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: 3.49). 02/2011; 29(10):1948-58. DOI: 10.1016/j.vaccine.2010.12.104
Source: PubMed

ABSTRACT 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, Aug 13, 2015
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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 · 2.83 Impact Factor
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    • "Other strategies that have been investigated for inducing a cellular response include using various vaccine regimens. One of the vaccine regimens that had proved successful in primates to stimulate a cellular response is a DNA prime followed by protein or viral vector boost (Barnett, Burke et al. 2010; Jaoko, Karita et al. 2010; Keefer, Frey et al. 2011). "
    HIV and AIDS - Updates on Biology, Immunology, Epidemiology and Treatment Strategies, 10/2011; , ISBN: 978-953-307-665-2
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    • "These have appeared to be safe and well tolerated [10] [11] [12]. However, limited immunogenicity has been usually reported when MVA is used alone [11] [12] [13] [14] [15] [16]. This low level of response is similar to other poxvirus used alone [17] [18] [19]. "
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    ABSTRACT: To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed. 30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1×10(8)pfu/dose) of MVA-B (n=24) or placebo (n=6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity. A total of 169 adverse events were reported, 164 of grade 1-2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288SFC/10(6)PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers. MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical identifier: NCT00679497.
    Vaccine 09/2011; 29(46):8309-16. DOI:10.1016/j.vaccine.2011.08.098 · 3.49 Impact Factor
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