Biomedical subjects

Zimra R Israel

Publications and source records attributed to Zimra R Israel.

7 recordsLinked to original sources

PubMed2006

Long-lasting decrease in viremia in macaques chronically infected with simian immunodeficiency virus SIVmac251 after therapeutic DNA immunization.

Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.

Animals↗

PubMed2005

A dose sparing effect by plasmid encoded IL-12 adjuvant on a SIVgag-plasmid DNA vaccine in rhesus macaques.

An experimental pDNA vaccine adjuvant expressing IL-12 was evaluated for its ability to augment the humoral and cellular immune responses elicited by a SIVmac239 gag p39 expressing pDNA vaccine. To determine the effect of vaccine dose on the immune response, rhesus macaques were immunized with 1.5 mg or 5.0 mg of SIVmac239 gag pDNA, with or without co-immunization of IL-12 pDNA at 1.5 mg and 5.0 mg, respectively. Serum antibody responses to simian immunodeficiency virus (SIV) gag were increased 10-fold (p=0.044, 0.002) in macaques receiving IL-12 pDNA. Cellular immune responses, monitored by SIV gag-specific IFN-gamma ELISpot assay, were also significantly higher (p=0.007, 0.019) when the pDNA vaccine was co-immunized with IL-12 pDNA at high and low doses. There was no statistical difference between the immune responses elicited by the high and low dose of IL-12 pDNA (p=0.221, 0.917), a finding which could allow a dose reduction of vaccine without the concomitant loss of imunogenicity. Furthermore, analysis of the breadth of the T-cell response during the vaccination schedule, using overlapping peptides to SIV gag, demonstrated a significant correlation (p=0.0002) between the magnitude and breadth of the immune responses in the vaccines. These results have important implications for the continuing development of an effective, safe low dose pDNA vaccine adjuvant suitable for human use.

Adjuvants, Immunologic↗

PubMed2005

Rational design of a plasmid DNA vaccine capable of eliciting cell-mediated immune responses to multiple HIV antigens in mice.

Given the importance of the HIV-specific cell-mediated immune response in the early control and resolution of HIV infection and the observed correlation between pre-challenge vaccine elicited CTL responses and post challenge outcome in SHIV/rhesus macaque experiments, we sought to identify several candidate plasmid DNA (pDNA) vaccine designs capable of eliciting robust and balanced cell-mediated immune responses to multiple HIV-1 derived antigens in mice for further vaccine development. To rationally construct candidate vaccines for immunogenicity testing, we determined the relative immunogenicity of the individual HIV-derived vaccine antigens (env, gag, pol, nef, tat and vif) and the relative strength of various transcriptional control elements (HCMV, SCMV, HSV Lap1) in Balb/c mice. Next, a number of 1-, 2-, 3- and 4-vector pDNA vaccine designs were tested for their ability to elicit HIV-1 antigen-specific CMI responses. For these studies, Balb/c mice were immunized with a fixed total pDNA vaccine dose of 100 mcg in combination with 25 mcg plasmid-based murine IL-12 and tested for the induction of HIV-1 antigen-specific CMI responses by IFN-gamma ELISpot analysis. The results of this study indicate that all pDNA vaccine designs were capable of eliciting CMI responses to multiple HIV-1 antigens. As a result of this iterative comparative analysis, we have identified a number of pDNA vaccine candidates capable of eliciting potent, balanced CMI responses to multiple HIV-1 derived antigens. These results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection.

Animals↗

PubMed2005

Priming with plasmid DNAs expressing interleukin-12 and simian immunodeficiency virus gag enhances the immunogenicity and efficacy of an experimental AIDS vaccine based on recombinant vesicular stomatitis virus.

Of the various approaches being developed as prophylactic HIV vaccines, those based on a heterologous plasmid DNA prime, live vector boost vaccination regimen appear especially promising in the nonhuman primate/simian-human immunodeficiency virus (SHIV) challenge model. In this study, we sought to determine whether a series of intramuscular priming immunizations with a plasmid DNA vaccine expressing SIVgag p39, in combination with plasmid expressed rhesus IL-12, could effectively enhance the immunogenicity and postchallenge efficacy of two intranasal doses of recombinant vesicular stomatitis virus (rVSV)-based vectors expressing HIV-1 env 89.6P gp160 and SIVmac239 gag p55 in rhesus macaques. In macaques receiving the combination plasmid DNA prime, rVSV boost vaccination regimen we observed significantly increased SIVgag- specific cell-mediated and humoral immune responses and significantly lower viral loads postintravenous SHIV89.6P challenge relative to macaques receiving only the rVSV vectored immunizations. In addition, the plasmid DNA prime, rVSV boost vaccination regimen also tended to increase the preservation of peripheral blood CD4+ cells and reduce the morbidity and mortality associated with SHIV89.6P infection. An analysis of immune correlates of protection after SHIV89.6P challenge revealed that the prechallenge SHIV-specific IFN-gamma ELISpot response elicited by vaccination and the ability of the host to mount a virus-specific neutralizing antibody response postchallenge correlated with postchallenge clinical outcome. The correlation between vaccine-elicited cell-mediated immune responses and an improved clinical outcome after SHIV challenge provides strong justification for the continued development of a cytokine-enhanced plasmid DNA prime, rVSV vector boost immunization regimen for the prevention of HIV infection.

