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

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

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

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

5. 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

6. 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

7. 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

8. 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

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

10. 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

11. 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

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

13. 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, ACIP assumed MCV4 will provide protection of >8 yrs

14. 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:

15. 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

16. 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
“Optimal” use of vaccine to impact burden
Other issues about vaccination schedule
Multiple partners (ACIP, AAP, AAFP)
Understanding of vaccine suboptimal

18. 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 yo, MCV4 preferred, MPSV4 acceptable

19. Rates of Meningococcal Disease (A/C/Y/W135) by Age, 11-30yo, United States, 1991-2002
, Rate among 11-19yo, 0.9/100,000
2004, Rate among 11-19yo, 0.5/100,000

20. 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 (

21. 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 (

22. 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

24. 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

25. 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 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)

26. 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%

27. 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, , Agency for Healthcre Research and Quality

28. 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

29. 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

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