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 
1×10(8) 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% (2×10(7) 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).