Understanding and Reducing the Risk of Meningococcal Disease

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. 2004959 2.
Rosenstein NE, et al. N Engl J Med.
20013441378 3. Jodar L, et al. Lancet.
20023591499.
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. 2004959 2.
Neal KR, et al. BMJ. 2000320846. 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 Vo
miting Rash1-3
1. Ross GH, et al. In PharmacotherapyA
Pathophysiologic Approach. 20021831 2. McGee
ZA, Baringer JR. In Principles and Practice of
Infectious Diseases. 1990741 3. Farley JA, et
al. In Pathophysiology The Biologic Basis for
Disease in Adults and Children. 1994587.
6
Most Common Clinical Presentations of
Meningococcal Disease

• Meningitis
• Fever and headache (flu-like symptoms)
• Stiff neck
• Nausea
• Altered mental status
• Seizures
• 50 of cases
• 310 fatality rate

• 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

1. Rosenstein NE, et al. N Engl J Med.
20013441378.
7
Serious Outcomes of Meningococcal Disease

• Meningitis
• Spastic quadriplegia
• Hearing loss
• Cerebral infarction
• Cortical venous thrombophlebitis
• Cerebral edema
• Cranial nerve palsies
• Mental retardation
• Hemiparesis

• Meningococcemia
• Skin scars from necrosis
• Limb loss from gangrene
• Renal failure
• Septic arthritis
• Pneumonia
• Epiglottitis
• Pericarditis

310 fatality rate
Up to 40 fatality rate
1. Fellick JM, et al. Arch Dis Child. 2001856
2. Erickson L, De Wals P. Clin Infect Dis.
19982611593. Erickson L, et al. Clin Infect
Dis. 200133737 4. Munford RS. In Harrisons
Principles of Internal Medicine. 2001927.
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. 2001341372.
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. 2004511 2. CDC. MMWR. 1997451 3. CDC.
National Vital Statistics Reports. 2003521 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
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
0-4
Age (years)
In California, Georgia, Maryland, Tennessee,
Connecticut, Minnesota, and Oregon, 199219961.
Rosenstein NE, et al. J Infect Dis. 19991801894.
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, 19921999 1. Harrison LH, et al. JAMA.
2001286694.
14
Clinically Significant N meningitidis Serogroups
1. Granoff DM, et al. In Vaccines. 2004959.
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, 19972005, available at
http//www.cdc.gov/ncidod/dbmd/abcs/survreports.ht
m 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 childrens hospitals, Jan 1, 2001 to Mar
15, 2005 From 146 surviving children during or
after hospitalization 1. Kaplan SL, et al.
Pediatrics. 2006118e979-e984.
17
Meningococcal Infection at 10 US Childrens
Hospitals, January 2001March 2005
Number
Age (Years)
From 159 total cases (19 years of age or
younger) 1. Kaplan SL, et al. Pediatrics.
2006118e979-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/dbm
d/abcs/reports.htmreports Accessed Nov 4, 2007
19
Age-Specific Fatalities From Meningococcal
Disease in the US (1996-2004)
Note Parexel to find more recent data?
1996-20022
1996-20041

• 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, 19992005 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.h
tmreports
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, lt 15 yrs vs 15-24 yrs
P 0.04, lt 15 yrs vs 15-24 yrs 1. Harrison
LH, et al. JAMA. 2001286694.


22
Individual Risk Factors for Meningococcal
Carriage and Disease in US College Students
Relative Risk
Clinical Setting
3.81.92.71.61.61.4
Carriage state Alcohol Ingestion (gt15 /
week) Bar patronage (last 2 weeks) Cigarette
smoking Dormitory residence Kissing
5008003122.4
Sporadic cases Household / intimate
contact Dormitory residence Upper respiratory
infection
7.816.7
Outbreaks Cigarette smoking Bar patronage
1. Apicella MA. Neisseria Meningitidis, In
Principles and Practice in Infectious Disease.
19951896 2. Froeschle, JE. Clin Infect Dis.
19991215 3. Neal et al. BMJ. 2000320846 4.
Imrey PB, et al. Am J Epidemiol. 1996143624 5.
Imrey PB, et al. J Clin Microbiol. 1995333133.
23
Meningococcal Vaccines

• Polysaccharide vaccine
• Meningococcal capsular polysaccharides
• A/C/Y/W-135 MenomuneA/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-conjugateUsed 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..
MenomuneA/C/Y/W-135, Meningococcal
Polysaccharide Vaccine, Groups A, C, Y and W-135
Combined is a registered trademark of Sanofi
Pasteur Inc..
24
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. 20013451042.
26
Impact of Polysaccharide Meningococcal Vaccines
in the US Military
Bars indicate hospitalization frequencies line
indicates rates 1. DeFraites RF. MSMR. 200062.
27
Efficacy of Quadrivalent Meningococcal
Polysaccharide Vaccine
1. Artenstein MS, et al. N Engl J Med.
1970282417 2. Gold R, et al. Bull World Health
Organ. 197145279 3. Rosenstein N, et al.
JAMA. 1998279435.
28
Conjugate Vaccine Components
29
Advantages of Successful Conjugate Vaccines
Property Polysaccharide Conjugate B-celldepend
ent immune response Yes Yes T-celldependent
immune response No Yes Immune memory No
Yes Lack of hyporesponsiveness No
Yes Booster effect No Yes Long-term
protection No 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. 20013451042.
31
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/topi
cs_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. 200220S58.
33
Carriage of Meningococci in 15- to 17-Year-Old
School Children in the UK
NG nongroupable 1. Maiden MC, et al. Lancet.
20023591829.
34
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. 2003326365.
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. 2004959 2.
Schuchat A, et al. N Engl J Med. 1997337970 3.
Whitney CG, et al. N Engl J Med. 20033481737.
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 Rates in Seronegative Adolescents
Seroconversion, participants with serum
bactericidal assay (SBA) titers ? 18 on Day 0
that reached ? 132 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.MenomuneA/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.MenomuneA/C/Y/W-135, Meningococcal
Polysaccharide Vaccine, Groups A, C, Y and W-135
Combined is a registered trademark of Sanofi
Pasteur Inc.
40
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.MenomuneA/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. MenomuneA/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.MenomuneA/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.MenomuneA/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 Loc
al and systemic reactions reported within 7
days Plt0.05 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.MenomuneA/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 MenomuneA/C/Y/W-135
  vaccine)
• Pain, 69 vs 30, Plt0.05
• Redness, 12.1 vs 6.3, Plt0.01
• Swelling, 14.4 vs 5.4, Plt0.001
• Systemic Events (Menactra vs MenomuneA/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.MenomuneA/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 MenomuneA/C/Y/W-135 in
  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. MenomuneA/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. 2001194566.
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 255 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.200756(31)794-795. 2. Food and Drug
Administration (FDA) approves MCV4 for younger
population http//www.cdc.gov/vaccines/programs/vf
c/downloads/resolutions/1007mening-mcv.pdf
Accessed Nov 4, 2007
49
Menactra Vaccines 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
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
51
Summary

• Meningococcal disease continues to cause
  significant morbidity and mortality in the United
  States
• Following childhood, meningococcal disease rates
  begin to rise again in early adolescence and
  peak between the ages of 15 and 24 years
• Older adolescents may have a case fatality rate
  that is up to 5 times higher than those lt15
  years of age
• Successful conjugate vaccines induce immunologic
  memory and herd protection
• The attributes of conjugate vaccines generally
  give them a more widespread utility than
  polysaccharide vaccines

1. Harrison LH, et al. JAMA. 2001286694.