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[SANET-MG] cervical cancer vaccines
* The article below is not directly applicable to sustainable
agriculture. However, I thought that many readers would appreciate
the implication of producing the vaccines in food crops and their
threat to the food supply..
October 8, 2005
Prof. Joe Cummins
Recombinant Cervical Cancer Vaccines
On October 6,2005 Merck Company released results of clinical studies on
a recombinant vaccine ,Gardasil, which is claimed to be 100% effective
in preventing cervical cancer caused by human papilloma virus (HPV)
strains 16 and 18.The two strains are believed to cause about 70% of
cervical cancers (1).GlaxoSmithKline company is also doing clinical
testing of a recombinant vaccine (the two vaccines will be described in
detail below.
The main cause of cervical cancer worldwide is the human papilloma virus
infection. HPV causes a squamus cell carcinoma of the uterine cervix.
The infection frequently causes warts of the genital mucosa. The virus
chromosome consists of a circular , 8 thousand base pair DNA genome ,
which is encased in a icosahedral capsid made up of protein alone. HPV
strains ,16,18, 31 and 45 are the main cause of cervical carcinoma, HPV
16 alone accounts for over half the cases worldwide. The HPV genome
consists of 8 genes coding for proteins and a non protein coding region
with regulatory genes. HPV infect the basal cells of the cervical
epithelium when integrity of the epithelium is compromised by micro
abrasion or other trauma. The viral genome becomes established in the
basal cells as an episome ( an independently replicating nuclear micro
chromosome). The episomes replicate in tandem with the chromosomes of
the cell and ultimately form virus particles. The complete virus
particles are in the outermost cells of the epithelium and the viruses
are spread as the cells slough of from the epithelium. Some virus
proteins functions as oncoproteins transforming the epithelial cells to
a precancerous state. HPV infection is necessary but not sufficient for
cancer formation. In high grade lesions and cancer an episome is
integrated into the cellular chromosome. Integration disrupts a viral
transcription regulatory protein that controls production of the onco
proteins leading to their continual and enhanced production (2).
Cervical cancer is the second most common cancer of women worldwide,
accounting for about 10% of all cancers. The highest risk areas for
cervical cancer include Africa, Melanesia, the Caribbean and Central
America. During the past 50 years cervical cancer declined in developed
countries thought eh use of Pap cytology (Pap smears). Pap screening has
not been available in developing countries and those countries now have
the highest levels of cervical cancer. The Pap smear, though effective,
is only 50% effective so that an effective cervical cancer vaccine will
be welcome in booth developed and developing countries (3),
Two main types of HPV vaccines are currently being developed,
prophylactic vaccines that ward off HPV infection and therapeutic
vaccines to to induce regression of precancerous lesions caused by HPV
or even remission of advanced cervical cancer (3). The main advances
have been achieved with prophylactic vaccines and further discussion
will deal with those recombinant HBV vaccines.
The two main clinical studies completed at this time are the Merck study
and the GalaxoSmithKline study. The two clinical studies are very
similar in design and outcome but differ mainly in the origin of the
recombinant vaccine. The Merck study vaccine was made up of the HPV 16
L1 capsid protein that forms a virus like particle totally lacking DNA.
The L1 capsid protein was produced using transgenic yeast. The
GalaxoSmithKline vaccine used HPV 16 and HPV 18 was also L1 capsid
protein from the two strains but that protein was produced using a
recombinant Baculovirus propagated in insect cells in vitro. Study
subjects received a single intramuscular inoculation. Subjects were
selected from United States citizens in the Merck study and from the
United States, Canada and Brazil in the GalaxoSmithKline study. There
were 768 vaccinated subjects in the Merck study and 560 in the
GalaxoSmithKline study with a nearly equal number of control and
vaccinated subjects in both studies. The age range of subjects ranged
from 15 to 25 years inb the two studies , the subjects had no history of
cervical lesions and few sexual partners. The Merck study was carried on
for 4 years while the GalaxoSmithKline study was carried on for 27
months. In both studies the vaccines were 100% effective in preventing
persistent virus infection and 100% effective in preventing pre-invasive
lesions. There were no serious adverse events in either of the two
studies Immunization against HPV has greatest value in developing
countries where 80% of the world’s cervical cancers appear and where Pap
screening is inadequate. Long lasting protection against HPV 16 may
prevent half of the worlds cervical cancer cases (3).
