Joseph Domachowske MD, FAAP Professor of Pediatrics Professor of Microbiology and Immunology SUNY Upstate Medical University Syracuse, NY Consultant: Sanofi Pasteur, Medimmune Research: Sanofi Pasteur, Medimrnune (AstraZeneca), Pfizer, Diassess, Novavax, Merck, GSK, Regeneron, Janssen, Novartis 1
Attendees will list the steps required and general timeline needed to move a preclinical vaccine idea to a vaccine that is available for widespread use Attendees will describe strategies for immunization and disease prevention Smallpox Diphtheria Polio Measles H. Flu b Tetanus Pertussis Pre vaccine Morbidity 29,005 21,053 16,316 530,217 20,000 580 200,752 Recent reported cases in US 0 0 1 187 31 26 28,639 % Decrease 100% 100% >99% >99% >99% 96% 86% CDC. Impact of Vaccines in the 20 th and 21 st century. Pink Book, Appendix E. 2015 2
Vaccines licensed for use in the US Adenovirus Diphtheria, tetanus, acellular pertussis Japanese encephalitis virus Measles, mumps, rubella Rotavirus Smallpox H. influenzae type b Meningococcal Typhoid ACWY Hepatitis A Meningococcal B Varicella Hepatitis B Pneumococcal Yellow Fever Human Polio Zoster papillomavirus Influenza Rabies Cholera 3
Highly regulated process Can take 10 15 years from concept to recommendation Most vaccines do not make it past pre clinical or early clinical trials (phase I) Vaccines Years to approval Varicella 25 30 LAIV 25 30 HPV* 14 16 Rotavirus* 14 16 Pediatric combination 10 12 vaccines * Excluding early pre clinical work Douglas RG. (2008). The Vaccine Industry. In Plotkin s Vaccines. (p39). Elsevier 4
Demand for vaccine in market Drivers of vaccine development Technically feasible Limited use product 10 15 years before marketing Uncertain demand in market Incorporation into immunization program Clinical Economic Vaccine development Clinical development Process development Assay development Vaccine effect on patients Safety, efficacy, immunogenicity Phase I, II, III clinical trials Vaccine prep by regulatory requirements Vaccine lots Consistent manufacturing methods Specific testing methods: Purity Stability Potency Assays for immunologic endpoints 5
Vaccine Development Pre clinical Phase I Phase II Phase III File Phase IV 1 10 years 2 3 years 2 5 years Vaccine concept Lab assays, animal models Identification of antigens 6
IND Application Manufacturing process Vaccine composition Pre clinical data Proposed clinical trials plan Vaccine safety Vaccine potency Vaccine efficacy Vaccine purity Small studies healthy subjects (~50) Short term Primary outcome Safety Phase I Other measures Prelim Immunogenicity Vaccine dosing Subjects at low risk for infection 7
RSV 12 17 month old, RSV sero positive infants Safety, reactogenicity, immunogenicity Dose escalation, with safety assessments Precursor to studying vaccination in sero negative infants Longer, larger ~2 years 1,000 subjects At risk population Expanded data Safety Vaccine dosing Phase II Proof of concept Immunogenicity Double blinded, placebo controlled, randomized 8
RSV monoclonal antibody, extended half life Healthy pre term infants, 29 34 6/7 weeks Entering first RSV season Efficacy: reduction in medically attended respiratory infections due to RSV Large scale 1000s of subjects At risk for infection Several years Phase III Assess Safety Efficacy Immunogenicity Clinical endpoints Immunologic response Randomized, placebocontrolled, blinded 9
RSV F nanoparticle vaccine Healthy third trimester pregnant women Immunologic endpoints Pregnant women Cord blood Newborns Clinical endpoints infants for 2 years Safety data collected Biologics License Application (BLA) submission Submit safety/efficacy to FDA Vaccines and related Biologic Product Advisory Committee Review data with VRBPAC 18 24 months Pre approval inspection of vaccine production 10
FDA Decides on licensure Restricted to study population ACIP Reviews data in context of current needs Makes vaccine recommendation FDA label indication Tdap one dose and done Tdap for people aged 10 64 years Quadrivalent meningococcal one dose MenB 10 24 years of age Influenza vaccine not specifically licensed for use during pregnancy ACIP recommendation Tdap every pregnancy Tdap for all 7years and older Quad mening 2 doses for all teens MenB 10 years and older for those at risk Influenza vaccine during pregnancy 11
Post licensure surveillance Safety surveillance VAERS, Vaccine Safety Data Link, manufacturer reports Case controlled studies when Red Flags appear Look for rare adverse events Long term efficacy evaluation During outbreaks, ongoing epidemiologic data collection Manufacturer production activities Cost of developing new vaccine $231 million in 1991 $800 million in 2010 Research and development costs of failed products Post licensure clinical studies Improvements in manufacturing processes 12
