Abstract

Modern human activity is profoundly and irreversibly changing our natural world.[1] In addition to the more publicized global warming and mass extinctions, human activity is altering our relationship with microorganisms to far-reaching effect.[2,3] The impact of this altered relationship can be seen by the startling rise in the rate of emerging infectious diseases (EIDs).[4] Increased global travel, agricultural expansion into wildlife habitats, deforestation and urbanization are all driving humans into greater and more intimate contact with animal populations, creating greater opportunity for human exposure to new microbes.[3–6] Although the particular animal species involved may never be known,[7] the 2014/2015 Ebola virus epidemic in West Africa shows that the global community remains ill-prepared for EIDs.[8,9] This lack of preparedness is multifactorial, but we suggest it includes the current risk adverse nature of scientific funding away from innovative and novel, ‘high-risk, high-reward’ science (i.e., science with a high risk of failure, but which is potentially transformative),[10] as well as insufficient allocation of resources toward the poorer countries that represent the most likely sites of future EIDs of global significance.[4] In the words of Albert Einstein quoted in the recent Advancing Research In Science and Engineering report that highlighted the worrying shift towards ‘low-risk’ science [10]:

If at first the idea is not absurd, then there is no hope for it.

Microbial movement into humans from animals (zoonotic transmission) has always been responsible for the majority of EIDs, including at one time EIDs that form such present day matrix diseases as malaria falciparum,[11] measles and TB.[12] For modern EIDs, it is estimated that over 70% of zoonotic pathogens originate in wildlife, entering either directly from wildlife reservoirs, or indirectly via an intermediate domestic animal host.[4,13] HIV, avian influenza, Hendra and Nipah viruses, SARS and MERS, and Ebola and Marburg filoviruses are all examples of zoonoses currently emerging from wildlife. All of these EIDs present a serious and increasing threat to health, biosecurity and economies worldwide. It is a sobering observation that most modern EIDs were entirely unknown before their entry into the human population. This pattern of emergence of new pathogens of global significance into humans from wildlife is expected to continue.

The task of identifying and preventing zoonoses is daunting, particularly given that the emerging pathogen may be completely unknown. The availability of limited resources and allocation of these resources over short-term funding periods further compounds the problem.[8,9] Recently, a landmark study from Daszak and colleagues examining conditions associated with emergence of >300 EIDs over the past 60 years highlighted the ineffectiveness with which resources for control of EIDs are being allocated.[4] Allowing for reporting bias, this study indicated that emergence of pathogens from wildlife, which represents the greatest threat to global health, is not uniform, but instead is localized to distinct geographic ‘hotspots’ in Africa, Asia and South America. These ‘high-risk’ EIDs were also shown to be biased toward a few ‘high-value’ wildlife species (bats, rodents and non-human primates (NHPs)). This realization that global resources need to be allocated toward countries that have the highest likelihood of high-risk EIDs [4] has led to the recent implementation of surveillance programs (e.g., USAID Emerging Pandemic Threats (EPT) program (superseded by EPT-2 in 2014)) targeting ‘high-value’ target wildlife species in ‘hotspot’ areas prone to EIDs. However, the recent 2014/2015 Ebola virus epidemic emphasizes the need for further investment in such EID surveillance and control programs.

Surveillance is only one component of a successful control program. Following identification, an emerging pathogen must then be controlled. For wildlife pathogens emerging through intermediate domestic animal host species, such as Nipah virus in swine or avian influenza in poultry, effective containment has been achieved either by mass vaccination using conventional vaccines, or by large-scale culling.[5,14] Although costly, the demonstrated ability to successfully contain these EIDs at source suggests the utility of these procedures for EID control in some domestic animals.[5] In contrast, restricted accessibility and idiosyncrasies of natural habitats present unique problems to the control of pathogens within wildlife species. For example, large-scale oral vaccination using vaccine-laden bait has been highly successful in eliminating rabies in wild fox populations in western Europe (for review, see [15]). Similarly, culling of European badgers to control the epizootic spread of Mycobacterium bovis to cattle has had some success in the control of bovine TB in Ireland and regions of the UK (for review, see [16]). However, the effectiveness of badger culling is variable and somewhat counterintuitively has also been associated with increased, rather than decreased, bovine TB incidence in some regions.[16] This unanticipated effect is believed to be due to the increased movement of surviving badgers following disruption of their social groups (perturbation effect) [16] – with levels of perturbation varying depending on landscape and intensity of culling. Culling of foxes to combat rabies prior to implementation of mass vaccination similarly led to an increased incidence of rabies in foxes.[15]

In non-temperate ‘hotspot’ regions of Africa, Asia and South America, the ability to contain even known EIDs such as Ebola virus in wildlife is currently not possible. Management of diseases that involve livestock in these regions, such as Rift Valley fever and Crimean Congo hemorrhagic fever, pose similar problems,[17,18] in that conventional vaccines are not suited for use in these environments. A major limitation of conventional vaccination is the requirement for individual inoculation of each animal (directly or via bait) for induction of immunity, which is costly and/or impractical for the target species most frequently involved in high-risk EIDs.[4] Combined with the anticipated intense competition for vaccine bait by non-target species, vaccine temperature lability issues [19] may also undermine the effectiveness of baiting strategies in hotspot regions – especially for far-ranging, low population density animals such as NHPs, which may take several days to come across the vaccine bait.