The complete Merck study was provided in the report by Koutsky et al
(4). However the study report did not provide detailed information on
the production of L1 protein in yeast. Production of HPV 16 L1 protein
included secretion pf the protein from the yeast cell was achieved by
adding a leader sequence from yeast to the HPV L1 sequence (5). Recently
a potential oral vaccine consisting of HPV 16 L1 protein produced in the
fission yeast S. pombe (6). Pombe yeast is used in brewing in Africa so
production of the vaccine seems feasible. The GalaxoSmithKline study was
described in report by Harper et al (7). The report did not provide
detailed information on production of recombinant L1 proteins using a
Baculovirus vector propagated in cultured insect cells. However, earlier
publications described the production of HPV protein using Baculovirus
vectors and insect cell lines(8,9). HPV vaccines production and
distribution in resource poor settings was discussed. Prophylactic
vaccines seem the best long term solution to the cervical cancer
problem. However, financing and distribution of such vaccines requires
considerable forethought and that is not a simple matter(10).
There has been a great deal of effort to promote the production of an
oral HPV vaccine in food plants or tobacco. The belief has been that the
plant based oral vaccines would be cheap to produce and to fill the
needs of the developing world where the need for the vaccine is the
greatest. Tobacco plants were modified to produce HPV 16 protein and
produced sufficient antigen to elicit a weak immune response in rabbits
(11). Tobacco and potato were used to produce HPV 16 virus like
particles that . Feed transgenic potato tubers to mice produced an LI
antibody response in only 3 of 24 mice and that response was transient
(12). The oral immunogenicity of HPV like particles produced in potato
produced a weak immune response in mice but that response was enhanced
by oral boosting with virus like particles produced in insect cell
culture (13). A vaccine against the papilloma virus oncogene product
causing human cervical cancer was
produced using a potato virus-X vector carrying an antigen of the viral
oncogene-encoded
protein [14]. These cancer vaccines are an important effort to control
cancer, but careless
environmental release of the vaccines in crop plants could greatly
increase people’s
susceptibility to specific cancers through the development of oral
tolerance.
Plant-based vaccines are mainly geared towards mucosal immunization
following oral intake. Oral vaccines may elicit oral tolerance on
repetitive exposure. Oral tolerance is the animal’s defense against
antigens in food. Thus, after repeated exposure to an oral antigen, the
mucosal immune system ceases to view the antigen as such, leaving the
animal susceptible to the pathogen for which the vaccine is supposed to
protect against (15). The problem of oral tolerance has been mentioned
in at least one review of plant-based vaccines (16). Oral tolerance to
pathogens is one main threat from the contamination of our food supply
with vaccine genes , this threat is seldom discussed by promoters of
plant genetic modification or by science journals reporting the studies.
Last year Cummins (17) pointed out the drawbacks of using food crops to
produce vaccines or therapeutic antibodies. Genes from tests sites or
production farms can be spread by pollen or mechanical dispersal of
seeds. Both genes and the vaccine proteins can be spread by
contaminating surface and groundwater with debris from the crops
producing antibody. Such debris may also spread with dust in the air
impacting on the airway mucosa directly. The plant based systems for
producing HPV 16 L1 vaccine included potato and tobacco, along with
those crops banana , maize and rice have been discussed as systems for
producing the vaccine. The fission yeast S. pombe was developed to
produce HPV vaccine , Pombe beer is produced locally in many parts of
Africa and pollution of that wild or brewer yeast with vaccine genes is
a strong possibility should the recombinant yeast be dispersed widely.
Exposure of an entire population of women and men of all ages to oral
immunization with polluted crops , beer, water or air would lead to
untoward consequences. A single exposure to antigen might immunize both
females and males, possibly limiting males as virus vectors and protect
females from infection as well. However, constant exposure to viral
antigen would likely cause oral tolerance rendering females defenseless
against the virus and rendering males strong vectors for the cancer virus.
