Ebola and Marburg virus are filoviruses that cause outbreaks of highly lethal haemorrhagic fever. Mortality rates in these diseases average more than 50%, with the highest recorded rates seen for Ebola Zaire virus (88%) and Marburg Angola virus (90%). Infection with these filoviruses produces a very high fever followed by interference with blood coagulation and vascular permeability, causing internal bleeding, bruising and skin rashes. After an asymptomatic incubation period, which can last days to weeks, symptoms of a typical filovirus infection emerge; headache, nausea, fever and malaise followed by more serious haemorrhagic symptoms and, in fatal cases, death results from multi-organ failure owing to shock.
Present treatments for filovirus infection are palliative, and consist primarily of supportive care, including hydration and pain management. There is no effective treatment or cure for these diseases. Therefore, vaccine development is crucially important as a strategy for fighting filovirus outbreaks. However, vaccine efficacy testing for Ebola virus is very difficult. There is no readily identifiable high-risk human population that can be targeted for a placebo-controlled clinical trials because disease outbreaks are unpredictable and sporadic, both geographically and temporally. Normally, clinical trials of medicines and vaccines intended for human use follow a lengthy but predictable sequence of safety and efficacy testing.
Because of its sporadic nature, the incidence of Ebola virus infection in human populations is not predictable and does not allow for adequate testing. Moreover, the immune correlates of protection from filovirus disease in humans remain unknown and therefore cannot be used to assess candidate vaccine efficacy. To facilitate the licensing of medicines when efficacy cannot be evaluated in the setting of natural infection, the U.S. Food and Drug Administration (FDA) introduced a new regulation in 2002 as an alternative licensing pathway for pharmaceutical products that target highly lethal pathogens. The FDA’s “animal rule” allows approval based on animal efficacy data. The animal rule is intended to be used as a pathway for regulatory approval only when there is no other way to licence a vaccine (Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. 2009 Nature Reviews Microbiology 7: 393-400).
In the case of Ebola virus, the relevant animal models are non-human primates and mice. The immune correlates of Ebola virus infection consist of immunoglobulin G responses, although other factors, such as T cells, are also likely to be important in a successful immune response. Current vaccine candidates against Ebola virus include the virus glycoprotein and nucleocapsid proteins. Initial animal testing of Ebola vaccines has shown a protective effect in non-human primates and positive antibody titres in humans.
To date, no vaccines have received regulatory approval and been licensed using the FDA animal rule. This pathway does not diminish the level of regulatory contol required for vaccine approval; extensive human testing is still required to demonstrate safety and immunogenicity. The predictive relationship between animals and humans for protective efficacy is unknown, and therefore an immune correlate is used to bridge the gap between animal efficacy studies and human immunogenicity trials. It has not yet been determined what level of efficacy in animals will be required for vaccine approval, but other vaccines currently administered to the U.S. population have shown efficacies in human trials that are as low as 18%. Even this level of efficacy will provide a benefit against pathogens such as filoviruses with high mortality rates, and therefore may be acceptable against emerging natural infections or bioterrorism threats.
- Congo confirms Ebola outbreak
- New species of Ebola virus discovered
- Marburg haemorrhagic fever in Uganda
- Deadly Marburg virus linked to fruit bat