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An evidence-based norm collectively established and reinforced through the work of generations of virologists is that laboratory modifications of self-spreading viruses are genetically too unstable to be used safely and predictably outside contained facilities. That norm now seems to be challenged. A range of transformational self-spreading applications have been put forward in recent years. In agriculture, for example, self-spreading viruses have been proposed as insecticides, or as vectors to modify planted crops. In health care, self-spreading viruses have been promoted as vaccines (1, 2). Yet, glossed over by these proposals is that the self-spreading dynamics of a virus repeatedly passing from host-to-host (passaging) give it substantial potential to alter its biological properties once released into the environment (see the box). We explore the consequences of this apparent norm erosion in the context of recent proposals to develop self-spreading genetically modified viruses, in wildlife management and in self-spreading vaccines.
Wildlife control using self-spreading viruses is not a new idea. In the late 1980s, Australian researchers started to develop multiple approaches to sterilize or kill pest wildlife (foxes, mice, and rabbits) using self-spreading viruses (3). A decade later, Spanish researchers began limited field-testing of self-spreading viruses for the opposite purpose: to protect native wild rabbits (4). Concerns about self-spreading viruses were apparent from the inception of these programs and were exacerbated by the unrelated escape of a rabbit hemorrhagic disease virus from a limited field trial at an Australian high-security island laboratory. The accidental release was followed by widespread irreversible transmission within Australia and subsequent illegal international transportation to New Zealand (5). By 2007, funding for the Australian research had ceased and, despite approximately 15 years of work, no applications for field trials were ever made to Australian regulators. The Spanish efforts to license their self-spreading rabbit vaccine with the European Medical Agency also ceased. As part of a special issue of Wildlife Research that represented a self-written requiem to the Australian efforts, an article concluded:
“It is clear that a single unwanted introduction of a GM [genetically modified viral] biocontrol agent could have serious consequences. Once a persisting transmissible GMO is released (whether intentionally, legally, or otherwise), it is unlikely that it could be completely removed from the environment. The scientific community involved in developing GM biocontrols therefore needs to demonstrate a highly precautionary attitude. Scientists also have an ethical responsibility to consider the full implications of the solutions they are researching: they must be seen to be acting openly, collaboratively and responsibly” (6, p. 583).
Indeed, as far back as 1993 both the World Organization for Animal Health (OIE) and the World Health Organization (WHO) expressed explicit concern at using self-spreading agents for wildlife management. Many regulatory issues arising from self-spreading approaches are widely acknowledged to have remained unresolved—such as who is responsible, or liable, if self-spreading viruses don’t behave as expected or cross national borders (3)?

