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Abstract The first cases of Ebola hemorrhagic fever were reported from Sudan and Zaire now Democratic Republic of the Congo in , but the virus has only received significant attention since Until recently, the development of therapeutics or vaccines was not considered a priority.
The knowledge gained during the past decade on the biology and pathogenesis of Ebola virus has led to the development of therapeutic strategies that are currently being investigated. Considering the aggressive nature of Ebola infections, in particular the rapid and overwhelming viral burdens, early diagnosis will play a significant role in determining the success of any intervention strategy.
Advanced understanding of the immune response has produced several vaccine candidates of which a few can be considered for further evaluation. This review will summarize and discuss the current therapeutic and prophylactic strategies for Ebola hemorrhagic fever. Updates in diagnosis and management of Ebola hemorrhagic fever.
Clinical characteristics of patients suspected of having Ebola virus disease in the Ebola holding center of Jui Government Hospital in Sierra Leone during the Ebola outbreak. Animal models for viral haemorrhagic fever. Ebola outbreak in Western Africa what is going on with Ebola virus? Therapeutics for filovirus infection: traditional approaches and progress towards in silico drug design. Similar Articles To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
Towards a vaccine against Ebola virus. Overview Fingerprint. Abstract The first cases of Ebola hemorrhagic fever were reported from Sudan and Zaire now Democratic Republic of the Congo in , but the virus has only received significant attention since Other files and links Link to publication in Scopus.
Link to citation list in Scopus. Fingerprint Dive into the research topics of 'Therapy and prophylaxis of Ebola virus infections'. Together they form a unique fingerprint. ZEBOV titration was performed by plaque assay on Vero E6 cells from all blood and selected organ adrenal, ovary, lymph nodes, liver, spleen, pancreas, lung, heart, brain and swab samples [ 23 ].
Briefly, increasing fold dilutions of the samples were adsorbed to Vero E6 monolayers in duplicate wells 0. Neutralization assays were performed by measuring plaque reduction in a constant virus:serum dilution format as previously described [ 9 , 26 ]. The mixture was used to inoculate Vero E6 cells for 60 min. Cells were overlayed with an agar medium, incubated for 8 d, and plaques were counted 48 h after neutral red staining. Peripheral blood mononuclear cells were isolated from rhesus macaque whole blood samples by separation over a Ficoll gradient.
Staining procedures were performed as previously described [ 27 ]. Animals were weighed every day and scored for clinical symptoms see Methods. Surprisingly, all treated mice survived independent of the time of treatment Figure 1 A. Those animals treated 24 h prior to challenge did not show any clinical symptoms, whereas animals treated post-challenge developed mild clinical symptoms.
With all protected groups, mild weight loss was observed during the first day post-challenge Figure S1 indicating virus replication prior to clearance and survival.
Next, we treated three groups of guinea pigs Hartley strain; six animals per group with i. Disease progression was followed and measured as described for the mice.
Unlike the mice, the treatment groups were not fully protected Figures 1 and S1. In all cases, the development of clinical symptoms, weight loss and time to death, were significantly delayed. All surviving animals lost weight and became sick with a degree of severity that correlated very well with disease outcome. Encouraged by the success in the rodent models, we treated eight rhesus monkeys subjects 1 to 8 with i.
The immunization and challenge doses were equivalent to what had been used in previous successful pre-exposure vaccine studies [ 6 , 9 ]. All animals became febrile by day 6 and haematology data indicated evidence of illness by day 6, usually manifested as lymphopenia, in most of these animals Table 1.
Pathology results showed that this macaque died from disseminated septicaemia and peritonitis caused by Streptococcus pneumoniae as demonstrated by immunohistochemistry unpublished data.
The source of the bacterial infection is unknown. In accordance with our previous results [ 9 , 10 ], VSV RNA was detected in most immunized animals only at day 3 post-immunization indicating transient viraemia of the vaccine vector. There was no correlation between VSV viraemia and survival. Viraemia was determined by plaque assay at indicated time points.
The asterisk indicates that on day 8 post-challenge viraemia levels were only determined for the control animals subjects c1 and c2. Subject 6 did not develop fulminant disease consistent with EBOV HF and succumbed on day 18 from a secondary bacterial infection. All four animals that survived the ZEBOV challenge subjects 1, 2, 5, and 7 , and the animal that survived until day 18 subject 6 , developed ZEBOV-specific humoral immune responses with low titre IgM antibodies detected on days 6—14 subjects 1, 5, and 7 Figure 3 A and moderate IgG antibody titres detected on days 10—22 subjects 1, 2, 5, 6, and 7 Figure 3 B.
Neutralizing antibody titres to ZEBOV were detected on days 14—37 after challenge in all four animals that survived the ZEBOV challenge subjects 1, 2, 5, and 7 and the animal that survived until day 18 subject 6 Figure 3 C. Humoral immune responses could not be detected in any of the non-survivors although these animals lived until day 9 and 10 post-challenge, which was sufficient to mount detectable IgM and IgG responses in the surviving animals.
