The preventive phase I trial with the HIV-1 Tat-based vaccine

Ensoli, Barbara; Fiorelli, Valeria; Ensoli, Fabrizio; Lazzarin, Adriano; Visintini, Raffaele; Narciso, Pasquale; Carlo, Aldo Di; Tripiciano, Antonella; Longo, Olimpia; Bellino, Stefania; Francavilla, Vittorio; Paniccia, Giovanni; Arancio, Angela; Scoglio, Arianna; Collacchi, Barbara; Alvarez, Maria Josefina Ruiz; Tambussi, Giuseppe; Din, Chiara Tassan; Palamara, Guido; Latini, Alessandra; Antinori, Andrea; D’Offizi, Gianpiero; Giulianelli, Marinella; Carta, Maria Paola; Monini, Paolo; Magnani, Mauro; Garaci, Enrico

doi:10.1016/j.vaccine.2009.10.038

Cited by 48 publications

(35 citation statements)

References 32 publications

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“…The viral control seen with recombinant Tat in non-human studies was not reproduced in human studies wherein recombinant Tat was safe and modestly immunogenic but did not lower HIV viral loads. 21,22 To circumvent the problem of extreme antigenic variation in HIV proteins, including Tat, we created a universally reactive synthetic HIV-1 Tat epitope vaccine, termed TUTI-16, by synthesizing a wobble peptide epitope sequence that induced antibodies reactive with all eight variant Tat epitope sequences known to occur in Tat, and by incorporating strong adjuvant components suitable for use in humans. 23 For the present first-in-humans study of this candidate prophylactic vaccine we first studied its use in untreated HIVinfected subjects, with established HIV set point viral load, to enable an assessment of whether Tat epitope immunization would lower the viral load and, if so, the antibody level required.…”

Section: Study Population and Safety Evaluationsmentioning

confidence: 99%

Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

Goldstein

Chicca

2012

Human Vaccines & Immunotherapeutics

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Section: Study Population and Safety Evaluationsmentioning

confidence: 99%

Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

Goldstein

Chicca

2012

Human Vaccines & Immunotherapeutics

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“…[5][6][7][8][9][10][11] Thus, the inclusion of Tat in preventive and therapeutic vaccines has been pursued by several groups showing promising results in nonhuman primates [12][13][14][15][16] and in phase I and II clinical trials. [16][17][18][19] However, the development of vaccines able to induce protective responses has to face some major challenges such as: i) the compliance requested for mass immunizations; ii) the induction of immune responses in mucosal tissues, which are the predominant sites of HIV acquisition; 20 and iii) the isotypes of antibodies elicited, which may influence the level of vaccine efficacy. 21 These factors may be modulated by the administration route.…”

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confidence: 99%

“…27 Therefore, the ID route may be a relevant strategy for mass immunization, and clade B Tat protein has been administered by this route in 2 phase II clinical trials 17 and unpublished data after having shown superior immunogenicity when administered ID rather than subcutaneously in phase I clinical trials. 18,19 At the same time, the oral administration is gaining interest for its high compliance and the capability of inducing mucosal responses. 28 However, to our knowledge, neither IM nor oral administration of the Tat protein have ever been compared to the ID route.…”

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confidence: 99%

Effects of different routes of administration on the immunogenicity of the Tat protein and a Tat-derived peptide

Finessi

Nicoli

Gallerani

et al. 2015

Human Vaccines & Immunotherapeutics

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The use of the Tat protein of HIV in vaccines against AIDS showed promising results in primate and human studies. To characterize the impact of the administration route on the induction of humoral responses at systemic and mucosal levels, we compared intradermal, intramuscular and mucosal immunizations with Tat and a Tat-derived peptide. Mice were immunized with the Tat protein by different routes and the titer and isotype of anti-Tat antibodies were assessed in serum and mucosal lavages. Intramuscular and intradermal administrations showed comparable immunogenicity, while the mucosal administration was unable to induce IgM in serum and IgG at mucosal sites but showed superior immunogenicity in terms of IgA induction. Anti-Tat antibodies were also obtained upon vaccination with the immunodominant Tat 1–20 peptide which was, however, less immunogenic than the whole Tat protein

