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Enhanced T-Cell Immunogenicity and Protective Efficacy of a Human Immunodeficiency Virus Type 1 Vaccine Regimen Consisting of Consecutive Priming with DNA and Boosting with Recombinant Fowlpox Virus

Kent, Stephen J.; Zhao, Anne; Best, Susan J.; Chandler, Jenalle D.; Boyle, David B.; Ramshaw, Ian A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/1998 EN
Relevância na Pesquisa
66.42%
The induction of human immunodeficiency virus (HIV)-specific T-cell responses is widely seen as critical to the development of effective immunity to HIV type 1 (HIV-1). Plasmid DNA and recombinant fowlpox virus (rFPV) vaccines are among the most promising safe HIV-1 vaccine candidates. However, the immunity induced by either vaccine alone may be insufficient to provide durable protection against HIV-1 infection. We evaluated a consecutive immunization strategy involving priming with DNA and boosting with rFPV vaccines encoding common HIV-1 antigens. In mice, this approach induced greater HIV-1-specific immunity than either vector alone and protected mice from challenge with a recombinant vaccinia virus expressing HIV-1 antigens. In macaques, a dramatic boosting effect on DNA vaccine-primed HIV-1-specific helper and cytotoxic T-lymphocyte responses, but a decline in HIV-1 antibody titers, was observed following rFPV immunization. The vaccine regimen protected macaques from an intravenous HIV-1 challenge, with the resistance most likely mediated by T-cell responses. These studies suggest a safe strategy for the enhanced generation of T-cell-mediated protective immunity to HIV-1.

Selective induction of immune responses by cytokines coexpressed in recombinant fowlpox virus.

Leong, K H; Ramsay, A J; Boyle, D B; Ramshaw, I A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1994 EN
Relevância na Pesquisa
66.38%
Avipoxviruses have recently been studied as potential vectors for the delivery of heterologous vaccine antigen. Because these viruses abortively infect mammalian cells yet still effectively present encoded foreign genes to the host immune system, they offer a safer but effective alternative to other live virus vectors. We have examined the effect of coexpressing the cytokine interleukin-6 or gamma interferon on immune responses to a recombinant fowlpox virus expressing influenza virus hemagglutinin. The encoded cytokine was expressed for prolonged periods in infected cell culture with little cytopathic effect due to the abortive nature of the infection. In mice, vector-expressed cytokine dramatically altered immune responses induced by the coexpressed hemagglutinin antigen. Expression of interleukin-6 augmented both primary systemic and mucosal antibody responses and primed for enhanced recall responses. In contrast, expression of gamma interferon markedly inhibited antibody responses without affecting the generation of cell-mediated immunity. The safety of these constructs was demonstrated in mice with severe combined immunodeficiency, and no side effects due to cytokine expression were observed. In summary, fowlpox virus vectors encoding cytokines represent a safe and effective vaccine strategy which may be used to selectively manipulate the immune response.

Different Levels of Immunogenicity of Two Strains of Fowlpox Virus as Recombinant Vaccine Vectors Eliciting T-Cell Responses in Heterologous Prime-Boost Vaccination Strategies

Cottingham, Matthew G.; van Maurik, Andre; Zago, Manola; Newton, Angela T.; Anderson, Richard J.; Howard, M. Keith; Schneider, Jörg; Skinner, Michael A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2006 EN
Relevância na Pesquisa
56.54%
The FP9 strain of Fowlpox virus has been described as a more immunogenic recombinant vaccine vector than the Webster FPV-M (FPW) strain (R. J. Anderson et al., J. Immunol. 172:3094-3100, 2004). This study expands the comparison to include two separate recombinant antigens and multiple, rather than single, independent viral clones derived from the two strains. Dual-poxvirus heterologous prime-boost vaccination regimens using individual clones of recombinant FP9 or FPW in combination with recombinant modified Vaccinia virus Ankara expressing the same antigen were evaluated for their ability to elicit T-cell responses against recombinant antigens from Plasmodium berghei (circumsporozoite protein) or human immunodeficiency virus type 1 (a Gag-Pol-Nef fusion protein). Gamma interferon enzyme-linked immunospot assay and fluorescence-activated cell sorting assays of the responses to specific epitopes confirmed the approximately twofold-greater cellular immunogenicity of FP9 compared to FPW, when given as the priming or boosting immunization. Equality of transgene expression in mouse cells infected with the two strains in vitro was verified by Western blotting. Directed partial sequence analysis and PCR analysis of FPW and comparison to available whole-genome sequences revealed that many loci that are mutated in the highly attenuated and culture-adapted FP9 strain are wild type in FPW...

