Transgenic plants as edible vaccines — reality and future prospects
This review describes the recent progress in the construction of transgenic plants for vaccine production Transgenic plants are an attractive and cost-effective alternative to microbial systems for the production of proteins with pharmaceutical value. Advances in biotechnology are enabling plants to...
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Інститут молекулярної біології і генетики НАН України
1999
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irk-123456789-1558692019-07-05T17:12:30Z Transgenic plants as edible vaccines — reality and future prospects Domansky, N.N. Обзоры This review describes the recent progress in the construction of transgenic plants for vaccine production Transgenic plants are an attractive and cost-effective alternative to microbial systems for the production of proteins with pharmaceutical value. Advances in biotechnology are enabling plants to be exploited the expression of candidate vaccine antigens with the goal of using the edible plant organs for economical delivery of oral vaccines. It has recently been shown that genes encoding antigens of bacterial and viral pathogens can be expressed in plants in a form in which they retain native immunogenic properties. Transgenic potato tubers expressing bacterial antigens stimulated humoral and mucosal immune response; when they were provided as a food. Although the utility of «edible vaccines» to prevent disease remains to be established, the successful implementation of this strategy can be the first step on the way to modern vaccines of new generation. Огляд сучасних літературних даних про створення трансгенних рослин для виробництва вакцин. Трансгенні рослини ни є дуже привабливою та дешевою альтернативою існуючим мікробіологічним системам виробництва білків для фармацевтики. Успіхи сучасної біотехнології відкрили можливість експерсувати у рослинах різні антигени, що використовуються для вакцинації, з метою використання їстівних частин рослий длятранспорту оральних вакцин. Було продемонстровано, що гени, котрі кодують антигени бактеріальних та вірусні – патогенів, можуть бути експресовані у рослинах із збереженням їхніх природних імунологічних властивостей. Гак, бульби трансгенної картоплі, що експресували бактеріальні антигени, стимулювали гуморальну та мукозну імунні відповіді при використанні їх у їжу. Хоча використання їстівних вакцин для запобігання хвороб ще не доведене, подальшій розробок цього напряму може стати першим кроком на шляху до вакцин нової генерації Обзор современных литературных данных о создание трансгенных растений для производства вакцин. Трансгенные растения являются весьма привлекательной и дешевой альтернативой существующим микробиологическим системам производства белков для фармацевтики. Успехи современной биотехнологии открыли возможность экспрессировать в растениях различные антигены, используемые при вакцинации, для применения съедобных частей растений при транспорте оральных вакцин. Было продемонстрировано, что гены, кодирующие антигены бактериальных и вирусных патогенов, могут быть эспрессированы в растениях с сохранением их природных иммунологических свойств. Так, клубни трансгенного картофеля, экспрессировавшие бактериальные антигены, стимулировали гуморальный и мукозный иммунные ответы при употреблении их в пищу. Хотя использование съедобных вакцин для предотвращения болезней еще не доказано, дальнейшее развитие этого направления может стать первым шагом на пути к созданию вакцин нового поколения. 1999 Article Transgenic plants as edible vaccines — reality and future prospects / N.N. Domansky // Биополимеры и клетка. — 1999. — Т. 15, № 1. — С. 5-9. — Бібліогр.: 15 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0004FD http://dspace.nbuv.gov.ua/handle/123456789/155869 en Биополимеры и клетка Інститут молекулярної біології і генетики НАН України |
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Обзоры Обзоры Domansky, N.N. Transgenic plants as edible vaccines — reality and future prospects Биополимеры и клетка |
| description |
This review describes the recent progress in the construction of transgenic plants for vaccine production Transgenic plants are an attractive and cost-effective alternative to microbial systems for the production of proteins with pharmaceutical value. Advances in biotechnology are enabling plants to be exploited the expression of candidate vaccine antigens with the goal of using the edible plant organs for economical delivery of oral vaccines. It has recently been shown that genes encoding antigens of bacterial and viral pathogens can be expressed in plants in a form in which they retain native immunogenic properties. Transgenic potato tubers expressing bacterial antigens stimulated humoral and mucosal immune response; when they were provided as a food. Although the utility of «edible vaccines» to prevent disease remains to be established, the successful implementation of this strategy can be the first step on the way to modern vaccines of new generation. |
| format |
Article |
| author |
