1. Evidence and control: meningococcal disease

2. Public health policy in UK Cases and contacts bp to case before admission rif or cipro to case and close contacts vaccinate close contacts if A,C,W135,Y give out information outbreaks: 2 or more cases in a school, wider public health action http://www.hpa.org.uk/cdph/issues/CDPHVol5/no3/ Meningococcal_Guidelines.pdf

3. Pre-admission antibiotics and mortality Systematic review Oral antibiotics (n=5) RR 0.17 (0.07 - 0.43) Parenteral antibiotics (n=12) marked heterogeneity unable to estimate RR

4. Parenteral pre-admission antibiotics and mortality

5. Relationship between risk ratio and proportion of treated cases

6. What doers it all mean? Confounding by severity inadequate stratification to deal with confounding in observational studies of physician behaviour need RCT Effect modification true harm in severe subset, true benefit for most

7. Carriage eradication in close contacts high risk in close contacts (RR >500, AR 1 in 200 – 1 in 300) highest in first 24 hours case infectious for very short period (<24hours) before illness may continue to be carrier afterwards asymptomatic carriers infectious for 1-2 years risk to close contacts likely from carrier among close contacts policy of carriage eradication should also prevent disease in newly acquired carrier

8. Antibiotics to households Risk reduction 1-30 days after index case

9. Risk ratio [95% CI] CDC 1976 Samuelsson 2000 Scholten 1993 0.11 [0.02, 0.58] Overall Risk Ratio 0 1 2 3 6.14 Antibiotics to households Risk reduction 1-30 days after index case

10. Measure of effect NNT = 1/RD = 1/(Ie – Iue) = 1000/4.6 = 218 95%CI 150- 367

11. Interval between 1st and 2nd cases in clusters

12. Vaccination low effectiveness in preventing illness among contacts, as risk is highest early on, before vaccination can generate immunity so, for prevention in Europe we rely mainly on antibiotics for close contacts Our aim is for primary prevention through vaccination

13. Polysaccharide vaccines A,C, W135, Y Produced from purified PS antigens from capsule of organism (Nm) No immunological memory, short term protection Antibody response is age dependent Low efficacy in infants (especially C)

14. Conjugate vaccines Monovalent (C, A) and quadrivalent ACW135Y PS antigen attached to carrier protein (e.g. TT, CRM-197) T cell dependent response Immunological memory and prolonged protection Good response in young infants but may need booster

15. Serogroup B and C cases 1998 – 2005 England and Wales Men C campaign

16. Vaccine efficacy to four years by catch-up cohort and time (England)

17. Herd immunity effect Conjugate vaccines shown to reduce carriage 70% reduction in carriage of serogroup C meningococci one year after vaccination in teenagers should lead to indirect protection in unvaccinated Reduced attack rates in unvaccinated before and 2 years after MenC programme In <20 year olds, attack rate reduced by 67% (52-77%) Followed by decline in >20 year olds (not included in vaccination programme)

18. Serogroup C cases by age group 1998-2005 Men C campaign

19. What’s next? Group B vaccines Group B polysaccharide not immunogenic Outer membrane proteins generate serosubtype specific immunity (New Zealand) Modified capsular polysaccharide with conjugation to a protein carrier (non starter) Genome “mining” for vaccine candidates -recombinant subunit proteins or outer membrane vesicles (Chiron) Neisseria lactamica vaccine (on trial)