1. An Approach to Demonstration of Effectiveness
Meningococcal Conjugate Vaccines in Children Younger Than 2 Years of Age
An Approach to Demonstration of Effectiveness
Vaccines and Related Biological Products Advisory Committee Meeting
April 6, 2011
Lucia H. Lee, M.D.
Food and Drug Administration
Center for Biologics Evaluation and Research

2. Neisseria meningitidis
Why are meningococcal conjugate vaccines for infants and young children important?

3. Meningococcal Disease Incidence in U. S
Meningococcal Disease Incidence in U.S. Children <5 years,

4. Neisseria meningitidis
Invasive meningococcal disease
Meningitis
Sepsis
Rapid onset of illness
Morbidity
10-20% of individuals experience sequelae
Limb loss, neurosensory hearing loss, cognitive deficits, seizure disorders
Mortality
Case-fatality rates of 10-14% 4 4

5. Neisseria meningitidis
Polysaccharide encapsulated organism
Disease-causing isolates
Serogroups
Classified based on biochemical composition of the PS capsule
Six serogroups (A, B, C, X, Y, W-135) cause invasive disease
Polysaccharide and PS-conjugate vaccines
A,C,Y,W-135 capsular polysaccharides are immunogenic
Anti-capsular functional antibodies are protective 5 5

7. Meningococcal Conjugate Vaccines in Children <2 years old
Approach
Effectiveness of a MCV for children <2 years old can be demonstrated by
Clinical efficacy studies
Low incidence of meningococcal disease and sporadic occurrence of cases in the U.S.
Alternative approach using a serological marker of protection
Bactericidal antibody

8. Meningococcal Conjugate Vaccines in Children <2 years old
Approach
Inferred effectiveness using serum bactericidal antibody measurement
Mechanisms of protection
Antibody-dependent complement-mediated bactericidal killing
Other mechanisms (e.g., opsonization)
Individuals who have circulating meningococcal-specific functional antibodies present at the time of exposure are protected from disease
Serum bactericidal activity with human complement (hSBA) is consistent with an in vivo biological mechanism of protection
Bactericidal antibodies directed against the polysaccharide capsule are protective
The presence of functional antibodies that are bactericidal, measured by hSBA assay, can be predictive of protection

9. Mechanisms of Protection
Antibody-dependent complement-mediated bactericidal killing (bactericidal activity)

10. Neisseria meningitidis
Principle mechanism of protection
Antibody-dependent complement-mediated killing
The complement cascade is activated by serum antibodies via the classical pathway.
The final complement pathwayfor the classical and alternative pathways of complement activation is formation of a lytic membrane attack complex, which results in cell lysis. 10

11. Immunity to Meningococcal Disease
Role of Bactericidal Antibody

12. Immunity to Meningococcal Disease Role of Bactericidal Antibody
Incidence of meningococcal disease and age-specific prevalence of bactericidal antibodies to the meningococcal-specific strain
Studies in U.S. Army recruits
Individuals deficient in serum complement components C5, C6, C7, or C8
Meningococcal-specific antibodies were measured by bactericidal activity in serum

13. Highest incidence of disease occurred at the lowest bactericidal antibody prevalence
Naturally-acquired
bactericidal antibodies
Maternal Antibodies
Meningococcal Disease Incidence
The incidence of meningococcal disease was inversely proportional to the age-specific prevalence of bactericidal antibodies to the Mn-specific strain.
Adapted from Pollard et al. Vaccine 2001; 19: ; and Goldschneider I, J Exp Med 1969;129:

14. Immunity to Meningococcal Disease Role of Bactericidal Antibody
N=14,744 U.S. Army recruits
60 cases of meningococcal serogroup C (MenC) disease
54 had pre-exposure blood sample + disease isolate
3 of 54 had pre-exposure hSBA titer >4
hSBA assay
Intrinsic human complement source
Single serum dilution 1:4
Almost all individuals who developed meningococcal disease lacked bactericidal antibodies to their pathogenic strain prior to exposure
Protection against meningococcal disease at the time of exposure is dependent on the presence of circulating meningococcal-specific bactericidal antibodies
Goldschneider I, J Exp Med 1969;129:

