http://www.twnside.org.sg/title/twr127c.htm

 
 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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