As the human population expands into previously untouched environments there are increasing reports of viruses that have co-existed for long periods of time in their reservoir hosts ‘spilling over’ to emerge as novel human infections. The recent example of such an agent, human immunodeficiency virus (HIV), demonstrates the devastating economic and social impact that these events may have on human populations. Although the virus was not identified until 1981, HIV is thought to have made the initial jump from chimpanzees into humans at the beginning of the 20th century. By 2010, 34 million people were living with acquired immunodeficiency syndrome (AIDS) and in the same year 2.4-2.9 million people were newly infected with HIV. HeV and NiV were also discovered relatively recently – HeV was isolated and identified in 1994 when it caused the death of 20 horses and 1 human  and NiV in 1998–9 after an outbreak in pigs and humans in Peninsular Malaysia and Singapore . They were identified as paramyxoviruses but were sufficiently distinct to be assigned to a new genus, Henipavirus, within the Paramyxoviridae[25, 26]. Their large genome was atypical as was their pathogenicity for a range of species, with reported mortality rates in humans of up to 100% for NiV and 57% for HeV. All human cases of HeV infection to date have resulted from close contact with secretions of infected horses either late in incubation period, during terminal illness, or at post mortem examination. There is no known instance of transmission directly to humans from the reservoir host, the bat, or of human-to-human transmission of HeV. In contrast, NiV in Bangladesh can be transmitted directly from bats to people and this has been linked epidemiologically to the consumption of contaminated palm sap; human-to-human transmission also occurs here and is thought to be facilitated by families nursing sick relatives with attendant copious exposure to infected bodily fluids . Repeated spillover events into human (and other animal populations) have been documented for both HeV and NiV  suggesting persistence of the environmental circumstances that facilitated the initial emergence event. Spillover is thus likely to be ongoing, and it is conceivable that a future incident with increasing host adaptation might result in establishment of HeV or NiV in human populations, with an impact exacerbated by high mortality rates and no pre-existing immunity.
The sporadic occurrence of viral spillover events creates major challenges for emergency disease preparedness activities. However, in the 15–20 years since HeV and NiV were first identified substantial progress has been made in the development of vaccines and therapeutics for the prevention and treatment of infection with these viruses. The HeVsG vaccine, which prevents HeV disease in horses, is the first to be registered for use against a BSL-4 agent, and a therapeutic monoclonal antibody is currently being assessed for human use [23, 28]. While the focus in Australia is on management of the infection risks posed by HeV infection, studies have shown that the HeVsG vaccine provides equally powerful cross-protection against NiV infection in cats and nonhuman primates.
Our current studies indicate that at the time of onset of protection the HeVsG vaccine can reliably protect ferrets from acute NiV disease and also prevent infection – providing so-called sterilizing immunity - consistent with earlier studies using HeV . Here we have also shown, in the first duration of protection study in an animal model, protection from disease persists at least 14 months after vaccination in ferrets. Recovery of viral genome (but not live virus) from the nasal washes of one animal and from the bronchial lymph nodes of another, in the absence of a rise in antibody titre, are consistent with self-limiting local virus replication at a level insufficient to generate an anamnestic immune response or to sustain a transmission event.
The animal numbers reported here are necessarily small due partly to the limitations of the BSL4 facility but also because 3 ferrets were euthanized before challenge leaving 3 groups in the 2 studies with a group size of 1. While no conclusion can be drawn from a group size of 1 there were 3 remaining groups where n = 2, the 20 μg group in both studies and the 4 μg group in study 2. Data from these groups indicated that the vaccine induced protection sufficient to suppress the course of a human pandemic persists for at least 12 months. The data from the reduced groups also support this conclusion.
Importantly, in the event of a spillover leading to sustained human-to-human transmission of HeV or NiV, proof of concept studies already exist for the sG subunit vaccine in two animal models of which one is a non-human primate. This is relevant to the US FDA animal rule that states where a medical countermeasure cannot be evaluated in humans, in vivo evaluation of a vaccine or therapeutic may be translated from the outcomes of work in two animal models. Finally, the experimental vaccine given to ferrets uses a formulation that is in clinical trials in humans.
Recrudescence in the form of encephalitis has been documented for both HeV and NiV and is thought to be due to persistence of the virus in some form within the central nervous system. A farmer from Mackay, Australia developed encephalitis 13 months after apparent recovery from acute meningencephalitis caused by HeV and died with evidence of HeV in the brain as detected by PCR, electron microscopy and immunohistochemistry . In the initial NiV outbreak in Malaysia 7.5% of survivors went on to develop relapsing encephalitis and 3.4% suffered late-onset encephalitis months to years after recovery from the initial infection [30, 31]. Recent studies have shown that HeV can infect the mouse brain via an anterograde route of infection, probably along the olfactory nerve  as also suggested for NiV in pigs . This suggests that an effective henipavirus vaccine will need to suppress the initial phase of replication in the upper respiratory tract (summarized in ) to a level that prevents infection of olfactory sensory neurons as well as preventing the onset of viremia.
The HeVsG subunit vaccine has proved highly effective in suppression of virus replication and disease prevention, with duration of protection that is sufficient to make the formulation attractive to industry. A vaccine incorporating the HeVsG antigen has now been released for use in horses and its application and observed effectiveness, along with ongoing work in animal models including nonhuman primates, will enable a more rapid response to any future henipavirus spillover events that threaten to cause large scale outbreaks in humans.