Targeted Delivery of Murine Interferon-γ using a Recombinant Fowlpox Virus: NK Cell Recruitment to Regional Lymph Nodes and Priming of Tumor-Specific Host Immunity

Zeytin, Hasan; Reali, Eva; Zaharoff, David A.; Rogers, Connie J.; Schlom, Jeffrey; Greiner, John W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/2008 EN
Relevância na Pesquisa
56.43%
IFN-γ is a pro-inflammatory cytokine which also acts as a potent immunomodulatory agent. In this study, a replication-deficient recombinant avian (fowlpox) virus was engineered to express the murine IFN-γ gene (rF-IFN-γ) with the rationale of delivering concentrated levels of the cytokine to a local tissue microenvironment. Subcutaneous (s.c.) rF-IFN-γ administration resulted in IFN-γ production that (1) was restricted to the tissue microenvironment of the injection site and (2) was biologically active as evidenced by a significant increase of class I MHC expression levels in s.c. growing tumors following rF-IFN-γ administration. Infection of a highly tumorigenic murine cell line, MC38, with rF-IFN-γ functioned as an effective tumor cell-based vaccine by protecting mice from the formation of primary tumors and from subsequent tumor challenge. The cell-based vaccine was completely ineffective if mice were vaccinated with MC38 cells either pretreated with recombinant IFN-γ or infected with the wild-type fowlpox virus. Analysis of the regional lymph nodes draining the site of injection of the rF-IFN-γ based tumor cell vaccine revealed the presence of tumor specific cell lysis (CTL) as well as significant amount of lysis directed at NK-sensitive YAC-1 cells. Flow cytometric analyses coupled with functional assays confirmed the sustained presence of NK1.1+ cells within those draining lymph nodes for up to 5 days following rF-IFN-γ injection. Mice treated with NK cell-depleting antibodies prior to the injection of the rF-IFN-γ-infected MC38 tumor cells were not protected from primary tumor growth; analysis of the lymph nodes draining the injection site in NK-depleted mice...

Characterization of Host Responses against a Recombinant Fowlpox Virus-Vectored Vaccine Expressing the Hemagglutinin Antigen of an Avian Influenza Virus ▿

Hghihghi, Hamid R.; Read, Leah R.; Mohammadi, Hakimeh; Pei, Yanlong; Ursprung, Claudia; Nagy, Éva; Behboudi, Shahriar; Haeryfar, S. M. Mansour; Sharif, Shayan
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
56.33%
There currently are commercial fowlpox virus (FPV)-vectored vaccines for use in chickens, including TROVAC-AIV H5, which expresses the hemagglutinin (HA) antigen of an avian influenza virus and can confer immunity against avian influenza in chickens. Despite the use of recombinant FPV (rFPV) for vaccine delivery, very little is known about the immune responses generated by these viruses in chickens. The present study was designed to investigate host responses to rFPV in vivo and in vitro. In cultured cells infected with TROVAC-AIV H5, there was an early increase in the expression of type I interferons (IFN), Toll-like receptors 3 and 7 (TLR3 and TLR7, respectively), TRIF, and MyD88, which was followed by a decrease in the expression of these genes at later time points. There also was an increase in the expression of interleukin-1β (IL-1β), IL-8, and beta-defensin genes at early time points postinfection. In chickens immunized with TROVAC-AIV H5, there was higher expression of IFN-γ and IL-10 at day 5 postvaccination in spleen of vaccinated birds than in that of control birds. We further investigated the ability of the vaccine to induce immune responses against the HA antigen and discovered that there was a cell-mediated response elicited in vaccinated chickens against this antigen. The findings of this study demonstrate that FPV-vectored vaccines can elicit a repertoire of responses marked by the early expression of TLRs...

Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity▿

Lousberg, Erin L.; Fraser, Cara K.; Tovey, Michael G.; Diener, Kerrilyn R.; Hayball, John D.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.26%
Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.

Induction of Both Cellular and Humoral Immunity following a Rational Prime-Boost Immunization Regimen That Incorporates Recombinant Ovine Atadenovirus and Fowlpox Virus ▿

Fraser, Cara K.; Diener, Kerrilyn R.; Lousberg, Erin L.; Both, Gerald W.; Ward, Larry; Brown, Michael P.; Hayball, John D.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
56.37%
Recombinant fowlpox viruses (rFPV) and ovine atadenoviruses (rOAdV) are being developed as safe, nonpathogenic, prophylactic and therapeutic vaccine vectors. There is scope, however, to improve the limited immune responses elicited by each of these vaccine vectors. Using previously determined and optimized routes of administration and viral doses, we characterized the primary adaptive immune responses elicited by recombinant variants of each virus. We demonstrate the contrasting nature of the response elicited by each recombinant virus. Whereas rFPV generates predominately cell-mediated immunity to our nominal target antigen, ovalbumin (OVA), rOAdV drives strong humoral responses. By defining the time taken to achieve maximal cytotoxic T cell responses and by studying the different patterns and kinetics of major histocompatibility complex class I-restricted OVA antigen expression postimmunization, we proposed a heterologous prime-boost regimen of immunization with rOAdV followed by rFPV. The subsequent experimental results showed that this approach produced robust cell-mediated and humoral immune responses against OVA that, importantly, were accompanied by weak anti-viral vector antibody responses. These results, therefore, represent a novel and potentially clinically applicable way to achieve broadly based and effective immunity to the antigens encoded by vectored vaccines.

Recombinant fowlpox virus elicits transient cytotoxic T cell responses due to suboptimal innate recognition and recruitment of T cell help

Diener, K.; Lousberg, E.; Beukema, E.; Yu, A.; Howley, P.; Brown, M.; Hayball, J.
Fonte: Elsevier Sci Ltd Publicador: Elsevier Sci Ltd
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
Relevância na Pesquisa
76.4%
Recombinant fowlpox viruses (FPVs) have been used in a variety of vaccine strategies; however strong data clearly demonstrating the characteristics of the strength and nature of the resultant immune response elicited by these vectors are lacking. By utilising a recombinant variant of FPV which expresses the nominal antigen chicken ovalbumin (OVA), and assessing innate FPV- and OVA-specific adaptive immune responses, we show that recombinant FPV induces a rapid type I interferon (IFN) response, mediated primarily by plasmacytoid dendritic cells (pDCs). These cells are necessary for the development of a strong but transient CD8(+) T cell effector response directed against OVA-expressing target cells. We propose that a combination of suboptimal type I IFN production, poor CD4(+) T cell helper function and inefficient DC licensing likely contribute to this transient response. These findings now provide a sound basis for rational modifications to be made to recombinant FPV, designed to improve subsequent vaccine responses.; http://www.elsevier.com/wps/find/journaldescription.cws_home/30521/description#description; Kerrilyn R. Diener, Erin L. Lousberg, Emma L. Beukema, Anastasia Yu, Paul M. Howley, Michael P. Brown and John D. Hayball; Copyright © 2008 Elsevier Ltd All rights reserved.