Self-disseminating vaccine vectors

Even with programs such as EPT, prediction of which animal pathogens will become established as globally significant EIDs within the human population still remains beyond our capability. However, pathogens emerging from an animal source are often initially poorly adapted to their new human host in terms of sustained human to human transmission.[20] Mechanisms involved in adaptation are unclear and will presumably be idiosyncratic to the particular emerging pathogen, but have been suggested to impart a requirement for repeated introductions into the human population before a successful adaptation event results in full human adaptation.[20] This requirement may provide a potential ‘window of opportunity’ for immunological targeting of the pathogen within the animal transmission species, thereby stemming its continued zoonotic flow prior to acquisition of full adaptation to humans. Self-disseminating vaccines are a vaccine strategy that may in some instances be better suited than conventional vaccines to immunologically contain emerging pathogens within their non-human host in challenging under-resourced ‘hotspots’. Disseminating vaccines are designed to exploit the ability of replicating virus-based vectors to spread through their animal host populations without the need for direct inoculation of every animal. In this strategy, vaccination of a limited number of ‘founder’ animals is used for initial introduction of the vaccine into the target population. As the vaccine is engineered to express target antigens from the EID pathogen of interest, its spread from vaccinated to non-vaccinated animals will result in coordinated spread of EID-specific immunity throughout the targeted animal population.

Expert commentary

It is becoming clear that the emerging pathogens which represent the greatest risk to global health will most likely be transmitted from a few key animal species in poorer areas of the world. Recent history also tells us that these pathogens will probably have never been seen before. The 2014/2015 Ebola virus outbreak shows the difference healthcare infrastructure can have on human-to-human transmission of EIDs. Until the time when overall healthcare infrastructure in all countries has been raised to a level that enables identification and control of high-risk EIDs at source, we as a global community will be fated to reactive responses to EID outbreaks. Innovative strategies are therefore urgently required to identify and then pre-emptively control EIDs in these under-resourced ‘hotspot’ regions. Self-disseminating vaccination is one innovative approach that may potentially overcome the problems associated with use of conventional vaccines for pre-emptive pathogen control in ‘high-value’ animal populations within these challenging environments. Although still in relatively early stages, the nascent field of self-disseminating transmissible vaccines has the potential to solve many current intractable public health and conservation problems that cannot be addressed by conventional vaccines (Table 1).

Five-year view

Identification of geographic ‘hotspots’ and ‘high-value’ wildlife species for EIDs is beginning to enable more informed decisions over allocation of finite resources to protect global health.[3,4] In recognition of the change in thinking, the USAID EPT programs in collaboration with multiple partners aims to ‘monitor for and increase the local capacity in “geographic hot spots” to identify the emergence of new infectious diseases in high-risk wildlife such as bats, rodents, and non-human primates’.[52] Identification of animal pathogens destined to become significant EIDs within the human population still remains beyond current technical capacity. However, the initial poor adaptation of many emerging zoonotic pathogens may provide a window of opportunity during the initial, stuttering transmission phase into humans enabling the nascent EID to be targeted within its animal host at a stage when it is still amenable to control. Following such pathogen identification, a self-disseminating vaccine platform provides one means to pre-emptively control the emerging pathogen. Adaptation of new technologies such as CRISPR/Cas9 will also greatly increase the ease and speed with which these new vaccine vectors can be constructed following identification of a target pathogen.[53] The next five years has the potential to place us in the position of being able to achieve high vaccine coverage against ‘nascent’ zoonotic pathogens in animal species involved in transmission that are otherwise inaccessible to conventional vaccination. For many ‘high-risk’ zoonotic pathogens, this reduction in zoonotic flow into the human population may decrease the probability of complete adaption to the human host with global significance.

Financial & competing interests disclosure

MA Jarvis and AA Murphy declare conflicts of interest: patents EP1766096B1, EP2497831B1 and application EP2772265A3 (MA Jarvis); and UK applications No. 1508136.7, No. 1514005.6 and No. 1514034.6 (MA Jarvis and AA Murphy). The authors would like to acknowledge support by the School of Biomedical and Healthcare Sciences, Plymouth University (MA Jarvis and AA Murphy), The Marie Skłodowska-Curie Programme (MA Jarvis) and The Institute for Immunology and Infectious Diseases, Murdoch University (AJ Redwood). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgement

Funding Statement

MA Jarvis and AA Murphy declare conflicts of interest: patents EP1766096B1, EP2497831B1 and application EP2772265A3 (MA Jarvis); and UK applications No. 1508136.7, No. 1514005.6 and No. 1514034.6 (MA Jarvis and AA Murphy). The authors would like to acknowledge support by the School of Biomedical and Healthcare Sciences, Plymouth University (MA Jarvis and AA Murphy), The Marie Skłodowska-Curie Programme (MA Jarvis) and The Institute for Immunology and Infectious Diseases, Murdoch University (AJ Redwood). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

References

** =landmark study showing that emergence of pathogens from wildlife representing the greatest threat to global health involves high-value animals localized to distinct geographic ‘hotspots’

** =extensive and informative review discussing characteristics and idiosyncracies of zoonotic pathogen emergence

** = first field trial conducted with a self- disseminating vaccine

* = study using a wild predator-prey system to assess primate CMV species restriction in nature

* = first demonstration that CMV-based vectors can provide protection against Ebola virus (in the mouse challenge model)

* = demonstrates HCMV superinfection is a relatively frequent occurrence in healthy humans

** = mechanistically defined the biology of superinfection in a primate CMV experimental system

* = first demonstration of natural transmission of laboratory manipulated tissue culture passaged primate CMV in an experimental model system