Recombinant Cervical Cancer Vaccines

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Recombinant Cervical Cancer Vaccines

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Tue, 20 Dec 2005 15:02:36 +0000

 

 

 

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This article can be found on the I-SIS website at

http://www.i-sis.org.uk/RCCV.php

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ISIS Press Release 20/12/05

 

Recombinant Cervical Cancer Vaccines

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Prof. Joe Cummins

 

A fully referenced version of this article is posted on ISIS

members' website http://www.i-sis.org.uk/full/RCCVFull.php.

Details here http://www.i-sis.org.uk/membership.php.

 

Human papilloma virus and cervical cancer

 

Merck Company released the results of clinical studies on a

recombinant vaccine Gardasil in October 2005, claiming 100

percent efficacy in preventing cervical cancer from human

papilloma virus (HPV) strains 16 and 18, believed to cause

about 70 percent of cervical cancers [1].

 

HPV infection frequently results in warts of the genital

mucosa, and certain strains – HPV16, 18, 31 and 45 - are

responsible for squamous cell carcinoma of the uterine

cervix; HPV16 alone accounts for over half the cases

worldwide.

 

The virus chromosome consists of a circular, 8 thousand base

pair DNA genome encased in an icosahedral capsid (coat) made

of protein. (An icosahedron is a solid with 20 triangular

faces.)

 

The HPV genome consists of 8 genes coding for proteins and a

non protein-coding region with regulatory genes. HPV infects

the basal cells of the cervical epithelium when it is

damaged in some way. The viral genome becomes established in

the basal cells as an episome (an independently replicating

nuclear micro-chromosome). The episome replicates in tandem

with the chromosomes of the cell and forms virus particles.

The complete virus particles are in the outermost cells of

the epithelium and the viruses are spread as the cells

slough off from the epithelium. Some virus proteins function

as oncoproteins, transforming the epithelial cells to a

precancerous state. HPV infection is necessary but not

sufficient for cancer formation, however. 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 percent 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 the use of Pap cytology (Pap smears) in

diagnosis. Pap screening has not been available in

developing countries and those countries now have the

highest levels of cervical cancer. The Pap smear is only 50

percent effective in detecting cervical cancer early, so an

effective cervical cancer vaccine will be welcome in both

developed and developing countries [3].

 

Clinical trials of vaccines against HPV

 

Two main types of HPV vaccines are currently being

developed: prophylactic vaccines that ward off HPV

infection, and therapeutic vaccines to induce regression of

precancerous lesions caused by HPV or even remission of

advanced cervical cancer [3].

 

The two clinical trials completed at this time are those

conducted by Merck and GlaxoSmithKline, which are very

similar in design and outcome, but differ mainly in the

origin of the recombinant vaccine. The Merck 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 the protein was produced using a

recombinant Baculovirus propagated in insect cells. 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. Subjects ranged in age from 15 to

25 years in both studies, with no history of cervical

lesions and few sexual partners. The Merck study lasted 4

years while the GalaxoSmithKline study lasted 27 months.

 

In the Merck study, the incidence of persistent HPV-16

infection was 3.8 per 100 woman-years at risk in the control

group compared to 0 per 100 woman-years at risk in the

vaccine group. In the GlaxoSmithKline study, 27 women in the

control group compared to two in the vaccine group had HPV-

16 and/or HPV-18 associated cytological abnormalities.

 

Also assessed were women with histologically confirmed

cervical intraepithelial neoplasia lesions (cancers),

resulting from HPV-16 or HPV-18 infection. Overall, seven

women (six in the placebo group and one in the vaccine

group), developed these lesions. However, the cancer

confirmed in the inoculated group resulted from infection

with a strain of the virus not vaccinated against.

 

Immunization against HPV has greatest value in developing

countries where 80 percent of the world's cervical cancers

appear and where Pap screening is inadequate. Long lasting

protection against HPV 16 may prevent half of the world's

cervical cancer cases [3].

 

Vaccines for resource-poor settings?

 

The report of the Merck study [4] did not provide detailed

information on the production of L1 protein in yeast, but

appears to involve secretion of the protein from the yeast

cell by adding a leader sequence from yeast to the HPV L1

gene [5]. Recently, a potential oral vaccine consisting of

HPV 16 L1 protein was produced in the fission yeast S. pombe

[6]. Pombe yeast is used in brewing in Africa so production

of the vaccine seems feasible. Report on the

GalaxoSmithKline study [7] also provided no detailed

information on vaccine production, but this was covered in

previous publications [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 require considerable

forethought and 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 for 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. Feeding transgenic potato tubers to mice produced

an LI antibody response in only 3 of 24 mice and that

response was transient [12]. The oral administration of HPV-

like particles produced in potato produced a weak immune

response in mice, which 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 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 response to antigens in food. Thus, after repeated

exposure to an oral antigen, the mucosal immune system

ceases to view the antigen as foreign, 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, I pointed out the drawbacks of using food crops

to produce vaccines or therapeutic antibodies [17]. Genes

from tests sites or production farms can be spread by pollen

or mechanical dispersal of seeds. Debris from transgenic

crops producing the antibody can spread both the genes and

the vaccine proteins by contaminating surface and

groundwater. 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 & tobacco, and banana, maize and rice have been

discussed as systems for producing the vaccine.

 

The fission yeast S. pombe developed to produce HPV vaccine

is also of questionable safety. Pombe beer is produced

locally in many parts of Africa and pollution of that 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, there is a

distinct danger of oral tolerance developing that not only

cancels out the protective effects of the vaccine against

infection, but could also leave females absolutely

defenseless against the virus while turning males into

carriers spreading the virus.

 

The recombinant vaccines producing viral proteins without

viral DNA are acceptable, but production of oral vaccines in

plants or yeast should be banned.

 

Please circulate this widely to your policy-makers and

regulators.

 

 

 

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http://www.i-sis.org.uk/RCCV.php

 

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