Multicomponent MenB Vaccine (4CMenB): An Innovative Step In the Global Fight Against Serogroup B Meningococcal Disease

Transcription

1 Multicomponent MenB Vaccine (4CMenB): An Innovative Step In the Global Fight Against Serogroup B Meningococcal Disease Jeffrey J. Stoddard, MD, FAAP Head, Global Medical Affairs Novartis Vaccines and Diagnostics

2 At-Risk Groups and Established Risk Factors Infants 1-2 Population with highest incidence (17.4-fold increase over average in Europe 3 ) Immature immune system Reduction of protective maternal antibody levels Adolescents 4-6 Population with highest carriage ( fold increase over other age groups 7 ) Close contact with a case Respiratory tract infection Smoking Crowding Dormitory Travel Concerts Most cases of meningococcal disease occur in previously healthy persons. 1. Rosenstein NE, et al. N Eng J Med. 2001;344: ; 2. Figueroa JE, et al. Clin Microbiol Rev. 1991;4: ; 3. European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe 2008/2009. Stockholm: ECDC; 2011; 4. Bilukha OO, et al. MMWR Recomm Rep. 2005;54:1-21; 5. Imrey PB, et al. J Clin Microbiol. 1995;33: ; 6. Neal KR, et al. BMJ. 2000;320: ; 7. Christiansen H, et al. Lancet Infect Dis. 2010;10:

3 Conjugate Vaccines Against Meningitis-Causing Pathogens Have Been Successful Using the Polysaccharide Capsule H. influenzae (1 pathogenic type) S. pneumoniae (25 pathogenic serotypes) N. meningiditis (5 pathogenic serogroups) INVASIVE DISEASE INVASIVE DISEASE FULMINANT INVASIVE DISEASE A C W -135 Y B Hib glycoconjugate vaccine Pneumococcal glycoconjugate vaccine Meningococcal glycoconjugate vaccine No effective broadly, protective capsular vaccine 3

4 A Multicomponent Approach to MenB Vaccination The polysaccharide capsule? A single subcapsular protein component? Multiple subcapsular components? Poorly immunogenic Susceptible to antigenic variability Enables broad coverage across a number of strains N. meningitidis 4

5 Antigenic Components of the 4CMenB 4CMenB antigens are important for meningococcal survival, function, or virulence NadA: neisserial adhesin A Promotes adherence to and invasion of human epithelial cells 1-3 Possible importance in carriage fhbp: factor H binding protein Primary function: Binds the bacterial siderophore enterobactin (in vitro) 4 Secondary function: Binds factor H, which enables bacterial survival 5,6 NHBA: Neisseria heparinbinding antigen Present in virtually all strains Binds heparin, which may increase the serum resistance of bacteria 7-9 NZ PorA 1.4: porin A Major outer membrane vesicles protein produces robust antibody response 1. Comanducci M, et al. J Exp Med. 2002;195: ; 2. Capecchi B, et al. Mol Microbiol. 2005;55: ; 3. Mazzon C, et al. J Immunol. 2007;179: ; 4. Veggi D, et al. Presented at IPNC. Banff, Canada. September 11-16, 2010; 5. Madico G, et al. J Immunol. 2006;177: ; 6. Schneider MC, et al. J Immunol. 2006;176: ; 7. Serruto D, et al. Proc Natl Acad Sci U S A. 2010;107: ; 8. Welsch JA, et al. J Infect Dis. 2003;188: ; 9. Plested, et al. Clin Vaccine Immunol. 2008;15:

6 Vaccine composition 4CMenB: Vaccine Composition Antigenic Component Amount Recombinant Neisseria meningitidis serogroup B NHBA fusion protein Recombinant Neisseria meningitidis serogroup B NadA protein Recombinant Neisseria meningitidis serogroup B fhbp fusion protein Outer membrane vesicles (OMV) from Neisseria meningitidis serogroup B strain NZ98/254 measured as amount of total protein containing the PorA μg 50 μg 50 μg 25 μg Each component is adsorbed on aluminum hydroxide adjuvant 0.5 mg of Al +3 6

7 OMV Vaccination Eliminated the epidemic in New Zealand Auckland Rate per population Proof of principle that MenB vaccines can work and can be safely used 7

8 4CMenB Clinical Development Program 8 studies were conducted 6 studies in infants from 2 months of age and toddlers 3 studies in adolescents 11 years of age and adults 7,938 total subjects 6,354 infants and toddlers 1,630 received a booster dose in the second year of life 1,584 adolescents and adults Geographically diverse (EU, North and South America) 4CMenB has been studied in the Northern and Southern Hemispheres 8

