1. Meningococcal Disease and Meningococcal Conjugate Vaccine National Immunization Conference March 7, 2007

2. Outline Overview of epidemiology Review of polysaccharide vaccine Conjugate vaccine characteristics Recommendations for vaccination Challenges to implementation Future opportunities for prevention

3. Incidence and Case-Fatality - US, 1920-2005* *NETSS data

4. Incidence and Case-Fatality - US, 1974-2005* *NETSS data

5. Rates of meningococcal disease by age group and year - ABCs, 1991-2005* *ABCs data

6. Rates of Meningococcal Disease by Age Group and Burden of Disease, U.S., 1991-2002* *ABCs data

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

8. Serogroup Distribution of Meningococcal Isolates - ABCs, 1991-2005* *ABCs data C=31 % Y=36 % B=25 %

9. Rates of Meningococcal Disease by Serogroup and Year - ABCs, 1991-2005* *ABCs data, excluding OR

10. Rates of Meningococcal Disease by Age Group and Serogroup - ABCs, 1992-2001* *ABCs data

11. Rates of Meningococcal Disease (A/C/Y/W135) by Age, 11-30yo, United States, 1991-2002 1991-2002, Rate among 11-19yo, 0.9/100,000 2004, Rate among 11-19yo, 0.5/100,000

12. Rates of Meningococcal Disease in College Students - 9/1/98-8/31/99* Number of Cases Population Rates per 100,000 2-5 year olds25514,886,5691.7 All 18-23 year olds30422,070,5351.4 College students9614,897,2680.6 Undergraduate9312,771,2280.7 Freshmen442,285,0011.9 Dormitory residents482,085,6182.3 Freshmen living in dormitories 30591,5875.1 * Bruce et al. JAMA 2001. 286:688-93

13. Quadrivalent Polyaccharide Vaccine (MPSV4/A, C, Y, W-135) Safe with mild adverse reactions Subcutaneous route of administration Efficacy >85% in older children, adults Poorly immunogenic (C>A) in toddlers Immunity of limited duration Possible immunological tolerance

14. Uses of Polyaccharide Vaccine Not routinely recommended High risk-groups (asplenia, travelers, microbiologists) Outbreak control “Permissive” use in college freshmen 3-5 years of protection = revaccination of those at ongoing risk

15. Benefits of Conjugate Vaccines T cell-dependent response Improved immunogenicity in infants, toddlers Immunity of longer duration Primes for immunologic memory Protects from acquisition of carriage

16. Carriage of meningococci by serogroup in 15-17 year-old school students in 1999 and 2000* Serogroup19992000Ratiop value B 578 (4.11%) 687 (4.14%) 1.010.98 C 63 (0.45%) 25 (0.15%) 0.340.0013 W135 158 (1.12%) 236 (1.42%) 1.270.18 Y 136 (0.97%) 174 (1.05%) 1.090.43 Other/NG 1413 (10.05%) 1860 (11.22%) 1.120.071 Total isolates 2348 (16.70%) 2982 (17.98%) 1.080.30 *Maiden MJ et al. Lancet 2002;359:1829-30.

18. Quadrivalent Conjugate Vaccine (MCV4) (Menactra, sanofi pasteur) Licensed January 2005 Use in 11-55 year-olds 0.5cc dose given intramuscularly –4μg capsular polysaccharide (ACYW135) –48μg diphtheria toxoid

19. MCV4 Characteristics Safety and reactogenicity Immunogenicity Economic analysis Efficacy Duration of protection Herd immunity

20. Safety: local reactions MCV4 range, % MPSV4 range, % Td (11-18 y) Typh Vi (18-55 y) range, % 11-18 years Pain Ind/swell/red* 18-55 years Pain Indur/swell/redn* 53-69 11-20 39-54 11-17 29-30 4-8 20-48 5-16 70-71 15-26 75-76 14-22 *induration, swelling, redness Sanofi Pasteur presentation at VRBPAC, 09/22/04 Studies MTA - 02, 04, 09, 11, 12, 14

21. Immunogenicity: 11-18 year olds FDA Clinical Briefing Document, VRBPAC 09/22/04 Study MTA-02

22. 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

23. Other Factors Affecting Recommendations Burden of disease vs. impact of cases Public vs. healthcare vs. public health “Optimal” use of vaccine to impact burden Limited financial resources Anticipated early supply limitations Other new vaccines/ vaccination schedule Multiple partners (ACIP, AAP, AAFP) Understanding of vaccine incomplete

24. ACIP Recommendations for Meningococcal Vaccination Routine vaccination of 4 groups Preadolescents at 11-12 year-old visit High school entry (14-15 year-olds) College freshmen living in dormitories Persons at high risk Outbreak control Others who wish to lower their risk may chose to be vaccinated MCV4 preferred, MPSV4 acceptable

25. Projected Direct 2-year Impact of Adolescent/College Strategy, MCV4 Assume: 90%VE, 5/6 million doses, 80% vaccine for 11-15yo, 20% for college freshmen

26. Goal Routine vaccination at preadolescent (11-12 year-old) healthcare visit

27. MCV4 Supply February 2005 - ACIP recognized potential supply limitations Summer 2005 - Significant demand caused a short-term supply limitation Spring 2006 - sanofi pasteur, CDC, ACIP anticipated summer demand would outpace supply, MMWR recommending deferral of MCV4 in 11-12 year-olds Winter 2006 – Supply/demand mismatch resolved, recall of persons in whom vaccine deferred

28. *sanofi pasteur; Immunization Services Division, CDC

30. Guillain-Barré Syndrome (GBS) among Recipients of MCV4 October 2005 – MMWR dispatch 5 reports of GBS to Vaccine Adverse Event Reporting System (VAERS) Letter to providers, change in product labeling, VIS updated April 2006 – MMWR update (8 cases) February 2007 – 19 cases reported –Within 6 weeks or receipt of MCV4 –17 (89%) aged 11-19

31. Number of GBS Reports to VAERS within 6 weeks of MCV4 Administration, by Age

32. What is Guillain-Barré Syndrome (GBS)? Inflammatory demyelination of peripheral nerves Spontaneously or after certain antecedent events Progressive symmetrical weakness, loss of reflexes Sensory abnormalities, cranial nerve involvement, respiratory paralysis may occur Background rate of GBS in 11-19yo is 1.4/100,000 persons per year (VAERS) –0.17/100,000 population in 6-week period Overall case fatality 5%; prolonged disability 20%

33. Interpretation of GBS and Menactra No statistically significant increase in risk in 11-19 year-olds Possible small increase in risk in 15-19 year-olds Limitations in data sources (VAERS, Healthcare Utilization Project, Vaccine Safety Datalink) contribute to uncertainty about true magnitude of risk Ongoing risk of meningococcal disease Continuation of vaccination

34. Future Opportunities for Prevention Herd immunity from ACYW135 conjugate vaccine Other conjugate vaccines Effective conjugate vaccines in infants, toddlers Effective serogroup B vaccines

35. Rates of Meningococcal Disease by Age Group and Burden of Disease, U.S., 1991-2002* *ABCs data