~

Pergamon

ACCEPTABILITY

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

OF BIO-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 G o d - - i s as old as mankind itself, and is impressively demonstrated

in the Bible from Exodus to Revelations:
... a n d t h e r e a r o s e a s m o k e o u t o f t h e pit, a s t h e s m o k e o f a g r e a t f u r n a c e ; a n d t h e s u n
a n d t h e a i r w e r e d a r k e n e d b y r e a s o n o f t h e s m o k e o f t h e pit. A n d t h e r e c a m e o u t o f t h e
smoke locusts upon the earth; and into them was given power, as the scorpions of the earth
h a v e p o w e r ( R e v . 9: 2 - 3 ) .
*World Association of Veterinary Microbiologists, Immunologists and Specialists in Infectious Diseases, 14th
International Symposium, 3-5 July 1996, Edinburgh, U.K.

K. Danner

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; F M D ) 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 " m a n 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:

K. D a n n e r

Legislation
Media

Industry
Authorities /
Scientists

Public j

~
User / Client / V e t / / ` /

Fig. 2. A c c e p t a n c e o f bio-technology. I n t e r d e p e n d e n c e 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].

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--acceptabilityof bio-engineeredvaccines

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 W H O 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

p r o d u c t s have entered the m a r k e t a n d have not, so far, met with objections. Pressure
groups, however, never tire a n d are always in search o f new targets. Therefore, we are
obliged to be p e r m a n e n t l y p r o v i d i n g the basis for further acceptance. This should be
possible because bio-engineered vaccines are safe vaccines, a n d because a n y possible risk
is well assessed by responsible people in i n d u s t r y a n d institutes a n d is controlled by the
authorities. O p e n c o m m u n i c a t i o n a n d p r u d e n t e d u c a t i o n will help to establish confidence
in bio-engineered products. A t last, the c o n s u m e r will decide in their favour, when their
o b v i o u s a n d p e r s o n a l benefits become a p p a r e n t . This is a n appeal to the scientific
c o m m u n i t y n o t to do just what is feasible b u t also to use technical achievements to generate
w a n t e d a n d necessary things. The representatives of the m e d i a are also urged to
d e m o n s t r a t e responsibility a n d fairness.
As with all new technologies, the acceptance o f gene technology is influenced by a series
o f factors such as general trends, the perception of morality, social a n d p e r s o n a l emotions.
Fear, specific or diffuse, is the m o s t p r o m i n e n t o f the o p p o s i n g factors. We, o n o u r side,
have to accept this fact. We have to accept that fear is h u m a n a n d is n o t a sign of stupidity.
O n the other h a n d , fear is n o t p r o o f o f wisdom. So we do hope to create sustainable
c o n s e n t for i n n o v a t i v e p r o d u c t s t h r o u g h a p r u d e n t dialogue with intelligent partners.

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12

K. Danner

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