1. Meningococcal infections in the United States F M LaForce, The Meningitis Vaccine Project, Ferney, France GIM Conference, Denver - December 16, 2008

2. 2 2 Neisseria meningitidis Gram-negative diplococcus Enveloped by polysaccharide capsule  Determines serogroup  Determinant of immunity Common disease-causing serogroups  A  B  C  Y  W-135

3. 3 3 Carriage and transmission of N. meningitidis Carried in human nasopharynx Transmission occurs through direct contact 5-10% of the population are carriers Proportion of carriers in population does not predict outbreaks

4. 4 4 Flow of Neisseria meningitidis through a population Courtesy Drs. Maiden and McLennan Courtesy Dr. Martin Maiden Reservoir

5. 5 5 Nasopharyngeal carriage, by Age

6. 6 6 Meningitis: most common presentation About half of all cases Secondary result of hematogenous dissemination Clinical findings fever headache stiff neck Cerebrospinal fluid: pleocytosis, N. meningitidis Clinical forms of meningococcal disease

7. 7 7 Meningococcemia: fulminant presentation About 40% of cases Case-fatality of 15-30%, death often in 12-48 hours Result of substantial endotoxemia Clinical findings petechial/purpuric rash hypotension disseminated intravascular coagulopathy Multi-organ failure Clinical forms of meningococcal disease

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11. 11 Incidence and Case-Fatality, U.S., 1920- 2005* *NETSS data

12. 12 Meningococcal Disease Incidence United States 1970-2005 NETSS data

13. 13 Cross-sectional View of the Cell Membrane Capsular polysaccharide (serogroup) Outer-membrane proteins serotype/subserotype

14. 14 Proportion of N. meningitidis Isolates by Serogroup, 1991–2005* *ABCs, n=3176 serogroup results (89.7% of total)

15. 15 The Goldschneider papers, J Exp Med 1969 Considered to be the definitive papers on human immunity against meningococci  The setting and the problem - High attack rates of meningococcal meningitis in military recruits undergoing basic training  Pressing need to develop an effective preventive approach (vaccine)

16. 16 Serum bactericidal activity was an accurate measure of susceptibility Using randomly collected sera they established that the age-related incidence of meningococcal meningitis in the US is inversely related to serum bactericidal activity against serogroups A, B and C  Susceptibility was a function of the absence of serum bactericidal activity

17. 17 Goldschneider et al. J. Exp. Med. 1969;129,1327-48. Age-specific meningococcal incidence and prevalence of SBA

18. 18 Serum bactericidal antibody assay

19. 19 Membrane attack complex

20. 20 First prospective study 14,744 recruits were bled during week 1 of basic training (12/67 to 3/68 – base line serum) There were 60 cases of meningococcal meningitis in this group (all serogroup C)  Baseline serum tested against individual infecting strain  Ten control sera randomly chosen from same platoon Bactericidal titer 1:4 or greater Cases Controls 3/54 (6%) 444/540 (82%) (sera from cases lacked bactericidal activity to disease producing strain) (bactericidal activity reconstituted with addition of gamma globulin) Conclusion: Absent bactericidal activity related to lack of antibody to infecting strain

21. 21 Second prospective study What happens to recruits who acquired the epidemic strain in the absence of bactericidal antibody 492 men in three companies followed for 7 weeks NP cultures and serum at weeks 1, 3, 5 and 7 Five men developed meningitis due to serogroup C Results Sera without NP pos Cidal activ Incidence of cidal activ Tot Men C to acq strain disease 54/492 44/54 24 11/24 5/13 (38%) (Conclusion: of the initial 54 susceptibles only 13 were exposed to the epidemic strain in the absence of bactericidal antibody; five developed meningitis – an incidence rate of 38%)

22. 22 Conclusions from the Goldschneider and Gotschlich papers Susceptibility to meningococcal disease in man is related to a selective deficiency of antibody to the offending organism Even during an epidemic meningococcal disease occurs in a fraction of susceptibles because the majority of susceptibles are not exposed to the epidemic strain These studies established a clear path that led to the development of PS meningococcal vaccines Introduction of PS meningococcal vaccines eliminated meningococcal meningitis as a threat to US military forces

