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1.
Cell Host Microbe ; 25(1): 49-58.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629918

RESUMO

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Ebolavirus/patogenicidade , Furões/virologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Linhagem Celular , Cercopithecus aethiops , Modelos Animais de Doenças , Feminino , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Células HEK293 , Doença pelo Vírus Ebola/virologia , Humanos , Células Matadoras Naturais , Macaca , Macaca fascicularis , Masculino , Primatas , Análise de Sobrevida , Resultado do Tratamento , Proteínas Virais/imunologia
2.
Nat Commun ; 10(1): 105, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631063

RESUMO

The 2013-2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/imunologia , Marburgvirus/imunologia , Doenças dos Primatas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Ebolavirus/classificação , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunoterapia/métodos , Marburgvirus/efeitos dos fármacos , Marburgvirus/fisiologia , Doenças dos Primatas/terapia , Doenças dos Primatas/virologia , Primatas , Resultado do Tratamento
3.
Sci Rep ; 6: 33987, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27703185

RESUMO

Epigraph is an efficient graph-based algorithm for designing vaccine antigens to optimize potential T-cell epitope (PTE) coverage. Epigraph vaccine antigens are functionally similar to Mosaic vaccines, which have demonstrated effectiveness in preliminary HIV non-human primate studies. In contrast to the Mosaic algorithm, Epigraph is substantially faster, and in restricted cases, provides a mathematically optimal solution. Epigraph furthermore has new features that enable enhanced vaccine design flexibility. These features include the ability to exclude rare epitopes from a design, to optimize population coverage based on inexact epitope matches, and to apply the code to both aligned and unaligned input sequences. Epigraph was developed to provide practical design solutions for two outstanding vaccine problems. The first of these is a personalized approach to a therapeutic T-cell HIV vaccine that would provide antigens with an excellent match to an individual's infecting strain, intended to contain or clear a chronic infection. The second is a pan-filovirus vaccine, with the potential to protect against all known viruses in the Filoviradae family, including ebolaviruses. A web-based interface to run the Epigraph tool suite is available (http://www.hiv.lanl.gov/content/sequence/EPIGRAPH/epigraph.html).


Assuntos
Vacinas contra a AIDS , Epitopos , Infecções por Filoviridae , Infecções por HIV , HIV-1 , Análise de Sequência de Proteína/métodos , Software , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Epitopos/genética , Epitopos/imunologia , Filoviridae/genética , Filoviridae/imunologia , Infecções por Filoviridae/genética , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/terapia , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/terapia , HIV-1/genética , HIV-1/imunologia , Humanos
4.
Artigo em Inglês | MEDLINE | ID: mdl-27103629

RESUMO

The Ebola outbreak of 2013-15 infected more than 28 000 people and claimed more lives than all previous filovirus outbreaks combined. Governmental agencies, clinical teams, and the world scientific community pulled together in a multifaceted response ranging from prevention and disease control, to evaluating vaccines and therapeutics in human trials. As this epidemic is finally coming to a close, refocusing on long-term prevention strategies becomes paramount. Given the very real threat of future filovirus outbreaks, and the inherent uncertainty of the next outbreak virus and geographic location, it is prudent to consider the extent and implications of known natural diversity in advancing vaccines and therapeutic approaches. To facilitate such consideration, we have updated and enhanced the content of the filovirus portion of Los Alamos Hemorrhagic Fever Viruses Database. We have integrated and performed baseline analysis of all family ITALIC! Filoviridaesequences deposited into GenBank, with associated immune response data, and metadata, and we have added new computational tools with web-interfaces to assist users with analysis. Here, we (i) describe the main features of updated database, (ii) provide integrated views and some basic analyses summarizing evolutionary patterns as they relate to geo-temporal data captured in the database and (iii) highlight the most conserved regions in the proteome that may be useful for a T cell vaccine strategy.Database URL:www.hfv.lanl.gov.


Assuntos
Bases de Dados Genéticas , Infecções por Filoviridae/virologia , Filoviridae/genética , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Humanos , Internet , New Mexico , Interface Usuário-Computador
5.
Viruses ; 7(10): 5489-507, 2015 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-26512687

RESUMO

Ebola- and marburgviruses are highly pathogenic filoviruses and causative agents of viral hemorrhagic fever. Filovirus disease is characterized by a dysregulated immune response, severe organ damage, and coagulation abnormalities. This includes modulation of cytokines, signaling mediators that regulate various components of the immune system as well as other biological processes. Here we examine the role of cytokines in filovirus infection, with an emphasis on understanding how these molecules affect development of the antiviral immune response and influence pathology. These proteins may present targets for immune modulation by therapeutic agents and vaccines in an effort to boost the natural immune response to infection and/or reduce immunopathology.


