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Approaches to Demonstrate Effectiveness of Vaccines for Prevention of Group B Meningococcal Disease Introduction Vaccines and Related Biological Products Advisory Committee April 7, 2011
Purpose • Consider a pathway for demonstration of effectiveness of sub-capsular meningococcal vaccines intended for the prevention of invasive group B meningococcal disease
MeningococcalVaccines • Surface structures • Capsule • Major OMPs • PorA, PorB, RMP, Opa • Minor OMPs • many are lipoproteins • LOS – endotoxin • Vaccines • Polysaccharide • A, C, ACYW-135 • B PS poorly immunogenic • PS-conjugates • ACYW-135 • B PS poorly immunogenic • Detoxified outer membrane vesicles (OMV)
N. meningitidis Genetic Diversity • Mechanisms • Naturally transformable • Extensive mechanisms for DNA uptake and incorporation • Impact on Disease Epidemiology • Capsule type, MLST type, OMP types • Epidemics and outbreaks - clonal • Endemic group B disease - diverse
Vaccine Effectiveness • Measured in what way? • Disease incidence in US is low • Inference from a serologic marker is a possible alternative • Against what? • Endemic US group B disease • Antigen sequence and expression diversity among disease strains
hSBA as a Measure of Vaccine Effectiveness • Evidence supports the use of bactericidal antibody, measured in hSBA assays, as a relevant serologic marker of protection • Studies of military recruits • Efficacy studies of OMP and OMV vaccines • Chile, Cuba, Norway, • Effectiveness • Brazil, New Zealand However, • hSBA correlation to effectiveness has been strain specific especially in pediatric populations • Clinically relevant indication is for prevention of invasive disease caused by group B N. meningitidis • Broadly protective, not strain specific
Demonstration of Effectiveness • Therefore, CBER has advised that demonstration of effectiveness will depend on both the immune response to vaccine antigens AND the proportion of disease isolates that are susceptible. • hSBA as a relevant measure of immunogenicity • Bactericidal antibodies to outer membrane protein antigens • Inference of effectiveness for prevention of group B meningococcal disease from immunogenicity • Added complexity due the diversity of strains causing endemic disease • Additional evaluation of effectiveness post marketing • Future product specific discussions
Demonstration of Effectiveness (cont.) • If hSBA testing of a large representative panel of disease strains is not feasible, then • CBER will consider bridging from immunogenicity in clinical studies using strain specific hSBA to diverse disease isolates using microbiologic markers as an alternative • Requires evidence that the marker is: • Predictive of strain susceptibility to antibody mediated killing • Sensitive to the impact of both antigen variant and expression diversity
? Clinical Endpoint Efficacy Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness
Y ? Y Y Y Y Y Y Y Y Y Y Clinical Endpoint Efficacy Y Y Bridge Immunogenicity to effectiveness Y X X X X X X X X X X X Y Y Susceptibility to antibody related to antigen variant and expression level Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness
Presentations • Epidemiology of Group B Invasive Meningococcal Disease in the US and Worldwide • Thomas Clark, MD, MPH • Molecular Epidemiology and Antigen Diversity of Candidate Vaccine Targets • Leonard Mayer, Ph.D. • Effectiveness of Sub-capsular Meningococcal Vaccines • Margaret Bash, MD, MPH • Novartis Approaches • Rino Rappuoli, Ph.D. • John Donnelly, Ph.D. • Pfizer Approaches • Kathrin Jansen, Ph.D.
VRBPAC Discussion • Please discuss the evaluation of effectiveness of vaccines for prevention of group B meningococcal disease based on: • Bactericidal antibodies to OMP antigens tested in hSBA assays • Bridging test strain specific hSBA to endemic disease isolates using microbiologic characterization that predicts strain susceptibility