Domansky, N.N. |
| author_facet |
Domansky, N.N. |
| author_sort |
Domansky, N.N. |
| title |
Transgenic plants as edible vaccines — reality and future prospects |
| title_short |
Transgenic plants as edible vaccines — reality and future prospects |
| title_full |
Transgenic plants as edible vaccines — reality and future prospects |
| title_fullStr |
Transgenic plants as edible vaccines — reality and future prospects |
| title_full_unstemmed |
Transgenic plants as edible vaccines — reality and future prospects |
| title_sort |
transgenic plants as edible vaccines — reality and future prospects |
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Інститут молекулярної біології і генетики НАН України |
| publishDate |
1999 |
| topic_facet |
Обзоры |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/155869 |
| citation_txt |
Transgenic plants as edible vaccines — reality and future prospects / N.N. Domansky // Биополимеры и клетка. — 1999. — Т. 15, № 1. — С. 5-9. — Бібліогр.: 15 назв. — англ. |
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Биополимеры и клетка |
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| fulltext |
ISSN 0233-7657. Биополимеры и клетка. 1999. Т. 15. № 1
ОБЗОРЫ
Transgenic plants as edible vaccines — reality
and future prospects
Nickolay N. Domansky
International Institute of Cell Hiology
148 Acad. Zabolotnoho str., Kyiv, 252143, Ukraine
This review describes the recent progress in the construction of transgenic plants for vaccine producti,v
Transgenic plants are an attractive and cost-effective alternative to microbial systems for the productior о
proteins with pharmaceutical value. Advances in biotechnology are enabling plants to be exploitea /·
expression of candidate vaccine antigens with the goal of using the edible plant organs for economical
delivery of oral vaccines. It has recently been shown that genes encoding antigens of bacterial and vira<
pathogens can be expressed in plants in a form in which they retain native immunogenic properties.
Transgenic potato tubers expressing bacterial antigens stimulated humoral and mucosal immune response,
when they were provided as a food. Although the utility of «edible vaccines» to prevent disease remains t<
be established, the successful implementation of this strategy can be the first step on the way to modern
vaccines of new generation.
Introduction. Research on new vaccines has used
molecular biology to identify the antigenic deter-
minants of infectious disease agents and to develop
genetic engineering approaches to produce and deliver
these antigens as subunit vaccines. In recent studies,
tools of plant biotechnology have been added to these
efforts. It has been found that transgenic plants
provide a novel system for production of recombinant
proteins that act as oral immunogens when the plant
products are consumed as food.
Many infectious agents colonize or invade epi-
thelial membranes; these include bacteria and viruses
that are transmitted via contaminated food or water
or by sexual contact.
Vaccines that are effective against these in-
fections must stimulate the mucosal immune system to
produce secretory IgA (S-IgA) at mucosal surface
such as the gut and respiratory epithelia. In general,
a mucosal immune response is more effectively achi-
eved by oral, rather then parenteral, antigen delivery.
Several particulate antigens have proven to be effec-
tive oral immunogens, including live and killed micro-
organisms. By comparison with parenteral immu-
nization, oral immunization using subunit or soluble
antigens is often inefficient at stimulating an immune
© N. N. DOMANSKYt 1998
response, and requires largeramounts (mg versus μ%>
of antigen.
Subunit vaccines based upon recombinant cell-
culture expression systems are feasible but, for con-
mercial-scale production, these systems require fei
mentation technology and stringent purification pro
tocols so that sufficient amounts of recombinan
protein can be obtained for oral delivery. Even witK
technological improvements, fermentation-based su
bunit vaccine production may be prohibitively ex
pensive technology for developing countries where
novel oral vaccines are urgently needed Transgenic
plants that express antigens in their edible tissue
might be possible simply through consumption of a
«edible vaccine».
The concept of vaccine production in transgenic
plants was introduced about 6 years ago by Charles
Arntzen and Hugh Mason at Texas A&M University
[1 ] greatly stimulating research in this directio!
[ 2 - 8 ].
In general, research in this field falls into t>)u:
general categories. First, experiments have been cc -
ducted to determine the capacity of plants to produce
foreign proteins that retain antigenic determinants
necessary for effective immunization. Second, the oral
immunogenicity of plant-derived proteins has beer·
evaluated with special emphasis on th<
<c
DOMANSKY Ν. Ν.
immunogenicity of food samples. Third, research has
been conducted Io find an appropriate food crop that
could be used for both production and distribution of
vaccines, with special emphasis on the developing
world.