Assuntos
Citocinas/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/patologia , Filoviridae/imunologia , Animais , Humanos
6.
Viruses ; 7(10): 5172-90, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26426036

RESUMO

The family Filoviridae contains several of the most deadly pathogens known to date and the current Ebola virus disease (EVD) outbreak in Western Africa, due to Ebola virus (EBOV) infection, highlights the need for active and broad research into filovirus pathogenesis. However, in comparison, the seven other known filovirus family members are significantly understudied. Many of these, including Marburgviruses and Ebolaviruses other than EBOV, are also highly virulent and fully capable of causing widespread epidemics. This review places the focus on these non-EBOV filoviruses, including known immunological and pathological data. The available animal models, research tools and currently available therapeutics will also be discussed along with an emphasis in the large number of current gaps in knowledge of these less highlighted filoviruses. It is evident that much research is yet to be done in order to bring the non-EBOV filovirus field to the forefront of current research and, importantly, to the development of more effective vaccines and therapeutics to combat potential future outbreaks.


Assuntos
Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/virologia , Filoviridae/fisiologia , Animais , Pesquisa Biomédica/tendências , Modelos Animais de Doenças , Surtos de Doenças , Filoviridae/imunologia , Filoviridae/patogenicidade , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/patologia , Humanos , Virulência
7.
J Infect Dis ; 212 Suppl 2: S384-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25957964

RESUMO

The filoviruses, Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 filoviruses.


Assuntos
Infecções por Filoviridae/imunologia , Filoviridae/imunologia , Vetores Genéticos/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Feminino , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Vesiculovirus/imunologia
8.
J Infect Dis ; 212 Suppl 2: S404-9, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26022440

RESUMO

Stat1(-/-) mice lack a response to interferon α, ß, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.


Assuntos
Filoviridae/imunologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Vacinas Atenuadas/imunologia , Estomatite Vesicular/imunologia , Vacinas Virais/imunologia , Animais , Cercopithecus aethiops , Modelos Animais de Doenças , Ebolavirus/imunologia , Infecções por Filoviridae/genética , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/virologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Doença do Vírus de Marburg/genética , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/virologia , Marburgvirus/imunologia , Camundongos , Fator de Transcrição STAT1/imunologia , Células Vero , Carga Viral/imunologia , Replicação Viral/genética , Replicação Viral/imunologia
9.
J Infect Dis ; 212 Suppl 2: S101-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25786916

RESUMO

Fruit bats are suspected to be a natural reservoir of filoviruses, including Ebola and Marburg viruses. Using an enzyme-linked immunosorbent assay based on the viral glycoprotein antigens, we detected filovirus-specific immunoglobulin G antibodies in 71 of 748 serum samples collected from migratory fruit bats (Eidolon helvum) in Zambia during 2006-2013. Although antibodies to African filoviruses (eg, Zaire ebolavirus) were most prevalent, some serum samples showed distinct specificity for Reston ebolavirus, which that has thus far been found only in Asia. Interestingly, the transition of filovirus species causing outbreaks in Central and West Africa during 2005-2014 seemed to be synchronized with the change of the serologically dominant virus species in these bats. These data suggest the introduction of multiple species of filoviruses in the migratory bat population and point to the need for continued surveillance of filovirus infection of wild animals in sub-Saharan Africa, including hitherto nonendemic countries.


Assuntos
Quirópteros/virologia , Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/virologia , Filoviridae/imunologia , África/epidemiologia , Animais , Anticorpos Antivirais/sangue , Ásia/epidemiologia , Linhagem Celular , Quirópteros/sangue , Quirópteros/imunologia , Surtos de Doenças , Ebolavirus/imunologia , Feminino , Infecções por Filoviridae/sangue , Infecções por Filoviridae/imunologia , Glicoproteínas/imunologia , Células HEK293 , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Imunoglobulina G/sangue , Masculino , Prevalência , Proteínas Virais/imunologia
10.
Am J Dermatopathol ; 37(2): 93-106, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25171430

