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

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

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

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

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

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

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

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

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

Immunity to Meningococcal Disease Role of Bactericidal Antibody

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

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

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;129:1307-1326

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

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 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

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

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

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

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

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 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 23 23

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

Vaccination Campaign in the United Kingdom Post-implemenation 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 25 Campbell et al. Clin Vaccine Immunol 2010; 17:840-847 25

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 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.

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