Suppressed Viral Evolution and Predetermined Lifetimes

In 2016, interest in self-spreading vaccines reignited. Proposals seem to have been largely motivated by wildlife immunization (1, 2, 79), but a whole range of applications have been proposed (8). Agencies funding projects that incorporate or focus on such approaches include the European Union (EU) through its Horizon 2020 program, the US National Institutes of Health, and the US Defense Advanced Research Projects Agency (10). This time, proposals were accompanied by repeated assertions from funders and scientists that approaches exist that enable suppression of viral evolution and that “researchers can fine-tune vaccines to have predetermined lifetimes, which could eliminate concerns over unwanted mutations or ongoing evolution of the vaccine organism” (7). It is hypothesized that this could be achieved by long-established laboratory manipulations of viral genomes, namely, synonymous codon replacement, genome rearrangement, and deletions (11). However, it remains to be experimentally tested if any combinations of these manipulations could simultaneously limit viral transmissibility to the extent that they could be perceived as controllable while maintaining sufficient transmissibility to be considered useful as vaccines in continually dynamic environments.
One of the purported uses of lab-modified self-spreading viruses is as wildlife vaccines to limit the risk of spillover events generating previously undescribed human pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Though an outwardly attractive application, there are notable hurdles that have been glossed over. First, the vast majority of virus species that currently exist are undescribed by science (12). This makes it very difficult to imagine how the considerable effort necessary to develop and test self-spreading vaccines could identify and then prioritize single viral species circulating in wildlife.
Second, the dynamic nature of mutation and recombination events in wild global viromes, which are speculated to play a defining role in many spillover events, makes it extraordinarily difficult to mitigate spillover risk using wildlife vaccines. Although a massive increase in viral monitoring in wildlife might in some theoretical circumstances provide a time-limited degree of insight upon which to base preemptive vaccine design, it could only have a very indirect impact on prioritizing what genetic event, in which wildlife species, and at what location might present a substantive risk for the emergence of a new virus.
In addition, the extraordinary practical complexity of wildlife vaccination, particularly in terms of sustaining and monitoring the immune response in wildlife populations, has not been explicitly addressed by funders or scientists promoting self-spreading vaccines (13). The combination of these concerns in the context of emerging new viral pathogens has led most virologists to consistently advocate for surveillance at the human–animal interface particularly in regions of ecological disturbance, rather than the riskier mass prospective development of self-spreading vaccines (8).
A more extreme application touted is the use of self-spreading viruses in human vaccination (8). This is often paired with an acknowledgment that use in humans would likely come with insurmountable ethical and safety concerns, as well as public outcry (1, 2). From a security perspective, it is important to note that, with the exception of heightened safety standards, it is broadly true that whatever self-spreading vaccines could be developed for wildlife could be more easily generated, from a technical perspective, for humans. This is because monitoring populations for levels of immunity and viral evolution is much easier in humans than in wildlife, and critically, the hurdles outlined above would not apply in quite the same way, as by definition, the target virus will be well known to science.
Theoretical claims of suppressed viral evolution and their assumed predetermined lifetimes in the environment currently remain peripheral within the scientific community. However, this seems paradoxical if the accumulating collection of more than 15 publications over the past 5 years does indeed outline a genuinely innovative path to safely achieving and maintaining high levels of immunity, using a fraction of the resources and time that conventional vaccination programs require. Why would recognition of this (re)emerging field be so low, if there is even a remote possibility of the promoted thoroughly transformational goals being realized?
One reason might be that experts from across relevant disciplines will view claims of suppressing viral evolution, or sustainably fine-tuning transmissibility in complex, dynamic environments, with a high degree of informed skepticism. Alternatively, perhaps they may see nothing genuinely new in the claims because it has been technically possible to generate such vaccines for decades (4). Indeed, the pervasive challenge had always been to minimize or eliminate transmission of human vaccines based on live viruses between individuals. This is for reasons of safety and ethics (e.g., the infection of immunocompromised individuals or nursing infants), but also for practical considerations (e.g., retaining the capacity to suspend or geographically restrict trials). It has been argued that existing live poliovirus vaccines are “self-spreaders” (2, 11). Although they are not self-spreading vaccines as the term is used here (see the box), the vaccine-associated paralytic poliomyelitis (caused by uncontrolled community transmission of Sabin type 2 polio vaccine) does present an object lesson in the risk of transmissibility. An ongoing example of efforts to further minimize the impact of unwanted transmission is the early-stage development of a Sabin type 2 polio vaccine strain that aims to limit back-mutation to virulence (14).

What are self-spreading viruses?