RESUMO

BACKGROUND: Cutaneous viral infections are increasing in recent years, particularly in immunocompromised patients. OBJECTIVE: Immunohistochemistry (IHC) provides a rapid and helpful tool that can be applied to confirm the diagnosis of specific viral infections that may be difficult to diagnose with certainty using routine microscopy alone. METHODS: Several immunostains that are useful in histopathology have been reviewed and tested in cutaneous samples of viral infections. Emphasis is placed on new stains and novel uses of existing stains. RESULTS: This article is an up-to-date overview of the potential uses of IHC in the histopathologic diagnosis of cutaneous viral infections by parvoviruses, polyomaviruses, poxviruses, paramyxoviridae, picornaviridae, retroviruses, and filoviruses. LIMITATIONS: Specific monoclonal antibodies are commercially available only for some members of these virus families. CONCLUSIONS: IHC may assist dermatopathologists to appropriately diagnose viral infections by parvoviruses, polyomaviruses, poxviruses, paramyxoviridae, picornaviridae, retroviruses, and filoviruses.


Assuntos
Antígenos Virais/imunologia , Infecções por Filoviridae/diagnóstico , Imuno-Histoquímica , Infecções por Paramyxoviridae/diagnóstico , Infecções por Parvoviridae/diagnóstico , Infecções por Picornaviridae/diagnóstico , Infecções por Poxviridae/diagnóstico , Infecções por Retroviridae/diagnóstico , Dermatopatias Virais/diagnóstico , Pele/imunologia , Anticorpos Monoclonais , Biomarcadores/análise , Biópsia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/patologia , Infecções por Filoviridae/virologia , Humanos , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/patologia , Infecções por Paramyxoviridae/virologia , Infecções por Parvoviridae/imunologia , Infecções por Parvoviridae/patologia , Infecções por Parvoviridae/virologia , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/patologia , Infecções por Poxviridae/virologia , Valor Preditivo dos Testes , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/patologia , Infecções por Retroviridae/virologia , Pele/patologia , Pele/virologia , Dermatopatias Virais/imunologia , Dermatopatias Virais/patologia , Dermatopatias Virais/virologia
11.
Viruses ; 6(7): 2673-97, 2014 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25010768

RESUMO

On August 22-23, 2013, agencies within the United States Department of Defense (DoD) and the Department of Health and Human Services (HHS) sponsored the Filovirus Medical Countermeasures (MCMs) Workshop as an extension of the activities of the Filovirus Animal Non-clinical Group (FANG). The FANG is a federally-recognized multi-Agency group established in 2011 to coordinate and facilitate U.S. government (USG) efforts to develop filovirus MCMs. The workshop brought together government, academic and industry experts to consider the needs for filovirus MCMs and evaluate the status of the product development pipeline. This report summarizes speaker presentations and highlights progress and challenges remaining in the field.


Assuntos
Anticorpos Antivirais/biossíntese , Infecções por Filoviridae/prevenção & controle , Filoviridae/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Filoviridae/patogenicidade , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/virologia , Cobaias , Haplorrinos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Camundongos , Estados Unidos , United States Department of Defense , United States Dept. of Health and Human Services , Vacinas de DNA , Vacinas Virais/administração & dosagem , Vacinas Virais/biossíntese , Replicação Viral/efeitos dos fármacos
12.
Virol Sin ; 28(2): 65-70, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23385315

RESUMO

Filoviruses are hemorrhagic fever viruses endemic to parts of Africa and the Philippines. Infection carries with it a mortality rate of up to 90% and currently there are no effective vaccines or therapeutics available to combat infection. However, the filovirus virus-like particles (VLP), which are currently under development, have been shown to be a promising vaccine candidate. They provide protection from infection in the mouse, guinea pig, and nonhuman primate models of infection, eliciting high anti-glycoprotein antibody titers and T cell responses to viral proteins. In this review, we will highlight the development of the filovirus VLP and describe the current understanding of VLP immunogenicity and correlates of protection.


Assuntos
Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Filoviridae/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia , Animais , Filoviridae/patogenicidade , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Vacinas Virais/uso terapêutico
13.
Viruses ; 4(10): 2312-6, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-23202465

RESUMO

The Filovirus Animal Non-Clinical Group (FANG) is a US interdepartmental and interagency group established to support and facilitate the advanced development of filovirus Medical Countermeasures (MCM), both vaccines and therapeutics. It is co-led by one representative from the Department of Defense (DoD), the first author, and one from the Department of Health and Human Services (HHS), the second author. The FANG membership includes operational level program staff and Subject Matter Experts (SME) from performing organizations as well as scientific staff and program managers from DoD and HHS funding and regulatory agencies. Focus areas include animal models, assays, reagents, product manufacture and characterization, and other interagency product development issues that will support Food and Drug Administration (FDA) licensure of safe and effective filovirus MCMs. The FANG continues to develop strategies to address broadly applicable and interagency product development challenges relevant to filovirus MCM development. This paper summarizes FANG structure and accomplishments and is meant to heighten community awareness of this government-led collaborative effort.


