Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.
2015 Sep 22
Journal Article
Authors:
Frey, S.E.;
Wald, A.;
Edupuganti, S.;
Jackson, L.A.;
Stapleton, J.T.;
Sahly, H.El;
El-Kamary, S.S.;
Edwards, K.;
Keyserling, H.;
Winokur, P.;
Keitel, W.;
Hill, H.;
Goll, J.B.;
Anderson, E.L.;
Graham, I.L.;
Johnston, C.;
Mulligan, M.;
Rouphael, N.;
Atmar, R.;
Patel, S.;
Chen, W.;
Kotloff, K.;
Creech, B.;
Chaplin, P.;
Belshe, R.B.
Secondary:
Vaccine
Volume:
33
Pagination:
5225-34
Issue:
39
PMID:
26143613
DOI:
10.1016/j.vaccine.2015.06.075
Keywords:
Adolescent; Adult; Antibodies, Neutralizing; Antibodies, Viral; Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Injections, Intradermal; Injections, Subcutaneous; Male; Smallpox Vaccine; Young Adult
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 1×10(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).