To date, proposed modified self-spreading viral approaches can usefully be placed in one of three types:
Experimental approaches to kill or sterilize mammalian wildlife or pests as a means to reduce their population sizes, also called wildlife management (3).
Experimental approaches to vaccinate mammalian wildlife to protect them from disease (4, 15) or to limit their capacity to act as reservoirs for vectored diseases (1, 2).
Speculations about applications in humans as vaccines (1, 2, 8).
The terms “self-spreading,” “transmissible,” “self-disseminating,” “contagious,” and “horizontally transferable” have all been used interchangeably to describe artificially modified viruses developed for applied uses that intentionally retain the capacity to transmit between individual hosts upon their release into the environment. Here we adopt the term “self-spreading virus,” defined as satisfying both of the following criteria:
Intentionally developed to be transmissible between individual hosts in the environment, where safety testing, efficacy testing, and regulatory approval incorporate the numerous consequences arising from this property.
Possessing deployment strategies that fundamentally rely upon transmission between individual hosts for their successful application (see the figure).
Viral transmissibility between individual hosts is in almost all circumstances dynamic, particularly in complex environments. For example, coinfection of wild-type and genetically modified released viruses has the capacity to enhance transmission rates of the latter through viral complementation. Furthermore, spontaneous recombination has the potential to alter the transmissibility of parts or all of the released viral genomes. In some recent publications the vague concept of “transferable vaccines” has been introduced (9), which are proposed to be in some respects intermediate between conventional and self-spreading vaccines. However, it is unclear to us if their hypothecated existence has any basis in fact, and as such their consideration is potentially unhelpful.
Currently, none of the licensed genetically modified viruses for use in the environment are transmissible, including the various widely applied oral-bait rabies vaccines for wildlife.
Self-spreading vaccine research continues to proceed despite a lack of new information that would compellingly refute long-standing evidence-based norms in virology, evolutionary biology, vaccine development, international law, public health, risk assessment, and other disciplines. Providing such evidence, along with anticipated benefits, possible harms and risks, and appropriate precautionary measures, should have been considered a critical first step in undertaking self-spreading vaccine research. Furthermore, there are currently no fully, or even partially, articulated proposals for regulatory pathways that could establish self-spreading vaccines as not only safe, effective, and useful but also, crucially, as the patchy uptake of COVID-19 vaccines has shown, publicly trusted.
And if, as claimed, self-spreading vaccines do indeed represent a flexible and transformational technology in areas as diverse as conservation, human health, and agriculture, then additional justification is needed for why efforts would not be exclusively focused on addressing pressing needs in the countries funding or developing these approaches. This was the case for the earlier Australian and Spanish efforts and remains so for ongoing EU-funded efforts to address African swine fever (7, 15). But one self-spreading vaccine development program—to prevent Lassa virus transmission to humans in West Africa—is focused on Mastomys rats, which are only distributed in sub-Saharan Africa (10), and motivations for other studies also imply target areas outside North America, where most of this research is currently taking place.
Potential for repurposing these technologies is also a concern, where adversaries could, for instance, deliberately use self-spreading viruses, or vaccines, to cause harm. This, too, needs to be addressed by those pushing self-spreading vaccine development.
Deployment strategies for self-spreading vaccines
At time T1, four members of a hypothetical population are directly vaccinated by injection (purple circles). Only with a self-spreading vaccine will immunity potentially expand to those not directly vaccinated (blue circles, teal circles). Transmission of the self-spreading vaccine occurs spatially (top) and temporally (bottom, to subsequent generations not shown). The self-spreading vaccine provides some outwardly attractive opportunities if there is a need for rapid vaccination of whole populations or difficulties in accessing individuals (this relies on the rather unrealistic assumption that all individuals in the population remain naïve to infection by the self-spreading vaccine).
GRAPHIC: K. FRANKLIN/SCIENCE, BASED ON LENTZOS ET AL.
The technologies available to the Australian and Spanish researchers’ decades ago were sufficient to develop multiple candidates, one of which progressed to field trials and a licensing application (4). Molecular biology tools have advanced since then, and arguably, little to no technological development is necessary to produce self-spreading viral vaccines today. Without open and inclusive engagement about potential benefits, risks, and appropriate precautionary measures from the scientific and international communities, self-spreading viruses for environmental release could arguably be developed very quickly, with limited funding or expertise and with potentially irreversible consequences for the planet’s biodiversity, ecosystems, and environments. With only modest technological innovation required, typical risk mitigation measures, such as increased education of scientists or the creation of new international forums to address governance, are likely to prove too slow to have a constructive impact. It is notable that the time between the very first peer-reviewed description of the Spanish self-spreading rabbit vaccine and the submission for publication of the results of a successful field trial (4) was just 12 months.

