Ebola therapeutics from China, Canada, Germany, US: promising but without human testing for Ebola, though the last article suggests already-licensed drugs may be useful

Virus Res. 2014 Jun 12;189C:254-261. doi: 10.1016/j.virusres.2014.06.001. 

A highly immunogenic fragment derived from Zaire Ebola virus glycoprotein elicits effective neutralizing antibody. 

Wang Y1, Liu Z1, Dai Q2.

In order to produce polyvalent vaccines based on single rVSV vector, we investigated the immunogenicity, antibody neutralizing activity, and antigenic determinant domain of Zaire Ebola's fragment MFL (aa 393-556) that contains furin site and internal fusion loop. Both the recombinant protein and the recombinant plasmid of fragment MFL elicited high levels of antibody, similar to those of Zaire Ebola GP (ZGP). The MFL fragment of ZGP also elicited high levels of neutralizing antibody and induced moderate cellular immune response in mice, as revealed by the proliferation and cytokine secretion of splenocytes. Through the analysis of the induction of neutralizing antibody by pVAX1-based recombinant plasmids that expressed truncated fragments of MFL, we found that the domain containing the internal fusion loop and the furin site was the major contributor of fragment MFL's immunogenicity. Furthermore, the rVSV-based bivalent vaccine expressing Sudan Ebola GP (SGP) and MFL fragment elicited efficient cross-immunity against ZGP and SGP with high levels of neutralizing antibody. Our results indicate that fragment MFL is an effective and novel antigen for the production of neutralizing antibody and polyvalent vaccines of Ebola virus.

Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8873-6. doi: 10.1073/pnas.1316902111. 

Vaccinating captive chimpanzees to savewild chimpanzees.

Warfield KL1, Goetzmann JE2, Biggins JE3, Kasda MB3, Unfer RC1, Vu H1, Aman MJ1, Olinger GG Jr3, Walsh PD4.

Infectious disease has only recently been recognized as a major threat to the survival of Endangered chimpanzees and Critically Endangered gorillas in the wild. One potentially powerful tool, vaccination, has not been deployed in fighting this disease threat, in good part because of fears about vaccine safety. Here we report on what is, to our knowledge, the first trial in which captive chimpanzees were used to test a vaccine intended for use on wild apes rather than humans. We tested a virus-like particle vaccine against Ebola virus, a leading source of death in wild gorillas and chimpanzees. The vaccine was safe and immunogenic. Captive trials of other vaccines and of methods for vaccine delivery hold great potential as weapons in the fight against wild ape extinction.

Antiviral Res. 2014 Jul;107:102-9. doi: 10.1016/j.antiviral.2014.04.014. Epub 2014 May 9. 

Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells.

Johnson JC1, Martinez O2, Honko AN1, Hensley LE1, Olinger GG1, Basler CF3.

Antigen presenting cells (APCs), including macrophages and dendritic cells, are early and sustained targets ofEbola virus (EBOV) infection in vivo. Because EBOV activates mitogen-activated protein kinase (MAPK) signaling upon infection of APCs, we evaluated the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV infection of human APCs and EBOV mediated cytokine production from human DCs. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated macrophage-like human THP-1 cells with an IC50 of 4.73μM (SB202190), 8.26μM (p38kinhIII) and 8.21μM (SB203580) and primary human monocyte-derived dendritic cells (MDDCs) with an IC50 of 2.67μM (SB202190). Furthermore, cytokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. A control pyridinyl imidazole compound failed to inhibit either EBOV infection or cytokine induction. Using an established EBOV virus-like particle (VLP) entry assay, we demonstrate that inhibitor pretreatment blocked VLP entry suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, our results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as leads for the development of therapeutics to treat EBOV infection.

Trends Microbiol. 2014 Aug;22(8):456-463. doi: 10.1016/j.tim.2014.04.002. Epub 2014 Apr 30. 

Post-exposure therapy of filovirus infections.

Filovirus infections cause fatal hemorrhagic fever characterized by the initial onset of general symptoms before rapid progression to severe disease; the most virulent species can cause death to susceptible hosts within 10 days after the appearance of symptoms. Before the advent of monoclonal antibody (mAb) therapy, infection of nonhuman primates (NHPs) with the most virulent filovirus species was fatal if interventions were not administered within minutes. A novel nucleoside analogue, BCX4430, has since been shown to also demonstrate protective efficacy with a delayed treatment start. This review summarizes and evaluates the potential of current experimental candidates for treating filovirus disease with regard to their feasibility and use in the clinic, and assesses the most promising strategies towards the future development of a pan-filovirus medical countermeasure.

J Antimicrob Chemother. 2014 Aug;69(8):2123-31. doi: 10.1093/jac/dku091. Epub 2014 Apr 7.

The clinically approved drugs amiodarone, dronedarone andverapamil inhibit filovirus cell entry.

Gehring G1, Rohrmann K2, Atenchong N1, Mittler E3, Becker S3, Dahlmann F4, Pöhlmann S4, Vondran FW5, David S6, Manns MP7, Ciesek S7, von Hahn T8.

Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors, we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties.

METHODS:

We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds.

RESULTS:

We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during anti-arrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant.

CONCLUSIONS:

The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.