MAIN OUTCOMES OF DISCUSSION FROM WHO CONSULTATION ON NUCLEIC ACID VACCINES I. Knezevic, R. Sheets 21-23 Feb, 2018 Geneva, Switzerland CONTEXT OF DISCUSSION • WHO Consultation held to determine whether the existing DNA guidelines were due for revision or if they remained relevant with today’s status of nucleic acid vaccine development and maturity towards licensure (marketing authorization) • Presentation will cover alignment to existing guidelines • Current status of development of DNA and RNA vaccines, both prophylactic & therapeutic • Main outcomes of discussion • Next steps already underway & planned STATUS OF DEVELOPMENT OF NUCLEIC ACID VACCINES • First likely candidate to licensure could be a therapeutic DNA vaccine against Human Papilloma Viruses • Anticipated to be submitted for licensure in 3-5 years • Other DNA vaccines are likely to follow shortly thereafter, e.g., Zika prophylaxis • RNA vaccines – less clinical experience, but therapeutic RNAs anticipated in 2021/22 timeframe to be submitted for licensure • For priority pathogens in context of public health emergencies, several candidates under development (e.g., MERS-CoV, Marburg, Ebola) MAIN OUTCOMES - GENERAL • Regulators expressed need for updated DNA guideline for prophylaxis and therapy • Less need at present for RNA vaccines in guideline but need some basic PTC • Flexibility needed now until more experience gained for RNA vaccines that will come in next few years • Revisit need for a more specific guideline at appropriate time for RNA vaccines • Institutional Biosafety Committees are regulated by national jurisdictions & vary considerably • How can WHO assist to streamline or converge these review processes? Particularly, during Public Health Emergency – can anything be done beforehand? MAIN OUTCOMES - DEFINITIONS • Clear Definitions are needed • Proposed definition of DNA vaccine: • A DNA plasmid(s) into which the desired immunogen(s) is (are) encoded and prepared as purified plasmid preparations to be administered in vivo. Typically, these plasmids possess DNA sequences necessary for selection and replication in bacteria. In addition, they can contain eukaryotic promoters and enhancers as well as transcription termination/-polyadenylation sequences to promote gene expression in vaccine recipients. They may contain or encode immunomodulatory elements. • Clarity provided that a DNA vaccine is not a gene transfer vector, nor is it a gene therapy, as it does not persist in the host nor repair or replace a host gene. A DNA vaccine is not a GMO – as it is not an organism – it is a plasmid DNA that cannot sustain itself outside of a bacterial cell (but national laws may vary from how term is used in guideline) DEFINITIONS 2 • Proposed definition for RNA vaccines (for PTC): • RNA vaccine: RNA molecule(s) administered in vivo in form of mRNA that can be translated in host cells and that encodes an immunogen; likely needs to be delivered in a stabilizing formulation. MAIN OUTCOMES - SCOPE • DNA and RNA vaccines are different in many respects and may have some overlapping, but many divergent issues • Proposal: Confine scope to DNA vaccines and write some PTC about RNA vaccines to be updated as more data emerge • Outside of scope: • RNA molecule(s) administered into host cells ex vivo and returned to autologous host = cell therapy • Self-amplifying RNA – these may be better viewed as viral vectors when administered in a particle consisting of viral proteins • Need for agnostic consideration of potential concerns & issues surrounding RNA vaccines so that data may be collected to address such identified issues, as has been done for DNA vaccines over past 20 years MAIN OUTCOMES – SCOPE 2 • Inclusion of Clinical part (part C) is proposed though this complicates inclusion of prophylactic & therapeutic vaccines into same guideline • Quality part (part A) might be same or similar • Part B (nonclinical) and Part C (clinical) would be quite divergent depending on use, disease indication, target population, etc. • Proposal – Confine scope to prophylactic vaccines against infectious diseases • Therapy for infectious diseases – some principles of guidelines may apply, but guidance on nonclinical and clinical trials needs to be sought from relevant NRA(s) • Immunotherapy for other indications (e.g., oncology) – guidelines may or may not apply – consult other guidelines and relevant NRA(s) MAIN OUTCOMES – INTRODUCTION AND GENERAL PRINCIPLES SECTIONS • In emergency settings, there is a great hope that novel technologies, like Nucleic Acid vaccines, could be amenable to more rapid & more facile development than traditional vaccine types • Data are now available due to increased experience with DNA vaccines that have lessened certain concerns present 20 years ago when there was a paucity of data • Removed significant portions of Part B (nonclinical) and described rationale in section re: changes to the revision MAIN OUTCOMES – DELIVERY DEVICES • Discussion is needed to describe the situation in regards to mechanical delivery devices that may be seen as medical devices • Address interchangeability vs. integral to efficacy of product (device used in pivotal efficacy studies) • Legal language on jurisdiction of review as device or as vaccine or other (e.g., combination product or other) may vary by country, so have to leave flexibility to accommodate this reality, but need to raise awareness to issue • Even for WHO pre-qualification, device might be independently assessed, though this could change in future MAIN OUTCOMES – QUALITY (PART A) • For DNA vaccines • Acknowledge that current production is biological, but enzymatic (still biological) or chemical synthesis could be used in future • For RNA vaccines • What is considered to be start of production – i.e., which material is biological starting material (plasmid DNA, WCB?) • Acknowledge that current production is enzymatic (biological), but chemical synthesis could be used in future MAIN OUTCOMES – QUALITY 2 • Drug substance, Drug Product • Align terminology to other WHO documents (not ICH parlance) • Rearrange certain parts that have gotten muddled between DS and DP parts • Allow for certain tests to be done at appropriate phase (e.g., potency normally done on DP, but might have justification to do at DS stage because of formulation) • Clarify or update acceptable or example methods • Animal potency assay not generally required for DNA vaccines, in vitro expression testing is adequate and acceptable – animal immunogenicity for characterization, not for routine lot release MAIN OUTCOMES – NONCLINICAL (PART B) • Reference existing general guidelines • WHO Guidelines for Nonclinical Evaluation of Vaccines • WHO Guidelines for Nonclinical Evaluation of Vaccine Adjuvants and Adjuvanted Vaccines • Will need to deal with RNA vaccines in necessary formulation; re: this guideline defines formulation with Ag as an adjuvant, but RNA is not the Ag, it encodes the Ag – so need to clarify whether this is an adjuvant or excipients; definition may vary by jurisdiction MAIN OUTCOMES – CLINICAL (PART C) • Need a section but can be short • Refer to existing general WHO Guidelines on Clinical Evaluation of Vaccines: Regulatory Considerations • Review sections on heterologous prime-boost and immunization in pregnancy for adequacy in general guideline re: DNA or RNA vaccines • Consider relevance of other existing or draft WHO guidelines re: emergency situations, emerging diseases NEXT STEPS • Meeting report to be published by end of 2018 • Revision of DNA guidelines: 2018-2020 • Develop Points to Consider-type document for RNA-based vaccines: 2019-2020 • Consultation with regulators, manufacturers, vaccine developers, & academia will be organized by WHO/EMP/RHT/TSN • Progress reports to ECBS: 2018, 2019 THANKS • WHO thanks all participants of consultation held on 21-23 Feb. 2018 at WHO/Geneva for their thoughtful discussion, useful comments, and diverse perspectives .