. <2m b. 2-5m c. 6-11m d. 1-4y e. 5-9y f. 10-79y g. 80+Age Group

7valent 9valent 11valent

Age group Annual no. (mean 1998-04)

No.with 7 valent serotype

Annual cases in 1st year with

<2 m 5 2 5

2-5 m 30 18 21

6-11 m 46 37 10

1-<2 yrs 25 21 6

2-4 yrs 17 14 17

5-14 yrs 10 5 10

15-44 yrs 43 18 43

45-64 56 23 56

65+ yrs 49 25 49

Total* 281 163 217*excludes 13 with age NK

Predicted effect in 1st year on number of pneumo meningitis cases of a 7 valent conjugate catch-up to 2 years, (no herd immunity,

100% instant uptake)

Meningococcal Disease

Annual meningococcal cases and deaths by serogroup

and year: E&W 1998-2004

0

200

400

600

800

1000

1200

1400

1600

1800

1998 1999 2000 2001 2002 2003 2004

BC

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003 2004

Cases Deaths

Number of deaths by age group from meningococcal serogroup B disease, 1998-2004

0

20

40

60

80

100

120

140

160

1 2 3-4 5-8 9-10 11-14 15-19 20-24 25+

Age (years) Total identified deaths 442

Mean 63/yr

Ideal requirements for a Men (B) vaccine

• Able to be licensed on basis of correlate of protection – Agreed protective level of serum bactericidal antibody– International standardisation of SBA assay– Supportive evidence from other assays e.g. OPA, CMI

• High coverage of prevalent strains

• Long-term persistence of SBA above protective threshold

Invasion can lead within 12 hours to fulminant sepsis

Time interval from exposure to onset in UK laboratory workers:

Case 1 Case 2 Case 3 Case 4 Case 5

3 days 5 days within 7 days 4 days 5 days

Carrier status of military recruits prior to disease

Day pre-admission 0 1-2 3-4 5-7 8-10 11-15No. men tested 36 5 11 6 5 9No. men +ve NP 36 1 4 0 0 0

Boutet et al. J Hosp Infect 2001;49:282-4.

Edwards et al. Scand J Infect Dis 1977;9:105-110.

Ideal requirements for a Men B vaccine

• Able to be licensed on basis of correlate of protection

– Agreed protective level of serum bactericidal antibody– International standardisation of assays– Supportive evidence from other assays e.g. OPA, CMI

• High coverage of prevalent strains

• Long-term persistence of SBA above protective threshold

• Reduce carriage and thus able to induce herd immunity:

– Continuing protection for vaccinated if efficacy wanes

– Able to protect the unvaccinated

Meningococcal OMV vaccine trials (2 doses)

Estimated efficacy

1987-89 4:P1.1510 - 14 years

83%

4:P1.153 months - 6 years 47-74%

Norway 15:P1.1611 - 16 years 57%

Chile 15:P1.31 - 21 years 51%

Year Age group VaccineCuba

Brazil 1989-91

1989-91

1987-89

% of adults given Norwegian strain OMV vaccine with > 4 fold rises in SBA and anti-OMV IgG (pre- to post-3rd dose) against

homologous and heterologous strains

0

10

20

30

40

50

60

70

80

90

Vaccinestrain

NewZealandstrain

UK strainMO1

240013

UK strainMO1

240101

UK strainM01

240149

UK strainM01

240185

UK strainM01

240355

SBA

Anti-OMV IgG

J Findlow et al – unpublished

The top 90%, PHLS MRU meningococcal group B serosubtype data, 01/10/2000 to 31/10/2001

0

20

40

60

80

100

serosubtype

Cumu

lative

plot of

each

serosu

btype

as a %

of all

menin

gococc

al B iso

lates

Serogroup distribution of IMD by year,all European countries in EU IBIS scheme

0%10%20%

30%40%50%60%70%

80%90%

100%

1999 2000 2001 2002 2003 2004

otherCB

Potential maximal coverage of serogroup B OMV vaccines in Europe, all countries and years combined

0%10%20%30%40%50%60%70%80%90%

100%

Cuban (P1.15) Walter Reed(P1.13)

Norwegian(P1.7,16)

NZ (P1.7,4) RIVM nonavalent

Potential coverage No coverage

Assumptions – any PorA variant that is picked up by monoclonal will be prevented by vaccine containing any variant of the same subtype family, ignoring any PorB protection

Serogroups A, C, Y and W135 Serogroup B

Conclusion

Acknowledgements

• Rob George and staff of the HPA Respiratory & Systemic Laboratory, Colindale

• Usha Gungabissoon and Mary Ramsay, HPA, Immunisation Department, Colindale

• Ray Borrow, Ed Kaczmarski and staff at the HPA Meningococcal Reference Unit

• MRF for funding our trials with OMV vaccines