Hepatitis B, flu, MMR (measles, mumps, and rubella) and DTP (diphtheria, tetanus, pertussis)
40% are produced in the United States and the rest is evenly split between Europe and the rest of the world
Drug Development Process Laboratory R+D Pre-IND - Safety/Toxicity -> IND filing Phase I - human safety/toxicity Phase II - efficacy Phase III - extended studies / other drug(s) NDA -> FDA Approval Post-licensure surveillance
2008 Success!: New HPV (Cervical Cancer) Vaccine almost 100% effective!
Correlates of Immunity one or many? (Ab? Ag? CMI?)
Critical Antigens - one or many?
Animal Model? Does it predict protection?
Prototype Vaccine - Preclinical Proof
Safety and Toxicity, GMP, Stability
FDA “IND” Approval
Post Clinical Phase
Clinical trials (Phase I, II, III)
Approval (and indication)
Distribution / Acceptance / Access
Is there Immunity (If not you are in trouble)
4. Correlates of Immunity one or many? (Ab? Ag? CMI?)
Basic Principles of Vaccine Immunology Innate immunity (e.g., macrophages, neutrophils, certain molecules) is the first line of defense. It is fast (usually good-to-go) and usually effective. Adaptive immunity (mediated by B and T cells) can be slow to respond (several days). It is highly effective when the innate immune system cannot fully deal with the threat.
Primary response (primary immunization) is relatively: Secondary response (secondary immunization or booster immunization) is relatively: slow (4-7days) small amount of antibody (low concentration of antibody) low affinity antibody IgM first, IgG second (equal amounts of IgM and IgG) fast (2-4 day) large amounts of antibody high affinity antibody mostly IgG
Often, a secondary (memory) response is so fast and effective in removing antigens (pathogens), there are few or no symptoms detected by the infected individual (protective immunity). Secondary responses are the reason we do not get certain infectious diseases more than once. Secondary responses also explain why vaccinations work. For vaccinations, instead of immunizing with something that makes you sick, a vaccine contains antigens prime the immune response.
The Even Newer Way In vitro screening epitope Bioinformatics
Less than the entire pathogen is required Hepatitis Virus or Vaccine Epitope Subset = Immunome Immune system ‘ filter’
T cell epitope At Intersection of Immune Response
EpiVax: Accelerating Vaccines and Biologics Research and Development Anne S. De Groot 1, 2,3, L.Moise 1, 3 , J.A. McMurry 1 , W. Yang 1 , William Martin 1 1 EpiVax, Inc. 2 Brown Medical School and 3 University of Rhode Island [email_address] http://www.EpiVax.com
We think about what a vaccine does. . . . . . Trains the immune system to recognize and fight infection . . . Without requiring exposure to the pathogen using “epitopes” = chains of amino acids
Current Vaccine–Related NIH Funding 1R43AI058376 "A novel Smallpox Vaccine Derived from the VV/VAR Immunome“ 1R43AI065036 "A Genome-Derived, Epitope-Driven H pylori Vaccine“ 1R43AI058326 "A Genome-Derived, Epitope-Driven Tularemia Vaccine" 1R43AI075830-01 “ Optimization of a Multivalent Tuberculosis Vaccine” 7R01AI050528 (new R21: Optimization of HIV Vaccine Delivery) Epitope Driven HIV Vaccine Development Unfunded : Influenza, HPV, EBV
EpiVax Genome-derived, epitope-driven vaccine approach : In Silico EpiMatrix / ClustiMer / OptiMatrix [class I and class II alleles] Conservatrix / BlastiMer/. EpiAssembler/ VaccineCAD In Vitro HLA binding assay ELISpot - ELISA - Multiplex ELISA - FACS - T regulatory T cell profiling In Vector DNA prime/peptide (pseudoprotein boost) vaccines Vaccine delivery / formulation optimization / detolerizing delivery agents In Vivo HLA DR3, DR4 transgenic mice HLA class I transgenic mice Vaccination, Comparative studies
Prime-boost Smallpox Vaccine Immunization Sacrifice Birth 1. epitope DNA vaccine prime 2. epitope peptide boost 1. control DNA prime 2. control peptide boost Week 0 Week 8-14 IFN-gamma and multiplex ELISA Challenge Lethal Intratranasal Challenge 3 mice week 16 Week 18
Results: 100% survival of Vaccinated mice vs. 17% of placebo 100% 100% 0 20 40 60 80 100
No significant weight loss in vaccinated mice – surviving mice in placebo arm are regaining weight
HIV Vaccine Development The GAIA HIV Vaccine • In Development since 1998 - More than 300 epitopes mapped • Highly Variable Pathogen – Conserved epitopes • HLA Diversity -- 6 HLA supertypes • T cell help -- Immunogenic consensus sequence epitopes • Validation in HLA transgenic mice -- Good progress.
Better Vaccines and Health for All Our Hope for the Future