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Understanding and Reducing the Risk of Meningococcal Disease

Understanding and Reducing the Risk of Meningococcal Disease . Brian Filipski Deputy Director, Medical Science Liaison sanofi pasteur . DISCLOSURE. I am an employee of Sanofi Pasteur. Meningococcal Disease Is Challenging. Persistent global health problem 1

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Understanding and Reducing the Risk of Meningococcal Disease

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  1. Understanding and Reducing the Risk ofMeningococcal Disease Brian Filipski Deputy Director, Medical Science Liaison sanofi pasteur

  2. DISCLOSURE • I am an employee of Sanofi Pasteur

  3. Meningococcal DiseaseIs Challenging • Persistent global health problem1 • Causes endemic and epidemic disease1 • Early disease can be easily misdiagnosed1 • May present with variable clinical manifestations1 • Signs and symptoms may be hard to distinguish from common viral illness • Displays rapid onset and progression1 • High morbidity and mortality, despite effective therapy1-3 1. Granoff DM, et al. In: Vaccines. 2004:959; 2. Rosenstein NE, et al. N Engl J Med. 2001;344:1378; 3. Jodar L, et al. Lancet. 2002;359:1499.

  4. Neisseria meningitidis • Gram-negative aerobic diplococcus with polysaccharide capsule1 • Typically carried asymptomatically in the nasopharynx1 • Transmitted via aerosol, secretions, person-to-person contact1 • May penetrate the mucosa to the bloodstream, leading to systemic meningococcal disease1 • In nonepidemic periods, ~10% of healthy individuals are colonized1 • Up to 34% of college freshmen are colonized2 1. Granoff DM, et al. In: Vaccines. 2004:959; 2.Neal KR, et al. BMJ. 2000;320:846. Photo courtesy of Eye of Science/Photo Researchers, Inc.

  5. Viral vs Bacterial Meningitis: Signs and Symptoms Viral3 Bacterial1-3 • Confusion and combativeness • Lethargy • Kernig/Brudzinski signs • Rigid arching of the back • Seizures • Loss of consciousness • Alert and oriented Headache Low-grade fever Stiff neck Photophobia Vomiting Rash1-3 1. Ross GH, et al. In: Pharmacotherapy—A Pathophysiologic Approach. 2002:1831; 2. McGee ZA, Baringer JR. In: Principles and Practice of Infectious Diseases. 1990:741; 3. Farley JA, et al. In: Pathophysiology: The Biologic Basis for Disease in Adults and Children. 1994:587.

  6. Most Common Clinical Presentations of Meningococcal Disease • Meningococcemia • Rash • Vascular damage • Disseminated intravascular coagulation • Multi-organ failure • Shock • Death can occur within 24 hours • ~5% to 20%of cases • Up to 40% fatality rate • Meningitis • Fever and headache (flu-like symptoms) • Stiff neck • Nausea • Altered mental status • Seizures • ~50% of cases • 3%–10% fatality rate 1. Rosenstein NE, et al. N Engl J Med. 2001;344:1378.

  7. Serious Outcomes of Meningococcal Disease • Meningococcemia • Skin scars from necrosis • Limb loss from gangrene • Renal failure • Septic arthritis • Pneumonia • Epiglottitis • Pericarditis • Meningitis • Spastic quadriplegia • Hearing loss • Cerebral infarction • Cortical venous thrombophlebitis • Cerebral edema • Cranial nerve palsies • Mental retardation • Hemiparesis 3%–10% fatality rate Up to 40% fatality rate 1. Fellick JM, et al. Arch Dis Child. 2001;85:6; 2. Erickson L, De Wals P. Clin Infect Dis. 1998;26:1159;3. Erickson L, et al. Clin Infect Dis. 2001;33:737; 4. Munford RS. In: Harrison’s Principles of Internal Medicine. 2001:927.

  8. Gangrene Caused byN meningitidis Infection Courtesy of R Rudoy, MD, Honolulu, Hawaii, USA

  9. Ecchymoses Courtesy of R Rudoy, MD, Honolulu, Hawaii, USA

  10. Severe Late-Stage Meningococcal Infection in a 15-Year-Old Boy Reprinted with permission from Schoeller T, Schmutzhard E. N Engl J Med. 2001;34:1372.

  11. Meningococcal Disease Is Endemic and Cyclical in the United States Menactra vaccinerecommended bythe ACIP Menomune vaccinerecommended by the ACIP *All age groups 1. CDC. MMWR Morb Mortal Wkly Rep. 2004;51:1; 2. CDC. MMWR. 1997;45:1; 3. CDC. National Vital Statistics Reports. 2003;52:1; 4. CDC. Active Bacterial Core Surveillance (ABCs) Report. Neisseria Meningitidis. 1997-2005. Available at www.cdc.gov/ncidod/dbmd/abcs.

