Meningococcal infections in the United States

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

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

5. Nasopharyngeal carriage, by Age

6. Clinical forms of meningococcal disease • 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

7. Clinical forms of meningococcal disease • 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

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

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

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

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

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

18. Serum bactericidal antibody assay

19. Membrane attack complex

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

27. Size of Association of GBS with MCV4 • Excess risk comparable to some prior seasonal influenza vaccines • In decision analysis, vaccination favored, even with larger magnitude of risk

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. 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. 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. 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. 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. Laboratory confirmed Serogroup C Laboratory confirmed Total Laboratory confirmed Serogroup B 160 140 120 100 80 60 40 20 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Laboratory-confirmed Cases of Meningococcal Disease England & WalesFive Weekly Moving Averages: 1997 to 2008 Health Protection Agency Meningococcal Reference Unit unpublished data

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

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”)