15. Susceptibility to Disease is Strain Specific
Goldschneider et al. J. Exp. Med. 129:1307, 1969
N=492
N=438
N=54
N=24
N=11
N=13
N=5
Sera + nasopharyngeal (NP)
cultures
(+) bactericidal Ab
+ MenC disease
Lacked bactericidal Ab to
the MenC disease isolate
Exposed to a MenC epidemic strain
Colonized, developed bactericidal Ab
+ Acquired MenC pathogenic strain in the NP,
(-) SBA to the same strain
No disease
Army Recruits- Fort Dix

16. Late Complement Component Deficiencies
Persons with inherited serum complement component C5,C6,C7, or C8 deficiency are markedly susceptible to systemic meningococcal disease

17. Measurement of Functional Antibodies
hSBA assay

18. Measurement of Functional Antibodies SBA assay
Serological marker of protection
A measure of a biological function important in protection from systemic disease
Functional antibodies that are measurable in a bactericidal assay can be predictive of protection
SBA with human complement is consistent with an in vivo biological mechanism of protection
Antibody-dependent complement-mediated bactericidal killing
Most relevant to individual protection and assessment of vaccine immunogenicity

19. Recently licensed U.S. vaccines
Serological Markers of Protection Use of hSBA for approval of new vaccines
Recently licensed U.S. vaccines
MenACYW-D and MenACYW-CRM197
hSBA has been used as a measure of immunogenicity to infer effectiveness
Post-licensure surveillance study in the U.S.
Post-vaccination seroresponses were consistent with observed vaccine effectiveness estimates

20. Meningococcal Conjugate Vaccine Experience in
Infants and Young Children
Bactericidal antibodies to the PS capsule are protective

21. Hyperendemic meningococcal disease
Vaccination Campaign in the United Kingdom Epidemiology prior to MenC vaccine introduction
Hyperendemic meningococcal disease
Virulent N meningititis serogroup C:2a clone
Awareness of increased MenC disease Canada and Spain
1998
Incidence of MenC disease in all ages: 1.85 cases/105
2418 confirmed meningococcal infections
Proportion of disease due to serogroup C
34% (26% in 1994)
Adolescents and young adults
High case fatality rate

22. Estimated Total Numbers of Deaths from Meningococcal C Disease, England and Wales, 1993-1998, by Age
The total number of deaths among meningococcal serogroup C cases was highest in children <1 year of age and children years of age.
Meningococcal Vaccines. Ed. A. Pollard, M Maiden. 2001

23. Vaccination Campaign in the United Kingdom
Implementation phase
Routine infant immunization at 2,3,4 months old
Catch-up in children 5 months to 18 years old
1999
November
Adolescents years old
3-doses: infants at 2,3,4 months old
2000
January
1-dose: children months old
2-doses: children 5-11 months old
March-September
Children 2-4 years old
Children 5-14 years old 23 23

24. Confirmed Cases of Meningococcal C Disease Pre- and Post-Introduction of MenC Conjugate Vaccines in the U.K.

25. Vaccination Campaign in the United Kingdom
Post-implemenation
Incidence of MenC disease in England and Wales
Children <1 years old
: cases/105
: cases/105
: 0.00
Children 1-4 years old
: cases/105
: cases/105
: cases/105 25
Campbell et al. Clin Vaccine Immunol 2010; 17: 25

26. Meningococcal C Vaccine Effectiveness in U.K. Immunized Cohorts
Overall vaccine effectiveness (VE) 4 years after vaccination
5 months to 18 years old: > 83%
Infant 3-dose series (2,3,4 months old): 66%
Waning immunity during the 1st year of life
Additional dose given in the 2nd year of life
Longer protection
Sustained disease control
Vaccine introduction and use was associated with reduced disease incidence
Decline in circulating bactericidal antibodies was associated with decreased vaccine effectiveness and resurgence of disease
Trotter et al. Lancet 2004; 364:

27. Summary and Conclusions Inferred effectiveness using serum bactericidal antibody measurement
Antibody-dependent complement-mediated bactericidal killing is a principle mechanism of protective immunity to meningococcal invasive disease in both children and adults.
Individuals who have circulating meningococcal-specific functional antibodies present at the time of exposure are protected from disease
Post-marketing surveillance data support that meningococcal conjugate vaccine-induced bactericidal antibodies directed against the PS capsule can be effective in controlling meningococcal disease in infants and young children.

28. Summary and Conclusions (cont.)
Inferred effectiveness using serum bactericidal antibody measurement
Serum bactericidal activity with human complement is consistent with an in vivo biological mechanism of protection
The presence of functional antibodies that are bactericidal, measured by hSBA assay, can be predictive of protection 28 28