Assuntos
Comportamento Cooperativo , Infecções por Filoviridae/prevenção & controle , Filoviridae/imunologia , Relações Interinstitucionais , Virologia/métodos , Antivirais/administração & dosagem , Antivirais/imunologia , Pesquisa Biomédica/organização & administração , Descoberta de Drogas/métodos , Filoviridae/patogenicidade , Infecções por Filoviridae/imunologia , Indicadores e Reagentes/normas , Estados Unidos , United States Department of Defense/organização & administração , United States Dept. of Health and Human Services/organização & administração , Virologia/normas
14.
PLoS One ; 7(10): e44769, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23056184

RESUMO

We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.


Assuntos
Epitopos de Linfócito T/imunologia , Infecções por Filoviridae/imunologia , Filoviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas Virais/imunologia , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Antivirais/imunologia , Biologia Computacional/métodos , Reações Cruzadas/imunologia , Desenho de Drogas , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Filoviridae/metabolismo , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Hepacivirus/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Vacinas contra Hepatite Viral/imunologia , Proteínas Virais/imunologia , Vacinas Virais/administração & dosagem
15.
Proc Natl Acad Sci U S A ; 109(13): 5034-9, 2012 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-22411795

RESUMO

Antibody therapies to prevent or limit filovirus infections have received modest interest in recent years, in part because of early negative experimental evidence. We have overcome the limitations of this approach, leveraging the use of antibody from nonhuman primates (NHPs) that survived challenge to filoviruses under controlled conditions. By using concentrated, polyclonal IgG antibody from these survivors, we treated filovirus-infected NHPs with multiple doses administered over the clinical phase of disease. In the first study, Marburg virus (MARV)-infected NHPs were treated 15 to 30 min postexposure with virus-specific IgG, with additional treatments on days 4 and 8 postexposure. The postexposure IgG treatment was completely protective, with no signs of disease or detectable viremia. MARV-specific IgM antibody responses were generated, and all macaques survived rechallenge with MARV, suggesting that they generated an immune response to virus replication. In the next set of studies, NHPs were infected with MARV or Ebola virus (EBOV), and treatments were delayed 48 h, with additional treatments on days 4 and 8 postexposure. The delayed treatments protected both MARV- and EBOV-challenged NHPs. In both studies, two of the three IgG-treated NHPs had no clinical signs of illness, with the third NHP developing mild and delayed signs of disease followed by full recovery. These studies clearly demonstrate that postexposure antibody treatments can protect NHPs and open avenues for filovirus therapies for human use using established Food and Drug Administration-approved polyclonal or monoclonal antibody technologies.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Filoviridae/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Animais , Fracionamento Químico , Ebolavirus/imunologia , Infecções por Filoviridae/virologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Marburgvirus/imunologia , Testes de Neutralização , Especificidade da Espécie , Análise de Sobrevida
16.
Antiviral Res ; 93(3): 416-28, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22333482

RESUMO

The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are highly lethal zoonotic agents of concern as emerging pathogens and potential bioweapons. Antigen-presenting cells (APCs), particularly macrophages and dendritic cells, are targets of filovirus infection in vivo. Infection of these cell types has been proposed to contribute to the inflammation, activation of coagulation cascades and ineffective immune responses characteristic of filovirus hemorrhagic fever. However, many aspects of filovirus-APC interactions remain to be clarified. Among the unanswered questions: What determines the ability of filoviruses to replicate in different APC subsets? What are the cellular signaling pathways that sense infection and lead to production of copious quantities of cytokines, chemokines and tissue factor? What are the mechanisms by which innate antiviral responses are disabled by these viruses, and how may these mechanisms contribute to inadequate adaptive immunity? A better understanding of these issues will clarify the pathogenesis of filoviral hemorrhagic fever and provide new avenues for development of therapeutics.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Ebolavirus/fisiologia , Infecções por Filoviridae/imunologia , Febres Hemorrágicas Virais/imunologia , Marburgvirus/fisiologia , Animais , Células Apresentadoras de Antígenos/virologia , Citocinas/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/virologia , Febres Hemorrágicas Virais/virologia , Humanos , Marburgvirus/imunologia
17.
Viruses ; 3(7): 982-1000, 2011 07.
Artigo em Inglês | MEDLINE | ID: mdl-21994766

