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Katharine J Bar - One of the best experts on this subject based on the ideXlab platform.

  • breakthrough virus neutralization resistance as a correlate of protection in a Nonhuman Primate heterologous simian immunodeficiency virus vaccine challenge Study
    Journal of Virology, 2015
    Co-Authors: Fanghua Lee, Mario Roederer, Rosemarie D Mason, Hugh C Welles, Gerald H Learn, Brandon F Keele, Katharine J Bar
    Abstract:

    ABSTRACT Comprehensive assessments of immune correlates of protection in human immunodeficiency virus (HIV) vaccine trials are essential to vaccine design. Neutralization sieve analysis compares the neutralization sensitivity of the breakthrough transmitted/founder (TF) viruses from vaccinated and control animals to infer the molecular mechanisms of vaccine protection. Here, we report a robust neutralization sieve effect in a Nonhuman Primate simian immunodeficiency virus (SIV) vaccine trial (DNA prime/recombinant adenovirus type 5 [rAd5] boost) (VRC-10-332) that demonstrated substantial protective efficacy and revealed a genetic signature of neutralization resistance in the C1 region of env . We found significant enrichment for neutralization resistance in the vaccine compared to control breakthrough TF viruses when tested with plasma from vaccinated Study animals, plasma from chronically SIV-infected animals, and a panel of SIV-specific monoclonal antibodies targeting six discrete Env epitopes ( P P in vivo relevance of our previous in vitro analyses of the SIVsmE660 challenge stock, which revealed a broad range of neutralization sensitivities of its component viruses. In sum, this report demonstrates proof-of-concept that phenotypic sieve analyses can elucidate mechanistic correlates of immune protection following vaccination and raises a cautionary note for SIV and SHIV (simian-human immunodeficiency virus) vaccine studies that employ challenge strains with envelope glycoproteins that fail to exhibit neutralization resistance profiles typical of TF viruses. IMPORTANCE With more than 2 million new infections annually, the development of an effective vaccine against HIV-1 is a global health priority. Understanding immunologic correlates of protection generated in vaccine trials is critical to advance vaccine development. Here, we assessed the role of vaccine-elicited neutralizing antibodies in a recent Nonhuman Primate Study of a vaccine that showed significant protection against simian immunodeficiency virus (SIV) challenge and suggested a genetic signature of neutralization sensitivity. We found that breakthrough viruses able to establish infection in vaccinated animals were substantially more resistant to antibody-mediated neutralization than were viruses from controls. These findings suggest that vaccine-elicited neutralizing antibodies selectively blocked the transmission of more sensitive challenge viruses. Sieve analysis also corroborated a genetic signature of neutralization sensitivity and highlighted the impact of challenge swarm diversity. Our findings suggest an important role for neutralization sieve analyses as an informative component of comprehensive immune-correlates analyses.

Jim Tartaglia - One of the best experts on this subject based on the ideXlab platform.

  • comparison of immunogenicity in rhesus macaques of transmitted founder hiv 1 group m consensus and trivalent mosaic envelope vaccines formulated as a dna prime nyvac and envelope protein boost
    Journal of Virology, 2015
    Co-Authors: Sandrine L Hulot, Bette T Korber, Elena E Giorgi, Nathan Vandergrift, Kevin O Saunders, Harikrishnan Balachandran, Linh Mach, Michelle A Lifton, Giuseppe Pantaleo, Jim Tartaglia
    Abstract:

    An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4+ and CD8+ T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this Study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this Study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies. IMPORTANCE There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This Nonhuman Primate Study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

Tomaras G.d. - One of the best experts on this subject based on the ideXlab platform.

  • Replication-Competent NYVAC-KC Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC.
    'American Society for Microbiology', 2019
    Co-Authors: Kibler K.v., Asbach B., Perdiguero B., García-arriaza J., Yates N.l., Parks R., Stanfield-oakley S., Ferrari G., Montefiori D.c., Tomaras G.d.
    Abstract:

    As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a Nonhuman Primate Study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 Study. With that goal in mind, we have tested in Nonhuman Primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 Study. The results of this Study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate

Roederer Mario - One of the best experts on this subject based on the ideXlab platform.

  • Replication-Competent NYVAC-KC Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC
    'American Society for Microbiology', 2021
    Co-Authors: Kibler K., Asbach Benedikt, Perdiguero Beatriz, Yates, Nicole L., Parks Robert, Stanfield-oakley Sherry, Ferrari Guido, Montefiori, David C., Tomaras, Georgia D., Roederer Mario
    Abstract:

    © 2019 Kibler et al.As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a Nonhuman Primate Study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 Study. With that goal in mind, we have tested in Nonhuman Primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 Study. The results of this Study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.This investigation was funded by the Bill & Melinda Gates Foundation Poxvirus T Cell Vaccine Discovery Consortium (PTVDC) (38599). The Vaccine Immune Monitoring Centers (OPP1032144 and OPP1032325) and the Vaccine Immunology Statistical Center (OPP1032317), as part of the Collaboration for AIDS Vaccine Discovery (CAVD), were funded by the Bill & Melinda Gates Foundation. Novartis Vaccines received support for this work under contract number HHSN266200500007C from DAIDS-NIAID-NIH

Omar Touzani - One of the best experts on this subject based on the ideXlab platform.

  • diffusion tensor mri reveals chronic alterations in white matter despite the absence of a visible ischemic lesion on conventional mri a Nonhuman Primate Study
    Stroke, 2011
    Co-Authors: Ebeline Bihel, Simon Roussel, Jerome Toutain, Myriam Bernaudin, Omar Touzani
    Abstract:

    Background and Purpose—The impact of stroke on white matter is poorly described in preclinical investigations mainly based on rodents with a low white (WM)/gray matter ratio. Using diffusion tensor imaging, we evaluated WM alterations and correlated them with sensorimotor deficits after stroke in the marmoset, a Nonhuman Primate that displays a WM/gray matter ratio close to that of humans. Methods—Marmosets underwent a transient brain ischemia (3-hour). Eight serial MRI examinations were made during ischemia and up to 45 days after reperfusion. The sensorimotor deficits were evaluated weekly over 45 days. To assess WM alterations, the SD of the angle of the first eigenvector projection was calculated in the cortex and in the internal and external capsules. The fiber-tracking approach was used to measure the number and the length of bundles. Results—Changes in the apparent diffusion coefficient and the fractional anisotropy values were similar during the temporal evolution of the lesion in the marmoset mod...