Hepatitis B surface proteins. The first studies of
candidate vaccine expression in transgenic plants have
been carried out using the gene encoding hepatitis B
surface antigen (HBsAg) [1, 3]. This protein was
chosen because the commercially available vaccine
and the associated human immune response have
been very well characterized, because the structure of
the immunogenic form of that protein was known, and
because the availability of a cost-effective recombinant
HBV vaccine is a high priority especially for the
developing countries. Moreover, the existence of com-
mercially available test systems for HBV detection
substantially simplified the procedure of HBsAg de-
tection in plant tissues.
The envelope of hepatitis B virus (HBV) consists
of three polypeptides which comprise the large (L),
middle (M) and major or small (S or HBsAg) protein
components. These three proteins are encoded in a
large open reading frame, which is divided into preSl,
preS2 and the S gene. The S protein or HBsAg is a
major component of the: hepatitis B virions and
contains 226 amino acids. The HBV M protein
contains additional 55 amino acid residues at the
N-terminal of the S protein, usually called the preS2
antigen. Similarly, the L protein contains additional
108—119 amino acids, depending on the serotype of
the virion, at the N-terminal of the M protein [9].
The S gene was introduced into cells of tobacco
[1] and potato [3] plants and individual trans-
formants were regenerated. When extracts from tran-
sgenic plant tissues were examined the presence of
HBsAg were revealed by ELlSA using monoclonal
antibodies directed against human-serum-derived
HBsAg. Further examination of plant-derived HBsAg
purified by immunoaffinity chromatography revealed
the presence of spherical virus-like particles with an
average size of 22 nm. These particles exhibited
properties that were very similar to the subvi^al
particles obtained from human serum and to the
recombinant HBsAg which is formulated in the com-
mercial vaccine produced in yeast cells [1 ]. Im-
portantly, HBsAg in the particle form was found to be
much more immunogenic than that in the form of the
peptide alone [10].
To evaluate the immunogenicity of plant-derived
HBsAg it was used for parenteral immunization of
mice. Anti-HBsAg antibodies were recovered which
reacted with authentic HBsAg from human serum.
This was the first indication, that antigenic properties
of the protein were maintained in transgenic plants
Subsequently, T cells were isolated from mice im-
munized with plant-derived HBsAg. When grown in
culture, these T cells could be activated using со α
mercial vaccine as well as a synthetic peptide which
mimics the «а» epitope determinant of HBsAg. in
total, the immunology studies conducted to date show
that the recombinant HBsAg recovered from plant
cells retain both B and T cell epitopes [5].
Although recombinant HBV vaccines have shown
that HBsAg alone is sufficient to induce a highly
protective immunity, experiments in animals have
highlighted the potential benefits which might resui*
from the inclusion of the preS2 domain in anti-HBV
vaccines [11 J. The preS2 domain is also immunogenic
in humans and elicit anti-preS2 responses during
natural HBV infection, which often occur prior to a ;
other anti-HBV response [12]. For this reason, me
HBV M protein gene (preS2 containing H BsAgj -
been recently expressed in plants 18 ] and physical
and immunological properties of this protein wen-
evaluated [13]. These studies have demonstrated th^i
plant cells have the capacity to not only synthesize M
protein but also to allow it to be assembled in ar
immunologically active form.
To evaluate the immune response to plant-de
rived M protein and to compare it to the response ic
HBsAg from serum (preS2 containing HBsAg), HBV
vaccine and plant-derived HBsAg, Balb/c mice were
immunized intraperitoneally with corresponding an-
tigens. Kinetics of antibody responses were studies j
to 14 weeks after primary immunization. The results
presented in Fig. 1 indicate that both plant-derived
HBV proteins can elicit the anti-HBsAg antibodies in
mice and that the plant-derived M protein is nearly
as immunogenic as the control preS2 containing
HBsAg isolated from serum. Moreover, the presence
of anti-preS2 antibodies in the sera of immunized
Balb/c mice was detected in mice immunized with the
preS2 containing proteins (Fig. 2). These result
suggest that plant system can provide an alternative
method of producing the HBV M protein suitable f.v
vaccination.
Recently, it was also shown that the plant-
derived HBV M protein given to mice by oral intu-
bation (gavage) stimulated serum antibody response
and corresponding specific antibodies were dt tecu .
[14].
