Product Development for Vaccines Advisory pDNA VACCINATION pDNA transfected Committee (PDVAC): Advances in nucleic acid cell Humoral (antibody-mediated) immune response Cell-mediated immune response Low-level, persistent immunogen Engulfed by Free immunogen Immunogen on directly activates transfected cell APC directly activates delivery vaccine platforms Stimulates Stimulates Stimulates B cell Helper CTL T cell Memory Gives rise to Stimulates Helper T cell Stimulates Gives rise to Memory Stimulates Memory th B cell T cell WHO PDVAC 4 Annual Meeting, 22 June 2017 Geneva Re-exposure to Immunogen Activated Plasma Memory Memory CTL cell B cell T cell Stimulates Antibodies Cytolysis/ Apoptosis David C. Kaslow, MD Exposure to pathogen Chair, Product Development for Vaccines Advisory Committee 1 Outline • Historical context • Current state of nucleic acid delivery platform technologies • Challenges facing next generation DNA and RNA Vaccines Page 2 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting In the beginning (27 years ago…) N.B. Gene transfer = DNA or RNA Page 3 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting The promise of nucleic acid-based technologies Disruptive technology? “typically cheaper, simpler, and more convenient-to-use...” pDNA VACCINATION Innovator’s Dilemma Clayton Christensen pDNA transfected cell Humoral (antibody-mediated) immune response Cell-mediated immune response Low-level, persistent immunogen Engulfed by Free immunogen Immunogen on directly activates transfected cell APC directly activates Stimulates Stimulates Stimulates B cell Helper CTL T cell Memory Gives rise to Stimulates Helper T cell Stimulates Gives rise to Memory Stimulates Memory B cell T cell Re-exposure to Immunogen Activated Plasma Memory Memory CTL cell B cell T cell Stimulates Antibodies Cytolysis/ Apoptosis Exposure to pathogen Page 4 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting The promise of nucleic acid-based technologies Disruptive technology? “typically cheaper, simpler, and more convenient-to-use...” Innovator’s Dilemma Clayton Christensen “when they first appear, they almost always offer lower FOREIGN OR VACCINESVACCINES performance…” SELF ANTIGENS “always improve in NUCLEIC performance (and) ACID-BASED CANCER eventually are able to take TECNOLOGIES over older markets… …because they are able to SELF PROTEINS PROTEIN THERAPEUTICS deliver sufficient performance… and they add some new ones.” Page 5 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting The promise of nucleic acid-based technologies Disruptive technology? “typically cheaper, simpler, and more convenient-to-use...” Innovator’s Dilemma Clayton Christensen Vaccines • Universal Infectious Diseases • Niche Infectious Diseases FOREIGN OR VACCINESVACCINES SELF ANTIGENS • Infectious Diseases, Therapeutic NUCLEIC • Self Antigen • Cancer ACID-BASED CANCER TECNOLOGIES Protein therapeutics • Cancer Immunotherapeutics SELF PROTEINS PROTEIN THERAPEUTICS • Regulated Therapeutic Proteins • Unregulated Therapeutic Proteins • Classic Gene Replacement Therapy Page 6 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting The promise of nucleic acid-based technologies Disruptive technology? “typically cheaper, simpler, and more convenient-to-use...” Innovator’s Dilemma Clayton Christensen Vaccines • Universal Infectious Diseases • Niche Infectious Diseases FOREIGN OR VACCINESVACCINES SELF ANTIGENS • Infectious Diseases, Therapeutic NUCLEIC • Self Antigen • Cancer ACID-BASED CANCER TECNOLOGIES Protein therapeutics • Cancer Immunotherapeutics SELF PROTEINS PROTEIN THERAPEUTICS • Regulated Therapeutic Proteins • Unregulated Therapeutic Proteins • Classic Gene Replacement Therapy Page 7 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Page 8 Slide courtesy of David Weiner WHO Meeting on Nucleic Acid Vaccines 17–18 May 1994 Geneva World Health Organization convened a meeting in Geneva to review the early findings for DNA vaccines: • Immunology • Gene therapy • Efficacy • Safety • Delivery 18 papers published (see Vaccine Volume 12 (16):1491-1568 (December 1994)) Page 9 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting WHO Meeting on Nucleic Acid Vaccines 17–18 May 1994 Geneva Historical note Second day—a vote taken to name the new technology: • Split vote between genetic immunization, polynucleotide vaccines, and nucleic acid vaccines, with majority voting: • Nucleic acid vaccines with sub terms: • DNA vaccines • RNA vaccines “The name nucleic acid vaccines was chosen to reflect the new technology not being designed to insert DNA