Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects
ABSTRACT Background. 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.Methods. The safety and immunogenicity of MVA was assessed in 91 HIV-infected adult subjects (CD4 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 uninfected subjects.Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV infected populations with only one significantly lower total antibody titer at 2 weeks post 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.Conclusions. 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.Clinical Trial Registration. NCT00189904.
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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; DOI:10.1093/infdis/jit105 · 5.78 Impact Factor
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ABSTRACT: Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4(+) and CD8(+) T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8(+) T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4(+) and CD8(+) T cells are generated and provide protection against M. tuberculosis. In a MHC class I-deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4(+) T cell response and significantly fewer Ag-specific CD8(+) T cells, but were still protected against M. tuberculosis, suggesting that CD4(+) Th1 T cells could compensate for the loss of CD8(+) T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-γ-producing CD4(+) T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity.The Journal of Immunology 07/2013; 191(5). DOI:10.4049/jimmunol.1301161 · 5.36 Impact Factor
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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 · 3.53 Impact Factor