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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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