The potential role of fowlpox virus in rational vaccine design

Beukema, E.; Brown, M.; Hayball, J.
Fonte: Future Drugs Ltd. Publicador: Future Drugs Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
Relevância na Pesquisa
76.52%
The design of optimal vaccines requires detailed knowledge of how protective immune responses are generated in vivo under normal circumstances. This approach to vaccine development, where the immune correlates of protection are defined and vaccines are designed to elicit the same response, is called rational vaccine design. Poxviruses are attractive candidates for inclusion in such design strategies owing to their large genome, which allows for the inclusion of multiple heterologous genes, including those encoding antigens, co-stimulatory molecules and cytokines. Fowlpox virus, the prototypical member of the Avipoxvirus genus, is particularly suitable, as it is also incapable of replicating in mammalian cells. The potential of recombinant fowlpox virus as a safe vaccine vector is being evaluated currently in a number of clinical trials for diseases, including HIV, malaria and various types of cancer. Despite their promise, intricate details regarding how fowlpox virus interacts with the host immune system have not been resolved. In this review, the issues surrounding the use of fowlpox virus as a vaccine vector and possible strategies for enhancing its efficacy are discussed.; Emma L. Beukema, Michael P. Brown and John D. Hayball

Type I interferons mediate the innate cytokine response to recombinant fowlpox virus but not the induction of plasmacytoid dendritic cell-dependent adaptive immunity

Lousberg, E.; Fraser, C.; Tovey, M.; Diener, K.; Hayball, J.
Fonte: Amer Soc Microbiology Publicador: Amer Soc Microbiology
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
76.33%
Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-{alpha}), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.

Induction of both cellular and humoral immunity following a rational prime-boost immunization regimen that incorporates recombinant ovine atadenovirus and fowlpox virus

Fraser, C.; Diener, K.; Lousberg, E.; Both, G.; Ward, L.; Brown, M.; Hayball, J.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
66.43%
Recombinant fowlpox viruses (rFPV) and ovine atadenoviruses (rOAdV) are being developed as safe, nonpathogenic, prophylactic and therapeutic vaccine vectors. There is scope, however, to improve the limited immune responses elicited by each of these vaccine vectors. Using previously determined and optimized routes of administration and viral doses, we characterized the primary adaptive immune responses elicited by recombinant variants of each virus. We demonstrate the contrasting nature of the response elicited by each recombinant virus. Whereas rFPV generates predominately cell-mediated immunity to our nominal target antigen, ovalbumin (OVA), rOAdV drives strong humoral responses. By defining the time taken to achieve maximal cytotoxic T cell responses and by studying the different patterns and kinetics of major histocompatibility complex class I-restricted OVA antigen expression postimmunization, we proposed a heterologous prime-boost regimen of immunization with rOAdV followed by rFPV. The subsequent experimental results showed that this approach produced robust cell-mediated and humoral immune responses against OVA that, importantly, were accompanied by weak anti-viral vector antibody responses. These results, therefore, represent a novel and potentially clinically applicable way to achieve broadly based and effective immunity to the antigens encoded by vectored vaccines.; Cara K. Fraser...

Antigen-specific T-cell responses to a recombinant fowlpox virus are dependent on MyD88 and interleukin-18 and independent of toll-like receptor 7 (TLR7)- and TLR9-mediated innate immune recognition

Lousberg, E.; Diener, K.; Fraser, C.; Phipps, S.; Foster, P.; Chen, W.; Uematsu, S.; Akira, S.; Robertson, S.; Brown, M.; Hayball, J.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
76.37%
Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPVOVA), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPVOVA in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling...

Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

Bridge, S.H.; Sharpe, S.A.; Dennis, M.J.; Dowall, S.D.; Getty, B.; Anson, D.S.; Skinner, M.A.; Stewart, J.P.; Blanchard, T.J.
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
66.5%
BACKGROUND: There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes. METHODS: Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-γ ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl β-galactosidase assay with primary isolates of HIV-1. RESULTS: This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However...

