Review Clinical trials with GMO-containing vaccines in Europe: Status and regulatory framework Florence Kauffmann a , Pierre Van Damme b , Geert Leroux-Roels c , Corinne Vandermeulen d , Nele Berthels e , Claire Beuneu e , Stéphanie Mali e,⇑ a GlaxoSmithKline Biologicals S.A., Rue de l’Institut 89, 1330 Rixensart, Belgium b Centre for the Evaluation of Vaccination, Vaccines & Infectious Disease Institute, University of Antwerp, Belgium c Centre for Vaccinology (CEVAC), Ghent University and Ghent University Hospital, Belgium d Leuven University Vaccinology Centre, KU Leuven, Belgium e Federal Agency for Medicines and Health Products (FAMHP), Belgium article info Article history: Received 26 April 2019 Received in revised form 25 July 2019 Accepted 12 August 2019 Available online 4 September 2019 Keywords: Genetically modified organism GMO Vaccines Vector-based vaccines Regulation Clinical trials, contained use Deliberate release abstract Recombinant technology has revolutionised the way novel vaccines are developed and manufactured. The possibility to genetically modify micro-organisms to bring immunogenic material (antigens/epi- topes) to the human (or animal) immune system to provoke an immune response, provides new hope to producing prophylactic vaccines against HIV, malaria and tuberculosis and emerging diseases. Regulatory requirements associated with the development of genetically-modified organism (GMO)- containing vaccines in Europe add an additional burden to the clinical trial application procedure and to the preparation and initiation of a clinical trial of such vaccines. Moreover, the GMO regulatory frame- work is complex and only partially harmonised across Europe, which may hamper multi-country clinical trials with GMO-containing vaccines. This paper provides an overview of clinical trial applications with GMO-containing vaccines in Europe and reviews the regulatory framework in countries where GMO- containing vaccine clinical trial authorisation (CTA) applications were submitted between 2004 and 2017. Ó 2019 Elsevier Ltd. All rights reserved. Contents 1. Introduction ........................................................................................................ 6145 2. Methods ........................................................................................................... 6145 2.1. Analysis of clinical trials with GMO-containing vaccines ............................................................... 6145 2.2. Overview of the EU regulatory framework and guidelines regarding GMO-containing vaccines................................ 6145 3. Results............................................................................................................. 6146 3.1. GMO-containing vaccine clinical trial in Europe: Applications and phases................................................. 6146 3.2. GMO-containing vaccines in Europe: Diseases targeted and GMO types .................................................. 6147 3.3. Regulatory framework for GMO-containing vaccines in the EU .......................................................... 6147 3.3.1. United Kingdom ........................................................................................ 6150 3.3.2. Germany .............................................................................................. 6150 3.3.3. Spain ................................................................................................. 6150 3.3.4. France ................................................................................................ 6150 3.3.5. Belgium ............................................................................................... 6150 4. Discussion .......................................................................................................... 6151 5. Conclusion ......................................................................................................... 6152 ICMJE criteria ....................................................................................................... 6152 https://doi.org/10.1016/j.vaccine.2019.08.018 0264-410X/Ó 2019 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: Stephanie.Mali@fagg-afmps.be (S. Mali). Vaccine 37 (2019) 6144–6153 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine