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Genetically engineered vaccines
'Inherently unpredictable and possibly dangerous'
In recent years, genetically engineered vaccine strategies
have been rushed into common use within such fields as
medicine, veterinary medicine and fish farming. Some
scientists contend that such vaccines are totally innocuous.
But a recent and major research report by Professor Terje
Traavik reduces the 'safe technology' to sheer naive
optimism, and warns in conclusion that 'many live,
genetically engineered vaccines are inherently unpredictable
(and) possibly dangerous.' Martin Jalleh highlights the
compelling findings of the report - which make the arguments
for genetically engineered vaccines look frail and move
Traavik to call on the scientific community to go beyond the
'Holy Grail' of medicine.
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'MODERN molecular biology, recombinant DNA technology and
genetic engineering have opened the road to a number of
alternative strategies for vaccine production,' reveals
Professor Terje Traavik of the Departments of Virology and
Medical Microbiology, University of Tromso, GENK-Norwegian
Institute of Gene Ecology, Tromso, Norway. He deems it
necessary to add: '...from an ecological and environmental
point of view many first generation live, genetically
engineered vaccines are inherently unpredictable, possibly
dangerous...' He emphasises that such vaccines 'should not
be taken into widespread use until a number of putative
problems have been clarified'.
He describes the risks and hazards as 'most certainly within
the realm of possibility, and according to the Precautionary
Principle they should be subject to preventive measures'. He
points out, 'In practice, however, the risks are considered
to be non-existent, since they have not been supported by
experimental or epidemiological investigations. This, again,
is a 'Catch-22' situation, in the sense that such
investigations have not been performed at all.'
Traavik's comments and conclusions on genetically engineered
vaccines can be found in his major study entitled An Orphan
in Science: Environmental Risks of Genetically Engineered
Vaccines, written on assignment with the Norwegian
Directorate of Nature Management.
According to Traavik, the report attempts to 'address the
potential ecological and environmental risks posed by some
types of genetically engineered (GE) or modified vaccines
that are now being developed, and may soon be in widespread
use'. (Most of the excerpts from Traavik's report quoted in
this article and accompanying boxes refer to GE live virus
vectors. Other quotations are either general in nature or
refer specifically to naked DNA vaccines.)
Traavik's report prompts a rather pertinent question, which
at the same time effectively brings to the fore the fact
that genetically engineered vaccines are inherently
unpredictable - does genetic engineering deserve the
'technology' label?
Unpredictable effects
According to Traavik, the word 'technology' is derived from
the Greek term 'tekhne' which is connected to handicrafts or
the arts. It is often associated with predictability,
control, and reproducibility. He then goes on to say that
'the parts of genetic engineering that concern construction
of vectors are truly technology.' On the other hand, and in
contrast, he argues, present-time techniques for moving new
genes into cells and organisms mean:
· No possibility of targeting the vector/transgene to
specific sites within the recipient genomes. In practical
terms, this means that modifications performed with
identical recipients and vector gene constructs under the
same standardised conditions may result in highly different
genetically modified organisms (GMOs) depending on where the
transgenes become inserted.
· No control of changes in gene expression patterns
for the inserted or the endogenous genes of the GMO.
· No control of whether the inserted transgene(s), or
parts thereof, move within or from the recipient genome, or
where transferred DNA sequences end up in the ecosystems.
Traavik also draws attention to the fact that the
unpredictability of genetically engineered vaccines is
further increased by the problems posed by some
environmental pollutants known as xenobiotics.
'Different xenobiotics have properties and biological
activities that enable us to envisage at least two different
sets of possible impacts on the fate of naked DNA in an
ecosystem. Some xenobiotics can act as mutagenes (this
applies to radioactive substances, polluting industrial
chemicals and plant protectants). Mutagenes can result in
naked DNA that escapes or is released having its sequence or
structure changed. This, in turn, can affect the
possibilities for DNA uptake in cells and organisms,
horizontal transfer and long-term establishment in the
ecosystems in ways which are totally unpredictable for us.
(There have been) reported examples of minor changes in a
DNA sequence altering the host spectrum of a transferable
genetic element.'
'Some xenobiotics can affect cell membrane and/or
intracellular functions in ways which can very well be
thought to influence the ability of cells to take up and
horizontally transfer naked DNA. This concerns the structure
of cell membranes and the content of both surface receptors
and transport canals, and also for intracellular signal
conversion and gene expression.
For instance, xenobiotics which mimic hormones or affect the
local conditions in the organ systems of mammals (e.g.
respiratory passages) may change the possibilities for both
uptake and establishment of foreign nucleic acids in animals
and people,' the report reveals.
'There are xenobiotics which are found in both categories,
and we do not know how the sum of the impacts of such
substances will turn out. Likewise, up to several
individual compounds from each category will often pollute
the same environment. We have no knowledge of how such
situations affect DNA uptake and dispersal in the
ecosystems,' it states.
'Unsafe' definition
Traavik's study also brings to light what he calls 'the
deplorable fact' of the very narrow and exclusive definition
of 'safety' in vaccinology, compared to the putative risks
and hazards vaccine use may imply.
'Primarily, 'safety' research is occupied with prospects of
unintended and unwanted side effects with regard to the
targeted vaccinees themselves. Secondly, such research may
be directed towards non-target effects on unvaccinated
individuals within the same species. Very small efforts
have been dedicated to unintended and non-target effects
across species-borders and biologic kingdom-borders,'
contends Traavik.
'This narrowing of conception as well as intellectual and
research strategies may leave many potential hazards and
harms related to various vaccine categories unapprised,
until one or more of them actually happen,' he warns.
'Very few research reports concerning environmental or
ecological effects of genetically engineered vaccines were
published as late as January 1999. On the other hand,
examples of scientists defending the total innocuousness
of vaccines, without taking environmental and non-target
effects into consideration, are numerous. Many seem
totally religious in their belief, and prescribe
strategies to convert the ignorant public and
politicians,' Traavik observes.
'Furthermore, I suspect that the lack of holistic and
ecological thinking with regard to vaccine risks is
symptomatic of the real lack of touch between medicine and
molecular biology on one side, and potential ecological and
environmental effects of these activities on the other.
'A frighteningly small number of original research reports
concerning environmental or ecological consequences of
molecular biology applications or genetic engineering were
published until January 1999. I believe that we are here
dealing with a void in medical education and cooperation
focus, as well as a dangerous lack of focused research
efforts,' he writes in his report.
According to Traavik, genetically engineered self-
replicating and/or self-expressing vaccines 'may turn out to
be good equipment in science, but too dangerous for
practical large-scale use'. It has also become evident to
him that 'the various putative risk factors and hazards
related to these vaccines ought to be adequately
investigated before we and the ecosystems are massively
exposed to them.'
'Many of the vaccine constructs may have obvious value
within basic and applied research, but should be kept
contained until credible ecological risk assessments are
possible. Such clarification will demand carefully planned
investigations and adequately designed model systems for
experimental research. In addition to basic knowledge
directly applicable to risk assessments, enhanced insight
into and awareness of general biologic and ecological
interactions ranging from the molecular to the ecosystem
level would be gained,' Traavik strongly suggests.
Unreliable risk assessments
Very close to the 'safety' factor is the issue of risk.
Traavik explains that the term 'risk' is very often confused
with 'probability', and hence used erroneously. 'Risk', by
his definition, is 'the probability that a certain event
will take place multiplied by the consequences arising if it
takes place'.
He notes: 'With regard to development and commercialisation
of genetically engineered nucleic acids, organisms and
viruses, we often are neither able to define probability of
unintended events nor the consequences of them.
Hence, the present state of ignorance makes scientifically
based risk assessments impossible.' This, according to
Traavik, calls for invoking the 'Precautionary Principle',
the need for which, he believes, can hardly be
overestimated, both for risk management and for generations
of risk-associated research.
In the context of gene technology and use of GMOs, he says,
the principle could be generally defined as follows: 'In
order to obtain sustainable development, policies should be
based on the Precautionary Principle.
Environmental and health policies must be aimed at
predicting, preventing and attacking the causes of
environmental or health hazards. When there is reason to
suspect threats of serious, irreversible damage, lack of
scientific evidence should not be used as a basis for
postponement of preventive measures.'
Traavik adds: 'In order to make reliable risk assessments
and perform sensible risk management with regard to genetic
engineering in general, and genetically engineered vaccines
in particular, much pertinent knowledge is (necessary, yet
this is) lacking.'
He strongly feels that risk-associated research should be
the responsibility of the authorities concerned and not the
industry: 'The prerequisite for obtaining such knowledge is
science and scientists dedicated to relevant projects and
research areas. It must be the responsibility of the
national governments and international authorities to make
funding available for such research.'
'On one hand, this is obviously not the responsibility of
producers and manufacturers. On the other hand, risk-
associated research must be publicly funded in order to keep
it totally independent, which is an absolute necessity for
such activities,' is his pertinent observation and
conclusion on this point.
Unanswered questions
Traavik, in his report, reviews some fundamental conceptions
on vaccination and the immune system. Vaccination is seen as
'a form of prevention or prophylaxis of infectious disease
and cancers', and Traavik feels the reasons for giving
priority to prevention and prophylaxis will become stronger
than ever, 'as development of resistance in microorganisms,
viruses and cancer cells are reducing the therapeutic
opportunities offered by chemotherapeutics and antibiotics.'
