Preparations of formalin-fixed or heat-inactivated virions were used in the early attempts to develop a vaccine against EBOV, using guinea pigs and non-human primates as the animal models. Unfortunately, the level of protection that was achieved was inconsistent.
Guinea pigs were partially protected 70 and in one study, four out of five baboons survived challenge with EBOV after vaccination with an inactivated EBOV vaccine However, other studies indicated that inactivated EBOV did not induce sufficient immunity to protect hamadryl baboons reliably against a lethal challenge Recently, investigators have mainly concentrated on the use of subunit vaccines that are based on a single or combinations of virus-encoded structural proteins to induce protective immunity against challenge with EBOV.
Only EBOV GP is exposed on the cell surface of the virion and so seems to be the only target for neutralizing antibody. Replicon immunization results in the production of virus antigen by host cells, leading to antigen presentation by dendritic cells in the context of both MHC class I and class II molecules. This should lead to the development of both cytotoxic and helper T-cell responses, in addition to the production of antibody, but unfortunately these T-cell responses were not measured.
Once again, the antibody titres that were determined for the vaccinia virus constructs using enzyme-linked immunosorbent assay ELISA and PRNT 80 were low but, notably, T-cell proliferation and cytotoxic T lymphocyte CTL responses were not measured, resulting in the loss of relevant, and possibly crucial, immunological data.
EBOV GP DNA vaccination of guinea pigs resulted in variable protection, depending on the vaccine regimen, and premature sacrifice of the experimental animals makes interpretation of the challenge results problematic Immune serum from the guinea pigs did not inhibit the growth of EBOV in vitro , and there was no passive protection conferred to naive animals after the transfer of serum.
The most successful strategy so far involves using a DNA prime followed by an adenovirus boost The monkeys were challenged with six plaque-forming units of ZEBOV and all four animals survived after challenge.
Antibody responses, T-cell proliferation and CTL responses indicated that antibody and T memory helper cells are essential for the protection, and that cell-mediated immunity, although possibly important, is not an absolute requirement.
This is in agreement with observations that passive transfer of serum can be protective and might give some support to the concept of antibody therapy discussed earlier. The use of human adenoviruses as vaccine vectors is problematic because pre-existing immunity in the human population might eventually limit the efficacy of this approach.
However, a study by Sullivan and colleagues 76 shows the first successful protection of non-human primates against challenge with EBOV, although this has been achieved previously for MARV using a GP-based alphavirus-replicon vaccine The study gives us insights into the mechanisms and indicates that appropriate live vaccine vectors or replication-deficient vectors might ultimately provide a successful human vaccine.
If further enhancements in vaccine strategies are to be possible, the full spectrum of assays that are available to immunologists in the twenty-first century must be used in future vaccine studies. Particularly important would be the use of MHC class I tetramers to determine responses of CTLs to EBOV-encoded antigens, as well as the use of intracellular flow cytometry to determine cytokine responses to immunization and detailed study of the immunopathological responses to EBOV infection in unimmunized animals.
Finally, the recent development of EBOV-like particles 82 might provide an interesting delivery system for a protective host immune response that seems to depend on both the cell-mediated effector mechanisms and the humoral immune response 69 , Virus-like particles, which are generated by the expression of virus membrane proteins, might overcome the safety limitations that are associated with the use of attenuated filovirus particles or live vaccine vectors, as well as pre-existing immunity to vectors such as vaccinia or adenovirus.
The first cases of EBOV were reported from Sudan and Zaire in , but the virus has only received real attention from scientists since Until recently, vaccine development was not considered to be a priority and despite several promising results, vaccine development is still in the experimental stages. The process of moving an experimental vaccine candidate into clinical trials is time-consuming and expensive.
It has become clear that the rodent models mouse and guinea pig , although important for the development of antivirals, therapeutics and vaccines, are not necessarily predictive for the efficacy of the same agents in non-human primates, which are the gold standard for predicting efficacy in humans. At present, there is no convincing evidence for any successful strategy in post-exposure prophylaxis. So, therapeutic antibodies might be the most promising short-term strategy.
Despite some evidence for antibody-mediated enhancement of disease, therapeutic antibodies should be carried into the next stage involving the humanization of monoclonal antibodies, the production of human monoclonal antibodies and the evaluation of polyclonal and reconvalescent sera.
A major drawback in the process of developing counter measures against EBOV, other viral haemorrhagic fevers and related diseases is the biocontainment that is required for animal work with these agents. Building new facilities is one way to respond and the political support is guaranteed in crisis situations.
However, aside from maintaining facilities and long-term funding, the availability of well-trained personnel becomes a crucial issue. Filoviruses constitute a separate family in the order Mononegavirales. Filoviruses consist of a single, negative-stranded, linear RNA genome that is non-infectious and does not contain a poly A tail. After entry into the cytoplasm of host cells, it is transcribed to generate polyadenylated subgenomic messenger RNA species.
Transcription and translation leads to the synthesis of seven structural polypeptides with presumed identical functions for all of the different filoviruses. The three remaining structural proteins are associated with the membrane. GP is a type I transmembrane protein that forms the spikes on the virus particle. It is synthesized as a precursor preGP that is post-translationally cleaved by furin or a furin-like endoprotease into the disulphide-linked fragments GP1 and GP2.