Urgent Next Steps

Although earlier work on self-spreading vaccines coincided with, or was preceded by, regulatory engagement in multiple international forums, like the OIE, WHO, the International Plant Protection Convention (IPPC), and the Convention on Biodiversity (CBD), current developments appear to be taking place without similar international efforts. The previous regulatory discussions ultimately concluded without resolving key safety and regulatory questions (3, 6), but there was a clear consensus that, given the near inevitability of transboundary movement, the appropriate forums to consult were international ones.
A clear priority for the international community must be to update existing phytosanitary, medical, and veterinary regulations to reflect contemporary societal values for responsible stewardship of science—and specifically with respect to environmental releases of self-spreading viruses. Key principles that should be endorsed and actively promoted include safety, intergenerational justice, accountability, and public engagement. Immediate opportunities are the CBD Conference of the Parties (COP) and the meeting of its Subsidiary Body on Scientific, Technical, and Technological Advice (SBSTTA) in spring 2022. Each provides a chance to build on earlier CBD work (3).
Additional steps would be to establish and implement a robust horizon-scanning process and to develop a global consensus on the criteria for safe, secure, and responsible research and the evidence needed to meet those criteria.
Echoing international efforts, national governments should clarify and, if necessary, update any relevant legislation and guidance. In parallel, current developers and funders of this research should articulate comprehensive and credible regulatory paths through which they believe the safety and efficacy of self-spreading approaches could be established and through which publics may accept the inherently coercive and mandatory nature of self-spreading vaccines.
Only a concerted, global governance effort with coherent regional, national, and local implementation can tackle the challenges of self-spreading viruses that have the potential to radically transform both wildlife and human communities. This is because, as the case for the rabbit hemorrhagic disease virus in Australia showed, for self-spreading techniques, there is a real possibility that the first regulatory approval for a limited field trial could turn into an unapproved international release (5).

Acknowledgments

This article stems from a panel discussion at the 2020 EuroScience Open Forum, which was partially facilitated by funding from the Max Planck Society. We thank participants for discussions as part of that panel, as well as participants in the 2019 “Going viral?” meeting that ran in parallel to the Biological Weapons Convention Meeting of Experts (Geneva).

References and Notes

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M. W. Smithson, A. J. Basinki, S. L. Nuismer, J. J. Bull, Vaccine 37, 1153 (2019).
2
S. L. Nuismer et al., Proc. Biol. Sci. 283, 20161903 (2016).
3
Conference of the Parties to the Convention on Biological Diversity, report of the Canada-Norway expert workshop on risk assessment for emerging applications of living modified organisms UNEP/CBD/BS/COP-MOP/4/INF/13, 39 (2007).
4
J. M. Torres et al., Vaccine 19, 4536 (2001).
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P. O’Hara, Rev. Sci. Tech. 25, 119 (2006).
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W. R. Henderson, E. C. Murphy, Wildlife Res. 34, 578 (2007).
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R. P. Ortega, “Can vaccines for wildlife prevent human pandemics?” Quanta Mag. (2020); www.quantamagazine.org/can-vaccines-for-wildlife-prevent-human-pandemics-20200824/.
8
M. Cogley, “Could self-spreading vaccines stop a coronavirus pandemic?” The Telegraph (UK) (2020); www.telegraph.co.uk/technology/2020/01/28/could-self-spreading-vaccines-stop-global-coronavirus-pandemic/.
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K. M. Bakker et al., Nat. Ecol. Evol. 3, 1697 (2019).
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PREEMPT, Prediction of Spillover and Interventional En Masse Animal Vaccination to Prevent Emerging Pathogen Threats in Current and Future Zones of US Military Operation (2021); www.preemptproject.org/about.
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J. J. Bull, M. W. Smithson, S. L. Nuismer, Trends Microbiol. 26, 6 (2018).
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M. Wille, J. L. Geoghegan, E. C. Holmes, PLOS Biol. 19, e3001135 (2021).
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K. M. Barnett, D. J. Civitello, Trends Parasitol. 36, 970 (2020).
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P. Van Damme et al., Lancet 394, 148 (2019).
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C. Gallardo et al., Transbound. Emerg. Dis. 66, 1399 (2019).

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Science
Volume 375 | Issue 6576
7 January 2022

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Published in print: 7 January 2022

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Acknowledgments

This article stems from a panel discussion at the 2020 EuroScience Open Forum, which was partially facilitated by funding from the Max Planck Society. We thank participants for discussions as part of that panel, as well as participants in the 2019 “Going viral?” meeting that ran in parallel to the Biological Weapons Convention Meeting of Experts (Geneva).

Authors

Affiliations

Filippa Lentzos [email protected]
Departments of Global Health and Social Medicine and of War Studies, King’s College London, London, UK.
Edward P. Rybicki
Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa.
Margret Engelhard
Federal Agency for Nature Conservation (BfN), Bonn, Germany.
Pauline Paterson
Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
Wayne Arthur Sandholtz
Department of Political Science and International Relations, University of Southern California, Los Angeles, CA, USA.
R. Guy Reeves [email protected]
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Plön, Germany.

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