1. Design of randomized, double-blind, controlled, multi-center phase IIb trials as part of the EU- funded UNISEC project to assess the safety, immunogenicity and clinical efficacy of cross-seasonal universal influenza vaccines with or without pandemic influenza vaccine in healthy adults Methods Marcy Heng Liu 1, Stuart Robinson 2, Tamar Ben-Yedidia 3, Wilson Caparros Wanderley 2, Olga Pleguezuelos 2, Tanya Gottlieb 3, Ron Babecoff 3, Ed Schmidt 4, Anke Huckriede 5, Eelko Hak 1 1 Department of PharmacoEpidemiology and PharmacoEconomics, University Center of Pharmacy, University of Groningen, Groningen, The Netherlands; 2 SEEK, United Kingdom; 3 BiondVax Pharmaceuticals, Israel; 4 Department of Pharmaceutical Technology and Biopharmacy, University Center of Pharmacy, University of Groningen, Groningen, The Netherlands; 5 Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Objective PharmacoEpidemiology & PharmacoEconomics Current seasonal influenza vaccines mainly induce immune responses against viral membrane glycoproteins. These proteins, however, undergo continuous mutations by a process called antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy not only poses inconvenience and cost- inefficiency, but also results in poor protective effectiveness when the vaccinated strains are mismatched with the actual circulating strains. The latter point is especially of concern during a pandemic outbreak, when a large geographical area is affected and the general population is naïve to the newly re- assorted viral strain due to antigenic shift. Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy. As part of the EU-funded Universal vaccines Secured (UNISEC) project (http:// www.unisecconsortium.eu), we aim to design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines targeting different conserved immunogenic regions of influenza A and B viruses. In two separate trials, a total of 1500 healthy adult study participants will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will also be given 21 and 42 days after the second administration, aiming to show enhanced response to pandemic influenza strains. Adverse events (AEs) will be collected during the study period. Immune correlates of protection will be assessed 21 days after the second administration and after each pandemic vaccine administration. Clinical symptom scores and the (severity of) incident RT- PCR-confirmed influenza A and/or B infection will be recorded to decide clinical efficacy of the tested vaccines. Fig.1 Trial study vaccines. Fig.2 Trial setup and study design Fig.3 Trial study endpoints UNISEC has been made possible by contributions from the European Commission DG-Research and the European member states. Conclusions Acknowledgement Background