4-1BBL coexpression enhances HIV-specific CD8 T cell memory ina poxvirus prime-boost vaccine

Harrison, Jodie; Bertram, Edward; Boyle, David B; Coupar, Barbara E H; Ranasinghe, Charani; Ramshaw, Ian
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
66.07%
We have constructed a recombinant fowlpox virus expressing HIV antigens and the costimulatory molecule 4-1BBL. When included in the boost, but not the prime of a poxvirus prime-boost strategy, 4-1BBL significantly enhanced the anti-HIV T cell response gen

Dose-response relationship of DNA and recombinant fowlpox virus prime-boost HIV vaccines: Implications for future trials

De Rose, Robert; Sullivan, Mark T; Dale, C Jane; Kelleher, Anthony D; Emery, Sean; Cooper, David A.; Ramshaw, Ian; Boyle, David B; Kent, Stephen J
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
76.51%
Estimating effective doses of novel HIV vaccines is challenging. Dose-response analyses of DNA and fowlpox virus HIV vaccines showed that 1 mg of DNA vaccine and 5 × 107 pfu of fowlpox virus booster was immunogenic in macaques. However, this dose was poo

Comparison of whole gene and whole virus scrambled antigen approaches for DNA prime and fowlpox virus boost HIV type 1 vaccine regimens in macaques

Pamungkas, Joko; De Rose, Robert; Iskandriati, Diah; Noviana, Rachmitasari; Paramastri, Yasmina; Dale, C Jane; Shoobridge, Maryanne; Medveczky, C; Ramshaw, Ian; Thomson, Scott; Kent, Stephen J
Fonte: Mary Ann Liebert Inc. Publicador: Mary Ann Liebert Inc.
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
86.49%
T cell immunity plays a critical role in controlling HIV-1 viremia, and encoding a limited set of HIV-1 genes within DNA and poxvirus vectors can, when used sequentially, induce high levels of T cell immunity in primates. However, a limited breadth of T cell immunity exposes the host to potential infection with either genetically diverse HIV-1 strains or T cell escape variants of HIV-1. In an attempt to induce maximally broad immunity, we examined DNA and recombinant fowlpox virus (rFPV) vaccines encoding all HIV-1 genes derived from a global HIV-1 consensus sequence, but expressed as multiple overlapping scrambled 30-amino acid segments (scrambled antigen vaccines, or SAVINEs). Three groups of seven pigtail macaques were immunized with sets of DNA and rFPV expressing Gag/Pol antigens only, the whole genome SAVINE antigens, or no HIV-1 antigens and T cell immunity was monitored by ELISpot and intracellular cytokine staining. High levels of cross-subtype HIV-specific T cell immunity to Gag were consistently induced in the seven macaques primed with DNA and rFPV vaccines expressing Gag/Pol as intact proteins. It was, however, difficult to repeatedly boost immunity with further rFPV immunizations, presumably reflecting high levels of anti-FPV immunity. Unfortunately...

Mucosally-administered human-simian immunodeficiency virus DNA and fowlpoxvirus-based recombinant vaccines reduce acute phase viral replication in macaques following vaginal challenge with CCR5-tropic SHIVSF162P3

Kent, Stephen J; Dale, C Jane; Ranasinghe, Charani; Stratov, Ivan; De Rose, Robert; Chea, Socheata; Montefiori, David C; Thomson, Scott; Ramshaw, Ian; Coupar, Barbara E H; Boyle, David B; Law, Matthew G; Wilson, Kim M; Ramsay, Alistair
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
66.44%
Further advances are required in understanding protection from AIDS by T cell immunity across mucosal sites of virus transmission. We analysed a set of multigenic HIV and SHIV DNA and Fowlpoxvirus (FPV) prime and boost vaccines for immunogenicity and protective efficacy in outbred pigtail macaques when delivered via mucosal surfaces (intranasally or intrarectally). Intranasally delivered DNA, even when adjuvanted and given as a fine droplet spray, was neither immunogenic nor protective in macaques. Some protection from acute infection with a pathogenic vaginal SHIVSF162P3 challenge was, however, observed with a regimen involving intramuscular DNA vaccine priming followed by either intranasally or intrarectally delivered rFPV boosting. Interestingly, animals boosted with rFPV vaccine via either of these mucosal routes had poor circulating T cell responses prior to challenge with SHIV compared to those boosted via the intramuscular route. Nevertheless, the mucosally-vaccinated animals generated equivalent anamnestic mucosal and systemic SHIV-specific CD4 and CD8 T cell responses following SHIV administration, with significant reduction in acute plasma viremia against this vaginal challenge. Our data suggest strategies for effective priming of partial immunity to mucosal HIV-1 exposure utilizing systemic prime and mucosal boost vaccination strategies.

