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Mariano Esteban - One of the best experts on this subject based on the ideXlab platform.
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interleukin 1 and type i interferon dependent enhanced immunogenicity of an nyvac hiv 1 env gag pol nef vaccine vector with dual deletions of type i and type ii interferon binding proteins
Journal of Virology, 2015Co-Authors: Julie Delaloye, Mariano Esteban, Carmen E Gomez, Abdelali Filalimouhim, Mark J Cameron, Elias K Haddad, Alexandre Harari, Jeanpierre Goulet, Beatriz Perdiguero, Giuseppe PantaleoAbstract:ABSTRACT NYVAC, a highly attenuated, replication-restricted Poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the Poxvirus genome is an attractive strategy for improving the immunogenic properties of Poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env , gag , pol , and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (Δ B19R ) or type II (Δ B8R ) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C-ΔB19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4 + T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector. IMPORTANCE NYVAC is a replication-deficient Poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by Poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC Poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC Poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.
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Enhancing Poxvirus vectors vaccine immunogenicity
Human vaccines & immunotherapeutics, 2014Co-Authors: Juan García-arriaza, Mariano EstebanAbstract:Attenuated recombinant Poxvirus vectors expressing heterologous antigens from pathogens are currently at various stages in clinical trials with the aim to establish their efficacy. This is because these vectors have shown excellent safety profiles, significant immunogenicity against foreign expressed antigens and are able to induce protective immune responses. In view of the limited efficacy triggered by some Poxvirus strains used in clinical trials (i.e, ALVAC in the RV144 phase III clinical trial for HIV), and of the restrictive replication capacity of the highly attenuated vectors like MVA and NYVAC, there is a consensus that further improvements of these vectors should be pursuit. In this review we considered several strategies that are currently being implemented, as well as new approaches, to improve the immunogenicity of the Poxvirus vectors. This includes heterologous prime/boost protocols, use of co-stimulatory molecules, deletion of viral immunomodulatory genes still present in the Poxvirus genome, enhancing virus promoter strength, enhancing vector replication capacity, optimizing expression of foreign heterologous sequences, and the combined use of adjuvants. An optimized Poxvirus vector triggering long-lasting immunity with a high protective efficacy against a selective disease should be sought.
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Vaccine Efficacy against Malaria by the Combination of Porcine Parvovirus-Like Particles and Vaccinia Virus Vectors Expressing CS of Plasmodium
PloS one, 2012Co-Authors: Dolores Rodríguez, Gloria González-aseguinolaza, Juan Ramón Rodríguez, Aneesh Vijayan, M. Magdalena Gherardi, Paloma Rueda, J. Ignacio Casal, Mariano EstebanAbstract:With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8+ T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with Poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8+ T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/Poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order Poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and Poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria.
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head to head comparison on the immunogenicity of two hiv aids vaccine candidates based on the attenuated Poxvirus strains mva and nyvac co expressing in a single locus the hiv 1bx08 gp120 and hiv 1iiib gag pol nef proteins of clade b
Vaccine, 2007Co-Authors: Carmen E Gomez, Jose Luis Najera, Eva Perez Jimenez, Victoria Jimenez, Ralf Wagner, Marcus Graf, Mariejoelle Frachette, Peter Liljestrom, Giuseppe Pantaleo, Mariano EstebanAbstract:In this investigation we have generated and defined the immunogenicity of two novel HIV/AIDS vaccine candidates based on the highly attenuated vaccinia virus strains, MVA and NYVAC, efficiently expressing in the same locus (TK) and under the same viral promoter the codon optimized HIV-1 genes encoding gp120 and Gag-Pol-Nef antigens of clade B (referred as MVA-B and NYVAC-B). In infected human HeLa cells, gp120 is released from cells and GPN is produced as a polyprotein; NYVAC-B induces severe apoptosis but not MVA-B. The two Poxvirus vectors showed genetic stability of the inserts. In BALB/c and in transgenic HHD mice for human HLA-A2 class I, both vectors are efficient immunogens and induced broad cellular immune responses against peptides represented in the four HIV-1 antigens. Some differences were observed in the magnitude and breadth of the immune response in the mouse models. In DNA prime/Poxvirus boost protocols, the strongest immune response, as measured by fresh IFN-gamma and IL-2 ELISPOT, was obtained in BALB/c mice boosted with NYVAC-B, while in HHD mice there were no differences between the Poxvirus vectors. When the prime/boost was performed with homologous or with combination of Poxvirus vectors, the protocols MVA-B/MVA-B and NYVAC-B/NYVAC-B, or the combination NYVAC-B/MVA-B gave the most consistent broader immune response in both mouse models, although the magnitude of the overall response was higher for the DNA-B/Poxvirus-B regime. All of the immunization protocols induced some humoral response against the gp160 protein from HIV-1 clone LAV. Our findings indicate that MVA-B and NYVAC-B meet the criteria to be potentially useful vaccine candidates against HIV/AIDS.