  12. A Peak of Meningococcal Disease Incidence Occurs in 15- to 19-Year-Olds* 6 Male Female 5 4 Incidence Rate (cases per100,000 population) 3 2 1 0 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥ 85 Age (years) *In California, Georgia, Maryland, Tennessee, Connecticut, Minnesota, and Oregon, 1992–19961. Rosenstein NE, et al. J InfectDis. 1999;180:1894.

  13. A Peak of Meningococcal Disease Incidence Occurs in 15- to 19-Year-Olds* Cases per 100,000 population Cases per 100,000 population Age (years) Age (years) *Average annual incidence rate by age in Maryland,1992–1999 1. Harrison LH, et al. JAMA.2001;286:694.

  14. Clinically Significant N meningitidis Serogroups 1. Granoff DM, et al. In: Vaccines. 2004:959.

  15. N meningitidis Serogroup Distributions Have Changed in the US (All Age Groups) 1997-2005 1990-1992 C 40% Y 28% C 23% Y 9% W-135 & Other 14% W-135 & Other 8% B 43% B 35% 1. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network, Neisseria meningitidis, 1997–2005, available at http://www.cdc.gov/ncidod/dbmd/abcs/survreports.htm; Emerging Infections Program Network, data on file.

  16. Morbidity Is High in Infants, Children, and Adolescents with Meningococcal Disease *From 159 cases (19 years of age or younger) at 10 US children’s hospitals, Jan 1, 2001 to Mar 15, 2005 †From 146 surviving children during or after hospitalization 1. Kaplan SL, et al. Pediatrics. 2006;118:e979-e984.

  17. Meningococcal Infection at 10 US Children’s Hospitals, January 2001–March 2005* Number Age (Years) *From 159 total cases (19 years of age or younger) 1. Kaplan SL, et al. Pediatrics. 2006;118:e979-e984.

  18. Average Annual Incidence of Meningococcal Disease by Age and Serogroup, US (1997-2005)a aCDC: ABCs data CDC. ABCs 1997-2005. http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm#reports Accessed Nov 4, 2007

  19. Note: Parexel to find more recent data? Age-Specific Fatalities From Meningococcal Disease in the US (1996-2004) [1996-2002]2 [1996-2004]1 • Composite of data obtained from the CDC, National Vital Statistics Reports. Deaths: Final Data for 1996-2004. • National Vital Statistics System, Mortality. Unpublished tabulations, 1996-2002.

  20. Most Cases in Adolescents and Young Adults Are Potentially Vaccine-Preventable* Potentially Vaccine-Preventable 65% 62% 41% 86% 70% 46% 72% 36% *Serogroup distribution by age group, United States, 1999–2005; potentially vaccine-preventable was calculated assuming 100% efficacy using an A/C/Y/W-135 quadrivalent vaccine 1. CDC. Active Bacterial Core Surveillance (ABCs) Report. Neisseria meningitidis. 1999-2005. Available at:. http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm#reports

  21. Meningococcal Disease Is Serious but Preventable in Adolescents and Young Adults Maryland Residents Diagnosed With Invasive Meningococcal Disease, January 1, 1990 to December 31, 1999 *Serogroup information was not available for all fatal cases †P = 0.001, < 15 yrs vs 15-24 yrs ‡P = 0.04, < 15 yrs vs 15-24 yrs 1. Harrison LH, et al. JAMA. 2001;286:694.

  22. Individual Risk Factors for Meningococcal Carriage and Disease in US College Students Clinical Setting Relative Risk Carriage state Alcohol Ingestion (>15 / week) Bar patronage (last 2 weeks) Cigarette smoking Dormitory residence Kissing 3.81.9–2.71.61.61.4 Sporadic cases Household / intimate contact Dormitory residence Upper respiratory infection 500–8003–122.4 Outbreaks Cigarette smoking Bar patronage 7.816.7 1. Apicella MA. Neisseria Meningitidis, In Principles and Practice in Infectious Disease. 1995:1896; 2. Froeschle, JE. Clin Infect Dis. 1999;1:215; 3. Neal et al. BMJ. 2000;320:846; 4. Imrey PB, et al. Am J Epidemiol. 1996;143:624; 5. Imrey PB, et al. J Clin Microbiol. 1995;33:3133.

  23. Meningococcal Vaccines • Polysaccharide vaccine • Meningococcal capsular polysaccharides • A/C/Y/W-135:Menomune®–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined • Conjugate vaccines • Meningococcal capsular polysaccharides covalently linked to carrier proteins • C-conjugate:Used in UK and most of Europe, Canada, Brazil, and Australia • A/C/Y/W-135-conjugate:Menactra®,Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a trademark of Sanofi Pasteur Inc.. Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc..

