Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects

University of Kentucky School of Medicine, Infectious Diseases Division, Lexington, Kentucky.
The Journal of Infectious Diseases (Impact Factor: 6). 12/2012; 207(5). DOI: 10.1093/infdis/jis753
Source: PubMed


Human immunodeficiency virus (HIV)-infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.

The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4(+) T-cell counts, ≥350 cells/mm(3)) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects.

MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola.

MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile.

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    • "Minimal toxicity is thus expected for vaccine 1. The tested target dose (1x108 plaque-forming units) corresponds to the standard dose tested for MVA vaccinations against smallpox [22,27] and to the dose selected in previous dose-escalation studies of MVA vectors with HIV and non-HIV inserts [20,24,28,29]. No dose escalation is thus planned for this vaccine in our development plan. "
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    ABSTRACT: Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.
    Trials 02/2014; 15(1):68. DOI:10.1186/1745-6215-15-68 · 1.73 Impact Factor
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    • "As a third-generation smallpox vaccine, MVA has shown an excellent safety profile and immunogenicity in the clinic [13–15]. In addition, MVA is well tolerated and immunogenic when administered to immunocompromised patients infected with human immunodeficiency virus (HIV), highlighting its potential as a safe vector for the development of vaccine and gene therapy candidates [16]. "
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    ABSTRACT: Modified vaccinia virus Ankara (MVA) has been shown to be suitable for the generation of experimental vaccines against cancer and infectious diseases, eliciting strong humoral and cellular immune responses. In viral vectored vaccines, strong recombinant antigen expression and timing of expression influence the quantity and quality of the immune response. Screening of synthetic and native poxvirus promoters for strong protein expression in vitro and potent immune responses in vivo led to the identification of the MVA13.5L promoter, a unique and novel naturally occurring tandem promoter in MVA composed of two 44 nucleotide long repeated motifs, each containing an early promoter element. The MVA13.5L gene is highly conserved across orthopoxviruses, yet its function is unknown. The unique structure of its promoter is not found for any other gene in the MVA genome and is also conserved in other orthopoxviruses. Comparison of the MVA13.5L promoter activity with synthetic poxviral promoters revealed that the MVA13.5L promoter produced higher levels of protein early during infection in HeLa cells and particularly in MDBK cells, a cell line in which MVA replication stops at an early stage before the expression of late genes. Finally, a recombinant antigen expressed under the control of this novel promoter induced high antibody titers and increased CD8 T cell responses in homologous prime-boost immunization compared to commonly used promoters. In particular, the recombinant antigen specific CD8 T cell responses dominated over the immunodominant B8R vector-specific responses after three vaccinations and even more during the memory phase. These results have identified the native MVA13.5L promoter as a new potent promoter for use in MVA vectored preventive and therapeutic vaccines.
    PLoS ONE 08/2013; 8(8):e73511. DOI:10.1371/journal.pone.0073511 · 3.23 Impact Factor
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    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. Twenty-four subjects who had previously undergone a hematopoietic stem cell transplant (HSCT) received one of two doses of MVA-BN (107 TCID50 vs 108 TCID50) or placebo in two subcutaneous administrations one month apart.Results. MVA-BN was generally well-tolerated at both dose levels. 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 administration and were greater for the higher dose. Median peak anti-VACV NAb titres were 1:49 in the low dose group and 1:118 in the high dose group. T cell immune responses to VACV were detected by IFN-γ ELISPOT and were higher in the higher dose group.Conclusion. MVA-BN is safe, well-tolerated, and immunogenic in subjects who have received a prior HSCT. These data support the use of a dose of 108 TCID50 in this population.
    The Journal of Infectious Diseases 03/2013; 207(12). DOI:10.1093/infdis/jit105 · 6.00 Impact Factor
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