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“…Notably, on the basis of these preclinical data, Tat has been tested in phase I preventative and therapeutic trials (2,(9)(10)(11)16) and is being evaluated in a phase II therapeutic trial (http://www.hiv1tat-vaccines.info/).…”

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confidence: 99%

Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeficiency Virus SHIV89.6P

Cafaro

Bellino

Titti

et al. 2010

J Virol

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The effects of the challenge dose and major histocompatibility complex (MHC) class IB alleles were analyzed in 112 Mauritian cynomolgus monkeys vaccinated (n ‫؍‬ 67) or not vaccinated (n ‫؍‬ 45) with Tat and challenged with simian/human immunodeficiency virus (SHIV) 89.6P cy243. In the controls, the challenge dose (10 to 20 50% monkey infectious doses [MID 50 ]) or MHC did not affect susceptibility to infection, peak viral load, or acute CD4 T-cell loss, whereas in the chronic phase of infection, the H1 haplotype correlated with a high viral load (P ‫؍‬ 0.0280) and CD4 loss (P ‫؍‬ 0.0343). Vaccination reduced the rate of infection acquisition at 10 MID 50 (P < 0.0001), and contained acute CD4 loss at 15 MID 50 (P ‫؍‬ 0.0099). Haplotypes H2 and H6 were correlated with increased susceptibility (P ‫؍‬ 0.0199) and resistance (P ‫؍‬ 0.0087) to infection, respectively. Vaccination also contained CD4 depletion (P ‫؍‬ 0.0391) during chronic infection, independently of the challenge dose or haplotype.Advances in typing of the major histocompatibility complex (MHC) of Mauritian cynomolgus macaques (14,20,26) have provided the opportunity to address the influence of host factors on vaccine studies (13). Retrospective analysis of 22 macaques vaccinated with Tat or a Tat-expressing adenoviral vector revealed that monkeys with the H6 or H3 MHC class IB haplotype were overrepresented among aviremic or controller animals, whereas macaques with the H2 or H5 haplotype clustered in the noncontrollers (12). More recently, the H6 haplotype was reported to correlate with control of chronic infection with simian immunodeficiency virus (SIV) mac251, regardless of vaccination (18).Here, we performed a retrospective analysis of 112 Mauritian cynomolgus macaques, which included the 22 animals studied previously (12), to evaluate the impact of the challenge dose and class IB haplotype on the acquisition and severity of simian/human immunodeficiency virus (SHIV) 89.6P cy243 infection in 45 control monkeys and 67 monkeys vaccinated with Tat from different protocols (Table 1).Study description. All animals were challenged intravenously with 10 (n ϭ 29), 15 (n ϭ 68), or 20 (n ϭ 15) monkey infectious doses (MID 50 ) of SHIV86.6P cy243 derived from a cynomolgus macaque inoculated with the original SHIV89.6P stock from rhesus monkeys (3, 5) ( Table 1). The SIV RNA load in plasma and CD4 T-cell counts were determined as described previously (23).MHC allele predictions were generated on the basis of the microsatellite profiles (26), with the alleles for class I and class II regions being inferred on the basis of established haplotypeallele associations (20,26). As shown in Fig. 1A, the distribution of the seven major haplotypes (haplotypes H1 to H7) in vaccinated and control animals was balanced. Due to the presence of the H7 haplotype in only 3 out of 112 monkeys, it was excluded from the analyses.As the factors investigated in this study may affect susceptibility to acute (1 to 4 weeks) or chronic (16 to 52 weeks) infection differently, these wer...

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The preventive phase I trial with the HIV-1 Tat-based vaccine

Cited by 48 publications

References 32 publications

Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

Exploratory clinical studies of a synthetic HIV-1 Tat epitope vaccine in asymptomatic treatment-naïve and antiretroviral-controlled HIV-1 infected subjects plus healthy uninfected subjects

Effects of different routes of administration on the immunogenicity of the Tat protein and a Tat-derived peptide

Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeficiency Virus SHIV89.6P

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