9 4CMenB: Clinical Trial data Gossger N, Snape MD, Yu LM, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012;307: Santolaya ME, O'Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet. 2012;379: Vesikari T, Esposito S, Kimura A, et al. Immunogenicity of an investigational, multicomponent, meningococcal serogroup B vaccine in healthy infants at 2, 4, and 6 months of age. Presented at: International Pathogenic Neisseria Conference; Sept 11-16, 2010; Banff, Canada. Esposito S, Vesikari T, Kimura A, et al. Tolerability of a three-dose schedule of an investigational, multicomponent, meningococcal serogroup B vaccine and routine infant vaccines in a lot consistency trial. Presented at: International Pathogenic Neisseria Conference; Sept 11-16, 2010; Banff, Canada. 9

10 MATS The Meningococcal Antigen Typing System MATS is based on a ELISA that measures the 3 recombinant protein antigens (fhbp, NadA, and NHBA) of 4CMenB against: Antigen quantity Similarity of strain antigens to vaccine antigens MATS links ELISA scores to hsba killing Developed using adult sera against a panel of 124 strains expressing a broad range of antigen variants; a subset of 57 strains were further tested using infant sera This allowed for the determination of the minimum amount of antigen measured by MATS needed to result in killing in the hsba assay Positive Bactericidal Threshold (PBT) PBT is established for the three recombinant protein antigens For PorA, conventional PCR genotyping is used to determine the similarity of the PorA gene sequence in the test strains to that in 4CMenB ELISA, enzyme-linked immunosorbent assay; fhbp, factor H-binding protein; hsba, human complement serum bactericidal assay; NadA, Neisserial adhesin protein A; NHBA, Neisseria Heparin Binding Protein; PorA, Porin A. Donnelly J, et al. PNAS. 2010;107:

11 MATS Results Correlate With hsba Infant pooled sera (13 months) Adult pooled sera # of strains tested Estimated killed in MATS Actual killed in hsba 1:8 77% 72% 74% 85% hsba, human complement serum bactericidal assay. Donnelly J, et al. PNAS. 2010;107:

12 MATS Allows for Systematic Estimation of 4CMenB Coverage for Any Given Region MATS methodology: Standardized and transferred across 5 reference laboratories Health Protection Agency, Institut Pasteur, Norwegian Institute of Public Health, University of Würzburg, Istituto Superiore di Sanità Transferred to 10 countries and transfer is ongoing in several more 12

13 4CMenB Has the Potential to Cover the Majority of MenB Strains in 5 European Countries Based on MATS, 4CMenB is predicted to cover 78% of strains 4CMenB European coverage estimates Norway: 85% [95% CI: 76%, 98%] n=41 England & Wales: 73% [59%, 88%] n=535 Germany: 82% [69%, 92%] n=222 France: 85% [70%, 93%] n=200 Italy: 87% [70%, 93%] n=54 Coverage based on MATS from pooled sera from 13-mo-old infants vaccinated at 2,4, 6, and 12 mo of age tested on 1,052 strains isolated during the epidemiological year. Boccadifuoco G, et al. Presented at: Meningitis and Septicaemia in Children and Adults 2011 (Organized by Meningitis Research Foundation); 8 9 November 2011; London, UK. Poster V36. 13

14 Proposed indications 4CMenB: Proposed Indications Population Age Dose series Infants 2 to 5 months 3 Interval 1 to 2 months Unvaccinated infants 6 to 11 months 2 2 months Unvaccinated toddlers and children Adolescents and adults 12 months to 10 years 11 years and older* months 1 to 2 months Booster recommended At 12 to 23 months At 12 to 23 months; 2 months from primary series *The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied. 14

15 Summary Serogroup B meningococcal disease is a feared and often deadly disease, affecting mainly infants It is easily misdiagnosed, can kill within 24 hours of onset and may cause serious, life-long disabilities despite appropriate treatment 4CMenB includes 4 components that are important for the survival, function, and/or virulence of the meningococci: fhbp, NadA, NHBA, and PorA Use of multiple well-chosen antigens is likely to maximize coverage of genetically varied and changing strains Of note, 50% of MenB strains tested are covered by more than one 4CMenB antigen In clinical studies, 4CMenB has demonstrated a protective immune response in infants, children and adults In clinical studies, reactions seen after vaccination with 4CMenB were similar to those seen after vaccination with other routine vaccines 4CMenB is the first vaccine to demonstrate potential coverage of the majority of meningococcal serogroup B strains hereby helping to predict the public health impact of vaccination 15