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1 Innovatative strategies for meningococcal vaccines Mariagrazia Pizza The Impact of Vaccines on Public Health Prague, March 24th, 2013

2 Neisseria meningitidis is a bacterium surrounded by a capsular polysaccharide (a polymer of sugars), each with distinct chemical composition 2

3 Meningococcus B Capsule Is a Self Antigen and Cannot Be Used for Vaccination

4 Tailor-made Vaccines to Specific MenB Strains Have Been Developed Blebbing meningococcus Extracted OMV vesicles Purified LPS-depleted OMV OMV-based serogroup B vaccines have been used in countries with outbreaks (e.g., New Zealand, Cuba, Normandy), which tend to be caused by a single strain PorA OMV LPS Class 5 PorB Class 4

5 OMV Vaccination Controlled the Epidemic in New Zealand Outer Membrane Vesicles (or OMV) used in vaccines succeeded in controlling the epidemic in New Zealand 3 million doses used in 2004 Problem: poor coverage, it works mainly against the New Zealand strain Rate per population Auckland Proof of principle that MenB vaccines can work and have an acceptable safety profile

6 Reverse Vaccinology A genomic-based approach to vaccine development An innovative approach to identifying protein antigens with high potential to induce bactericidal antibodies 1. Tettelin H, et al. Science. 2000; 287: ; 2. Rappuoli R. Vaccine. 2001;19: ; 3. Pizza M, et al. Science. 2000; 287:

7 Novartis 4CMenB Vaccine Contains Key Surface-Exposed Antigens Conserved surface antigens selected that induce bactericidal antibody response against the broadest number of strains fhbp variant 1 NadA NHBA NZ PorA 1.4 (as part of OMV) Pizza et al. Science. 2000;287(5459): ; Giuliani et al. Proc Natl Acad Sci USA. 2006;103(29): ; Cantini F, et al. J Biol Chem. 2009;284(14): ; Data on File; Novartis Vaccines

8 4CMenB Vaccine Composition N N Three protein antigens (two fusion proteins and one single polypeptide) Outer Membrane Vesicle (OMV) component (NZ PorA is P1.4) Dose NHBA GNA2091 N 4CMenB is a suspension for injection NHBA- GNA1030 NadA GNA1030 fhbp fhbp- GNA2091 C NadA OMV Al ml 50 g 50 g 50 g 25 g 0.5 mg C C PorA Class 5 OMV PorB LPS Class 4

9 Antigenic Components of the 4CMenB: Important for Meningococcal Survival, Function, or Virulence NadA: neisserial adhesin A Promotes adherence to and invasion of human epithelial cells 1-3 Antibodies could interfere in colonization fhbp: factor H binding protein Binds factor H, which enables bacterial survival 5,6 in the blood Binds the bacterial siderophore enterobactin (in vitro) NHBA: neisserial heparin-binding antigen Present in virtually all strains Binds heparin and heparan sulfate PGs via the Arg-rich region. Binding increas the serum resistance Mediate adhesion NZ PorA 1.4: porin A Major outer membrane vesicles protein induces strain specific bactericidal response

10 Clinical Trials of the new 4CMenB vaccine

11 4CMenB Clinical Development Program 4CMenB was evaluated in 12 studies with 7,190 subjects (from 2 months of age) who received at least one dose of 4CMenB 5,395 infants and toddlers from 2 months to 2 years of age - 1,630 received a booster dose in the second year of life 169 children 2 to 10 years of age 1,712 adolescents and adults 11 years of age Geographically diverse (EU, North and South America) 4CMenB has been studied in the Northern and Southern Hemispheres

12 Two Factors Are Considered When Evaluating the Potential Public Health Impact of 4CMenB Demonstrated immunogenicity (Measured using the hsba, the accepted correlate marker of protection) Estimation of strain coverage (Proportion of circulating, disease-causing strains within a given region or country that is killed by vaccine-elicited immune sera)

13 Reference Men B Strains Used to Measure Antigen-Specific SBA Responses in Vaccinees Serum sample The 4CMenB vaccine has 4 major antigenic components: fhbp, PorA, NadA, and NHBA. Test bactericidal response against MenB indicator strains, each one primarily susceptible to killing by bactericidal antibodies against one of the major vaccine antigens. Indicator MenB Strain 5 99 H44/76SL NZ98/254 M10713 hsba titers 1:4 is the protective level of antibody(titer of 1:5 gives 95% confidence)

14 % Subjects with bactericidal titers 1:5 4CMenB Immunogenicity in Infants Percentage of infants with bactericidal titers 1:5 and immune response to a booster dose Strain Antigen Baseline Post-primary* Pre-booster Post-booster /76-SL fhbp 5/99 NadA NZ98/254 PorA P M10713 NHBA 98 *Blood drawn at 7 months, N= Blood drawn at 13 months, N= N=100. Phase III in Infants Study V72P13 and V72P13E1 in EU Countries

15 Co-administration of 4CMenB With Routine Vaccines Percentage of seroresponders to routine vaccines when given with 4CMenB or routine alone at 2, 4, and 6 months of age % Seroresponders % (-1, 2) Diphtheria Tetanus Pertactin Pertussis FHA Polio 1 Polio 2 Polio 3 HBV PRP-Hib % 0.1 IU/mL 0% (-2, 2) % 0.1 IU/mL -4% (-8, -1) -2% (-5, -1) -4% (-8, -1) Antigens -1% (-5, 2) -5% (-11, -1) % 1:8 *Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib; n= Criteria met for LL 95% CI for difference in seroresponders > -10%. Blood drawn at 7 months. 4CMenB plus routine vaccines * Routine vaccines alone * -1% (-4, 2) -2% (-5, -1) % 10 miu/ml -1% (-3, 1) % 0.15 mcg/ml Phase III in Infants Study V72P13 in EU Countries

16 Co-administration of 4CMenB With Routine Vaccines Percentage of seroresponders to pneumococcal vaccine when given with 4CMenB or routine alone at 2, 4, and 6 months of age % Seroresponders ( 0.35 mcg/ml) % 0% 0% -1% (-4, 0) 0% 2% (-2, 1) (-4, 8) (-4, 3) B 9V 14 18C 19F 23F Pneumococcal serotype (-3, 1) 4CMenB plus routine vaccines * Routine vaccines alone * (-3, 4) -3% (-8, 2) *Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib. n= Criteria met for LL 95% CI for difference in seroresponders > -10%. Blood drawn at 7 months. Vesikari T, et al. Presented at the 17 th International Pathogenic Neisseria Conference (IPNC); September 2010; Banff, Canada; Poster #180. Phase III in Infants Study V72P13 in EU Countries

17 4CMenB Tolerability in Infants % of infants % of infants 100 4CMenB+Routine 2-4-6* Tenderness Erythema Induration Swelling Changed eating habits Sleepiness Vomiting Diarrhea Irritability Unusual crying MenC+Routine 2-4-6* 4CMenB+Routine 2-4-6* MenC+Routine 2-4-6* Routine 2-4-6* Rash Fever *Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib. 4CMenB+Routine: n=493; MenC+Routine: n=470. 4CMenB+Routine: n=2478; Routine: n=659; MenC+Routine: n=490. Esposito S, et al. Presented at the 17 th International Pathogenic Neisseria Conference (IPNC); September 2010; Banff, Canada; Poster #182. Phase III in Infants Study V72P13 in EU Countries

18 Fever rates following any vaccination with 4CMenB, administered according to different schedules in infants % of Subjects CMenB + Routine Concomitant 4CMenB + Routine 4CMenB Alone Routine Routine 4CMenB 40 C 39 to 40 C 38 to 39 C Routine vaccines: DTaP, Hib, HBV, Pnc. 18

19 Conclusions on 4CMenB It was created using an innovative approach to vaccine development known as reverse vaccinology Can induce bactericidal antibodies in infants, toddlers and adolescents against diverse MenB strains because it contains more targeting antigens Includes antigen components that are important for the survival, function, and/or virulence of the meningococci: fhbp, NadA, NHBA, and PorA 19