In conclusion, the HPV recombinant vaccines produced in protected
laboratory environments pose little obvious threat to humans or to the
environment. The virus like structures making up the vaccine do not
contain DNA and cannot be replicated in the cell. In the event that
trans-capsidation (virus DNA being incorporated into the vaccine
structures) took place the recombinant virus would replicate only the
original DNA and protein of the capsid. However, once oral vaccines are
produced in crop plants or in yeast a situation dangerous to both humans
and to the environment would be initiated . Recombinant vaccines are
acceptable but production of oral vaccines in plants or yeast should be
banned.
References
1.CNN.com - Study: Vaccine blocks cervical cancer - Oct 6, 2005
http://www.cnn.com/2005/HEALTH/conditions/10/06/cancer.vaccine.ap/
2. Scheurer ME, Tortolero-Luna G. and Adler-Storthz K. Human
papillomavirus infection: biology, epidemiology, and prevention. Int J
Gynecol Cancer. 2005 Sep-Oct;15(5):727-46
3. Franco EL and Harper DM. Vaccination against human papillomavirus
infection: a new paradigm in cervical cancer control. Vaccine. 2005 Mar
18;23(17-18):2388-94
4. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB,
Chiacchierini LM. and Jansen KU. A controlled trial of a human
papillomavirus type 16 vaccine. N Engl J Med. 2002 Nov 21;347(21):1645-51
5. Carter JJ, Yaegashi N, Jenison SA. and Galloway DA Expression of
human papillomavirus proteins in yeast Saccharomyces cerevisiae
Virology. 1991 Jun;182(2):513-21
6. Sasagawa T, Tani M, Basha W, Rose RC, Tohda H, Giga-Hama Y, Azar KK,
Yasuda H, Sakai A. and Inoue M. A human papillomavirus type 16 vaccine
by oral delivery of L1 protein. Virus Res. 2005 Jun;110(1-2):81-90
7. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A,
Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J,
Blatter MM, Korn AP, Quint W. and Dubin G. Efficacy of a bivalent L1
virus-like particle vaccine in prevention of infection with human
papillomavirus types 16 and 18 in young women: a randomised controlled
trial. Lancet. 2004 Nov 13-19;364(9447):1757-65
8. Luxton JC, Rose RC, Coletart T, Wilson P. and Shepherd PS.
Serological and T-helper cell responses to human papillomavirus type 16
L1 in women with cervical dysplasia or cervical carcinoma and in healthy
controls. J Gen Virol. 1997 Apr;78 ( Pt 4):917-23
9. Beljelarskaya,S. A baculovirus expression system for insect cells
Molecular Biology 2002 36,281-92
10. Jacob M, Bradley J. and Barone MA. Human papillomavirus vaccines:
what does the future hold for preventing cervical cancer in
resource-poor settings through immunization programs? Sex Transm Dis.
2005 Oct;32(10):635-40
11. Varsani A, Williamson AL, Rose RC, Jaffer M. and Rybicki EP.
Expression of Human papillomavirus type 16 major capsid protein in
transgenic Nicotiana tabacum cv. Xanthi. Arch Virol. 2003 Sep;148(9):1771-86
12. Biemelt S, Sonnewald U, Galmbacher P, Willmitzer L. and Muller M.
Production of human papillomavirus type 16 virus-like particles in
transgenic plants. J Virol. 2003 Sep;77(17):9211-20
13. Warzecha H, Mason HS, Lane C, Tryggvesson A, Rybicki E, Williamson
AL, Clements JD. and Rose RC Oral immunogenicity of human
papillomavirus-like particles expressed in potato. J Virol. 2003
Aug;77(16):8702-11
14. Franconi R, Di Bonito P, Dibello F, Accardi L, Muller A, CirilliA,
Simeone P, Dona‘ M, Venuti A. and Giorgi C. Plant-derived human
papillomavirus 16 E7 oncoprotein induces immune response and specific
tumor protection. Cancer Research 2002, 62, 3654-8.
15. Ogra P. Mucosal immunity: Some historical perspectives on host
pathogen interactions and implications for mucosal vaccines. Immunology
and Cell Biology 2003, 81, 23-33.
16. Bonetta L. Edible vaccines: not quite ready for prime time. Nature
Medicine 2002, 8, 94-7.
17. Cummins,J. Pharm crops for vaccines and therapeutic antibodies
Science and Society 2004 24, 22-3
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