~ Pergamon Comp. Immun. Microbiol. infect. Dis. Vol. 20, No. I, pp, 3-12, 1997

Copyright 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved

PII : S0147-9571(96)00032-X 0147-9571/97 $17.00 + 0.00

ACCEPTABIL ITY OF B IO-ENGINEERED VACCINES*

KURT DANNER

Hoechst Roussel Vet, Rheingaustral3e 190, D-65203, Wiesbaden, Germany

(Received for publication 12 August 1996)

Abstract--For hundreds of years bacterial and viral vaccines have been--in a way--bioengineered and were generally well received by the public, the authorities, and the medical profession. Today, additional tools, e.g. molecular biology, enable new approaches to the development of better and safer products. Various vaccines derived from gene technology have now been licensed for commercial use and are acknowledged within the scientific community. Acceptance by the public and the politicians is, however, negatively influenced by the discussions encompassing gene manipulation in man and animals, transgenic plant, and "novel food". Lack of information leads to confusion and fear. Concurrently, the absence of spectacular and life-threatening epidemics limits the perceived value of immune prophylaxis and its benefits. Scientists in institutes and industry are in a position to stimulate acceptability of bio-engineered vaccines by following some simple rule: (1) adherence to the principles of safety; (2) establishment of analytical and control methods; (3) well functioning regulatory and reporting systems; (4) demonstration of usefulness and economic benefits; (5) open communication; and (6) correct and prudent wording.

Key words: Recombinant vaccines, biotechnology, GMO release, biosafety.

R6sum~-Depuis des centaines d'ann6es, les vaccins bact6rials et viraux sont--d'une certaine mani~re--biotechnologiques et ils ont 6t6 en g6n6ral bien accept6s par le public, les autorit6s et la profession m6dicale. Aujourd'hui, des outils suppl6mentaires, comme la biologie mol6culaire, permettent de nouvelles approches quant au d6veloppement de produits meilleurs et plus stirs. De nombreux vaccins d6rivant du g6nie g6n6tique sont maintenant licenci6s pour l'usage commercial et sont reconnus au sein de la communaut6 scientifique. N6anmoins, la r6action du public et des hommes politiques est n6gativement influenc6e par les discussion sau sujet des manipulations g6n6tiques chez l'homme et l'animal, et des plantes transg6niques. Le manque d'information entra~ne confusion et peur. En m~me temps, l'absence d'6pid6mies spectaculaires r6duit la valeur per~ue de la prophylaxie immunologique et de ses avantages. Les scientifiques en institut et dans l'industrie sont en mesure de stimuler l'acceptation des vaccins recombinants en suivant de simples r~gles: (1) adhesion aux principes de s6curit6; (2) 6tablissement de m6thodes analytiques et de contr61e; (3) bon fonctionnement des syst~mes d'enregistrement et de rapport; (4) d6monstration de l'utilit6 et du ben6fice 6conomique de produits recombinants; (5) communication ouverte; et (6) formulation correcte et sens6e.

Mots clefs: Vaccins recombinants, biotechnologie, environnement, s6curit6 biologique, g6nic g6n6tique.

Fear of Nature---or God-- is as old as mankind itself, and is impressively demonstrated in the Bible from Exodus to Revelations:

... and there arose a smoke out o f the pit, as the smoke o f a great furnace; and the sun and the a i r were darkened by reason o f the smoke o f the pit. And there came out o f the smoke locusts upon the ear th ; and in to them was g iven power , as the scorp ions o f the ear th have power (Rev. 9: 2-3) .

*World Association of Veterinary Microbiologists, Immunologists and Specialists in Infectious Diseases, 14th International Symposium, 3-5 July 1996, Edinburgh, U.K.

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iRisksl Test tube babies

Monsters

Nazi/Hitler Escaping virus

Mad scientists

Medical progress

Fig. 1. Spontaneous perceptions of, and associations with, gene technology.

Fear is also widespread today. In a recent European poll [1], out of several new technologies, gene technology was found to be the least accepted. North Carolina and New Jersey residents showed a great lack of knowledge of biotechnology, and the spontaneous reaction was fear of the risks rather than confidence in the benefits. This was shown by the mental association of gene technology with "mad scientists" and "escaping viruses", rather than "medical progress" (Fig. 1) [2, 3].

Fear, however, is a bad adviser.