Private Vaccine Companies Government agencies CDC, FDA, DOD, USAID, NIH NGO Gates Foundation, PATH Contributions to Vaccine R&D Highly regulated Single set of rules applied to all vaccines Regulations of manufacturing process Regulations of clinical trials Complicated, costly, with more failures than successes 13
Clinicaltrials.gov Search: vaccine 6,670 registered vaccine trials 1,100 open vaccine trials 642 trials actively recruiting 14
clinicaltrials.gov clinicaltrials.gov 15
universal flu vaccine group B strep Meningococcal ABCWY RSV Ebola MERS CoV Ebola Pneumococcus Hepatitis C Malaria Meningococcal ACWY Shigella Hexavalent peds Tuberculosis RSV HIV Universal flu CMV Rabies Tdap 16
pneumococcus Men ACWY rotavirus VZV C. diff MMR Ebola Flu RSV 17
Virus attachment to host cell Virus entry into host cell cdc.gov Types A, B, C A, B: most of human disease C: uncommonly causes human disease Influenza A H1, H2, H3; N1, N2 Seasonal epidemics Vaccination is most effective method for disease prevention 18
IIV: intradermal, IM Trivalent, quadrivalent A (H1N1) A (H3, N2) B LAIV: intranasal Cell based Egg based Recombinant CDC and WHO provide candidate vaccine viruses Egg based: Virus injected into fertilized hen s egg Cell based: Virus inoculated into mammalian cells Recombinant: HA protein isolated from wild type virus and combined with proteins to grow in insect cells incubate for virus replication virus containing fluid harvested virus inactivated and purified FDA testing, approval, shipment 19
Vaccine efficacy ~30 60% Most effective when vaccine strains closely match circulating viruses Circulating strains change yearly Do not protect against pandemics Universal influenza vaccine??? Goals At least 75% effective Protects against multiple types of influenza A (pandemic strains included ) Duration over a year Suitable for all age groups www.niaid.nih.gov/diseases conditions/universal influenza vaccine research 20
Current vaccines induce antibody to HA head Changes frequently Lofano, Giuseppe & Kumar, Arun & Finco, Oretta & Del Giudice, Giuseppe & Bertholet, Sylvie. (2015). B Cells and Functional Antibody Responses to Combat Influenza. Frontiers in immunology. 6. 336. 10.3389/fimmu.2015.00336. More conserved Vaccine to induce antibody to stalk Lofano, Giuseppe & Kumar, Arun & Finco, Oretta & Del Giudice, Giuseppe & Bertholet, Sylvie. (2015). B Cells and Functional Antibody Responses to Combat Influenza. Frontiers in immunology. 6. 336. 10.3389/fimmu.2015.00336. 21
nanoparticles 4 H subtypes into one vaccine More conserved Vaccine to induce antibody to stalk DNA based vaccine prime [phase 1, 2] M 001: antigenic peptides from many strains [phase 2] Lofano, Giuseppe & Kumar, Arun & Finco, Oretta & Del Giudice, Giuseppe & Bertholet, Sylvie. (2015). B Cells and Functional Antibody Responses to Combat Influenza. Frontiers in immunology. 6. 336. 10.3389/fimmu.2015.00336. 22
F glycoprotein Mediates fusion reaction delivery of virus capsid core contents into cell Disrupting activity would reduce virus entry into cell protect host from infection Highly conserved among strains Infants Active immunization Passive immunization Pregnant mothers RSV Ab efficiently transferred across placenta High cord blood RSV Ab levels incidence of severe RSV LRTI Passive immunization lower 23
Formalin inactivated RSV vaccine Infants 2 7 months of age Enhanced disease Hospitalizations: 80% of vaccinated vs 5% placebo 2 deaths from RSV infection among vaccinated Thought to be due to Ab produced: non neutralizing and did not inhibit fusion Inflammatory CD4 T cell driven cytokine response Live Attenuated Whole Inactivated Particle based Subunit Nucleic Acid Vectors Immunoprophylaxis 24
ID genetic sequence of RSV F protein Clone gene into baculovirus Spodoptera frugiperda (Fall armyworm) Engineered baculovirus infects the SF9 cells Only infects insects Engineered to express genes of interest Used to infect Sf9 cells to efficiently produce desired protein RSV F proteins produced Transported to surface, extracted, purified Safe and inexpensive High capacity Infect cells Express encoded antigens Induce immune response Adenovirus type 5 Most common human Adenovirus serotype 30% + Ad Ab less immunogenic Can express multiple proteins Chimpanzee adenovirus Related to human adenovirus Low neutralizing antibodies in human population Genetically engineered recombinant CHAd155 Same vector used in ebola vaccine Non-alum composition core fibre Double stranded DNA Target RSV genes 25
Passive protection Palivizumab Prevention of RSV Licensed in 1998 Monthly injections during RSV season Costly YTE technology substitutes 3amino acids in the Fc region of IgG. recombinant human IgG1 kappa monoclonal antibody Targets prefusion F Derived from D25 (human mab with 100x greater potency than palivizumab in vitro YTE technology 26
Rigorous regulations in vaccine development Significant amount of time and money to ensure safe and effective vaccines Novel vaccine strategies are being developed to improve disease prevention New vaccines are becoming available in the US and worldwide 27