20 Two Factors Are Considered When Evaluating the Potential Public Health Impact of 4CMenB Demonstrated immunogenicity (Measured using the hsba, the accepted correlate marker of protection) Estimation of strain coverage (Proportion of circulating, disease-causing strains within a given region or country that is killed by vaccine-elicited immune sera)

21 How to predict strain coverage Sequence information is important but non sufficient to predict coverage Antigens can also differ in their expression level fhbp NHBA

22 Collect Isolate and grow strainbacterial strain cultured (test strain) MATS ELISA: Defining the Public Health Benefit of Protein-Based Vaccines Spectrometer Create suspension quantifies amount with standardized of bacteria concentration of bacteria Detergent Lyse cells with detergent to free antigens Wells Coat coated wells with with primary capture antibody antibody for for individual individual antigens antigens Compare quantities of vaccines antigens expressed in test strains to those in reference strains to determine relative potency Introduce detecting antibody Introduce free antigens to each coated well, incubate, and wash away unbound antigen 1

23 Using MATS to Predict Whether Strains Are Covered by BEXSERO Example fhbp Identification # of strain (Antigen-specific) Donnelly J, et al. Proc Natl Acad Sci U S A. 2010;107:

24 Using MATS to Predict Whether Strains Are Covered by BEXSERO Example fhbp fhbp-pbt Killed Not Killed Identification # of strain (Antigen-specific) Donnelly J, et al. Proc Natl Acad Sci U S A. 2010;107:

25 MATS Allows for Systematic Estimation of BEXSERO Coverage for Any Given Region Standardized assay developed in conjunction with reference labs worldwide 1. Health Protection Agency (HPA), Manchester, United Kingdom 2. University of Würzburg, Germany 3. Pasteur Institute, France 4. National Center for Microbiology, Institute of Health Carlos III, Spain * * 5. Norwegian Institute of Public Health, Norway 6. Queensland Paediatric Infectious Diseases Lab (QPID), Australia 7. Istituto Superiore di Sanità, Italy 8. Centers for Disease Control and Prevention (CDC), United States *Under qualification

26 Online Lecture Library Slide withheld at request of author

27 Just published in The Lancet Infectious Diseases Ulrich Vogel, Muhamed-Kheir Taha, Julio A Vazquez, Paola Stefanelli, Dominique A Caugant, Paula Kriz, Ray Borrow

28 MenB Vaccine UK media CHMP positive opinion 16 November 2012

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30 Towards a meningitis free world Can we eliminate meningococcal meningitis?

31 Acknowledgments MenB Team Novartis NV&D Jeannette Adu-Bobie Mauro Agnusdei Beatrice Aricò Stefania Bambini Alessia Biolchi Giuseppe Boccadifuoco Phil Boucher Brunella Brunelli Barbara Capecchi Elena Cartocci Laura Ciucchi Sara Comandi Maurizio Comanducci Isabel Delany Elena Del Tordello Federica Di Marcello John J. Donnelly Luca Fagnocchi Ilaria Ferlenghi Francesca Ferlicca Barbara Galli Marzia M. Giuliani Enrico Luzzi Vega Masignani Duccio Medini Alessandro Muzzi Francesca Oriente Emmanuelle Palumbo Laura Santini George Santos Silvana Savino Maria Scarselli Kate L. Seib Davide Serruto Isabella Simmini Marta Tontini Irene Vacca Daniele Veggi Annett Kleinschmidt Peter Dull Alan Kimura Daniela Toneatto NV&D TD Team Rino Rappuoli Collaborators TIGR, Maryland, USA Craig Venter CERM, Florence, Italy Lucia Banci University of Massachusetts, Worcester, USA Sanjay Ram CHORI, Oakland, USA Dan Granoff CDC Atlanta, USA Nancy Messonier Imperial College, London, UK Simon Kroll Chris Tang Weatherall Institute, Oxford, UK Richard Moxon MRC, London UK Annalisa Pastore HPA Manchester UK Ray Borrow