Escherichia coli heat-labile enterotoxin B su
bunit. The choice of which antigens to use in ih
initial studies has been strongly influenced by
desire to determine if transgenic plant materia ?
containing foreign antigens will result in oral immu-
nization and stimulate a mucosal immune response
6
TRANSGENIC PLANTS AS EDIBLE VACCINhS
Fig. 1. Kinetics of anti-HBsAg antibody responses in Balb/c mice:
1 — serum HBsAg; 2 - М protein; 3 — vaccine; 4 — S protein;
5 — negative control. Mice were immunized intraperitoneally with the
same amounts of plant-derived M and S proteins, HBsAg from serum
and Engerix vaccine. Solid arrows indicate the time of vaccination
(0, 2nd and 6th week). The presence of anti-HBsAg antibody were
monitored by ELISA
Fig. 2. Comparison of anti-preS2 antibody responses in mice. 12
weeks post-immunization sera from individual mice immunized with
plant-derived M protein (Ml—M6), plant-derived S protein (Si —
S5), Engeruc vaccine (VI — V5) and HBsAg from serum (SRI —
SR5) were tested for (he presence of anti-preS2 antibody by ELISA
Thus, antigens with the high mucosal immune res-
ponse have been the early targets for plant based
expression.
The binding subunit of the heat-labile ente-
rotoxin of E. coli (LT-B) was an obvious candidate
for evaluation in plant expression system since it has
been extensively characterized in structural and im-
munological studies.
The heat-labile enterotoxin (LT) from E. coli is
a multimeric protein that is structurally, functionally
and antigenically very similar to cholera toxin (CT).
It was found that LT has one A subunii (LT-A) and
a pentamer of B subunits (LT-B). Specific binding oi
the nontoxic LT-B pentamer to the Gmi gangliosioes
present on epithelial cell surfaces allows entry of th
toxic LT-A subunit into cells [15]. Antibody Iil
terference with binding of the B subunit ίο cells, lhir
blocking toxin activity, is the basis of attempts to u <
the B subunit as a vaccine component. Because L t
is very similar in structure and immunological pro-
perties to the CT-B, immunization with CT-B lcaas
to cross-protection against enterotoxigenic E. coli
LT-B and CT-B are both potent strong oral im-
munogens.
LT-B also has recently been expressed in plan s
although the levels of expression were low [2 j Th*
oral immunogenicity of recombinant LT-B was tesuc
in mice and compared with bacterial LT-B. Vvh'к
given orally to mice by gastric intubation, the plani-
derived antigen stimulated humoral and mucosa;
immune responses with titers comparable to the
bacteria-derived LT-B. In addition, the antibodies
produced against the tobacco-derived LT-B were abl
to neutralize LT activity, indicating the potentia'
protective value of the immune response.
The oral immunogenicity of unpurified recom-
binant LT-B was also assessed by feeding raw
transgenic potato tubers to mice. After only four
feedings of 5 g tuber samples to mice, mucosal and
serum antibodies were recovered. No immune res-
ponse was observed in animals that were fed non-
transformed tubers.
It should be also noted that CT and LT are
excellent oral adjuvants, which stimulate immune
responses against co-fed antigens at concentration.,
well below those that cause diarrhea.
Norwalk virus capsid protein. Further evidence to
support the concept of edible vaccines have recently
been obtained in experiments with plant-derived Not
walk virus capsid protein (NVCP). Norwalk virus is a
member of the Caliciviridae family and causes epi-
demic acute gastroenteritis in humans. As in the case
of HBV, expression of NVCP in plant cells yields ..
protein that self-assembles in plant cells into virut
7
DO MANS KY N. N.
like particles. The plant-derived NVCP was orally
immunogenic in mice. Extiacts of tobacco leaf exp-
ressing NVCP were given to CDl mice by gavage and
the treated mice developed both serum IgG and
secretory IgA specific for Norwalk virus-like particles.
Furthermore, when potato tubers expressing NVCP
were fed directly to mice, they developed serum IgA
specific for Norwalk virus [7 ].
Vaccines for animal diseases. Edible vaccines can
also provide efficient and humane strategies for
disease prevention in production of companion ani-
mals, as well as feral populations. It is practically
possible to generate vaccines against viral and bac-
terial infections by expressing corresponding antigens
in plant tissues edible for animals. The already
mentioned LT-B subunit is the most likely candidate
for the first commercial vaccine, as enterotoxigenic E.
coli strains readily infect animals as well. Admittedly,
vaccines for animals are a more likely target for
edible-vaccine technology in the near future than
vaccines for human as the latter need more detailed
inspections for safety.
Recently, transgenic plants have been generated
that expressed the gene encoding the glycoprotein
(G-protein) that coats the outer surface of the rabies
virus [6, 14 |.
Although the immunogenicity of these material
has yet to be evaluated, it is encouraging, to note that
ba t containing some G~protein produced in a more
traditional in vitro system was effective in immunizing
raccoons orally, providing protection against «street
virus» challenge.
