SCIENCE science.orgBy Filippa Lentzos^1 , Edward P. Rybicki^2 ,
Margret Engelhard^3 , Pauline Paterson^4 ,
Wayne Arthur Sandholtz^5 , R. Guy Reeves^6A
n evidence-based norm collectively es-
tablished 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 pre-
dictably outside contained facilities. That
norm now seems to be challenged. A range
of transformational self-spreading applica-
tions 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 ap-
parent norm erosion in the context of recent
proposals to develop self-spreading geneti-
cally modified viruses, in wildlife manage-
ment and in self-spreading vaccines.
Wildlife control using self-spreading vi-
ruses 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 accidentalrelease was followed by widespread irre-
versible transmission within Australia and
subsequent illegal international transporta-
tion 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 vac-
cine with the European Medical Agency also
ceased. As part of a special issue of Wildlife
Research that represented a self-written re-
quiem to the Australian efforts, an article
concluded:
“It is clear that a single unwanted intro-
duction of a GM [genetically modified viral]
biocontrol agent could have serious conse-quences. Once a persisting transmissible
GMO is released (whether intentionally, le-
gally, or otherwise), it is unlikely that it could
be completely removed from the environ-
ment. The scientific community involved in
developing GM biocontrols therefore needs
to demonstrate a highly precautionary atti-
tude. Scientists also have an ethical responsi-
bility 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 us-ing self-spreading agents for wildlife man-
agement. Many regulatory issues arising
from self-spreading approaches are widely
acknowledged to have remained unre-
solved—such as who is responsible, or li-
able, 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 , 7 – 9 ), 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 ac-
companied 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 vac-
cine 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 ma-
nipulations could simultaneously limit vi-
ral 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-mod-
ified 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 applica-
tion, there are notable hurdles that have
been glossed over. First, the vast major-
ity of virus species that currently exist are
undescribed by science ( 12 ). This makes it
very difficult to imagine how the consid-
erable effort necessary to develop and test
self-spreading vaccines could identify and
then prioritize single viral species circulat-
ing in wildlife.
Second, the dynamic nature of mutation
and recombination events in wild globalBIORISK MANAGEMENT
Eroding norms over release
of self-spreading viruses
POLICY FORUM
Risky research on lab-modified self-spreading viruses
has yet to present credible paths to upsides
(^1) Departments of Global Health and Social Medicine and of War Studies, King’s College London, London, UK. (^2) Biopharming Research Unit, Department of Molecular and Cell Biology, University of
Cape Town, Cape Town, South Africa.^3 Federal Agency for Nature Conservation (BfN), Bonn, Germany.^4 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical
Medicine, London, UK.^5 Department of Political Science and International Relations, University of Southern California, Los Angeles, CA, USA.^6 Department of Evolutionary Genetics, Max Planck
Institute for Evolutionary Biology, Plön, Germany. Email: [email protected]; [email protected]
“...current developers
and funders of this
research should articulate
comprehensive and
credible regulatory paths...”
7 JANUARY 2022 • VOL 375 ISSUE 6576 31