ACCEPTANCE OF OLD AND NEW VACCINES

Variolation was commonplace in India and later in China and other parts of the world in the 10th century, and might be called a form of early biological manipulation. This was certainly also true for the England of the 18th century, when pox material from cows and horses was used fresh or after several passages in humans for vaccination. One hundred years after Edward Jenner's courageous trials, Pasteur manipulated the rabies virus, anthrax bacillus and fowl cholera pasteurella, in order to create efficient vaccines. Calmette and Gu6rain performed passages of tuberculosis bacterium on potato cultures, Smith and Salmon inactivated Salmonella cholerae suis by heat, and Paul Ehrlich detected the principle of immunization with toxoids, which we would call subunits today. Cannot all of these procedures - - passaging in heterologous hosts or artificial substrates, semi-inactivating, inactivating, detoxifying - - be called bio-engineering?

In those days, especially in Jenner's era, vaccination was, of course, subject to misunderstanding and mockery. However, the benefits became apparent against a background of dreadful epidemics, and thus vaccination, with all its failures, was generally approved by the medical and veterinary professions, the authorities and the public [4]. Today, it is sometimes difficult to demonstrate the value of vaccinations. Their success is

Review--acceptability of bio-engineered vaccines

not immediately visible, antibiotics are at hand, and epidemics are mostly remote. Especially in the human field, examples of vaccine failure or damage are known and even lead to anti-vaccination campaigns [5]. Modern tools, especially molecular biology, make possible the development of better and safer products. Various vaccines, derived from gene technology, have now been licensed for commercial use and are acknowledged within the scientific community. Acceptance by the public and by some political groups is, however, negatively influenced by the discussions encompassing gene manipulation in man and animals, transgenic plants, and "novel foods". Even hormones in meat, bovine spongiform encephalopathy (BSE), and food irradiation are becoming "arguments". A lack of correct information leads to confusion and fear. Therefore, we perceive the necessity of establishing a catalogue of measures which will inspire confidence and, thus, acceptance.

WHY DO WE NEED NEW VACCINES?

Many of the existing, so-called conventional, vaccines will continue for several years or decades. Nevertheless, there is a significant need for new vaccines for various reasons:

Unsatisfactory efficacy or safety of existing vaccines Antigenic variation of infectious agents New diseases Replacement of antiparasitics or anti-infectives with vaccines Interest in antihormonal vaccines Immunological approaches to tumours and metabolic disorders

Here are some examples of hazards in connection with vaccines to serve as a reminder (see also Martinod [6]):

Infection of man during microbial/viral propagation Escape of virus (e.g. foot-and-mouth disease; FMD) from the manufacturing plant

causing disease Specific vaccine-derived infection through inappropriate or insufficient inactivation

(FMD) or through insufficient attenuation (many of the actual poultry vaccines) Specific infection of contact individuals (e.g. poliomyelitis vaccine, type 2 and

especially type 3 virus) Disease by microbial/viral contamination of vaccines (e.g. with pestiviruses) Immune suppression by live vaccines as, for example, discussed in the case of some

canine and bovine vaccines Local inflammation and systemic side-effects caused by adjuvants, endotoxins or

allergenic substances Epidemiological consequences due to insufficient efficacy

WHO NEEDS TO ACCEPT BIO-ENGINEERED VACCINES?

Who should be addressed? Who should give approval to bio-engineered animal health products, especially vaccines? Focusing on the end consumer - - the vaccinee - - would be an easy task in veterinary medicine, but the system is more complex (Fig. 2).

The famous "man in the street" is involved, as are the media, opportunistic lobby groups, industry, and scientists. At the political level, in the debate between hard-liners, victory or defeat seems to be a more important issue than fair discussion or prevention of possible dangers [7]. The central role of the authorities must be emphasized:

J Media

Public j

K. Danner

Legislation

Authorities /

Industry

Scientists

~ User / Client / Vet / / ` /

Fig. 2. Acceptance of bio-technology. Interdependence of different groups.

manufacturing and research licences, product registration, market authorization, and their influence on legislation and on the public.

DIFFERENT TYPES OF BIO-ENGINEERED VACCINES

Which product types do we discuss? Fermentation techniques and galenic formulation are often described as biotechnology, but within this paper I would like to concentrate on technologies where nucleic acid and its modification in the laboratory is concerned. There are different categories of recombinant biologicals which, in the United States, are pragmatically divided into three categories [8], as shown in Table 1.

