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

doi:10.1371/journal.pone.0195897

Abstract

BackgroundModified 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.MethodsThe 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.ResultsBetween 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.ConclusionsThe 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 registrationClinicalTrials.gov NCT01144637

Highlights

Despite the eradication of smallpox in 1980 [1], the risk of reoccurrence still remains due to its potential use in biological warfare [2, 3]
The specific roles of the authors are articulated in the "author contributions" section
Bavarian Nordic did not have any additional role in the data collection and analysis, decision to publish or preparation of the manuscript

Summary

Introduction

Despite the eradication of smallpox in 1980 [1], the risk of reoccurrence still remains due to its potential use in biological warfare [2, 3]. A series of cardiac adverse events, including myo-/pericarditis, have been observed in close temporal relationship to the administration of replicating smallpox vaccines such as ACAM2000 [5,6,7,8,9]. Their use in a pre-emergency situation is restricted to high-risk populations (e.g. military personnel), disregarding other relevant groups such as first-line responders. MVA is a live, highly attenuated Modified Vaccinia Ankara virus currently in advanced clinical development as a non-replicating smallpox vaccine and is considered to be a safer alternative over replicating smallpox vaccines [10]. 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.

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