부산대학교 도서관

Summary Background Long-term protection and herd immunity induced by existing pertussis vaccines are imperfect, and a need therefore exists to develop new pertussis vaccines. This study aimed to investigate the safety, colonisation, and immunogenicity of the new, live attenuated pertussis vaccine, BPZE1, when given intranasally. Methods This phase 1b, double-blind, randomised, placebo-controlled, dose-escalation study was done at the phase 1 unit, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden. Healthy adults (18--32 years) were screened and included sequentially into three groups of increasing BPZE1 dose strength (10.sup.7 colony-forming units [CFU], 10.sup.8 CFU, and 10.sup.9 CFU), and were randomly assigned (3:1 within each group) to receive vaccine or placebo. Vaccine and placebo were administered in phosphate-buffered saline contained 5% saccharose as 0*4 mL in each nostril. The primary outcome was solicited and unsolicited adverse events between day 0 and day 28. The analysis included all randomised participants who received a vaccine dose. Colonisation with BPZE1 was determined by repeatedly culturing nasopharyngeal aspirates at day 4, day 7, day 11, day 14, day 21, and day 28 after vaccination. Immunogenicity, as serum IgG and IgA responses were assessed at day 0, day 7, day 14, day 21, day 28, 6 months, and 12 months after vaccination. This trial is registered at Clinicaltrials.gov, NCT02453048. Findings Between Sept 1, 2015, and Feb 3, 2016, 120 participants were assessed for eligibility, 48 of whom were enrolled and randomly assigned (3:1) to receive vaccine or placebo, with 12 participants each in a low-dose, medium-dose, and high-dose vaccine group. Adverse events between day 0 and day 28 were reported by one (8%, 95% CI 0--39) of 12 participants in both the placebo and low-dose groups, and two (17%; 2--48) of 12 participants in both the medium-dose and high-dose groups, including cough of grade 2 or more, oropharyngeal pain, and rhinorrhoea and nasal congestion. During this time, none of the participants experienced any spasmodic cough, difficulties in breathing, or adverse events following immunisation concerning vital signs. The tested doses of BPZE1 or placebo were well tolerated, with no apparent difference in solicited or unsolicited adverse events following immunisation between groups. Colonisation at least once after vaccination was observed in 29 (81%; 68--93) of 36 vaccinated participants. The tested vaccine doses were immunogenic, with increases in serum IgG and IgA titres against the four B pertussis antigens from baseline to 12 months. Interpretation The tested vaccine was safe, induced a high colonisation rate in an adult population, and was immunogenic at all doses. These findings justify further clinical development of BPZE1 to ultimately be used as a priming vaccine for neonates or a booster vaccine for adolescents and adults, or both. Funding ILiAD Biotechnologies. Author Affiliation: (a) Public Health Agency of Sweden, Solna, Sweden (b) University of Bordeaux, National Institute for Health and Medical Research (Inserm), Bordeaux Population Health Research Center, Bordeaux, France (c) University Hospital Centre CHU, Bordeaux, France (d) EUCLID/F-CRIN Clinical Trials Platform, Bordeaux, France (e) Inria SISTM team, F-33405, Talence, France (f) Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden (g) ILiAD Biotechnologies, New York, NY, USA (h) University of Lille, National Centre for Scientific Research (CNRS), National Institute for Health and Medical Research (Inserm), University Hospital Centre CHU Lille, Lille, France (i) Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille, France * Correspondence to: Dr Camille Locht, Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille F-59019, France Byline: Maja Jahnmatz, PhD (a), Laura Richert, PhD (b,c,d,e), Nabil al-Tawil, MD (f), Jann Storsaeter, PhD (a), Céline Colin, MSc (b,c,d), Claire Bauduin, MSc (b,c,d), Marcel Thalen, PhD (g), Ken Solovay, MSc (g), Keith Rubin, MD (g), Nathalie Mielcarek, PhD (h,i), Rigmor Thorstensson, PhD (a), Camille Locht, PhD [camille.locht@pasteur-lille.fr] (h,i), Lena Dager, Nina Ekholm, Margareta Gustafsson, Åsa Linde, Cecilia Lång, Maria Nastase, Inga-Lill Reinholdsson, Erla Sigurdardottir, Anneli Wahlberg, Izabella Zarea, Teodora Aktas, Ingrid Andersson, Eva Hanson Pihlainen, Margaretha Ljungman, Maj Ringman, Teghesti Tecleab, Lena Wehlin, Florence Allais, Alex Assuied, Geneviève Chêne, Camille Gilbert, Delphine Jean, Fabien Le Marec, Laetitia Moinot, Philippe Reboud, Emilie Rousseau, Céline Roy, Christine Schwimmer, Ludivine Taïeb, Cédrick Wallet, Gabrielle Derocle, Sonia Gueguen, Claire Lévy-Marchal, Hélène Esperou, Anne-Sophie Debrie, Dominique Raze, Loïc Coutte, Alpha Diallo, Noémie Mercier