Product Development for Vaccines Advisory Committee (PDVAC): Advances in nucleic acid delivery vaccine platforms

Transcription

1 Product Development for Vaccines Advisory Committee (PDVAC): Advances in nucleic acid delivery vaccine platforms Humoral (antibody-mediated) immune response Free immunogen directly activates B cell pdna VACCINATION Stimulates pdna transfected cell Low-level, persistent immunogen APC Helper T cell Engulfed by Stimulates Cell-mediated immune response Stimulates Immunogen on transfected cell directly activates CTL WHO PDVAC 4 th Annual Meeting, 22 June 2017 Geneva Gives rise to Memory Stimulates Helper T cell Stimulates Memory Stimulates Memory B cell T cell Re-exposure to Immunogen Gives rise to Plasma cell Memory B cell Stimulates Memory T cell Activated CTL David C. Kaslow, MD Chair, Product Development for Vaccines Advisory Committee Antibodies Exposure to pathogen Cytolysis/ Apoptosis 1

2 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 4 th Annual (2017) PDVAC meeting

3 In the beginning (27 years ago ) N.B. Gene transfer = DNA or RNA Page 3 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

4 The promise of nucleic acid-based technologies Disruptive technology? typically cheaper, simpler, and more convenient-to-use... Innovator s Dilemma Clayton Christensen Humoral (antibody-mediated) immune response Free immunogen directly activates pdna VACCINATION pdna transfected cell Low-level, persistent immunogen APC Engulfed by Stimulates Cell-mediated immune response Immunogen on transfected cell directly activates B cell Stimulates Helper T cell Stimulates CTL Gives rise to Stimulates Memory Helper T cell Stimulates Gives rise to Memory B cell Stimulates Memory T cell Plasma cell Memory B cell Re-exposure to Immunogen Stimulates Memory T cell Activated CTL Antibodies Exposure to pathogen Cytolysis/ Apoptosis Page 4 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

5 The promise of nucleic acid-based technologies Disruptive technology? typically cheaper, simpler, and more convenient-to-use... Innovator s Dilemma Clayton Christensen NUCLEIC ACID-BASED TECNOLOGIES FOREIGN OR SELF ANTIGENS SELF PROTEINS VACCINES CANCER PROTEIN THERAPEUTICS when they first appear, they almost always offer lower performance always improve in performance (and) eventually are able to take over older markets because they are able to deliver sufficient performance and they add some new ones. Page 5 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

6 The promise of nucleic acid-based technologies Disruptive technology? typically cheaper, simpler, and more convenient-to-use... Innovator s Dilemma Clayton Christensen NUCLEIC ACID-BASED TECNOLOGIES FOREIGN OR SELF ANTIGENS SELF PROTEINS VACCINES CANCER PROTEIN THERAPEUTICS Vaccines Universal Infectious Diseases Niche Infectious Diseases Infectious Diseases, Therapeutic Self Antigen Cancer Protein therapeutics Cancer Immunotherapeutics Regulated Therapeutic Proteins Unregulated Therapeutic Proteins Classic Gene Replacement Therapy Page 6 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

7 The promise of nucleic acid-based technologies Disruptive technology? typically cheaper, simpler, and more convenient-to-use... Innovator s Dilemma Clayton Christensen NUCLEIC ACID-BASED TECNOLOGIES FOREIGN OR SELF ANTIGENS SELF PROTEINS VACCINES CANCER PROTEIN THERAPEUTICS Vaccines Universal Infectious Diseases Niche Infectious Diseases Infectious Diseases, Therapeutic Self Antigen Cancer Protein therapeutics Cancer Immunotherapeutics Regulated Therapeutic Proteins Unregulated Therapeutic Proteins Classic Gene Replacement Therapy Page 7 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

8 Page 8 Slide courtesy of David Weiner

9 WHO Meeting on Nucleic Acid Vaccines 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): (December 1994)) Page 9 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

10 WHO Meeting on Nucleic Acid Vaccines 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): , 1997 Page 10 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