Fowlpox virus vaccines for HIV and SHIV clinical and pre-clinical trials

Coupar, Barbara E H; Purcell, Damian F J; Thomson, Scott; Ramshaw, Ian; Kent, Stephen J; Boyle, David B
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
86.59%
DNA prime and recombinant fowlpox virus (rFPV) boost vaccines were designed to express multiple HIV or SIV antigens for use in human clinical trials and in pre-clinical trials in macaques. Three sets of vaccines with matching HIV or SIV antigen sets, modified for vaccine safety considerations, were constructed and shown to express the relevant proteins. The rFPV vaccines with inserts at up to three sites, were stable on passage in chick cell culture, including during GMP manufacture of vaccines for human Phase I clinical trials. Cellular and humoral immunogenicity in mice was demonstrated using a DNA prime/rFPV boost and vaccinia virus challenge model. These data establish a preliminary safety and efficacy profile for these multigenic vaccines suggesting they are suitable for advanced development as candidate HIV vaccines.

Evaluation of fowlpox-vaccinia virus prime-boost vaccine strategies for high-level mucosal and systemic immunity against HIV-1

Ranasinghe, Charani; Medveczky, C; Woltring, Donna; Gao, Ke; Thomson, Scott; Coupar, Barbara E H; Boyle, Brian John; Ramsay, Alistair; Ramshaw, Ian
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
76.48%
We have tested the efficacy of recombinant fowl pox (rFPV) and recombinant vaccinia virus (rVV) encoding antigens of AE clade HIV-1 in a prime-boost strategy, using both systemic and mucosal delivery routes. Of the various vaccine routes tested, intranasal/intramuscular (i.n./i.m.) AE FPV/AE VV prime-boosting generated the highest mucosal and systemic T cell responses. Peak mucosal T cell responses occurred as early as 3 days post-boost vaccination. In contrast only low systemic responses were observed at this time with the peak response occurring at day 7. Current data also revealed that, due to better uptake of the rFPV, intranasal viral priming was much more effective than intranasal rDNA priming tested previously. The i.m./i.m. prime-boost delivery also generated strong systemic but poor mucosal responses to Gag peptides. Interestingly, the oral administration of AE FPV followed by i.m. AE VV delivery elicited strong systemic responses to sub-dominant Pol 1 peptides that were absent in mice that received vaccine by other routes. Moreover, priming with AE FPV co-expressing cytokine IL-12 significantly enhanced the T cell responses to target antigens, whilst co-expression of IFNγ decreased these responses. The results also indicated that the route of inoculation and the vaccine vector combination could radically influence not only the magnitude but also the antigen specificity of the immune response generated. Further...

A randomized, placebo-controlled phase I trial of DNA prime, recombinant fowlpox virus boost prophylactic vaccine for HIV-1

Kelleher, Anthony D; Puls, Rebekah; Bebbington, Mark; Boyle, David B; Ffrench, Rosemary A; Kent, Stephen J; Kippax, Susan; Purcell, Damian F J; Thomson, Scott; Wand, Handan; Cooper, David A.; Emery, Sean; Munier, Mee Ling; Coupar, Barbara E H; Fielden, Ro
Fonte: Lippincott Williams & Wilkins Publicador: Lippincott Williams & Wilkins
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
86.38%
An HIV-vaccine consisting of a DNA prime, recombinant fowlpox virus (rFPV) boost was evaluated in a double-blind placebo controlled trial. One milligram of pHIS-HIV-B expressing mutated gag, pol, env, vpu, tat and rev was administered at weeks 0 and 4 boosted by 5 × 107 pfu rFPV-HIV-B expressing gag/pol at week 8. The vaccine regimen was safe, but there was no difference between vaccine (n = 18) and placebo recipients (n = 6) for Gag or Pol-specific T-cell immune responses at week 9.