Genetically engineered vaccines

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. ‘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 Tromsø, GENØK-Norwegian Institute of Gene Ecology, Tromsø, 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. —————————————————————————————————-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. This article is based on the report "An Orphan in Science: Environmental Risks of Genetically Engineered Vaccines" which was commissioned by the Norwegian Government is available here.