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ISIS Report 12/09/12
DNA Contamination in HPV vaccines

A serious safety issue that should not be swept under the regulatory carpet.
Professor Joe Cummins

When the Human Papilloma Virus (HPV) vaccine Gardasil was recently found to be
contaminated with DNA, the US Food and Drug Administration (FDA) lost no time in
declaring that the DNA was not a contaminant but a harmless by-product of
vaccine production. I disagree; that extraneous DNA is potentially harmful. It
should also be noted that the safety and efficacy of HPV vaccines have been
controversial from the start (see [1] The HPV Vaccine Controversy and other
articles in the series, SiS 41).

The virus

HPV establishes productive infections only in keratinocytes of the skin or
mucous membranes. While the majority of the known HPV types cause no symptoms in
most people, some types can cause warts (verrucae), while others can lead to
cancers of the cervix, vulva, vagina, penis, oropharynx and anus.

Recently, HPV has been linked to an increased risk of cardiovascular disease. In
addition, HPV 16 and 18 infections are strongly associated with an increased
risk of developing throat cancer. Worldwide in 2002, an estimated 561 200 new
cancer cases (5.2 %) were attributable to HPV, making HPV one of the most
important infectious causes of cancer, and cervical cancer is the second most
common cancer in women worldwide. In 2008, there were an estimated 529 000 new
cases of cervical cancer and 274 000 deaths; more than 85 % of the deaths in
developing countries, where it accounts for 13 % of all female cancers [2]. 

The viral genome

The HPV genome consists of 8 genes coding for proteins and a non-protein-coding
region with regulatory genes. The genes are distinguished as early and late
functioning in virus development. The early genes include those involved in
virus replication and transcription along with the oncogenes for cancer
development. The late genes encode the two structural proteins L1 and L2 of the
virus capsid. 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 cell chromosome. Integration disrupts a viral transcription regulatory
protein that controls the production of the cancer proteins, leading to their
continual and enhanced production [3] (Recombinant Cervical Cancer Vaccines, SiS
29). HPV integration into human chromosomes is non-random; with integration hot
spots in chromosome regions homologous to the oncogene E5 of HPV or the
structural protein L2 [4]. Women with cervical cancer have been found with viral
chromosomes integrated completely or partially as chromosome fragments, or as
independent episomes. Partially integrated HPV was most prevalent in women with
cancer while complete virus integration was about half as frequent and the
episomal form rare. The cancer- causing integration breaks the HPV chromosome at
the E1/E2 region, causing a loss of that region.  This in turn results in loss
of control of the cancer genes E6 and E7. The E7 cancer gene produces a protein
that inactivates the retinoblastoma gene ­ a cancer suppressor gene - of the
host cell, thereby promoting cancer [5]. (Retinoblastoma is an inherited cancer
of the eye caused by loss of the retinoblastoma gene.)  The main lesson is that
fragmentation  or breakage of the  HPV DNA is an important factor in cancer
progression of the host cell.

Gene transcription

The viral genes have a complex transcription pattern. There is a single promoter
for all of the early genes. The early promoter initiates production of a large
pre-messenger RNA from which messages containing exons and introns are then
spliced to generate each of the early proteins. The other viral promoter
initiates production of pre-messenger for structural proteins L1 and L2, which
also contain exons and introns, and are similarly spliced prior to translation
of the messenger RNA into protein.  There are early and late polyadenylation
(poly A) signals for the large pre-messenger RNA transcripts. Gene expression of
HPV is tightly coupled to the developmental status of the host cells [6].

Micro RNAs are very small (around 22 nucleotides in chains) non-coding
regulatory gene products of cells. Micro RNAs are altered in a number of human
cancers and one is significantly elevated in HPV anal cancer [7]. A cluster of
micro RNAs was found associated with HPV head and neck cancers [8]. The natural
history of HPV cancers shows a complex pattern of gene transcription and micro
RNAs are implicated in the development of HPV cancers.

HPV vaccines

HPV vaccines have been deployed worldwide since 2006. Two vaccines have been
commercialized: Gardasil, manufactured by Merck and Cervarix, manufactured by
GlaxoSmithKline. They are prophylactic, that is, they prevent cervical cancer
but do not cure existing infections, and are based on the L1 virus-like
particles to achieve immunity against HPV. The L1 protein is capable of self-
assembly to form empty virus like particles that activate the human immune
system to form antibodies. The HPVs targeted by the vaccines are “high risk”
types 16 and 18 and “low risk” types 6 and 11. The two commercial HPV vaccines
are both made using genetically modified (GM) microbes in a laboratory. Gardasil
protects against all four HPV types because it contains virus like particles
with mixtures of the four subunit proteins, and is called a tetravalent vaccine.
The four L1 proteins are manufactured using GM baker’s yeast. Cervarix protects
against the HPV types 16 and 18, and is a bivalent vaccine, and is manufactured
using GM baculovirus (a soil-born insect virus) in cultured insect cells [9].

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