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.