23. 23 Development and testing of meningococcal vaccines US Army led in the development of Men A/C polysaccharide vaccine  Test results for Men C PS vaccine were dramatically positive in military recruits  One case/13,733 vaccinees  38 cases/68,072 non-vaccinees (87% reduction) Finnish studies showed Men A PS vaccine effective from 3 months to 5 years

24. 24 Quadrivalent Polyaccharide Vaccine (Menommune, Sanofi Pasteur) SQ - Safe with mild adverse reactions Good efficacy (>85%) in older children & adults Poorly immunogenic (C>A) in children <18- 24 mo Immunity of limited duration Possible immunological tolerance

25. 25 Quadrivalent Conjugate Vaccine (MCV4) (Menactra, Sanofi Pasteur) Jan 2005, licensed for IM use in 11-55yo October 2007, license extension for 2-10yo 0.5cc dose contains 4ug of capsular polysaccharide from serogroups A, C, Y, W-135 Conjugated to 48ug of diptheria toxoid Similar to conjugated Hib, S. pneumonia and serogroup C meningococcal vaccines  Conjugation changes immune response to T-cell dependent, increasing response in infants & anamnestic response at re-exposure

26. 26 GBS cases among 11-19 year-olds within 6 weeks of receipt of MCV4, by month of onset, 1/05-7/07 (n=22)* *October 2007 MCV4 Licensed 2 nd MMWR 1 st MMWR 3 rd MMWR

27. 27 Size of Association of GBS with MCV4 Expected Cases Cases Observed IRR (95% CI) Excess Risk per Million Doses 11-19 Year Olds1822 1.3 (0.8-1.9) 0.4 15-19 Year Olds1220 1.7 (1.0-2.5) 1.3 Excess risk comparable to some prior seasonal influenza vaccines In decision analysis, vaccination favored, even with larger magnitude of risk

28. 28 Duration of Protection, MCV4, 11-18yo MPSV4 in adults > 3-5 years protection Conjugate vaccines induce memory and higher antibody levels which should provide longer protection UK studies =90% VE at 3 yrs in 11-18 yo Therefore, ACIP assumed MCV4 will provide protection of >8 yrs in adolescents

29. 29 Summary of Cost Effectiveness Analyses, MCV4 Adolescent Strategy High cost per case prevented ($100Ks) Compared to infant or toddler strategy Least expensive Fewer cases and deaths prevented Greater impact on disease could be achieved at lower cost with herd immunity

30. 30 Revised ACIP Recs, Menactra – 2/2008 Adolescents aged 11-18 years recommended for routine MCV4 vaccination AND high-risk people aged 2-54 years

31. 31 Future Prospects: Control & Prevention of Meningococcal Disease in U.S. Conjugate A/C/Y/W135 vaccine offer substantive opportunity to reduce disease Effect on carriage and herd immunity? Implementation? Other meningococcal conjugate vaccines Age groups, formulations, combinations Availability of serogroup B vaccines?

32. 32 Public health impact after introduction of the Men C conjugate vaccine Complete success of the Men C conjugate vaccine in the UK  Catch-up strategy (single dose for 1-25 year olds – 80% coverage) plus immunizing birth cohorts  Strong herd immunity with clear protection of the unvaccinated  Disappearance of the disease The Men C conjugate vaccines significantly decreased Group C N mening colonization

33. 33 Laboratory-confirmed Cases of Meningococcal Disease England & Wales Five Weekly Moving Averages: 1997 to 2008 0 20 40 60 80 100 120 140 160 199719981999200020012002200320042005200620072008 Laboratory confirmed Serogroup B Laboratory confirmed Serogroup CLaboratory confirmed Total Health Protection Agency Meningococcal Reference Unit unpublished data

34. 34 Courtesy Dr.Martin Maiden Population Effects of Men C Conjugate Vaccines: The development of herd immunity reservoir

35. 35 Herd Immunity After Conjugate Vaccine Use (Mening, pneumo and H influenzae) Comprehensive use of conjugate polysaccharide vaccines against encapsulated pathogenic bacteria spread by “respiratory droplets” has resulted in a major fall in colonization rates (carriage) in the general population with resultant protection of the unimmunized (so-called “herd immunity”)