Joseph Torresi1, Leon G Heron2, Ming Qiao3, Joanne Marjason4, Laurent Chambonneau5, Alain Bouckenooghe6, Mark Boaz7, Diane van der Vliet5, Derek Wallace6, Yanee Hutagalung6, Michael D Nissen8, Peter C Richmond9. 1. Department of Infectious Diseases, Austin Hospital, Heidelberg, Melbourne, VIC, Australia; Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, Australia. Electronic address: josepht@unimelb.edu.au. 2. National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The Children's Hospital at Westmead, Westmead, NSW, Australia. 3. Royal Adelaide Hospital, SA Pathology, Adelaide, SA, Australia. 4. Q-Pharm Pty Ltd, Herston 4006, QLD, Australia. 5. Clinical Development, Sanofi Pasteur, Marcy l'Etoile, France. 6. Clinical Development, Sanofi Pasteur, Singapore, Singapore. 7. Global Clinical Immunology, Sanofi Pasteur, Swiftwater, PA, USA. 8. Clinical Trials Centre, Queensland Paediatric Infectious Diseases Laboratory, Queensland Children's Medical Research Institute, Royal Children's Hospital, Herston, QLD, Australia. 9. University of Western Australia School of Paediatrics and Child Health and Vaccine Trials Group, Telethon Kids Institute, Subiaco, WA, Australia.
Abstract
BACKGROUND: The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has undergone extensive clinical trials. Here safety and consistency of immunogenicity of phase III manufacturing lots of CYD-TDV were evaluated and compared with a phase II lot and placebo in a dengue-naïve population. METHODS:Healthy 18-60 year-olds were randomly assigned in a 3:3:3:3:1 ratio to receive three subcutaneous doses of either CYD-TDV from any one of three phase III lots or a phase II lot, or placebo, respectively in a 0, 6, 12 month dosing schedule. Neutralising antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were compared in sera collected 28 days after the third vaccination-equivalence among lots was demonstrated if the lower and upper limits of the two-sided 95% CIs of the GMT ratio were ≥0.5 and ≤2.0, respectively. RESULTS:712 participants receivedvaccine or placebo and 614 (86%) completed the study; 17 (2.4%) participants withdrew after adverse events. Equivalence of phase III lots was demonstrated for 11 of 12 pairwise comparisons. One of three comparisons for serotype 2 was not statistically equivalent. GMTs for serotype 2 in phase III lots were close to each other (65.9, 44.1 and 58.1, respectively). CONCLUSIONS: Phase III lots can be produced in a consistent manner with predictable immune response and acceptable safety profile similar to previously characterised phase II lots. The phase III lots may be considered as not clinically different as statistical equivalence was shown for serotypes 1, 3 and 4 across the phase III lots. For serotype 2, although equivalence was not shown between two lots, the GMTs observed in the phase III lots were consistently higher than those for the phase II lot. As such, in our view, biological equivalence for all serotypes was demonstrated.
RCT Entities:
BACKGROUND: The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has undergone extensive clinical trials. Here safety and consistency of immunogenicity of phase III manufacturing lots of CYD-TDV were evaluated and compared with a phase II lot and placebo in a dengue-naïve population. METHODS: Healthy 18-60 year-olds were randomly assigned in a 3:3:3:3:1 ratio to receive three subcutaneous doses of either CYD-TDV from any one of three phase III lots or a phase II lot, or placebo, respectively in a 0, 6, 12 month dosing schedule. Neutralising antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were compared in sera collected 28 days after the third vaccination-equivalence among lots was demonstrated if the lower and upper limits of the two-sided 95% CIs of the GMT ratio were ≥0.5 and ≤2.0, respectively. RESULTS: 712 participants received vaccine or placebo and 614 (86%) completed the study; 17 (2.4%) participants withdrew after adverse events. Equivalence of phase III lots was demonstrated for 11 of 12 pairwise comparisons. One of three comparisons for serotype 2 was not statistically equivalent. GMTs for serotype 2 in phase III lots were close to each other (65.9, 44.1 and 58.1, respectively). CONCLUSIONS: Phase III lots can be produced in a consistent manner with predictable immune response and acceptable safety profile similar to previously characterised phase II lots. The phase III lots may be considered as not clinically different as statistical equivalence was shown for serotypes 1, 3 and 4 across the phase III lots. For serotype 2, although equivalence was not shown between two lots, the GMTs observed in the phase III lots were consistently higher than those for the phase II lot. As such, in our view, biological equivalence for all serotypes was demonstrated.
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