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

Neisseria meningitidis

Why are meningococcal conjugate vaccines for infants and young children important?

Meningococcal Disease Incidence inU.S. Children <5 years, 1999-2008

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• 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%

Neisseria meningitidis

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• 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

Neisseria meningitidis

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• 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

Meningococcal Conjugate Vaccines in Children <2 years oldApproach

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

Meningococcal Conjugate Vaccines in Children <2 years oldApproach

Mechanisms of Protection

Antibody-dependent complement-mediated bactericidal killing (bactericidal activity)

Antibody-dependent complement-mediated killing

Neisseria meningitidisPrinciple mechanism of protection

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.

Immunity to Meningococcal Disease

Role of Bactericidal Antibody

Immunity to Meningococcal DiseaseRole 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

Highest incidence of disease occurred at the lowest bactericidal antibody prevalence

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: 1327-1346; and Goldschneider I, J Exp Med 1969;129:1307-1326

Naturally-acquired

bactericidal antibodies

Maternal Antibodies

Meningococcal Disease Incidence

Immunity to Meningococcal DiseaseRole 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;129:1307-1326

Susceptibility to Disease is Strain Specific

Goldschneider et al. J. Exp. Med. 129:1307, 1969

N=492

N=438 N=54

N=24N=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

No disease

Army Recruits- Fort Dix

Late Complement Component Deficiencies

• Persons with inherited serum complement component C5,C6,C7, or C8 deficiency are markedly susceptible to systemic meningococcal disease

Measurement of Functional Antibodies

hSBA assay

Measurement of Functional AntibodiesSBA 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

Serological Markers of ProtectionUse 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

Meningococcal Conjugate Vaccine Experience in Infants and Young Children

Bactericidal antibodies to the PS capsule are protective

Vaccination Campaign in the United KingdomEpidemiology 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

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 15-18 years of age.

Meningococcal Vaccines. Ed. A. Pollard, M Maiden. 2001

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Implementation phase- Routine infant immunization at 2,3,4 months old- Catch-up in children 5 months to 18 years old

1999• November

- Adolescents 15-17 years old- 3-doses: infants at 2,3,4 months old

2000• January

- 1-dose: children 12-23 months old- 2-doses: children 5-11 months old

• March-September- Children 2-4 years old- Children 5-14 years old

Vaccination Campaign in the United Kingdom

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

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Incidence of MenC disease in England and Wales

• Children <1 years old- 1998-1999: 16.63 cases/105

- 2001-2002: 1.02 cases/105

- 2008-2009: 0.00

• Children 1-4 years old- 1998-1999: 8.13 cases/105

- 2001-2002: 0.92 cases/105

- 2008-2009: 0.04 cases/105

Vaccination Campaign in the United KingdomPost-implemenation

Campbell et al. Clin Vaccine Immunol 2010; 17:840-847

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; 364:365-367

Summary and ConclusionsInferred 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.

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• 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

Inferred effectiveness using serum bactericidal antibody measurement

Summary and Conclusions (cont.)