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1.
Immunol Lett ; 150(1-2): 134-44, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23261719

RESUMO

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract illness in infants, the elderly, and other high-risk individuals. Despite years of research in this field, there is no effective licensed vaccine to prevent RSV infection. We have generated candidate RSV vaccines using a recombinant vesicular stomatitis virus (rVSV) replicon in which the attachment and fusion domains of the VSV glycoprotein (G) have been deleted (rVSV-Gstem), rendering the virus propagation-defective except in the presence of complementing VSV G provided in trans. A form of this vector encoding the RSV fusion protein (F) gene expressed high levels of F in vitro and elicited durable neutralizing antibody responses as well as complete protection against RSV challenge in vivo. Mice vaccinated with rVSV-Gstem-RSV-F replicons also developed robust cellular responses characterized by both primary and memory Th1-biased CD8+ and CD4+ T cells. Furthermore, a single high dose of the Gstem-RSV-F replicon was effective against challenge with both RSV A and B subgroup viruses. Finally, addition of an RSV glycoprotein (G)-expressing Gstem vector significantly improved the incomplete protection achieved with a single low dose of Gstem-RSV-F vector alone.


Assuntos
Vetores Genéticos/genética , Vetores Genéticos/imunologia , Imunidade Celular , Imunidade Humoral , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/genética , Vírus Sinciciais Respiratórios/imunologia , Vesiculovirus/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Ordem dos Genes , Vetores Genéticos/administração & dosagem , Humanos , Imunização , Memória Imunológica , Camundongos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Células Th1/imunologia , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/imunologia
2.
Vaccine ; 27(22): 2930-9, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19428903

RESUMO

Recombinant vesicular stomatitis viruses (rVSVs) are being developed as potential HIV-1 vaccine candidates. To characterize the in vivo replication and dissemination of rVSV vectors in mice, high doses of a highly attenuated vector expressing HIV-1 Gag, rVSV(IN)-N4CT9-Gag1, and a prototypic reference virus, rVSV(IN)-HIVGag5, were delivered intramuscularly (IM), intranasally (IN), or intravenously (IV). We used quantitative, real-time RT-PCR (Q-PCR) and standard plaque assays to measure the temporal dissemination of these viruses to various tissues. Following IM inoculation, both viruses were detected primarily at the injection site as well as in draining lymph nodes; neither virus induced significant weight loss, pathologic signs, or evidence of neuroinvasion. In contrast, following IN inoculation, the prototypic virus was detected in all tissues tested and caused significant weight loss leading to death. IN administration of rVSV(IN)-N4CT9-Gag1 resulted in detection in numerous tissues (brain, lung, nasal turbinates, and lymph nodes) albeit in significantly reduced levels, which caused little or no weight loss nor any mortality. Following IV inoculation, both prototypic and attenuated viruses were detected by Q-PCR in all tissues tested. In contrast to the prototype, rVSV(IN)-N4CT9-Gag1 viral loads were significantly lower in all organs tested, and no infectious virus was detected in the brain following IV inoculation, despite the presence of viral RNA. These studies demonstrated significant differences in the biodistribution patterns of and the associated pathogenicity engendered by the prototypic and attenuated vectors in a highly susceptible host.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/farmacocinética , Vetores Genéticos , Vesiculovirus/crescimento & desenvolvimento , Vesiculovirus/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Vacinas contra a AIDS/efeitos adversos , Administração Intranasal , Animais , Feminino , Injeções Intramusculares , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/farmacocinética , Ensaio de Placa Viral
3.
Virology ; 367(2): 275-87, 2007 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-17599381

RESUMO

Widespread use of a live-attenuated influenza vaccine (LAIV) in the United States (licensed as FluMist) raises the possibility that vaccine viruses will contribute gene segments to the type A influenza virus gene pool. Progeny viruses possessing new genotypes might arise from genetic reassortment between circulating wild-type (wt) and vaccine strains, but it will be difficult to predict whether they will be viable or exhibit novel properties. To begin addressing these uncertainties, reverse-genetics was used to generate 34 reassortant viruses derived from wt influenza virus A/Sydney/5/97 and the corresponding live vaccine strain. The reassortants contained different combinations of vaccine and wt PB2, PB1, PA, NP, M, and NS gene segments whereas all strains encoded wt HA and NA glycoproteins. The phenotypes of the reassortant strains were compared to wt and vaccine viruses by evaluating temperature-sensitive (ts) plaque formation and replication attenuation (att) in ferrets following intranasal inoculation. The results demonstrated that the vaccine virus PB1, PB2, and NP gene segments were dominant when introduced into the wt A/Sydney/5/97 genetic background, producing recombinant viruses that expressed the ts and att phenotypes. A dominant attenuated phenotype also was evident when reassortant strains contained the vaccine M or PA gene segments, even though these polypeptides are not temperature-sensitive. Although the vaccine M and NS gene segments typically are not associated with temperature sensitivity, a number of reassortants containing these vaccine gene segments did exhibit a more restricted ts phenotype. Overall, no reassortant strains were more virulent than wt, and in fact, 33 of the 34 recombinant viruses replicated less efficiently in infected ferrets. These results suggest that genetic reassortment between wt and vaccine strains is unlikely to produce viruses having novel properties that differ substantially from either progenitor, and that the likely outcome of reassortment will be attenuated viruses.


Assuntos
Genes Virais , Vírus da Influenza A/genética , Vacinas contra Influenza/biossíntese , Vírus Reordenados/genética , Recombinação Genética , Vacinas Atenuadas/genética , Proteínas Virais/genética , Animais , Furões , Engenharia Genética , Genótipo , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Fenótipo , RNA Polimerase Dependente de RNA/metabolismo , Vírus Reordenados/fisiologia , Temperatura , Células Tumorais Cultivadas , Vacinas Atenuadas/química , Vacinas Atenuadas/imunologia , Proteínas do Core Viral/química , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Ensaio de Placa Viral , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral
4.
Vaccine ; 25(12): 2296-305, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17239997

RESUMO

The safety of a propagation-defective Venezuelan equine encephalitis virus (VEEV) replicon particle vaccine was examined in mice. After intracranial inoculation we observed approximately 5% body weight loss, modest inflammatory changes in the brain, genome replication, and foreign gene expression. These changes were transient and significantly less severe than those caused by TC-83, a live-attenuated vaccinal strain of VEEV that has been safely used to immunize military personnel and laboratory workers. Replicon particles injected intramuscularly or intravenously were detected at limited sites 3 days post-administration, and were undetectable by day 22. There was no evidence of dissemination to spinal cord or brain after systemic administration. These results demonstrate that propagation-defective VEEV replicon particles are minimally neurovirulent and lack neuroinvasive potential.


Assuntos
Vírus da Encefalite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/imunologia , Replicon/genética , Proteínas do Envelope Viral/genética , Animais , Peso Corporal , Encéfalo/metabolismo , Encéfalo/virologia , Vírus da Encefalite Equina Venezuelana/genética , Encefalomielite Equina Venezuelana/prevenção & controle , Injeções Intramusculares , Injeções Intravenosas , Camundongos , RNA Viral/genética , RNA Viral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/metabolismo , Medula Espinal/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Replicação Viral/genética
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