He points out that while vaccination intends to provide
individuals with immunological protection before an
infection actually takes place, it is crucial to take
cognizance of the fact that 'the immune system is very
complex, and immunity against different infectious agents is
based on fine-tuned balances between the various types of
cells, signal substances and antibodies that make up the
total immune system.'
When providing the contrast between traditional vaccines and
modern vaccines, he makes it clear that the latter are not
without drawbacks such as short-lived general immune
responses, weak local immune responses, and the most
prominent being the danger that 'they (live vaccines) may
revert to their full disease-causing potential'.
The report also deals with the strategies used to achieve
various types of vaccines by recombinant DNA techniques and
genetic engineering and the equally unpredictable outcome of
the recombination of a genetically engineered vaccine virus
with naturally occurring relatives.
His findings on the strategies can be summed up as follows:
'Genetically modified viruses and genetically engineered virus-
vector vaccines carry significant unpredictability and a
number of inherently harmful potentials and hazards.
'The immunological advantages of such vaccines are related
to the fact that the viruses are 'live' and infect the
vaccinated individuals. It has, however, been demonstrated
that minor genetic changes in, or differences between,
viruses can result in dramatic changes in host spectrum and
disease-causing potentials. For all these vaccines,
important questions concerning effects on other species than
the targeted one (have been) left unanswered so far.'
Unearthing knowledge
In the concluding chapter of his report, Traavik reiterates
the seriousness of the situation: 'it is not possible for
the moment to either assess or manage the environmental
risks (posed by many first generation live, genetically
engineered vaccines). Most probably we have not even
conceived all theoretical risks at the present time.'
He calls to mind the all-too-often-tragic past concerning
the use of 'technology': 'Recent years have witnessed
many examples of unforeseen side effects from 'safe
technology' having led to health risks and threatened to
disturb the ecological balance. Dogmas concerning absence
of hazards have often been proven wrong... Absolute
biological and ecological truths are, however, very rare,
and rare phenomena may have important consequences when
they take place.'
He stresses that to the extent that any prior investigations
of damaging effects had been undertaken, methods and
approaches had been used that were only capable of
disclosing short-term effects, whereas in ecological
contexts it is the long-term impacts that are most important
and most serious.
'Long-term impacts in these contexts, and also in connection
with the possible damaging effects of the dispersal of
genetically engineered vaccines means not months or years,
but at least ten to hundreds of years,' Traavik warns.
Traavik is of the opinion that 'many of the vaccine
constructs may have obvious value within basic and applied
research', but he adds these 'should be kept contained until
credible ecological risk assessments are possible.'
'Such clarification will demand carefully planned
investigations and adequately designed model systems for
experimental research. In addition to basic knowledge
directly applicable to risk assessments, enhanced insight
into and awareness of general biologic and ecological
interactions ranging from the molecular to the ecosystem
level would be gained.'
He believes that there are 'no controversies connected to
the fact that subunit or peptide vaccines are the inherently
safest alternatives with regard to unintended side effects,
as well as unpredictable non-target effects. Such vaccines
are also, beyond reasonable doubt, the potentially safest
from an ecological and environmental point of view'.
He is also optimistic with regard to the intensive search
for alternative vaccine strategies, which he says will lead
to 'new insights into basic immunological mechanisms and new
delivery systems'.
His final recommendation is that: 'It must always be kept in
mind that although vaccinology is the 'Holy Grail' of
medicine, there are other ways of preventing infectious
diseases in humans and animals that must not be ignored.
Many of the most burdening infectious agents of mankind and
its domesticated animals are caused by pathogens that have
reservoirs and are circulating among wildlife animals.
'By increasing our knowledge about these reservoirs, their
occurrence, the transmission routes within and out of the
indigenous ecosystems, we might be able to break
transmission chains or keep our activities out of dangerous
ecosystems. There is a void in knowledge about the
ecological interactions for many important pathogens. This
field is to some extent subdued by the confidence in
vaccines, and hence another scientific orphan.'
Martin Jalleh is a research officer with the Third
World Network.
Box stories:
Genetically engineered vaccines
BELOW are some GE vaccines referred to by Professor Terje
Traavik in his report, An Orphan in Science: Environmental
Risks of Genetically Engineered
Vaccines:
Subunit vaccines: They represent technologies ranging from
the chemical purification of components of the pathogen
grown in vitro to the use of recombinant DNA techniques to
produce a single viral or bacterial protein, such as
Hepatitis B surface antigen for example. The disadvantage of
such vaccines is that immune responses, especially T-
lymphocyte activation, are too weak.