Future prospects. The research conducted to date
has demonstrated that transgenic plants have the
capacity to synthesize and accumulate subunit anti-
genic proteins that retain immunological properties of
their native counterparts. In the case of HBV proteins
and NVCP, virus-like particles accumulated in plant
cells. It is very significant as the particulate form is
very important in determining immunogenic pro-
perties and has greater oral immunogenicity than
soluble proteins.
Studies remaining to be conducted will involve
the evaluation of dosage requirements for plant-
delivered vaccines. Successful experiments conducted
thus far have used proteins (LT-B and NVCP) with
very high oral immunogeniciity. It will be necessary to
determine if other proteins, which may not be nor-
mally transmitted orally, will be as effective in
inducing an oral response. From this point of view the
results of the oral immunization with the plant-
derived HBV M protein are rather encouraging.
Multi-subunit vaccines, including oral adjuvants such
as LT or CT (or derivatives thereof), and various
fused proteins could be also used for enhancing the
oral response.
It is well recognized that most food proteins do
not trigger an immune response. In general it is due
to the induction of a state of immune tolerance. It will
be necessary to determine if food-based vaccines also
would induce oral tolerance to the desired antigen If
so, controlled use and dosage will be a requirement
for edible vaccines.
The type of plant material that would best serve
as an edible vaccine also has yet to be determined
First studies has focused primarily on tobacco and
potato, but other plants such as corn, soybean-
bananas and others are currently under research.
Lastly, a thorough study of the safety oi the
future edible vaccines needs to be undei'cken. Rc
searches in this area are likely to nci ease oui
understanding of the basic mechanisms, which can be
applied to the development of the new generation o.
vaccines.
M. M. Доманський
Трансгенні рослини як їстівні вакцини — реальність
та перспективи
Резюме
Огляд сучасних літературних даних про створ тя трансген
них рослин для виробництва вакцин. Трансгенні рослини є дух
привабливою та дешевою альтернативою існуючим мікря
біологічним системам виробництва білків б.гя фармацевтики.
Успіхи сучасної біотехнології відкрили можливість експресуво
ти у рослинах різні антигени, що використовуються с:,я
вакцинації, з метою використання їстівних частин рослин для
транспорту оральних вакцин. Було продемонстровано, що
гени, котрі кодують антигени бактеріальних та віруїні. •
патогенів, можуть бути експресовані у рослинах із збережен-
ням їхніх природних імунологічних властивостей. Tак, бульби
трансгенної картоплі, що експресували бактеріальні антигі
ни, стимулювали гуморальну та мукозну імунні відповіді к<«
використанні їх у їжу. Хоча використання їстівних вакцин для
запобігання хвороб ще не доведене, подальшій розвиток цюго
напряму може стати першим кроком на шляху до векцин
нової генерації.
Η. Н. Доманский
Трансгенные растения как съедобные вакцины — реальность и
перспективы
Резюме
Обзор современных литературных данных о создании тра
генных растений для производства вакцин Трансгенные ρ
тения являются весьма привлекательной и дешевой альтерна
тивой существующим микробиологическим системам произ-
водства белков для фармацевтики. Успехи современной био-
технологии открыли возможность экспрессировать в расте-
ниях различные антигены, используемые при вакцинации, для
применения съедобных частей растений при транспорте ора-
льных вакцин. Было продемонстрировав, что гены, кодирую-
щие антигены бактериальных и вирусных патогенов, могут
8
TRANSGENIC PLANTS AS EDIBLE VACCINES
быть экспрессировапы в растениях с сохранением их природ-
ных иммунологических свойств. Так, клубни трансгенного
картофеля, жспрессировавиїие бактериальные антигены, сти-
мулировали гуморальный и мукозный иммунные ответы при
употреблении их в пищу. Хотя использование съедобных вак-
цин для предотвращения болезней еще не доказано, дальнейшее
развитие этого направления может стать первым шагом на
пути к созданию вакцин нового поколения.
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2. Hoq Τ. A., Mason H. S., Clements J. D., Arntzen C. J. Oral
immunization with a recombinant bacterial antigen produced in
transgenic plants 11 Science.—1995.—268.—P. 714—715.
3. Domansky N. N.. Ehsani P., Salmanian A-H., Medvedeva T.
Organ-specific expression of hepatitis B surface antigen in
potato / / Biotectmol. Lett.—1995.—17.—P. 863—866.
4. Mason H. S., Arntzen C. .1. Transgenic plants as vaccine
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Received 26.01.98
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