Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial

Abstract

Background: Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important.

Methods: We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo.

Results: MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group.

Conclusions: MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population.

Clinical trials registration: NCT00565929.

Keywords: clinical trial; dose; immunogenicity; modified vaccinia ankara; safety; stem cell transplant.

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) subject flow diagram demonstrating the number of patients recruited into the study, reasons for dropout, number of subjects randomized and vaccinated, and number of subjects analyzed. MVA-BN, modified vaccinia Ankara; TCID50, median tissue culture infective dose

Figure 2.

Proportion of vaccinees experiencing local reactogenicity (including pain or tenderness) (A), local erythema and induration (B), or systemic symptoms (C) after the first or second modified vaccinia Ankara vaccination, by dose group. Severity of symptoms were graded on the basis of Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases toxicity tables. TCID50, median tissue culture infective dose.

Figure 3.

Baseline neutralizing antibody responses against modified vaccinia Ankara (A) and vaccinia virus (B), stratified by the type of hematopoietic stem cell transplant (HSCT) the subjects had received. The limit of detection was a serum median infective dose (ID50) titer of 1:10.

Figure 4.

Neutralizing antibody responses elicited by modified vaccinia Ankara (MVA) prime/boost immunization. Serum samples were obtained at days 0, 14, 28, 42, 56, 84, and 180 following MVA immunization. Serial dilutions were tested for neutralizing activity against a modified vaccinia Ankara recombinant strain containing a luciferase reporter gene (A) or a vaccinia virus recombinant strain containing a luciferase reporter gene (B). Data are presented as median infective dose (ID50) titers with interquartile ranges for each dose group. The limit of detection was a serum ID50 titer of 1:10, and arrows indicate days of immunization. *P ≤ .01 for the 108 median tissue culture infective dose (TCID50) group vs the placebo group; **P ≤ .04 for the 108 TCID50 group vs the 107 TCID50 group.

Figure 5.

Cellular immune responses elicited by modified vaccinia Ankara (MVA) prime/boost immunizations. Peripheral blood mononuclear cells (PBMCs) were obtained on days 0, 14, 28, 42, 56, 84, and 180 following MVA vaccination and tested by the interferon γ enzyme-linked immunosorbent spot assay against autologous MVA-infected (A) and Western Reserve vaccinia virus strain–infected (B) target cells. Data are presented as the median number of spot-forming cells per 106 effector PBMCs with interquartile ranges for each dose group, following subtraction of responses to medium alone. *P ≤ .02 for the 108 median tissue culture infective dose (TCID50) group vs the placebo group; **P ≤ .02 for the 107 TCID50 group vs the placebo group; ***P ≤ .04 for the 108 TCID50 group vs the 107 TCID50 group.