Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

Edgar Turner Overton, Steven J Lawrence, Eva Wagner, Katrin Nopora, Siegfried Rösch, Philip Young, Darja Schmidt, Christian Kreusel, Sonja De Carli, Thomas P Meyer, Heinz Weidenthaler, Nathaly Samy, Paul Chaplin, Edgar Turner Overton, Steven J Lawrence, Eva Wagner, Katrin Nopora, Siegfried Rösch, Philip Young, Darja Schmidt, Christian Kreusel, Sonja De Carli, Thomas P Meyer, Heinz Weidenthaler, Nathaly Samy, Paul Chaplin

Abstract

Background: Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.

Methods: The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.

Results: Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.

Conclusions: The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.

Trial registration: ClinicalTrials.gov NCT01144637.

Conflict of interest statement

Competing Interests: I have read the journal`s policy and the authors of this manuscript have the following competing interests: The trial was funded by the Biomedical Advanced Research and Development Authority (BARDA, http://www.phe.gov/about/BARDA/Pages/default.aspx). Bavarian Nordic was the sponsor receiving the fund (BARDA Contract No.: HHSO100200700034C). Bavarian Nordic reimbursed the clinical trial investigators and the design and conduct of the trial were managed by Bavarian Nordic A/S. Authors EW, KN, SR, PY, DS, CK, SDC, TPM, HW, NS and PC were employed by Bavarian Nordic GmbH, the manufacturer of MVA-BN. Patents relevant to this study are part of the supporting information as there are too many to list. The statistical analysis plan was written by PY. Data collection, management and analysis were performed by Chiltern International Inc. (Bristol, TN). The specific roles of the authors are articulated in the "author contributions" section. There are no further patents, marketed products or products in development to declare. This does not alter the authors`adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Subject disposition.
Fig 1. Subject disposition.
FAS = full analysis set; IAS = Immunogenicity Analysis Set, subset used for immunogenicity analysis (first ~ 700 subjects enrolled per group); PPS = per protocol set; n = number of subjects in the specified category.

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