Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naive subjects

• Type of Material: Article
• Authors: Sharon E Frey, Saint Louis University School of Medicine; Anna Wald, University of Washington; Srilatha Edupuganti, Emory University; Lisa A Jackson, Group Health Cooperative, Seattle; Jack T Stapleton, University of Iowa; Hana El Sahly, Baylor College of Medicine; Samer S El-Karnary, University of Maryland; Kathryn Edwards, Vanderbilt University; Harry Keyserling, Emory University; Patricia Winokur, University of Iowa; Wendy Keitel, Baylor College of Medicine; Heather Hill, Emmes Corporation; Johannes B Goll, Emmes Corporation; Edwin L Anderson, Saint Louis University; Irene L Graham, Saint Louis University; Christine Johnston, University of Washington; Mark Mulligan, Emory University; Nadine Rouphael, Emory University; Robert Atmar, Baylor College of Medicine; Shital Patel, Baylor College of Medicine; Wilbur Chen, University of Maryland; Karen Kotloff, University of Maryland; Buddy C Creech, Vanderbilt University; Paul Chaplin, Bavarian Nordic GmbHv; Robert B Belshe, Saint Louis University
• Language: English
• Date: 2015-09-22
• Publisher: ELSEVIER SCI LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Elsevier Ltd. Published by Elsevier Ltd. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.vaccine.2015.06.075
• Title of Journal or Parent Work: VACCINE
• Volume: 33
• Issue: 39
• Start Page: 5225
• End Page: 5234
• Grant/Funding Information: This project was funded fully or in part by: National Institute of Allergy and Infectious Diseases (NIAID) Contract HHSN272200800003C (Saint Louis University); NIH National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA) grants UL1TR000423, KL2TR000421 and TL1TR000422 (University of Washington Institute of Translational Health Science); NIAID Contract HHSN272200800005C (Emory University); NIAID Contract HHSN272200800004C (Group Health Cooperative); NIH Grant UL1RR024979 and NIAID Contract HHSN272200800008C (University of Iowa); NIAID Contract HHSN272200800002C (Baylor College of Medicine); NIAID Contract HHSN272200800001C (University of Maryland); NIAID Contract HHSN272200800007C (Vanderbilt University); and NIAID Contract HHSN272200800013C (EMMES); NIAID Contract HHSN266200400072C (Bavarian Nordic).
• Keywords: Science & Technology; HEPATITIS-B VACCINATION; PNEUMOCOCCAL CONJUGATE VACCINE; Life Sciences & Biomedicine; Lyophilized; IMMUNOGENICITY; Subcutaneous; SMALLPOX VACCINE; INFLUENZA VACCINE; Smallpox; Medicine, Research & Experimental; MVA; SERUM ANTIBODY; Vaccinia-naive; NEUTRALIZATION; Immunology; Variola; Research & Experimental Medicine; IMVAMUNE; MALARIA VACCINATION; ELISA; Plaque reduction neutralizing antibody; SAFETY; CONTROLLED-TRIAL; Intradermal

Abstract

Background: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×108 TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. Methods: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×107 TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. Results: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P= 0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P= 0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months.After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. Conclusions: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).