Ebola virus outbreaks are sporadic in nature, and compared to other infectious diseases, have only a limited impact on public health in terms of case numbers and fatalities. However, outbreaks of Ebola virus disease often result in closure of affected health facilities and the death of health care providing staff, thus causing a much higher impact on public health than is apparent based on case numbers alone. Also, ebolaviruses are perceived by the public as a considerable threat, and are classified as potential bioterrorism agents. These properties of Ebola virus create particular requirements for an Ebola virus vaccine.
Conventional inactivated vaccines have been generated through inactivation of Ebola virus (EBOV) by heat, formalin, or γ-irradiation. Several conventional vaccine candidates were not effective at stimulating protective immune responses. Later attempts at using inactivated virus for vaccination utilized irradiated ZEBOV, which was 100% protective in a nearly 100% lethal mouse model of infection after two vaccinations if formulated together with liposomes and given intravenously. Protection in non-human primates (NHPs) against EBOV was not observed following vaccination with inactivated virus, with or without liposome or adjuvant.
Ebola virus (EBOV) genes inserted into a DNA plasmid can be injected directly into a patient's muscle, where expression of the antigen can elicit an immune response to the corresponding virus par -ticle. The use of DNA vaccines can be advantageous as they can lead to the generation of antibody and cytotoxic T lymphocytes. Several ZEBOV-specific mouse cytotoxic T lymphocyte epitopes have been identified from the amino acid sequence of the EBOV proteins NP, VP35, VP40, GP, VP30 and VP24. DNA vaccines expressing EBOV antigens GP, NP, VP40 or VP35 alone or in combination have been evaluated in mice, guinea pigs and NHPs. Full protection was reported in mice and later in guinea pigs with optimized strategies. In studies using EBOV DNA vaccines, consistently low survival rates have been documented for NHPs
VLP vaccines, unlike viral vaccines inactivated by heat, chemical or γ-irradiation, can present filoviral antigens in a presumably native form. EBOV-like particles have been examined as poten -tial vaccine candidates and can be generated by the expression of VP40 alone or along with GP. While these surface proteins assemble much like infectious EBOV particles, VLPs lack NP, VP35, VP30, VP24 and L proteins. The EBOV RNA genome is also absent and the particle is therefore non-infectious. Mice vaccinated with VLPs expressing Zaire Ebola Virus (ZEBOV) VP40 and ZEBOV GP followed by either two booster injections, or one booster with QS-21 adjuvant, resulted in complete protec -tion from a challenge with a lethal dose of mouse-adapted Zaire Ebola Virus (ZEBOV).
Viruses can be used as vaccine vectors when genes encoding antigens of Ebola virus are inserted and expressed from the viral carrier. Viral vectors can be replication competent or defective. While replication competent vectors generally elicit strong and long-lasting immune responses following immunization, these platforms may not be recommended for use in immunocom -promised individuals. Defective viral vectors, while potentially safer, may require multiple doses to achieve optimal immunity.