11 Intervening years three licensed vaccines, all in veterinary applications 2005 IHNV DNA vaccine (Apex-IHN, Novartis), containing a CMV promoter driving expression of the IHNV G gene, approved for commercialization in July 2005 by the Canadian Food Inspection Agency, Veterinary Biologist and Biotechnology Division WEST NILE-INNOVATOR vaccines contain the adjuvant MetaStim, presentation which is designed for safe, enhanced of antigens to the horse s immune system. MetaStim features a dual-phase formulation shown to stimulate both cell-mediated and humoral immunity to West Nile virus 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 February 16, 2010 Duluth, GA Merial, a world-leading animal health company, has gained full-licensure from the U.S. Department of Agriculture for ONCEPT Canine Melanoma Vaccine, DNA. ONCEPT is a breakthrough vaccine indicated for aiding in extending survival of dogs with stage II or stage III oral canine melanoma, a common yet deadly form of cancer in dogs. Side note: LifeTideSW5, an electroporation-delivered DNA plasmid expressing porcine growth hormone releasing hormone (GHRH) licensed as a product for use in Page 11 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

12 And huge amount of R&D on DNA vaccines pubmed - (DNA vaccine) NOT cancer count N=22, ClinicalTrials.gov Infectious Disease DNA Vaccine N= 159 (July 2014) (N=173 (June 2017)) US EU Phase Phase Phase N.B. >55,000 articles in PubMed+/-Google Scholar Racz R et al. BMC Bioinformatics 15:S See also: DNAVaxDB ( a Web-based database and analysis resource of experimentally verified DNA vaccines HIV 66 Influenza 15 Tregoning JS, Kinnear E Microbiol Spectrum 2(6):PLAS doi: /microbiolspec.plas Page 12 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

13 Evolution of Regulatory Environment (US FDA) for Plasmid DNA Vaccines for Preventive Infectious Diseases See also: Klinman DM et al. FDA guidance on prophylactic DNA vaccines: analysis and recommendations. Vaccine 28: , Page 13 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

14 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 4 th Annual (2017) PDVAC meeting

15 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 4 th Annual (2017) PDVAC meeting

16 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 vaccineencoded 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 disease. Page 16 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

17 Updated Guidance 2007: Tolerance Published studies to address whether DNA vaccines could induce neonatal tolerance yielded divergent results (see Section VI, References). Most DNA vaccines did not induce tolerance in neonatal animals, but idiosyncratic examples of neonatal tolerance have been observed (see Section VI, References). Tolerance has never been observed following vaccination of mature animals. Taken together, these studies suggest that the capacity of a DNA vaccine to induce tolerance may depend on the nature of the encoded antigen and the age at which, and frequency with which, the vaccine is administered. Based on these findings and other considerations, we recommend that prior to use of a DNA vaccine in children or newborns that: i) you first test the vaccine for safety and immunogenicity in adults, and ii) you utilize appropriate preclinical models to evaluate the potential of such vaccines to induce neonatal tolerance. Page 17 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

18 Updated Guidance 2007: Biodistribution and Integration Analysis Plasmid biodistribution, persistence and integration studies were initially recommended by CBER to determine whether subjects in DNA vaccine trials were at heightened risk from i) the long-term expression of the encoded antigen either at the site of injection or an ectopic site, and/or ii) integration of the plasmid that might increase susceptibility to malignant transformation. Publications resulting from the use of DNA vaccines in clinical studies under IND indicate that intramuscular, subcutaneous, intradermal, or particle-mediated delivery does not result in long-term persistence of plasmid at ectopic sites, and that <30 copies of plasmid per 10 5 host cells persist at the site of injection after 60 days (see Section VI, References). Before conducting biodistribution/persistence studies, you should contact FDA for advice concerning the need for these studies in particular, when: i) new or significantly modified plasmids are proposed for clinical use, and/or ii) the formulation of the DNA vaccine and/or its method/route of delivery may significantly increase cellular uptake or alter plasmid distribution Page 18 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

