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Clinical Trial
. 2015 Sep 22;33(39):5225-34.
doi: 10.1016/j.vaccine.2015.06.075. Epub 2015 Jul 2.

Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects

Sharon E Frey  1 , Anna Wald  2 , Srilatha Edupuganti  3 , Lisa A Jackson  4 , Jack T Stapleton  5 , Hana El Sahly  6 , Samer S El-Kamary  7 , Kathryn Edwards  8 , Harry Keyserling  9 , Patricia Winokur  5 , Wendy Keitel  6 , Heather Hill  10 , Johannes B Goll  10 , Edwin L Anderson  11 , Irene L Graham  11 , Christine Johnston  2 , Mark Mulligan  3 , Nadine Rouphael  3 , Robert Atmar  6 , Shital Patel  6 , Wilbur Chen  12 , Karen Kotloff  12 , C Buddy Creech  8 , Paul Chaplin  13 , Robert B Belshe  11
Affiliations
Clinical Trial

Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects

Sharon E Frey et al. Vaccine. .

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).

Keywords: ELISA; IMVAMUNE; Intradermal; Lyophilized; MVA; NCT00914732; Plaque reduction neutralizing antibody; Smallpox; Subcutaneous; Vaccinia-naïve; Variola.

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Figures

Fig. 1
Fig. 1
Consort diagram representing the number of subjects assessed for eligibility, randomized to treatment and available for per protocol immunogenicity analysis.
Fig. 2
Fig. 2
Maximum severity grade for reactogenicity collected by subjects in the Lyophilized-SC, Liquid SC and Liquid-ID groups for 15 days (Days 0–14) after each vaccination. Systemic reactogenicity events were graded using a functional scale of mild (present but easily tolerated), moderate (able to tolerate routine activity with effort), and severe (unable to continue routine activity). Fever grading scale for oral temperature was mild ≥37.8–<38 °C, moderate ≥38–<39 °C, and severe ≥39 °C; fever is included in the systemic reactogenicity. Local injection site reactogenicity events other than erythema and induration were graded using a functional scale of mild (present but easily tolerated), moderate (able to tolerate routine activity with effort), and severe (unable to continue routine activity). Local injection site erythema and induration were measured and graded as mild (<15 mm), moderate (15–30 mm) or severe (>30 mm). * P < 0.05, ** P < 0.01.
Fig. 3
Fig. 3
Per protocol Analysis of Geometric Mean Titers (GMT) and 95% Confidence Intervals (CI) by Group and Day Post First Vaccination for (a) BN PRNT, (b) SLU PRNT, (c) BN ELISA and (e) SLU ELISA. PRNT = Plaque reduction neutralizing antibody. ELISA = Enzyme linked immunosorbent assay.
Fig. 4
Fig. 4
(a) Per protocol Non-inferiority Evaluation of Liquid-SC vs. Lyophilized-SC 97.5% confidence interval (CI) for the log 2 difference in the geometric means of the peak titers (GMT) for the Liquid-SC and Lyophilized-SC group. The black circles mark the point estimate of the difference and the bars mark the upper and lower limits of the 97.5% CI. The dotted black line marks the non-inferiority margin. The grey dashed line marks a zero difference. If the circle is to the right of the grey dashed line, Liquid SC has higher GMTs than the Lyophilized SC group; if the circle is to the left of the dashed line, Liquid SC has lower GMTs than the Lyophilized SC group. For all assays, the Lyophilized SC group obtained higher GMTs. As the upper bounds of the CIs were below 1 (to the left of the black dotted non-inferiority margin), non-inferiority was established. As the upper bound was also below 0 (grey dashed line) for SLU PRNT60, BN PRNT50, and BN ELISA, for these assays, the Lyophilized-SC group was superior to the Liquid-SC group. (b). Per protocol Non-inferiority Evaluation of Liquid-SC vs. Liquid-ID 97.5% confidence interval (CI) for the log2 difference in the geometric means of the peak titers (GMT) for the Liquid-SC and Liquid-ID group. As the upper bounds of the CIs were below 1 (to the left of the black dotted non-inferiority margin), non-inferiority was established. Superiority was not established for any assay as the upper bounds of the CIs were not below 0 (grey dashed line).
Supplementary Figure 1
Supplementary Figure 1
The antibody half-life is shown for each assay (PRNT and ELISA) by site (SLU and BN) for each of the three vaccines. The mean antibody is represented by the red triangle. LOD = level of detection. Individual antibody titers are provided for each of the three timepoints. The half-life in days is provided in the legend box.
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