Phase 2 Study of an HIV-1 Canarypox Vaccine (vCP1452) Alone and in Combination With rgp120

Russell, Nina D.; Graham, Barney S.; Keefer, Michael C.; McElrath, M. Juliana; Self, Steve; Weinhold, Kent J.; Montefiori, David C.; Ferrari, Guido; Horton, Helen; Tomaras, Georgia D.; Gurunathan, Sanjay; Baglyos, Lynn; Frey, Sharon E.; Mulligan, Mark J.; Harro, Clayton; Buchbinder, Susan; Baden, Lindsey R.; Blattner, William A.; Koblin, Beryl A.; Corey, Lawrence

doi:10.1097/01.qai.0000248356.48501.ff

Cited by 97 publications

(76 citation statements)

References 34 publications

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“…Results from more recent trials are not yet available, however. In a phase 2 study, a multigenic ALVAC-HIV recombinant vaccine followed by boosting with gp120 was not advanced to a proof-of-concept trial as it failed to elicit a CD8+ CTL frequency of 30% in healthy volunteers [110]. However, results of a phase III efficacy trial in Thailand of an ALVAC-HIVenv(B/E), gag, pol prime and gp120(B/E) boost are pending [111].…”

Section: Replication Defective Vectorsmentioning

confidence: 99%

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

Patterson

Robert-Guroff

2008

Expert Opinion on Biological Therapy

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Background-In the last few years the HIV vaccine field has moved forward a number of promising vaccine candidates into human clinical trials.Objective-In this review we briefly discuss the advances made in vaccine development and HIV pathogenesis and give an overview of the body of work our lab has generated in multiple animal models on replication-competent Ad recombinant vaccines.Methods-Emphasis is placed on comparative examination of vaccine components, routes of immunization and challenge models using replicating Ad vectors.Results/conclusion-The overall findings make the case that replicating Ad vectors are superior in priming multiple arms of the immune system, and in conjunction with protein boosting, have resulted in dramatic protective efficacy leading to their advancement to phase 1 trials. Implications of the recent halting of the Merck Ad5-HIV phase 2b clinical trial for our vaccine approach and other vectored vaccines are discussed.

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Section: Replication Defective Vectorsmentioning

confidence: 99%

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

Patterson

Robert-Guroff

2008

Expert Opinion on Biological Therapy

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“…Subunit proteins alone have elicited high titers of neutralizing antibodies against TCLA strains, where a minimum of three to four inoculations generally achieves peak titers [32][33][34][35][36]. Peak responses with recombinant pox-virus vectors have been lower, but can increase dramatically after one or two subunit protein boosts [37][38][39][40][41][42], suggesting effective B-cell priming by the vectored immunogen. Similar secondary neutralizing antibody responses are observed post-AIDS virus infection in macaques that are previously immunized with recombinant Env-containing DNA and viral vectors [43][44][45][46][47][48][49].…”

Section: Hiv-1 Immunogensmentioning

confidence: 99%

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Haynes¹,

Montefiori²

2006

Expert Review of Vaccines

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103

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Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

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“…In contrast, so-called replication-deficient viruses do not complete that initial round of replication. These two attenuation strategies have been adopted for use with many different viruses including, but not limited to, adenovirus (Ad), vaccinia virus (VV), canarypox virus (CPV), herpes simplex virus (HSV), vesicular stomatitis virus (VSV), and, more recently, RV (4,6,9,18,21,33,35,36,38). However, the results regarding the immunogenicity of such vectors are mixed.…”

mentioning

confidence: 99%

“…For example, both the replication-deficient Ad5 vector and modified vaccinia Ankara (MVA) showed reduced humoral and cellular immunogenicity compared to their replication-competent counterparts, but the use of higher titers and multiple immunizations did increase such responses (18,33,35). In the case of CPV, the replication-deficient vector provided poor HIV-specific cellular responses, causing the termination of phase II HIV-1 vaccine trials (38). In contrast, single-cycle VSV, a rhabdovirus closely related to RV, has been shown to induce HIV-1 Env-specific CD8 ϩ T-cell responses equivalent to full-length VSV when administered intramuscularly (36).…”

mentioning

confidence: 99%

Characterization of a Single-Cycle Rabies Virus-Based Vaccine Vector

Gomme¹,

Faul²,

Flomenberg

et al. 2010

J Virol

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Recombinant rabies virus (RV)-based vectors have demonstrated their efficacy in generating long-term,antigen-specific immune responses in murine and monkey models. However, replication-competent viral vectors pose significant safety concerns due to vector pathogenicity. RV pathogenicity is largely attributed to its glycoprotein (RV-G), which facilitates the attachment and entry of RV into host cells. We have developed a live, single-cycle RV by deletion of the G gene from an RV vaccine vector expressing HIV-1 Gag (SPBN-⌬G-Gag). Passage of SPBN-⌬G-Gag on cells stably expressing RV-G allowed efficient propagation of the G-deleted RV. The in vivo immunogenicity data comparing single-cycle RV to a replication-competent control (BNSPGag) showed lower RV-specific antibodies; however, the overall isotype profiles (IgG2a/IgG1) were similar for the two vaccine vectors. Despite this difference, mice immunized with SPBN-⌬G-Gag and BNSP-Gag mounted similar levels of Gag-specific CD8؉ T-cell responses as measured by major histocompatibility complex class I Gag-tetramer staining, gamma interferon-enzyme-linked immunospot assay, and cytotoxic T-cell assay. Moreover, these cellular responses were maintained equally at immunization titers as low as 10 3 focus-forming units for both RV vaccine vectors. CD8؉ T-cell responses were significantly enhanced by a boost with a single-cycle RV complemented with a heterologous vesicular stomatitis virus glycoprotein. These findings demonstrate that single-cycle RV is an effective alternative to replication-competent RV vectors for future development of vaccines for HIV-1 and other infectious diseases.

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Phase 2 Study of an HIV-1 Canarypox Vaccine (vCP1452) Alone and in Combination With rgp120

Abstract: Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.

Cited by 97 publications

References 34 publications

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Characterization of a Single-Cycle Rabies Virus-Based Vaccine Vector

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