DNA vaccines: They employ genes encoding proteins of
pathogens rather than using the proteins themselves, a live
replicating vector, or an attenuated version of the pathogen
itself. They consist of a bacterial plasmid with a strong
viral promoter, the gene of interest, and a
polyadenylation/transcriptional termination sequence. The
plasmid is grown in bacteria (e. coli), purified, dissolved
in a saline solution, and then simply injected into the
host. In present versions only very small amounts of
antigens are produced within the vaccinated individual.
Recombinant (DNA) vaccines: Made by isolation of DNA
fragment(s) coding for the immunogen(s) of an infectious
agent/cancer cell, followed by the insertion of the
fragment(s) into vector DNA molecules (i.e. plasmids or
viruses) which can replicate and conduct protein-expression
within bacterial, yeast, insect or mammalian cells. The
immunogen(s) may then be completely purified by modern
separation techniques. The vaccines tend to give good
antibody responses, but weak T-cell activation.
Naked DNA vaccines: They are engineered from general
genetic shuttle vectors and constructed to break species
barriers. They may persist much longer in the environment
than commonly believed. Upon release or escape to the wrong
place at the wrong time. Horizontal gene transfer with
unpredictable long- and short-term biological and
ecological effects is a real hazard with such vaccines.
There may be harmful effects due to random insertions of
vaccine constructs into cellular genomes in target or non-
target species.
Live vector vaccines: These are produced by the insertion of
the DNA fragment(s) coding for an immunogen(s) intended for
vaccination into the genome of a 'non-dangerous' virus or
bacterium, the vector. The insertion is performed in such a
way that the vector is still infectious 'live'.
RNA vaccines: This involves the use of in vitro synthesised
RNA (a single-stranded relative of DNA). RNA are different
from DNA vaccines in that there is no risk of chromosomal
integration of foreign genetic material.
Edible vaccines: These are produced by making transgenic,
edible crop plants as the production and delivery systems
for subunit vaccines. Little is known about the consequences
of releasing such plants into the environment, but there are
examples of transgenic plants that seriously alter their
biological environment. A number of unpredicted and unwanted
incidents have already taken place with genetically
engineered plants.
Unanswered questions
CONSIDERING the unpredictability of genetically engineered
vaccines, Professor Terje Traavik has come up with a list of
questions which he feels have to be answered in a
satisfactory way before any vaccinia virus vectored GE
vaccines are released:
*Can the virus engage in genetic recombination, or by other
means achieve new genetic material? If so, will the hybrid
offspring have changed their host preferences and virulence
characteristics?
*Can other viruses that are present within the ecosystem
influence the infection with the released virus or its
offspring? Can insects or migrating birds or animals
function as vectors for the released virus or its offspring,
to disseminate viruses out of their intended release areas?
*For how long can the virus and its offspring survive
outside host organisms under realistic environmental and
climatic conditions?
*Is the virus and its offspring genetically stable
over time?
*Can the virus or its offspring establish long-lasting,
clinically mute, persistent or latent infections in
naturally accessible host organisms?
*Can the virus or its offspring activate or aggravate
naturally occurring latent or persistent virus infections?
The stark reality, he points out, is that most of these
questions are unaccounted for, when they are related to
vaccinia virus vectored GE vaccines (VV). 'Even when they
have been answered by experimental investigations,
ecological non-target effects cannot be excluded because
even carefully designed model studies will not directly
reflect the real ecosystem conditions, which in addition are
dependent on local variable parameters.'
Warning signals
PROFESSOR Traavik provides growing evidence of the
unpredictability of GE virus recombinants:
*During the human small pox eradication campaign,
vaccinia virus vectored GE vaccines (VV) found a new host
species and established themselves in a new reservoir,
namely the buffalo.
*It is a general experience that inserts may change the
virulence and host preferences of viruses.
· MRV (Malignant rabbit virus) seems to be a
recombinant between SFV (Shope fibroma virus) and myxoma
virus. It seems to have arisen by mixed infection in wild
rabbits. MRV causes an invasive malignant disease and
profound immunosuppression in adult rabbits, much more
serious than the diseases caused by any of the parental
viruses. MRV has received more than 90% of its DNA from one
parent (myxoma virus) in a coupled recombination and
transposition event. The MRV story exemplifies the
unpredictability of virus recombinants with regard to
biological characteristics and virulence.
· A recombinant field isolate of capripoxvirus has
also been detected. The new virus was the result of
recombination between a capripoxvirus vaccine strain and a
naturally occurring virus strain.
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