New Vaccines for Meningococcal Disease Presented by Nancy Rosenstein, MD Meningitis and Special Pathogens Branch Division of Bacterial and Mycotic Diseases March 2005

Incidence and Case-Fatality, U.S., 1920-1996

Outline Epidemiology of Meningococcal Disease MCV4/Menactra™ (Sanofi Pasteur) Use of MCV4 and MPSV4

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

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

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

Changing Serogroup Distribution in the U.S.* Y 37% B 43% Y 9% B 25% W135 2% W135 3% 1997-2001 1990-1992 *ABCs

MCV4 (A/C/Y/W-135) Licensed for 11-55yo Reactogenicity Immunogenicity Efficacy (no data) 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 Next I will briefly summarize the immunogenicity and safety data for MCV4 as compared with MPSV4. This graph shows the percentage of 11-18 year old subjects achieving 4 fold or higher increase in SBA titers 28 days after vaccination, by serogroup. MCV4 results are in orange, MPSV4 results in green. As can be seen, the percentage of subjects achieving 4 fold increase in SBA is similar for both vaccines. 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, we assume 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 *Shephard C et al, submitted ** Ortega-Sanchez O, Meltzer M et al, in preparation

ACIP Recommendations for Use of MCV4 and MPSV4 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

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 (

Routine Vaccination of Adolescents Other adolescent who wish to decrease their risk of meningococcal disease may elect to receive MCV4 All 11-18 yo covered by VFC (

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

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

Other age groups Other 11-55 yrs: risk of disease is low, routine vaccination not indicated Individuals may elect vaccination 2-10 yrs and >55 yrs: MCV4 not considered for licensing in these age groups; routine vaccination with MPSV4 not recommended

Revaccination MPSV4 Those previously vaccinated with MPSV4 may be revaccinated after 3-5 years if risk remains increased MCV4 ACIP expects that MCV4 will provide longer protection than MPSV4; however, studies will be needed to confirm this. We anticipate that more data will become available within the next 5 years to guide recommendations on revaccination for persons who were previously vaccinated with MCV4.

Post-Licensure Studies Vaccine efficacy Herd immunity Molecular epidemiology Duration of protection Programmatic evaluation

ACIP Meningococcal Working Group Paul McKinney Martin Meltzer John Moran Paul Offit Ismael Ortega-Sanchez Georges Peter Nancy Rosenstein Bill Schaffner Colin Shepard Jim Turner Gregory Wallace Kirk Winger Reginald Finger, Chair Jon Abramson Carol Baker Oleg Bilukha Guthrie Birkhead Richard Clover George Curlin Geoffrey Evans Janet Gilsdorf Lucia Lee Martin Mahoney Alison Mawle

Duration of antibody response 3 years after vaccination SBA GMT: MCV4>MPSV4 p<0.05 for A and W-135 p=0.12 for C and Y rSBA titers >128 in MCV4 group: Over 90% for serogroups A, Y, W-135 Over 75% for serogroup C Aventis Pasteur presentation at VRBPAC, 09/22/04 Study MTA-19

Revaccination: MCV4 3 years after MCV4 100% of subjects achieved SBA GMT >128 at 28 days after MCV4 re-vaccination, for all serogroups Aventis Pasteur presentation at VRBPAC, 09/22/04 Study MTA-19

Efficacy and Duration of Protection, Mening C Conjugate Vaccine, UK* Age at vaccination VE at 1 yr VE at 2-4y 2-4m (3 doses) 93% (67-99) -81% (-7430-71) 5-11m 87% (11-99) 82% (-8-97) 1-2y 88% (65-96) 61% (-327-94) 3-4y 98% (90-100) 93% (78-98) 11-16y 96% (89-99) 90% (77-96) *Trotter et al, Lancet 2004

Chemoprophylaxis Rifampin Ciprofloxacin (adults, non-pregnant) Ceftriaxone Azithromycin may be effective Rifampin, ciprofloxacin and ceftriaxone remain the dugs of choice for chemoprophylaxis. One recent study from Egypt showed that a single oral dose of azithromycin was effective in eradicating nasopharyngeal carriage of meningococci. Azithromycin, in addition to being safe and easy to administer, is also available in a suspension form, and is approved for use in children. Further evaluation of both effectiveness of azithromycin in eradicating meningococcal carriage, and of the potential for development of microbial resistance to this drug, if widely used for chemoprophylaxis, is warranted.

Chemoprophylaxis: Azithromycin Safe in children, convenient to administer One study showed 93% eradication of carriage after 1 dose (500 mg PO) Concern about inducing resistance Is it really needed?

Vaccinating Microbiologists Microbiologists vs. hematologists, chemists, pathologists etc. Isolates vs. clinical specimens Estimated annual incidence rate: Microbiologists: 13 per 100,000 General population 30-59 yrs: 0.2 per 100,000

Distribution of mean annual meningococcal disease incidence rates, United States, 1996-2001* .78 2.75 .73 .91 .98 .84 1.05 1.23 1.15 Incidence rates per 100,000 population per year, averaged 1996-2001 by state. Shading represents rate quartiles. 0 to 0.79 >0.95 to 1.16 >0.79 to 0.95 >1.16 *NETSS data

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

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

Serogroup Distribution of Meningococcal Isolates, 1991-2002* Y=37 % Y=24 % 1991-1996 1997-2002 *ABCs data

Estimated vaccination coverage of Td by age, in adolescents with and without a written shot record* Age, years Written record No written record % 95% CI 11 14.2 +7.9 92.7 + 2.6 12 13.3 + 6.5 94.1 + 2.7 13 24.2 + 9.7 95.1 + 2.2 14 36.9 + 10.5 95.6 + 2.1 15 37.0 96.5 + 1.8 16 33.1 + 9.1 95.8 + 2.0 17 38.4 + 11.4 + 1.9 *NHIS 2002

Percent Annual Well Visits Well Visits By Age 100 80 Percent Annual Well Visits 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 Age (years) IMS National Disease and Therapeutic Index (NDTI) Projected-Total Diagnosis Visits - Calendar 2003 (000)NDTI. US Census Bureau National Population Projections - Last Revised Date: January 19, 2001.