AIDS Vaccines↗

PubMed2004

A comparative evaluation of nasal and parenteral vaccine adjuvants to elicit systemic and mucosal HIV-1 peptide-specific humoral immune responses in cynomolgus macaques.

Cynomolgus macaques were immunized by either the intramuscular (i.m.) or intranasal (i.n.) route with a HIV-1 peptide-based immunogen (C4-V3 89.6P) alone, or formulated with novel adjuvants to evaluate the ability of the adjuvants to augment peptide-specific systemic and mucosal immune responses. A mutant cholera toxin, CT-E29H, or the combination of recombinant human IL-1alpha (rhIL-1alpha) protein and recombinant human GM-CSF (rhGM-CSF) protein were tested as adjuvants for i.n. immunization, while a stable emulsion of a synthetic monophosphoryl lipid A (MPL) analogue (RC529-SE) plus rhGM-CSF protein was tested as an adjuvant for i.m. immunization. Macaques immunized i.n. with peptide alone failed to elicit an anti-C4-V3 89.6P antibody response in serum. In contrast, all the tested peptide/adjuvant formulations elicited peptide-specific immune responses. RC529-SE/rhGM-CSF elicited the highest peak anti-peptide IgG geometric mean titer in serum (1:32,768 at week 25) followed by rhIL-1alpha/rhGM-CSF (1:1217 at week 10) and CT-E29H (1:256 at week 25). Measurable SHIV neutralizing antibody responses were detectable in only one macaque immunized i.m. with peptide formulated with RC529-SE/rhGM-CSF. Macaques immunized by the i.n. route with peptide in combination with CT-E29H failed to elicit measurable antibody responses at nasal or genital mucosal surfaces. In contrast, antibody responses at the nasal and genital mucosa were detected in macaques immunized by the i.n. route with peptide in combination with rhIL-1alpha/rhGM-CSF. However, antibody responses at the nasal and genital mucosa were highest in macaques immunized parenterally with peptide in combination with the adjuvants RC529-SE/rhGM-CSF. These results suggest that parenteral vaccine administration in combination with the appropriate adjuvant formulation can elicit vaccine-specific humoral immune responses in both systemic and mucosal compartments.

AIDS Vaccines↗

PubMed2004

Immunogenicity of attenuated vesicular stomatitis virus vectors expressing HIV type 1 Env and SIV Gag proteins: comparison of intranasal and intramuscular vaccination routes.

An experimental AIDS vaccine based on attenuated, recombinant vesicular stomatitis virus (rVSV), when administered by a combination of parenteral and mucosal routes, has proven effective at preventing AIDS in a rhesus macaque model (Rose NF, et al.: Cell 2001;106:539-549). In an effort to determine the optimal route of vaccine administration we evaluated the ability of rVSV-based vaccine vectors expressing HIV-1 Env and SIV Gag proteins, when given either intramuscularly (i.m.) or intranasally (i.n.), to elicit antigen-specific cellular and humoral immune responses, and to protect from a subsequent vaginal challenge with simian-human immunodeficiency virus (SHIV89.6P). Our results demonstrate that macaques vaccinated by the i.n. route developed significantly higher antigen-specific cellular immune responses as determined by MHC class I tetramer staining, IFN-gamma ELISPOT, and cytotoxic T cell assays. However, systemic and mucosal humoral immune responses did not vary significantly with the route of vaccine administration. Given the importance of cell-mediated immune responses in slowing AIDS progression, intranasal delivery of a VSV-based AIDS vaccine may be an optimal as well as practical route for vaccination and should be considered in design of clinical trials.

AIDS Vaccines↗

PubMed2002

Boosting of SIV-specific T cell responses in rhesus macaques that resist repeated intravaginal challenge with SIVmac251.

Despite repeated high-risk exposure to infectious HIV-1, some individuals remain HIV-1 seronegative and apparently uninfected. The use of nonhuman primate model systems to study SIVmac transmission may help to elucidate the factors responsible for protection in exposed, seronegative (ESN) humans. In an earlier vaccination study, three control rhesus macaques that were exposed to three sequential intravaginal challenges with pathogenic SIVmac251 failed to show evidence of infection after 5 years of observation. 51Cr release assay results suggested that these animals had low-level cytotoxic T lymphocyte responses to SIVmac proteins. We hypothesized that these responses might be an important component of protection from mucosal challenge. We performed an additional intravaginal challenge of all three macaques and monitored SIV-specific T cell responses in peripheral blood, using the sensitive enzyme-linked immunospot (ELISpot) assay. After the fourth challenge, one animal became infected; this animal did not mount a strong SIV-specific T cell response. Two other macaques remained uninfected as determined by peripheral blood mononuclear cell (PBMC) coculture, polymerase chain reaction (PCR), and branched DNA (bDNA) analysis of peripheral blood and lymphoid tissues, but demonstrated boosting of SIV-specific T cell responses after challenge. These results support a protective role for SIVmac-specific T cells in repeatedly exposed, persistently seronegative rhesus macaques.

Animals↗