Contributors: CIC Cochin Pasteur (CIC 1417); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Centre de Recherche Translationnelle - Center for Translational Science (CRT); Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Clinical Pharmacology Unit Antwerp Antwerp, Belgium; SGS Life Science Services (SGS); SGS (SGS)-SGS (SGS); Institut National de la Santé et de la Recherche Médicale (INSERM); SGS (SGS); Themis Bioscience GmbH; Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)); Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Département de Santé Globale - Department Global Health; BIOASTER Microbiology Technology Institute Lyon; Service développement de l'innovation - Innovation Office; Direction des Applications de la Recherche et des Relations industrielles - The Technology Transfer and Industrial Partnership Department (DARRI); Institut Pasteur Paris (IP)-Institut Pasteur Paris (IP); HT was supported by a post-doctoral fellowship from ANRS|Maladies Infectieuses Émergentes. The study was funded by Themis Bioscience GmbH, a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA, and by the Coalition for Epidemic Preparedness Innovations (CEPI) as part of the project “Outbreak Response to Novel Coronavirus (COVID-19): Development of a vaccine against novel coronavirus SARS-CoV-2 using the clinical Phase III measles vector technology“.; We thank all study participants for their time and support. We thank the staff at the Centre d'Investigation Clinique (CIC) Vaccinologie Cochin-Pasteur, the Centre de Ressources Biologiques (CRB), and the Pharmacie à Usage Interieur (PUI) at Hôpital Cochin/APHP, Paris France, at the Clinical Pharmacology Unit (CPU), Antwerp, Belgium, at SGS, Mechelen, Belgium, and at Institut Pasteur, who contributed with their work to make the clinical study possible. We are grateful to Sylvain Baize (Institut Pasteur) for advice for the T cell assays, Brigitte Blumen (Institut Pasteur) for technical assistance, and Kevin Russell, Deborah D. Brown, Eseng Lai (all MSD) and Bruno Hoen (Institut Pasteur) for critical review of the manuscript. We acknowledge Prof. Dr. Herwig Kollaritsch (Medical University of Vienna, Austria), Assoc. Prof. Dr. Laura Richert (University of Bordeaux, France), and Dr. Yves Van Laethem (CHU Saint-Pierre, Brussels, Belgium) for agreeing to be members of the Data Safety Monitoring Board.; We further thank the CEPI project team for their continuous support and helpful discussions.
نبذة مختصرة : International audience ; Background V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein.Methods We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a dou- ble-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each compris- ing 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 £ 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 £ 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immuno- genicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298.Findings Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment- related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiv- ing the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine.Interpretation While V591 was generally well tolerated, the immunogenicity was not sufficient to support further ...
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