The homotrimeric GP1—GP2 functions in receptor binding and fusion and is the target for the neutralizing host immune response. The structure and function of VP24 has not yet been studied. Ultrastructural studies indicate an association of virus particles with coated pits for the initiation of infection, indicating that filoviruses enter cells by receptor-mediated endocytosis.
GP mediates receptor binding and subsequent fusion. Uncoating is presumed to occur in a manner analogous to that of other negative sense RNA viruses. Transcription and genome replication take place in the cytoplasm and follow, in general, the models of Paramyxoviridae and Rhabdoviridae. Transcription starts at the conserved start site and polyadenylation occurs at a series of uridine residues in the stop site.
Replication involves the synthesis of a full-length positive-stranded copy. During infection, nucleocapsids accumulate intracellularly and form intracytoplasmic inclusion bodies. Virions are released by budding through the plasma membrane For further reading on the history, epidemiology, molecular biology and pathogenesis of filoviruses, we refer the reader to several review articles and books Refs 2 , 36 , 87 — World Health Organization.
Ebola haemorrhagic fever in Sudan, WHO 56 , — Pattyn, S. Google Scholar. Ebola haemorrhagic fever in Zaire, Siegert, R. Jahrling, P.
Preliminary report: isolation of Ebola virus from monkeys imported to USA. Lancet , — LeGuenno, B. Isolation and partial characterization of a new strain of Ebola virus. CAS Google Scholar. Walsh, P. Catastrophic ape decline in western equatorial Africa. Nature , — Borio, L. Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA , — PubMed Google Scholar. Volchkov, V.
Science , — Neumann, G. Reverse genetics demonstrates that proteolytic cleavage of the Ebola virus glycoprotein is not essential for replication in cell culture. Three of the four nucleocapsid proteins of Marburg virus, NP, VP35, and L, are sufficient to mediate replication and transcription of Marburg virus-specific monocistronic minigenomes. Comparison of the transcription and replication strategies of Marburg virus and Ebola virus by using artificial replication systems. Yang, Z. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury.
Nature Med. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Natl Acad. USA 95 , — Schnittler, H. Molecular pathogenesis of filovirus infections: role of macrophages and endothelial cells. Baskerville, A. Ultrastructural pathology of experimental Ebola haemorrhagic fever virus infection. Geisbert, T. Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States.
Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Feldmann, H. Ryabchikova, E. An analysis of features of pathogenesis in two animal models of Ebola virus infection.
Infection and activation of monocytes by Marburg and Ebola viruses. Baize, S. Defective humoral response and extensive intravascular apoptosis are associated with fatal outcome of Ebola virus-infected patients. Villinger, F. Leroy, E. Human asymptomatic Ebola infection and strong inflammatory response. Inflammatory responses in Ebola virus-infected patients.
Harcourt, B. Basler, C. USA 97 , — EVD most commonly affects people and nonhuman primates such as monkeys, gorillas, and chimpanzees. It is caused by an infection with a group of viruses within the genus Ebolavirus :. Reston virus can cause disease in nonhuman primates and pigs, but there have not been cases in people.
Bombali virus was first identified in bats in , and experts do not know yet if it causes disease in either animals or people. Ebola virus was first discovered in near the Ebola River in what is now the Democratic Republic of Congo.
Since then, the virus has been infecting people from time to time, leading to outbreaks in several African countries. Scientists do not know where Ebola virus comes from. Based on similar viruses, they believe EVD is animal-borne, with bats or nonhuman primates being the most likely source. In addition, the use of disposable equipment, such as needles, was introduced.
During the Kikwit, Zaire now DRC outbreak, the international public health community played a strong role, as it was now widely agreed that containment and control of Ebola virus were paramount in ending outbreaks. The local community was educated on how the disease spreads; the hospital was properly staffed and stocked with necessary equipment; and healthcare personnel was trained on disease reporting, patient case identification, and methods for reducing transmission in the healthcare setting.
In the Ebola outbreak in West Africa, healthcare workers represented only 3. Direct contact with the bodies of those who died from EVD proved to be one of the most dangerous — and effective — methods of transmission. Changes in behaviors related to mourning and burial, along with the adoption of safe burial practices, were critical in controlling that epidemic. The Pathogenesis of Ebola Virus Disease.
The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses external icon. Nature Microbiology. Clinical Excellence for Nurse Practitioners. Vol 2. Accessed June 20, This year Ebola outbreaks have been declared in the Democratic Republic of the Congo and Guinea, but it is the first time an outbreak has occurred in a large capital city such as Abidjan since the West Ebola outbreak.
The country is one of the six that WHO has supported recently to beef up their Ebola readiness and this quick diagnosis shows preparedness is paying off. WHO is helping to coordinate cross-border Ebola response activities and Ebola vaccines doses which the organization helped secure to fight the outbreak in Guinea are now being transferred to Cote d'Ivoire, following an agreement between the ministries of health of Cote d'Ivoire and Guinea.
An aircraft is departing Abidjan soon to collect the vaccines which will be used to vaccinate people at high risk, including health workers, first responders and contacts of confirmed cases.
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