into the germ line of vaccinees. If this novel form of vaccination were to achieve general acceptance, the perception would need to be that this was a vaccine, and not a therapy for modifying genetic information.” Harriet L. Robinson Vaccine 15(8): 785-787, 1997 Page 10 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Intervening years—three licensed vaccines, all in veterinary applications 2005 2005 2007 → 2010 MERIAL Receives Full License Approval for ONCEPT™ Canine Melanoma Vaccine ONCEPT is the First and Only USDA-Approved, Therapeutic Vaccine for the Treatment of Cancer IHNV DNA vaccine (Apex-IHN, Novartis), containing a CMV February 16, 2010 Duluth, GA — Merial, a world-leading promoter driving expression of animal health company, has gained full-licensure from the IHNV G gene, approved for the U.S. Department of Agriculture for ONCEPT™ Canine commercialization in July 2005 Melanoma Vaccine, DNA. ONCEPT is a breakthrough by the Canadian Food WEST NILE-INNOVATOR vaccines contain the adjuvant vaccine indicated for aiding in extending survival of dogs ® Inspection Agency, Veterinary MetaStim , presentation which is designed for safe, enhanced of with stage II or stage III oral canine melanoma, a Biologist and Biotechnology antigens to the horse’s immune system. MetaStim features a common yet deadly form of cancer in dogs. Division. dual-phase formulation shown to stimulate both cell-mediated and humoral immunity to West Nile virus. Side note: LifeTideSW5, an electroporation-delivered DNA plasmid expressing porcine growth hormone releasing hormone (GHRH) licensed as a product for use in 2007. Page 11 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting And huge amount of R&D on DNA vaccines pubmed - (DNA vaccine) NOT cancer count ClinicalTrials.gov N=22,957 1400 Infectious Disease | DNA Vaccine 1200 N= 159 (July 2014) 1000 (N=173 (June 2017)) 800 US EU 600 400 Phase 1 121 3 200 Phase 2 38 9 0 Phase 3 0 0 1949 1961 1963 1965 1967 1969 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 N.B. >55,000 articles in PubMed+/-Google Scholar HIV 66 Racz R et al. BMC Bioinformatics 15:S2 2014 Influenza 15 See also: DNAVaxDB ( http://www.violinet.org/dnavaxdb), Tregoning JS, Kinnear E. 2014. Microbiol Spectrum 2(6):PLAS- 0028-2014. a Web-based database and analysis resource of doi:10.1128/microbiolspec.PLAS-0028-2014 experimentally verified DNA vaccines Page 12 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Evolution of Regulatory Environment (US FDA) for Plasmid DNA Vaccines for Preventive Infectious Diseases 1996 2007 See also: Klinman DM et al. FDA guidance on prophylactic DNA vaccines: analysis and recommendations. Vaccine 28: 2801-2805, 2010. Page 13 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Circa 1996 Guidance “Until such time that CBER has accrued sufficient information regarding the safety of plasmid DNA preventive vaccines, a new plasmid construct using a common vector and differing only in the antigen to be expressed may be considered a new product and subject to preclinical safety evaluation as delineated in later sections. Once CBER has more experience in the review of plasmid DNA vaccine products, abbreviated preclinical development programs may be proposed for common plasmid vectors.” Page 14 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Circa 1996 Guidance Circa 1996 concerns: • Measures of potency: In vivo required • Autoimmunity: IgG anti-DNA autoantibodies • Persistent expression: At site of injection or distally • Tolerance: Increased disease risk upon subsequent infection • Integration: Enhanced risk of malignant transformation Page 15 Advances in nucleic acid delivery vaccine platforms 4th Annual (2017) PDVAC meeting Updated Guidance 2007: Autoimmunity Published preclinical studies indicate that DNA vaccination can activate autoreactive B cells to secrete IgG anti-DNA autoantibodies (See Section VI, References). However, the magnitude and duration of this response appears to be insufficient to cause disease in normal animals or accelerate disease in autoimmune-prone mice. These preclinical studies helped to establish that systemic autoimmunity is unlikely to result from DNA vaccination. Similarly, the absence of an immune response against cells expressing the vaccine- encoded antigen (including muscle cells and dendritic cells) suggests that an autoimmune response directed against tissues in which such cells reside is unlikely. Based on these findings, we will no longer expect that you perform preclinical studies to specifically assess whether vaccination causes autoimmune