Future catalogues will certainly include additional classes, such as, for example, antigens expressed via plants and naked nucleic acid vaccines.

Products in Category I were licensed many years ago, and their acceptance as products has never been in question. As non-viable products they do not pose a risk to the environment. However, their production - - starting from viable microorganisms - - deserves all the necessary attention and the application of relevant security measures.

The discussion on acceptability is focusing on products containing live recombinant micro-organisms. We speak of the "deliberate release" of genetically modified organisms (GMOs) and "placing on the market", and must consider the possible environmental risks. Category II products have also been commercially available for some years; all of them are deleted pseudorabies vaccines (gI is the obligatory marker for eradication purposes within the EU). They have been licensed and marketed without much public attention, although the enthusiasm of the authorities has been limited in some countries. The first vector vaccines (Category III) are also available now (e.g. fowlpox virus carrying Newcastle Disease (ND) genes [9]).

Table 2 shows some examples of commercial recombinant vaccines. The experiences of the first years of commercial recombinant vaccines have been

positive. New products within the existing categories will soon emerge. They will be

Table 1. Categories (U.S.A.) of recombinant vaccines [8]

Category I:

Category II: Category Ill:

Inactivated r-DNA viral and bacterial vaccines Viral, bacterial or other subunit products

Monoclonal antibodies Vaccines containing live organisms modified by gene insertion or deletion

Vaccines using live vectors to carry r-derived foreign genes

Review--acceptability of bio-engineered vaccines

Table 2. Commercial recombinant veterinary vaccines

Category I:

Category II: Category III:

E. coli bacterins for pigs E. coli toxoids for pigs

Pseudorabies vaccine, killed Bovine rhinotracheitis vaccine, killed

Feline leukemia virus, killed Feline leukemia virus subunits

E. coli monoclonal antibodies for newborn calves Canine lymphoma monoclonal antibodies

Pseudorabies vaccine, modified live Fowlpox/ND vector vaccine

Vaccinia/rabies vector vaccine

licensed as long as some principal rules are followed by the researchers and manufacturers. This should also be true for further categories, e.g. naked nucleic acid vaccines [10], or even vaccine antigens expressed by plants [11].

HOW CAN THE ACCEPTABILITY OF BIO-ENGINEERED VACCINES BE PROVIDED AND SAFEGUARDED?

Adherence to the principles of safety and security A whole series of security and safety measures are in place to avoid vaccinal risks, e.g.

GMP (good manufacturing practice) rules, the classic search for adventitious agents in seed materials, stringent quality control and proof of environmental safety. It is not necessary to recapitulate all these aspects, which have been addressed by many conferences, publications and legal issues.

In contrast to conventional products, recombinant vaccines are genetically defined and are thus safer than ever before. Nevertheless, additional measures are legally required for recombinant vaccines. A description of procedures and requirements is given by Gay [8] and Gay and Roth [12] for the United States and by Lee [13] for Europe (see also References 14 and 15).

Discussions on risk assessment and risk management in connection with veterinary vaccines, especially bio-engineered ones, have been held at the Arlington Meeting in 1994 and published by the Office International des l~pizooties (OIE)[16].

Safety and security factors meet the understandable requests of the licensing authorities. Irrespective of the real necessity for them, safety factors will, psychologically, enhance the general acceptance of products by the public.

1n-built safety mechanisms

In addition to in-process and quality control tests, there exists a range of sophisticated techniques to make recombinant products even safer:

Multiple deletions of glycoprotein genes with the specific consideration of virulence-determining factors. The NYVAC strain of vaccinia virus, for example, was derived by the deletion of 18 ORFs encoding for pathogenicity and replication [17]. With multiple deletions it is most unlikely that natural remutation or in vivo recombination occurs where virulence is regained.

In the case of pseudorabies virus, the gD gene seems to be needed for cell penetration and its deletion might be the basis for a non-spreading live vaccine (i.e. natural biological containment) [18].

8 K. Danner

Use of virus systems, for example canarypox virus constructs, which do not replicate in non-avian vaccinees. Inserted foreign genes, however, are expressed and even lead to immunity [19].

Suicidal viral and bacterial strains have been developed, where self-inactivation is genetically in-built [20].

