A phase I trial of preventive HIV vaccination with heterologous poxviral-vectors containing matching HIV-1 inserts in healthy HIV-uninfected subjects

Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Michael
Vaccine (Impact Factor: 3.62). 02/2011; 29(10):1948-58. DOI: 10.1016/j.vaccine.2010.12.104
Source: PubMed


We evaluated replication-defective poxvirus vectors (modified vaccinia Ankara [MVA] and fowlpox [FPV]) in a homologous and heterologous vector prime-boost vaccination regimen containing matching HIV inserts (MVA-HIV and FPV-HIV) given at months 0, 1, 3, 5 and 7 in 150 healthy HIV-negative vaccinia-naïve participants. FPV-HIV alone was poorly immunogenic, while the high dose (10(9)pfu/2 ml) of MVA-HIV alone elicited maximal responses after two injections: CD4+ and CD8+ T-cell responses in 26/55 (47.3%) and 5/60 (8.3%) of participants, respectively, and IFN-γ ELISpot responses in 28/62 (45.2%). The infrequent CD8+ T-cell responses following MVA-HIV priming were boosted only by the heterologous (FPV-HIV) construct in 14/27 (51.9%) of participants post 4th vaccination. Alternatively, HIV envelope-specific binding antibodies were demonstrated in approximately two-thirds of recipients of the homologous boosting regimen, but in less than 20% of subjects after the heterologous vector boost. Thus, a heterologous poxvirus vector prime-boost regimen can induce HIV-specific CD8+ T-cell and CD4+ T-cell responses, which may be an important feature of an optimal regimen for preventive HIV vaccination.

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Available from: Artur Olhovetchi Kalichman, Oct 06, 2015
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    • "MVA is a safe vector and despite its limited replication in human and most mammalian cell types, provides a high level of gene expression and triggers antigen-specific immune responses when delivered to animals and humans [1], [2], [4]. Many MVA recombinants expressing different HIV-1 antigens have been generated worldwide, and tested in different animal models and in several clinical trials in humans [1], [5], [6], [7], [8], [9], [10], [11], [12], [13], showing that they are safe, able to induce high levels of expression of HIV-1 antigens, and triggered immune responses to HIV-1 antigens. In particular, we have constructed a recombinant MVA expressing Env, as monomeric gp120, and the codon-optimized polyprotein Gag-Pol-Nef (GPN) of HIV-1 from clade B (referred as MVA-B), that in mice induced strong, broad, polyfunctional and durable HIV-1 specific CD4+ and CD8+ T cell immune responses (with a bias for CD8+) [14], [15], [16], [17]. "
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    ABSTRACT: Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.
    PLoS ONE 06/2013; 8(6):e66894. DOI:10.1371/journal.pone.0066894 · 3.23 Impact Factor
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    • "Among poxviruses, the highly attenuated modified vaccinia virus Ankara (MVA) strain is one of the most promising vectors to be used as an effective vaccine against HIV- 1 (Esteban, 2009; Pantaleo et al., 2010). A great number of MVA vectors expressing different HIV-1 antigens have been generated and tested in different animal models and in several clinical trials in humans (Cebere et al., 2006; Currier et al., 2010; Goepfert et al., 2011; Gomez et al., 2011a; Goonetilleke et al., 2006; Keefer et al., 2011; Kutscher et al., 2010; Ramanathan et al., 2009; Sandstrom et al., 2008; Vasan et al., 2010), showing that they are safe, able to induce high levels of expression of HIV-1 antigens, and to trigger strong, broad, polyfunctional and durable HIV-1-specific immune responses. In our lab we have constructed an HIV/AIDS vaccine candidate termed MVA-B (Fig. 1A), based in a recombinant MVA expressing Env, as monomeric gp120, and the codon-optimized polyprotein Gag-Pol-Nef (GPN) of HIV-1 from clade B (Gomez et al., 2007). "
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    ABSTRACT: MVA-B is an attenuated poxvirus vector expressing human immunodeficiency virus type 1 Env, Gag, Pol, and Nef antigens from clade B, and is considered a promising HIV/AIDS vaccine candidate. Recently, a phase I clinical trial in human healthy volunteers has shown that MVA-B is safe and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4(+) and CD8(+) T cell responses to HIV-1 antigens, with preference for effector memory T cells; and it also triggers the induction of specific antibodies to Env in most of the vaccines. While MVA recombinants expressing HIV-1 antigens are being used or plan to use in therapeutic clinical trials, little is known on the effect of HIV-1 highly active antiretroviral therapy in MVA life cycle. To define this role, here we have evaluated in established cell cultures and human dendritic cells to what extent different HIV-1 protease inhibitors affect virus replication and expression of HIV-1 antigens during MVA-B infection. The results obtained revealed that the most commonly used HIV-1 protease inhibitors (atazanavir, ritonavir, and lopinavir) had no effect on MVA-B virus growth kinetics, even at higher concentrations than those normally used on HAART. Furthermore, expression of gp120 and the fused Gag-Pol-Nef polyprotein in permissive and non-permissive cells infected with MVA-B were also not affected. These findings are relevant information for the therapeutic use of MVA-B as an HIV-1/AIDS vaccine.
    Virus Research 05/2012; 167(2):391-6. DOI:10.1016/j.virusres.2012.05.020 · 2.32 Impact Factor
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    • "The most advanced poxvirus vector with an attenuated phenotype is the canarypox ALVAC expressing gp120/Gag-Pro that has shown partial efficacy when combined with the protein gp120 in the phase III clinical trial in Thailand [1]. Other attenuated poxvirus vectors like NYVAC [9], [24], MVA [12], [25], [26], [27], [28], [29], [30] or Fowlpox [31] have shown different immunogenic profiles when used alone or in combination with other heterologous vectors in clinical trials, probably due the nature of the vector, virus dose and HIV antigens being expressed. We have previously shown that when poxvirus vectors MVA and NYVAC expressing gp120/Gag-Pol-Nef are compared head-to-head, there are clear differences in the induction of cellular genes in response to virus infection that might lead to differences in the activation of host cell immune responses [14], [32]. "
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    ABSTRACT: Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world.
    PLoS ONE 04/2012; 7(4):e35485. DOI:10.1371/journal.pone.0035485 · 3.23 Impact Factor
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