  24. Bacterial Capsule Capsular Polysaccharide Polysaccharide Vaccine Components

  25. Antibody Responses, Polysaccharide Vaccines Some B cells undergo antibody class switching and produce IgG(not shown in above graphic) Adapted from Ada G. N Engl J Med.2001;345:1042.

  26. Monovalent (group C) Bivalent(A/C) Quadrivalent (A/C/Y/W-135) Impact of Polysaccharide Meningococcal Vaccines in the US Military *Bars indicate hospitalization frequencies; line indicates rates 1. DeFraites RF. MSMR. 2000;6:2.

  27. Trial Location Author Design Study Population Follow-up Period Efficacy Against C(95% CI) US Army Artenstein et al1 Randomized controlled 68,072 (military recruits) 2 months 87% (57%-100%) US Army Gold et al2 Randomized controlled 74,654 (military recruits) 2 months 86% (52%-100%) Gregg County, TX Rosenstein et al3 Case Control 106,076(2-29 years of age) 2 years 85% (27%-97%) Efficacy of Quadrivalent Meningococcal Polysaccharide Vaccine 1. Artenstein MS, et al. N Engl J Med. 1970;282:417; 2. Gold R, et al. Bull World Health Organ. 1971;45:279; 3. Rosenstein N, et al. JAMA. 1998;279:435.

  28. ProteinCarrier Capsular Polysaccharide Conjugate Vaccine Components

  29. Advantages of Successful Conjugate Vaccines PropertyPolysaccharide Conjugate B-cell–dependent immune response Yes Yes T-cell–dependent immune responseNo Yes Immune memory No Yes Lack of hyporesponsiveness No Yes Booster effect No Yes Long-term protectionNo Yes Reduction of carriage No Yes Herd protection No Yes Adapted from Granoff DM, et al. In: Vaccines. 2004: 959.

  30. Antibody Responses & Memory Cells: Conjugate Vaccines (Isotype switching affinity maturation) Adapted from Ada G. N Engl J Med.2001;345:1042.

  31. 1998 / 1999 1999 / 2000 2000 / 2001 (to Week 16/2001) Serogroup C Disease Decreased Dramatically After C-Conjugate Vaccination in the UK 150 BEFORE 100 Immunization with serogroup C-conjugate vaccine in 15- to 17-year-olds began on Nov 1, 1999 DURING Cumulative Cases 50 AFTER 0 1 5 10 15 20 25 30 35 40 45 50 Week Number (total from mid-year) Vaccination was offered to all UK citizens 18 years of age. 1. Health Protection Agency Web site. Available at: www.hpa.org.uk/infections/topics_az/meningo/graph_meni-groupC.htm. Accessed May 2004.

  32. Reduction of Serogroup C Disease in the UK After Nationwide Immunization With C-Conjugate Vaccine 1. Miller E, et al. Vaccine. 2002;20:S58.

  33. % With Meningococci Serogroup 1999 (N = 14,064) 2000 (N = 16,583) Ratio 2000 : 1999 B 4.11 4.14 1.01 66%decrease C 0.45 0.15 0.34 Y 0.97 1.05 1.09 P = 0.04 W-135 1.12 1.42 1.27 NG or Other 10.05 11.22 1.12 Carriage of Meningococci in 15- to 17-Year-Old School Children in the UK NG = nongroupable 1. Maiden MC, et al. Lancet. 2002;359:1829.

  34. Cohort July 1998–June 1999 Attack Rate/100,000* July 2001–June 2002 Attack Rate/100,000† % Reduction in Unvaccinated Infants 7.49 1.56 79 Toddlers 6.82 2.05 70 Preschool 3.94 1.20 70 School Years, 1–6 1.94 1.00 48 School Years, 7–10 5.54 1.11 80 Older Adolescents 5.28 1.79 66 Herd Protection: Serogroup C Attack Rates in Unvaccinated Children Before and After UK Program *Before universal UK vaccination program †After universal UK vaccination program 1. Ramsay ME, et al. BMJ. 2003;326:365.

  35. Rationale for Meningococcal Immunization • Meningococcal disease can be a serious, rapidly progressive infection that leaves little time for diagnosis and treatment1 • Early meningococcal disease can present with symptoms similar to common viral illness, making diagnosis difficult 1,2 • N meningitidis is now the most prevalent etiology of bacterial meningitis among children and adolescents 2 to 18 years of age in the US3 1. Granoff DM, et al. In: Vaccines. 2004:959; 2. Schuchat A, et al. N Engl J Med. 1997;337:970; 3. Whitney CG, et al. N Engl J Med. 2003;348:1737.