Similarly, a marked increase in B cells was noted for all animals regardless of treatment or outcome on day 6, followed by a decline in B cell number on day Although no EBOV vaccine is currently licensed for human use, recent advances have been made and efficacy studies in nonhuman primates with several platforms have been encouraging [ 6 , 7 , 9 ].
Far less progress has been made in developing treatment interventions for EBOV infections [ 5 , 13 , 14 ]. Additionally, the potential EBOV exposure involving a researcher at a United States Army laboratory [ 16 ] and the unfortunate death of a Russian scientist after an accidental exposure to EBOV [ 15 ], underscore the need for medical countermeasures for post-exposure prophylaxis.
Here, we show a significant advance in treating EBOV infections. Our data clearly demonstrate the efficacy of the VSV-based EBOV vaccine vector in post-exposure treatment in three relevant animal models. In the mouse model it was possible to protect all animals following challenge with treatment as late as 24 h post infection. It is known from previous data that treatments and vaccines given to mice are more effective than seen in guinea pigs and nonhuman primates [ 1 , 2 , 13 ].
It should be noted that mice received about 10 or times more vaccine per weight than guinea pigs and nonhuman primates, respectively. Thus, it is possible that further optimization of dosing strategies could improve the results.
The rhesus macaques that survived infection all controlled the virus within the first 6 d of infection. The data clearly show that moderate or high-level viraemia on day 6 invariably resulted in a fatal outcome Figure 2. In the current study, we can conclude that neutralizing antibodies were not essential for infection control Figure 3 since they were not detected until after the animals had cleared the EBOV infection.
The primary immune correlate of protection seems to be the rapid development of non-neutralizing antibody that was only seen in the protected animals Figure 3.
An important role of NK cells for protection has also been described for immunization with virus-like particles [ 29 ]. However, other mechanisms probably contribute as well. Recently, Noble and colleagues described a new paradigm for an interfering vaccine in which one of the antiviral mechanisms of action is intracellular interference with the replication of the lethal wild-type virus [ 30 ].
Clearly, even mild to moderate inhibition of ZEBOV replication may delay the course of infection and tip the balance in the favor of the host. VSV has been shown to be a potent inducer of the innate and adaptive immune system [ 32 — 34 ].
In contrast, EBOV has acquired mechanisms to counteract the innate immune responses of the host at different levels [ 1 , 2 , 35 ]. Recently, it was suggested that VP24 blocks the downstream signaling cascades activated by type I interferon by inhibiting the phosphorylation of p38 [ 40 ]. Therefore, treatment with the VSV vectors might induce or boost the innate immune response in the host, and thus, counteract the immune inhibitory effect of EBOV. In this case, the host will mount a nonspecific innate immune response allowing for time to develop a specific adaptive response that can overcome the EBOV infection and again tip the balance in favor of survival of the host.
In a historical context, it is important to note that the mechanism for post-exposure protection of humans against smallpox and rabies are also not fully understood. For post-exposure treatment of rabies, levels of neutralizing antibodies have been used as a measure of protection. However, several studies of HIV-infected patients with likely or proven exposure to rabies showed that these patients failed to develop neutralizing antibodies after post-exposure rabies vaccination, yet there were no reports of death of these patients attributed to rabies [ 41 , 42 ].
Moreover, studies in mice suggest that cell-mediated immunity may play an essential role in post-exposure protection [ 43 ]. In the case of smallpox, post-exposure protection is presumed to be due in part to differences in the route of exposure and growth kinetics of the wild-type variola virus versus the vaccinia vaccine [ 20 ].
Briefly, infection with variola usually starts in the upper and lower respiratory tract with subsequent spread to lymphoid tissues.
Thus, the natural variola infection proceeds much slower than post-exposure i. In addition, it appears that vaccinia has a shorter incubation period than variola virus resulting in a more rapid development of cell-mediated immunity and neutralizing antibody.
However, a recent study using monkeypox in the macaque model demonstrated better results with antiviral therapy than post-exposure vaccination [ 44 ].
The efficacy of the VSV-based EBOV vector in post-exposure treatment might be increased by a higher treatment dose or multiple treatments over a longer period of time as is being done in post-exposure treatment of rabies [ 46 ]. Alternatively, combination therapy should be considered to increase therapeutic efficacy.
It is likely that the mechanism of protection by the VSV-based vaccine is multifactorial; while NK cells and antibody responses appear to be important to survival, viral interference and innate immune response are almost certainly essential in delaying the progression of the ZEBOV infection and extending the window for the adaptive response to become functional.
Post-exposure treatment is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate releases. Our results also suggest that this VSV platform might be even more beneficial as a fast-acting single-shot preventive vaccine.
Finally, this system also provides an excellent opportunity to study the fundamental mechanisms that lead to such devastating disease following infection with ZEBOV. We also thank Peter Jahrling for helpful discussions. We thank John Rose Yale University for kindly providing us with the vesicular stomatitis virus reverse genetics system.
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