19 WHO TRS Guidelines on DNA Vaccines Measures of potency: in vitro assay should be shown to correlate with immunogenic activity or efficacy in an animal model Autoimmunity: IgG anti-dna autoantibodies analysis in nonclinical programmes not generally warranted Persistent expression: Biodistribution and persistence studies are required, unless substantial experience has already been gained with an almost identical or similar product Tolerance: Tolerance has not been observed in adult animals and humans and the initial concern may have been overstated; the possibility of tolerance may remain a concern, particularly in neonates Integration: Integration studies may not be necessary for a plasmid DNA vaccine if prior information on a similar plasmid, with the same mode of administration already exists. Risks of genes encoding cytokines or costimulatory molecules: Studies should continue to address the possibility that some cytokines may produce local or systemic toxic effects Page 19 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

20 Naked Plasmid DNA: Advantages, limitations and alternatives Advantages Simple design; low complexity production Easy to scale up; large scale production methods available Safety Noninfectious, non-replicative; unable to revert to virulent forms Stable formulation Easy storage and shipping; no cold chain requirement for transport Cost effective, depending on dose Immunogenic in animals Humoral and cellular specific immune responses (including CTL) Limitations Weak to moderate immunogenicity in humans Limited to protein immunogens Potential for atypical processing of bacterial and parasite proteins Gene gun Electroporation Jet injection Liposome delivery Self-amplifying RNA vaccines Page 20 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

21 Next Gen DNA Vaccines: Growing pipeline in infectious diseases HIV (B) Electroporation Delivery 7 of 15 current programs in clinical development in infectious disease indications: All Phase subjects in trials 1500 safety database HIV (ACD) HIV (ABCD) Flu Universal Ebola MERS Zika accessed 20 June 2017 Page 21 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

22 What about RNA Vaccines? DNA Vaccines RNA Vaccines pubmed - (DNA vaccine) NOT cancer count N=22, pubmed - (RNA vaccine) NOT cancer count N=9, Page 22 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

23 Early barriers to RNA Vaccines Instability Hydrolysis RNases Billion year old barriers Cell membrane Escape from endosomes Innate immune responses (e.g., Toll-like receptors, RNA helicase RIG-I and protein kinase R) Production requires clean enzymes Dowdy Nature Biotechnology 35: (2017) Unmodified mrna Low expression levels in vivo Page 23 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

24 RNA Vaccine enhancements Stability and/or expression levels 5 cap (m7gpppg) 3 poly(a) tail to the end, Optimizing codon usage and GC content 5 and 3 untranslated elements 2 o structure to increase ribosome engagement Traversing the billion year barrier Lipid nanoparticle (LNP) Cationic delivery and protection against RNAses Anionic targeting dendritic cells Modified bases (e.g., pseudouridine, 5-methylcytidine) Self-amplification Encoding viral replicases (e.g., alphavirus replicon) Nature Biotechnology 35, (2017) Page 24 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

25 RNA Vaccines in Clinical Development Adapted from Nature Biotechnology 35, (2017) 10 of 19 in clinical development in infectious disease indications: 4 Pre-clinical; 4.5 Phase 1; 1.5 Phase 2 Page 25 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

26 Challenges facing next generation Nucleic Acid Vaccines New products, from a regulatory perspective Moving from full to abbreviated preclinical studies? Disruptive technology * without bridges to immunological surrogates/correlates of protection for conventional vaccines Modernizing legacy vaccines? Well-characterized biologics v conventional vaccine mrna platform v gene of interest (product-specific) quality control and lot release testing? Scale-up synthetic manufacturing Enzymes and raw materials (COGs) Distributed manufacturing (self-contained modules) Acceptability *Trans R Soc Trop Med Hyg 98 (10): (2004). Page 26 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

27 Progress is being made Courtesy of Dr. Frank Bähner, CureVac Page 27 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting

28 Next Gen Nucleic Acid Vaccines Outstanding Questions Efficacy in adequately powered studies in humans Duration of Immunity Long Term Safety Demonstrating scalability of Manufacturing and Formulation presentations for commercial scale Courtesy of Dr. Mike Watson, Moderna Page 28 Advances in nucleic acid delivery vaccine platforms 4 th Annual (2017) PDVAC meeting