It is not advisable to seek these factors principally, but altogether they are able to reduce virulence and any possible risks, and in this way they can make recombinant products more acceptable.

Establishment of analytical and control methods The molecular tools leading to the development of recombinant products also provide

the keys for highly sensitive analyses. Vaccine strains can be exactly traced by molecular methods, and any vaccine-derived disease or epidemic event can be detected. On the regulatory side, special and intensive controls are required for recombinant products as described earlier.

In summary, a controlled risk appears to be a smaller risk and thus is more acceptable to the authorities and the public.

Well functioning regulatory and reporting systems It is a sad fact that the public has little confidence in industry, where profitability seems

to be the only criterion. Therefore, it is important that licensing and regulation is a matter of governmental control. To the general public, the authorities appear to be neutral and objective institutions where risk assessment and final judgement are exercised in a proper and consumer-oriented way. A well-assessed risk seems to be an acceptable risk. Only a few political groups are questioning and opposing official decisions, sometimes even with the use of violence. An example is the recent destruction of genetically modified rapeseed, corn, and potato plantations in Germany.

Regulatory authorities could, in addition, fulfil another duty. An interesting and valid proposal put forward by Jungb~ick [21] is that registration offices should publish parts of the dossier, e.g. on environmental safety, and thereby create a climate of trust in the public. The Freedom of Information Act in the United States also allows insights into parts of data submitted for registration, and produces a feeling of security on the consumers' part.

Authorities should also react flexibly to new experiences. Where risks have proved to be minimal or non-existent, regulations should reflect the fact. Exaggerated requirements are as unreasonable as weak ones and are equally untrustworthy.

The possible hazardous consequences of the application of any product can only be detected when a fully functioning reporting system is in place. Confidence in bio-engineered products will therefore be linked to the quality of pharmacovigilance. Well-defined systems should not be a problem in the civilized world.

Demonstration of usefulness One of the first chapters in the designer's handbook tells that appeal and beauty must

be matched by usefulness and functionality. Even in the world of fashion, the latest creations of Haute Couture may be artistically overwhelming - - money is earned with blue jeans. But usefulness alone is not enough. Would Germans accept speed limitations on their Autobahns? Although low speed would be to their advantage, they would not

Review--acceptability of bio-engineered vaccines 9

perceive that, and would rather start a revolution. In the same way in the field of gene technology, today we observe the trend that reservations are no longer caused by the risk of product application, but rather by the perceived lack of any obvious benefits. All amateur gardeners would immediately appreciate a slowly growing lawn.

The vaccine industry is obliged to generate acceptable products. What then are the perceived benefits of bio-engineered vaccines? Generally, it is relatively difficult to demonstrate the benefits of vaccines in times when there are no striking or deleterious epidemics and epizootics. Moreover, the perception of a benefit is different within and specific to the various relevant groups.

The farmer is most interested in cost reduction. In fact, a product such as the Newcastle Disease vaccine vectored by a turkey herpesvirus is economic because it provides lifelong immunity after one single application [22]. Vector vaccines are designed to combine the advantages of live and killed vaccines without suffering from their respective disadvantages [23]. Veterinarians will welcome access to more efficacious and safer vaccines and the higher margins offered by premium products.

Epidemiologists should welcome bio-engineered vaccines that have marker qualities conferred by genetic deletions, thus enabling eradication programmes to become valid and applicable.

The scientific community should be pleased by the fact that gene technology enables vaccinations against diseases where an immune prophylaxis has not previously been possible. Here I am thinking of the detection and utilization of concealed antigens, as in the case of the bovine tick Boophilus microplus and other parasites [24], and also of vaccinations in the hormonal or metabolic field.

Licensing authorities will appreciate all products with enhanced safety whether produced by recombinant or other technologies. The lack of residues and problems of resistance also have to be acknowledged.

Environmentalists and consumers should be delighted with the advantages offered by new (bio-engineered) vaccines over chemical treatments, e.g. of parasites and bacteria.

Politicians in Europe, after a period of reluctance, are now regarding biotechnology and its potential with increasing favour [25].

The public should be made aware of the economic advantages that a new technology and its industrial exploitation is able to provide. In Germany, a programme called "BioRegio" has been designed to create regional synergies between research institutes, banks, industry and others. In contrast to the United States, Europe showed little interest in a public stock market for small technology driven businesses. This may now change as a result of the activities of new capital exchange groups.