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administration to mice of a monoclonal antibody that neutralizes the intracellular mature virus form of vaccinia virus limits virus replication efficiently under prophylactic and therapeutic conditions
Journal of General Virology, 2002Co-Authors: Juan C Ramirez, Esther Tapia, Mariano EstebanAbstract:The WHO smallpox eradication program was concluded 21 years ago and the non-vaccinated population is now at risk of Poxvirus infections, either by contact with monkeypox or through bioterrorism. Since drugs specific against Poxvirus infections are limited, neutralizing monoclonal antibodies (mAbs) that are effective in vivo may be an important tool in controlling Poxvirus infections. To this end, we studied the efficacy of the mAb C3, reactive against the trimeric 14-kDa protein of vaccinia virus (VV) localized in the membrane of the intracellular form of mature virus, for its ability to neutralize VV infection in mice. The results show that prophylactic as well as therapeutic administration of mAb C3 can be an effective means of control of VV replication within the host. The interval of antibody efficacy following a single administration, before and after VV inoculation, has been defined. This study reinforces the notion that neutralizing mAbs should be developed to control health-related human infections by Poxviruses.
Lisa R King - One of the best experts on this subject based on the ideXlab platform.
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modeling a safer smallpox vaccination regimen for human immunodeficiency virus type 1 infected patients in immunocompromised macaques
The Journal of Infectious Diseases, 2003Co-Authors: Yvette Edghillsmith, David Venzon, Tatiana S Karpova, James G Mcnally, Janos Nacsa, Wenpo Tsai, Elzbieta Tryniszewska, Marcin Moniuszko, Jody Manischewitz, Lisa R KingAbstract:We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient Poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated Poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent Poxvirus.
Michael Chastain - One of the best experts on this subject based on the ideXlab platform.
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Heterologous Human Immunodeficiency Virus Type 1 Priming-Boosting Immunization Strategies Involving Replication-Defective Adenovirus and Poxvirus Vaccine Vectors
Journal of virology, 2004Co-Authors: Danilo R. Casimiro, Andrew J. Bett, Mary-ellen Davies, Aimin Tang, Keith A. Wilson, Minchun Chen, Romnie Long, Troy W. Mckelvey, Michael ChastainAbstract:We compared the human immunodeficiency virus type 1 (HIV-1)-specific cellular immune responses elicited in nonhuman primates by HIV-1 gag-expressing replication-defective adenovirus serotype 5 (Ad5) or Poxvirus vectors, used either alone or in combination with each other. The responses arising from a heterologous Ad5 priming-Poxvirus boosting regimen were significantly greater than those elicited by homologous regimens with the individual vectors or by a heterologous Poxvirus priming-Ad5 boosting regimen. The heterologous Ad5 priming-Poxvirus boosting approach may have potential utility in humans as a means of inducing high levels of cellular immunity.
Taeho Hwang - One of the best experts on this subject based on the ideXlab platform.
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preclinical safety evaluation of hepatic arterial infusion of oncolytic Poxvirus
Drug Design Development and Therapy, 2018Co-Authors: Fen Jiang, Ung Bae Jeon, Taeho HwangAbstract:Purpose: Oncolytic Poxvirus has shown promise in treating various solid tumors, such as liver cancer, and administration of oncolytic Poxvirus via the hepatic artery may provide more survival benefits than other routes of administration. However, there is a lack of safety information to guide the application of hepatic arterial infusion (HAI) of oncolytic Poxvirus in human studies. To investigate the acute and chronic toxicity of HAI administration of oncolytic Poxvirus in animals and provide safety information for future human studies. Methods: VVtk-, a vaccinia Poxvirus with inactivated thymidine kinase gene, was administered via HAI to rabbits with normal liver function under angiography (1×108 or 1×109 pfu), and rats with N-nitrosomorpholine-induced precancerous liver cirrhosis under open surgery (1×108 pfu). Body weights and survival were monitored and blood samples were collected for hematological and biochemical tests. Distribution of A56 (a specific marker for Poxvirus infection) in rabbit organs was evaluated using immunofluorescence assays. Results: HAI of high doses of VVtk- did not cause any acute or chronic changes in body weight, survival or in biochemical, hematological tests in the 2 animal models, and none of the changes showed dose dependency (in rabbit study), or were influenced by liver cirrhosis (in rat study). A56 was not detected in any of the major rabbit organs. Conclusion: HAI may provide a safe alternative route of oncolytic Poxvirus administration for human studies.
Yvette Edghillsmith - One of the best experts on this subject based on the ideXlab platform.
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modeling a safer smallpox vaccination regimen for human immunodeficiency virus type 1 infected patients in immunocompromised macaques
The Journal of Infectious Diseases, 2003Co-Authors: Yvette Edghillsmith, David Venzon, Tatiana S Karpova, James G Mcnally, Janos Nacsa, Wenpo Tsai, Elzbieta Tryniszewska, Marcin Moniuszko, Jody Manischewitz, Lisa R KingAbstract:We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient Poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated Poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent Poxvirus.