  36. Expected Attributes of Quadrivalent Meningococcal Conjugate in the US • Broad serogroup coverage (A, C, Y and W-135) • The majority of adolescent cases are covered by the vaccine • High-quality immune response in adolescents and young adults • Immunological memory induced by T cells • Herd protection through nasopharyngeal carriage reductions

  37. Menactra Vaccine Clinical Studies MKT 9194-3 Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.

  38. Seroconversion Ratesin Seronegative Adolescents *Seroconversion, participants with serum bactericidal assay (SBA) titers  1:8 on Day 0 that reached  1:32 on Day 28 post-immunization. 1. Sanofi pasteur, data on file. Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  39. Percentage of Adolescents Who Demonstrated 4-Fold Increase in Antibody Titer *Serum bactericidal assay (SBA) titers Sanofi pasteur, data on file. Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  40. P < 0.001 Geometric Mean Titers in Adolescents Serogroup A SBA, serum bactericidal assay Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  41. Geometric Mean Titers in Adolescents P =0.07 Serogroup C SBA, serum bactericidal assay Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc. Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  42. Geometric Mean Titers in Adolescents P =0.21 Serogroup Y SBA, serum bactericidal assay Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  43. Geometric Mean Titers in Adolescents P =0.86 Serogroup W-135 SBA, serum bactericidal assay Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  44. Comparative Safety in Adolescents *Occurring within 30 minutes post-vaccination †Local and systemic reactions reported within 7 days ‡P<0.05 Menactra vaccine vs Menomune A/C/Y/W-135 vaccine §All of the Serious Adverse Events (SAEs) were unrelated to vaccination except for one (esophagitis), which was reported as possibly related Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  45. Safety of Menactra Vaccine in Adolescents • Local Events (Menactra vs Menomune–A/C/Y/W-135 vaccine) • Pain, 69% vs 30%, P<0.05 • Redness, 12.1% vs 6.3%, P<0.01 • Swelling, 14.4% vs 5.4%, P<0.001 • Systemic Events (Menactra vs Menomune–A/C/Y/W-135 vaccine) • Headache, 45% vs 40% • Fatigue, 28% vs 24% • Most local and systemic events were mild* *Mild, did not interfere with daily activitiesMenactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc.Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  46. Conclusion for Safety and Immunogenicity Trial • The immunogenicity of the quadrivalent conjugate vaccine Menactra was equivalent to that of the polysaccharide vaccine Menomune–A/C/Y/W-135in 11- to 18-year-olds • Local and systemic adverse events were generally mild and resolved within 2 to 3 days 1. Keyserling H et al. Presented at ICAAC. 2003; 2.Sanofi pasteur, data on file. Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is a registered trademark of Sanofi Pasteur Inc. Menomune–A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined is a registered trademark of Sanofi Pasteur Inc.

  47. Predicted Reduction of Meningococcal Disease by Different Immunization Programs in the US* Estimated reduction of meningococcal disease 10 years after large-scale immunization programs with a C + Y conjugate vaccine *Analysis does not factor in potential benefits of herd protection 1. Lingappa JR, et al. Vaccine. 2001;19:4566.

  48. Revised ACIPa Recommendations for Use of Meningococcal Conjugate Vaccine1,2 • Routine immunization of all adolescents 11 through 18 years of age with one dose of MCV4 • Routine vaccination of other populations at increased risk 2–55 years of age1 • Incoming college freshmen living in dormitories • Microbiologists who are routinely exposed to isolates of Neisseria meningitidis • Military recruits • Persons who travel to or reside in countries in which N meningitidis is hyperendemic or epidemic • Complement-deficient and asplenic patients a Advisory Committee on Immunization Practices Reference: 1. Centers for Disease Control and Prevention (CDC). Revised recommendations of the Advisory Committee on Immunization Practices to vaccinate all persons aged 11-18 years with meningococcal vaccine. MMWR.2007;56(31):794-795. 2. Food and Drug Administration (FDA) approves MCV4 for younger populationhttp://www.cdc.gov/vaccines/programs/vfc/downloads/resolutions/1007mening-mcv.pdf Accessed Nov 4, 2007

  49. 2007 2005 2006 Menactra Vaccine’s 2007 Full Year Claims (Jan - Dec) Increased Significantly Over the Same Period in 2006 (+157%) Number of Electronic Physician Office Based Menactra Claims per Month Source: Surveillance Data Inc.’s electronic healthcare claims data base. Vaccines which are not submitted for reimbursement, such as Vaccines for Children program and vaccines paid 100% out-of-pocket, are not captured in this database. Covers CPT codes 90734 (Menactra vaccine).

  50. Good news 2005 Production timeline met and exceeded CDC commitments 2006 Dose availability exceeded 2005 production End-of-year doses carried into 2007 2007 Dose availability exceeded demand End-of-year doses to be carried into 2008 And beyond New facility will allow for significant market growth opportunities 2005a 2008d 2007c 2006b Menactra Vaccine Supply Will Increase Steadily Through 2008 and Beyond a Available supply from March through September b 6M total doses produced in 2006. c Actual and projected supply d Projected supply

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