RESUMO

Filoviruses can cause severe, often fatal hemorrhagic fever in humans. Recent advances in vaccine and therapeutic drug development have provided encouraging data concerning treatment of these infections. However, relatively little is known about immune responses in fatal versus non-fatal filovirus infection. This review summarizes the published literature on correlates of immunity to filovirus infection, and highlights deficiencies in our knowledge on this topic. It is likely that there are several types of successful immune responses, depending on the type of filovirus, and the presence and timing of vaccination or drug treatment.


Assuntos
Infecções por Filoviridae/imunologia , Filoviridae/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
18.
Travel Med Infect Dis ; 9(3): 126-34, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21208830

RESUMO

Recent case reports of viral hemorrhagic fever in Europe and the United States have raised concerns about the possibility for increased importation of filoviruses to non-endemic areas. This emerging threat is concerning because of the increase in global air travel and the rise of tourism in central and eastern Africa and the greater dispersion of military troops to areas of infectious disease outbreaks. Marburg viruses (MARV) and Ebola viruses (EBOV) have been associated with outbreaks of severe hemorrhagic fever involving high mortality (25-90% case fatality rates). First recognized in 1967 and 1976 respectively, subtypes of MARV and EBOV are the only known viruses of the Filoviridae family, and are among the world's most virulent pathogens. This article focuses on information relevant for health care practitioners in travel medicine to include, the epidemiology and clinical features of filovirus infection and efforts toward development of a filovirus vaccine.


Assuntos
Doenças Transmissíveis Emergentes/imunologia , Doenças Transmissíveis Emergentes/virologia , Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/imunologia , Filoviridae/imunologia , Medicina de Viagem , Vacinas Virais/imunologia , Adulto , Animais , Antígenos Virais/imunologia , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/psicologia , Feminino , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Geografia , Humanos , Países Baixos/etnologia , Uganda , Estados Unidos/etnologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem
19.
Clin Vaccine Immunol ; 17(11): 1723-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20861331

RESUMO

Several enzyme-linked immunosorbent assays (ELISAs) for the detection of filovirus-specific antibodies have been developed. However, diagnostic methods to distinguish antibodies specific to the respective species of filoviruses, which provide the basis for serological classification, are not readily available. We established an ELISA using His-tagged secreted forms of the transmembrane glycoproteins (GPs) of five different Ebola virus (EBOV) species and one Marburg virus (MARV) strain as antigens for the detection of filovirus species-specific antibodies. The GP-based ELISA was evaluated by testing antisera collected from mice immunized with virus-like particles as well as from humans and nonhuman primates infected with EBOV or MARV. In our ELISA, little cross-reactivity of IgG antibodies was observed in most of the mouse antisera. Although sera and plasma from some patients and monkeys showed notable cross-reactivity with the GPs from multiple filovirus species, the highest reactions of IgG were uniformly detected against the GP antigen homologous to the virus species that infected individuals. We further confirmed that MARV-specific IgM antibodies were specifically detected in specimens collected from patients during the acute phase of infection. These results demonstrate the usefulness of our ELISA for diagnostics as well as ecological and serosurvey studies.


Assuntos
Anticorpos Antivirais/sangue , Antígenos Virais , Infecções por Filoviridae/diagnóstico , Infecções por Filoviridae/veterinária , Filoviridae/isolamento & purificação , Virologia/métodos , Animais , Antígenos Virais/genética , Reações Cruzadas , Ebolavirus/genética , Ebolavirus/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Haplorrinos , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Marburgvirus/genética , Marburgvirus/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Primatas , Proteínas Recombinantes/genética , Sensibilidade e Especificidade
20.
Nat Med ; 16(9): 991-4, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20729866

RESUMO

Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects>60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.


Assuntos
Infecções por Filoviridae/genética , Infecções por Filoviridae/prevenção & controle , Vacinas Sintéticas/uso terapêutico , Vacinas Virais/uso terapêutico , Animais , Ebolavirus/isolamento & purificação , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/mortalidade , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Macaca mulatta/imunologia , Doença do Vírus de Marburg/genética , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/prevenção & controle , Marburgvirus/isolamento & purificação , Primatas , Segurança
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