Marburg Virus Vaccines Based upon Alphavirus Replicons Protect Guinea Pigs and Nonhuman Primates

Hevey, Michael; Negley, Diane L.; Pushko, Peter; Smith, Jonathan; Schmaljohn, Alan L.

doi:10.1006/viro.1998.9367

Cited by 250 publications

(230 citation statements)

References 19 publications

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“…Our finding that EBOV-specific immune sera alone is insufficient for protection is supported by previous studies in which high levels of neither total nor neutralizing Abs correlated with protection (13,15,16,19,28,39). In contrast, administration of monoclonal EBOV-specific Abs protected mice and guinea pigs from EBOV challenge (16,17).…”

Section: Discussionsupporting

confidence: 86%

“…Hence, at this time, there are no licensed vaccines, prophylactics, or treatments for filovirus infections in humans. Recently, several vaccine regimens have elicited protective immunity against filoviruses in nonhuman primates, although the correlates of immunity for these vaccine approaches are not fully characterized (13,14). Because human efficacy studies are not feasible for EBOV and MARV vaccine candidates, surrogate markers of immunity will have to be identified in animal studies.…”

mentioning

confidence: 99%

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Induction of Humoral and CD8+ T Cell Responses Are Required for Protection against Lethal Ebola Virus Infection

Warfield

Olinger

Deal

et al. 2005

The Journal of Immunology

127

142

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Ebola virus (EBOV)-like particles (eVLP), composed of the EBOV glycoprotein and matrix viral protein (VP)40 with a lipid membrane, are a highly efficacious method of immunization against EBOV infection. The exact requirements for immunity against EBOV infection are poorly defined at this time. The goal of this work was to determine the requirements for EBOV immunity following eVLP vaccination. Vaccination of BALB/c or C57BL/6 mice with eVLPs in conjunction with QS-21 adjuvant resulted in mixed IgG subclass responses, a Th1-like memory cytokine response, and protection from lethal EBOV challenge. Further, this vaccination schedule led to the generation of both CD4+ and CD8+ IFN-γ+ T cells recognizing specific peptides within glycoprotein and VP40. The transfer of both serum and splenocytes, but not serum or splenocytes alone, from eVLP-vaccinated mice conferred protection against lethal EBOV infection in these studies. B cells were required for eVLP-mediated immunity to EBOV because B cell-deficient mice vaccinated with eVLPs were not protected from lethal EBOV challenge. We also found that CD8+, but not CD4+, T cells are absolutely required for eVLP-mediated protection against EBOV infection. Further, eVLP-induced protective mechanisms were perforin-independent, but IFN-γ-dependent. Taken together, both EBOV-specific humoral and cytotoxic CD8+ T cell responses are critical to mediate protection against filoviruses following eVLP vaccination.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Induction of Humoral and CD8+ T Cell Responses Are Required for Protection against Lethal Ebola Virus Infection

Warfield

Olinger

Deal

et al. 2005

The Journal of Immunology

127

142

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“…Nearly all these vaccines use filovirus glycoprotein (GP) as the protective immunogen. These vaccines completely protected NHPs against lethal disease and are mostly replication-defective or replication-competent viral vectors, including alphavirus replicons 241,242 , human adenoviruses [243][244][245][246][247] , chimpanzee adenoviruses 248 , paramyxoviruses 249,250 , rabies viruses 251,252 and several different strategies with recombinant vesicular stomatitis viruses (rVSVs), including both the prototype rVSV vaccine [253][254][255][256][257] and a newer rVSV vaccine developed for enhanced safety (VesiculoVax) 258 . Virus-like particles [259][260][261] , a biologically contained EBOV lacking viral protein 30 (VP30) 262 , DNA 244 and several combinations of vaccines that include DNA, modified vaccinia Ankara (MVA) and various adenoviruses can also completely protect NHPs from lethal filovirus disease 244,248,263 .…”

Section: Box 2 | Vaccination To Prevent Filovirus Infectionmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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“…Significantly, this "variable" region of GP is highly immunogenic as determined in part by monoclonal antibodies obtained against MARV and EBOV GP [18][19][20]. GP from both MARV and EBOV have been implicated in the pathogenesis of these infections including an increase in vascular permeability [17,21].…”

Section: The Filoviridaementioning

confidence: 99%

“…The first approach to meet with success (defined as ≥80% protection) in protecting NHP against a filovirus made use of MARV VRP derived from Venezuelan equine encephalitis (VEE) virus [19]. Because VEE virus has a positive-sense RNA genome, full-length cDNA clones of VEE virus can be used to generate RNA transcripts that, when introduced into susceptible cells, will initiate a complete viral replication cycle and generate infectious virus [83].…”

Section: Virus-like Replicon Particles (Vrp)mentioning

confidence: 99%