Presented by Nancy Rosenstein, MD March 2006 MCV4 – A Case Study Presented by Nancy Rosenstein, MD March 2006

Incidence and Case-Fatality, U.S., 1920-2002* *NETSS data

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

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

Rates of Meningococcal Disease in College Students, 9/1/98-8/31/99 Number of Cases Population Rates per 100,000 2-5 year olds 255 14,886,569 1.7 All 18-23 year olds 304 22,070,535 1.4 College students 96 14,897,268 0.6 Undergraduate 93 12,771,228 0.7 Freshmen 44 2,285,001 1.9 Dormitory residents 48 2,085,618 2.3 Freshmen living in dormitories 30 591,587 5.1 * Bruce et al. JAMA 2001. 286:688-93

Quadrivalent Polyaccharide Vaccine (MPSV4/A, C, Y, W-135) 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

Uses of Polyaccharide Vaccine Routine vaccination of civilians not recommended Recommended for use among high risk-groups (asplenia, travelers, microbiologists) Recommended for control of outbreaks College freshmen should be educated about disease and vaccine

Quadrivalent Conjugate Vaccine (MCV4) (Menactra, Sanofi Pasteur) Jan 2005, licensed for IM use in 11-55yo 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

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

Safety: local reactions MCV4 range, % MPSV4 Td (11-18 y) Typh Vi (18-55 y) range, % 11-18 yr Pain Indur/swell/redn* 18-55 yr 53-69 11-20 39-54 11-17 29-30 4-8 20-48 5-16 70-71 15-26 75-76 14-22 (This may be attributed to the fact that MCV4 is administered intramuscularly whereas MPSV4 is administered subcutaneously.) MCV4 however, had similar or slightly lower rate of local reactions when compared with Td vaccine administered to adolescents and Typhoid vaccine administered to adults. * induration, swelling, redness Sanofi Pasteur presentation at VRBPAC, 09/22/04 Studies MTA - 02, 04, 09, 11, 12, 14

Safety: systemic* reactions MCV4 % with any (severe) reaction MPSV4 11-18 yr olds study MTA-02 study MTA-04 18-55 yr olds study MTA-09 study MTA-14 57.2 (3.9) 55.1 (4.3) 61.9 (3.8) 53.4 (2.2) 51.9 (4.1) 48.7 (2.6) 60.3 (2.6) 49.2 (5.5) * fever, chills, malaise, rash, seizures, headache, fatigue, anorexia, diarrhea, vomiting, arthralgia Sanofi Pasteur presentation at VRBPAC, 09/22/04

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

Duration of Protection, MCV4 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

Herd Immunity, Serogroup C Conjugate Vaccine in the U.K. Age (yrs) Ramsey et al (% reduction) Balmer et al (% reduction) <1 79 1-2 70 50 3-4 5-10 48 57 11-14 80 34 15-19 66 61 >25 35 Ramsay et al., BMJ, 2003: 326:365-366 Balmer et al., J. Medical Microbiology, 2002: 51:717-722

Summary of Economic Analysis Mening Vaccine, Adolescent Strategy Expensive - high cost per case prevented Compared to infant or toddler strategy Least expensive Fewer cases and deaths prevented If herd immunity induced, substantially greater impact on disease

Complicated Issues with U.S. Recommendations for Conj Vaccines Burden of disease vs. impact of cases Public perception vs health providers vs public health Limited financial resources Limited supply of vaccine in 2005-6 “Optimal” use of vaccine to impact burden Other issues about vaccination schedule Multiple partners (ACIP, AAP, AAFP) Understanding of vaccine suboptimal

ACIP Recommendations for Use of MCV4 and MPSV4, 2/2005 Vaccination recommended for Preadolescent visit and high school entry College freshmen living in dormitories Other groups at high risk Catch-up campaigns not recommended Other individuals can chose to be vaccinated In 11-55 yo, MCV4 preferred, MPSV4 acceptable

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

Routine Vaccination of Adolescents with MCV4 Goal is routine vaccination of young adolescents at pre-adolescent visit (11-12 year old) For adolescents who have not already received vaccine, vaccination at high school entry (15 years old) is recommended as an effective strategy to reduce meningococcal disease incidence in adolescents and young adults. ACIP recognizes that supply may be an issue for the first few years (

College freshmen living in dormitories Routine vaccination for college freshmen living in dormitories Because of feasibility of campaign targeting, colleges may target all matriculating freshmen Other students may elect to receive vaccination MCV4 preferred, MPSV4 acceptable (

Other groups at increased risk Routine vaccination for groups that have elevated risk: microbiologists who are routinely exposed to isolates of N. meningitidis persons who travel to, or reside in countries in which N. meningitidis is epidemic military recruits complement deficient and asplenic patients Vaccination for outbreak control MCV4 preferred, MPSV4 acceptable

MCV4 Supply Initial sales of MCV4 slow Starting in June 2005, sales increased rapidly Recommendations published Money available for VFC grantees Traditional peak season for college freshmen Vaccine distribution issues Age groups Public/private

Guillain-Barré Syndrome (GBS) among Recipients of MCV4 As of 3/1/2006, 7 reports of GBS following MCV4* to Vaccine Adverse Event Reporting System (VAERS) patients received MCV4 6/10-11/4 Symptom onset 14-31 days after MCV4 vaccination Different lots of vaccine Patients reside in the 5 states (AZ, OH, NJ, NY, and PA) 3.16 million doses of Menactra vaccine distributed (12/31)

What is Guillain-Barré Syndrome (GBS)? Inflammatory demyelination of peripheral nerves Spontaneously or after certain antecedent events such as infections or vaccines Subacute onset of progressive symmetrical weakness with loss of reflexes Sensory abnormalities, cranial nerve involvement, paralysis of respiratory muscles possible. Symptoms progress for days to 4 weeks Case fatality 5%; prolonged disability 20%

GBS and MCV4 Incidence of GBS in 11-19yo 1-2/100,000 person-yrs* Substantial uncertainty as to actual rate Rate of GBS based on number of cases reported within 6 weeks of MCV4 is similar to expected Timing of onset of symptoms within 2-5 weeks of vaccination is of concern Extent of underreporting to VAERS unknown *CDC unpublished data, Healthcare Utilization Project Nationwide Inpatient Sample, 1989-2001, Agency for Healthcre Research and Quality

CDC Recommendations MCV4 and GBS* Insufficient evidence to conclude MCV4 causes GBS Ongoing risk of serious meningococcal disease Continuation of current vaccination strategies FDA and CDC alerting healthcare providers and actively investigating Adolescents and caregivers should be informed of this ongoing investigation as part of consent process *MMWR dispatch, October 6, 2005

Approaches to Meningococcal Conjugate Vaccine Development Major vaccine companies Sanofi Pasteur, Baxter, Chiron, Merck, GSK, Wyeth Public-private partnerships (MVP) Potential formulations C, A/C, A/C/Y/W135, A, A/W135 Multiple combinations S. pneumonaie, Hib, DTP, Hepatitis B, IPV Target age groups Infant, toddler, adolescent, college

Rates of Meningococcal Disease by Age Group and Serogroup, U. S *ABCs data