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

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

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

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

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

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

7. Changing Serogroup Distribution in the U.S.*
Y 37%
B 43%
Y 9%
B 25%
W135 2%
W135 3%
*ABCs

8. MCV4 (A/C/Y/W-135) Licensed for 11-55yo
Reactogenicity
Immunogenicity
Efficacy (no data)
Duration of protection
Herd immunity
Economic analysis

9. 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

10. 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

11. 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 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

12. 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 yo
Therefore, we assume MCV4 will provide protection of >8 yrs

13. 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:
Balmer et al., J. Medical Microbiology, 2002: 51:

14. 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

15. 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 yo, MCV4 preferred, MPSV4 acceptable

16. Rates of Meningococcal Disease (A/C/Y/W135) by Age, 11-30yo, United States, 1991-2002

17. 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 (

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

19. 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 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 :688-93

20. 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 (

21. 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

22. Other age groups
Other 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

23. 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.

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

25. 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

26. 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

27. 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

28. 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% ( )
5-11m
87% (11-99)
82% (-8-97)
1-2y
88% (65-96)
61% ( )
3-4y
98% (90-100)
93% (78-98)
11-16y
96% (89-99)
90% (77-96)
*Trotter et al, Lancet 2004

29. 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.

30. 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?

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

32. 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 by state. Shading represents rate quartiles.
0 to >0.95 to 1.16
>0.79 to 0.95
>1.16
*NETSS data

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

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

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

36. 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

37. 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.