Nobody should have the feeling that "mad scientists" and profit-oriented multinationals are playing their secret and selfish game.

Open communication Advantages and benefits have to be made apparent to the different groups and persons

involved. Therefore, appropriate education is necessary. We know now that it is far better to address different groups directly rather than carrying out broad information campaigns. Journalists, teachers, and representatives of consumer organizations must get the right information as well as responsible people in government and the authorities.

This does not mean that the public should not be informed. Nothing would be more detrimental than hiding facts or doing things clandestinely. We have an impressive example

10 K. Danner

of such misbehaviour from the old days of bio-engineered vaccines, when a vaccinia-based rabies vaccine was applied in cattle in Argentina. Argentinian officials had not been informed, but the trial became public knowledge and was discussed all over the world. It appeared to be proof of the risks of gene technology and the lack of a sense of responsibility on the part of scientists [26].

Only recently, an industrial company in Austria was blamed for planting genetically modified potatoes illegally. It is not surprising that irrational connections with BSE were constructed and the plants called "mad potatoes" [27].

All of us within the scientific community must prevent the public from obtaining a wrong view of gene technology. Alexander von Humboldt says: "It is not the facts that lead human behaviour but the opinion man is forming about facts." Or, more clearly uttered by Hamlet (to Rosencrantz and Guildenstern): "Nothing either good or bad, but thinking makes it so."

FEDESA, the European Federation of Animal Health (Industry) only recently issued a guideline for the establishment of a meaningful dialogue that will help to find the right level of communication.

Statements by official organizations will certainly carry more weight with the public than those of industrial associations. The OIE, by organizing conferences and issuing publications, has taken responsibility for a discussion within the scientific community. Public actions and communications from WHO or FAO officials would enhance the overall effect. The communication of correct data and balanced interpretations via the Internet might be another area worth considering.

Prudent wording Information, communication, and education are sensible things to do in biotechnology.

Correct and prudent wording is an essential part of this task. Karl Jaspers teaches: "It is not at all unimportant how we call things. Already a name includes a tendency of perception, it can meet well or lead away." This is especially true with gene technology, which is not eternal or unchangeable either as an item or as a term. For contrast look at a rose, which is and will remain a rose in any situation. How says Juliet to Romeo?

What's in a name? That which we call a rose By any other name would smell as sweet.

Gene technology unfortunately does not smell sweet! We, as responsible persons, should avoid creating fear of gene technology by using such

words as "gene manipulation", "bio-reactors", "chimaeric constructs" or even "gene technology". Too easy a mental association can be provoked with terms such as "dictatorship", "Chernobyl", "monsters" or "inhumanity".

I must confess that I had difficulty in finding the right word for the title of my paper. "Bio-engineering" may be an example of imprudent wording; "recombinant" may be better, but all the more it shows the importance of finding the right terms in every language. For some it would not be enough to reach mere "acceptance" but "assent", because only assent is an active process of democracy.

CONCLUSIONS

Medicinal applications of gene technology are becoming more and more accepted by the public. Vaccines for human and animal use are also included within this category. Some

Review--acceptability of bio-engineered vaccines 11

products have entered the market and have not, so far, met with objections. Pressure groups, however, never tire and are always in search of new targets. Therefore, we are obliged to be permanently providing the basis for further acceptance. This should be possible because bio-engineered vaccines are safe vaccines, and because any possible risk is well assessed by responsible people in industry and institutes and is controlled by the authorities. Open communicat ion and prudent education will help to establish confidence in bio-engineered products. At last, the consumer will decide in their favour, when their obvious and personal benefits become apparent. This is an appeal to the scientific community not to do just what is feasible but also to use technical achievements to generate wanted and necessary things. The representatives of the media are also urged to demonstrate responsibil ity and fairness.

As with all new technologies, the acceptance of gene technology is influenced by a series of factors such as general trends, the perception of morality, social and personal emotions. Fear, specific or diffuse, is the most prominent of the opposing factors. We, on our side, have to accept this fact. We have to accept that fear is human and is not a sign of stupidity. On the other hand, fear is not proof of wisdom. So we do hope to create sustainable consent for innovative products through a prudent dialogue with intelligent partners.

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