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One of our colleagues has posed the questions from Mitchel and others to one
of the developers of the HPV vaccine, Doug Lowy, who is also a coauthor of
the paper in J Clin Invest that Phil referred us to. He has responded as
follows.


Hi Arlene,



I'm in southern California for a few days with intermittent email access.
If you share my comments with others, please disclose that I am an inventor
of the vaccine, and the NIH has licensed its HPV vacciine technology to
Merck (and to GlaxoSmithKline, the other pharmaceutical company that is
developing the vaccine).   I have not been involved in the Merck trials.



I have commented on the questions below after each of them.  Here I comment
on the relationship between HPV infection and cervical cancer.



As you suspect, the evidence that HPV causes cervical cancer goes far beyond
an epidemiological association with the cancer.  Observations with clinical
samples include: cervical HPV infection precedes the development of cervical
precancer and cancer, virtually all cervical cancers contain HPV DNA, and
the cancers preferentially retain and express the viral genes E6 and E7,
which continue to be expressed in cell lines derived from cervical cancer.



There is a wealth of experimental data that E6 and E7 contribute to the
development and maintenance of the tumor.  Suppression of E6 and E7
expression in cervical cancer cell lines eliminates their tumor forming
activity.  In the model, expression of E6 and E7 in the genital tract can
result in cervical cancer.  In cultured cells, E6 and E7 together can
immortalize human epithelial cells, and when you add an oncogene such as Ras
to the immortalized cells the cells will form a tumors in mice.  E6 and E7
induce the inactivation of several cell-encoded tumor suppressor genes, most
notably (but not exclusively) p53 and pRb (the retinoblastoma susceptibility
protein).  In cultured cells and animal models, this inactivation can be
shown to be important for the biological activities of E6 and E7.



In addition, a noteworthy molecular feature of human cervical cancer is that
both p53 and pRb are wild type in almost all tumors.  This feature is in
marked contrast most other cancers, where p53 and pRb are frequently
inactivated by mutation.  The simplest (and most plausible) explanation for
this finding is that E6 and E7  inactivate p53 and pRb sufficiently so there
is no selective advantage to mutation of p53 or pRb in the tumor.  In this
regard, I personally find the situation with oral cancer especially
instructive.  Some oral cancers appear to be caused by HPV infection
(predominantly HPV16, the HPV type found most frequently in cervical
cancer), while others are not (smoking and/or alcohol are other major causes
of oral cancer).  In the oral cancers that contain HPV DNA and express E6
and E7, p53 and pRb are almost always wild type.  In the other oral cancers,
p53 and pRb are frequently mutated.  As noted above, these observations are
all consistent with the conclusion that E6 and E7 contribute to the
development and maintenance of the tumor.



The results of the vaccine clinical trials also support the conclusion that
genital HPV infection causes cervical cancer.  For me, the GSK results
published last year are noteworthy.   Without even considering the question
of whether or not there was HPV infection, there were 11 cases of high grade
cervical dysplasia in the placebo group, versus 3 cases of in the vaccinated
group (the vaccine was a bivalent HPV16/HPV18 vaccine).



Finally, since the 1930s, infection by some animal papillomaviruses has been
known to cause cancer.



Doug



Doug-
   I think that the evidence for "HPV causes cancer" is not "just"
epidemiological. Can you help me address the questions raised below?
     -A

-----Original Message-----
From: Science for the People Discussion List
[mailto:[log in to unmask]] On Behalf Of Mitchel Cohen
Sent: Monday, February 26, 2007 9:25 AM
To: [log in to unmask]
Subject: Re: HPV is the major cause of cervical cancer

I am not saying that HPV is not correlated with cervical cancer.
Correlation and "cause" are two different things, though I appreciate

 the acceptance of epidemiological findings as legitimate science,
here. (Please remember this for other discussions on HIV/AIDS, etc.)

The main questions on Gardasil are:

1) Is there sufficient evidence in the research studies Merck
performed to conclude, as Merck does, that Gardasil prevents cervical
cancer?



*Comment:*  Merck is simply repeating the conclusion of the FDA.  When they
approved the vaccine, the FDA stated, "Gardasil is a vaccine indicated...for
the prevention of...cervical cancer."  It would be unethical to carry out a
phase III placebo-controlled study that used cervical cancer as an
end-point, as such a study requires standard of care, and the standard of
care requires regular cervical cancer screening and treatment of
pre-cancers.  The causal relationship between cervical precancer and
cervical cancer has been accepted for decades, and the treatment of
precancers is almost certainly what has changed the United States from being
a high rate cervical cancer country prior the introduction of the Pap smear
into a low rate cervical cancer country.  More recently, persistent
infection with a high-risk HPV type (i.e., an HPV type associated with
cervical cancer) has been shown to be associated with a high risk of
progression to precancer and cancer.  As Gardasil prevents the infection and
the precancer, it is valid to conclude that it will prevent cervical cancer.





2) Have there been sufficient (or ANY) studies done on the longterm
effects of the vaccine, particularly when given to young girls?



*Comment:* For girls under 16, the answer is no, to the best of my
knowledge.  Merck reported last year on 4 year follow-up data for a
monovalent vaccine (HPV16 only).  Protection continued to be excellent.  GSK
also reported last year on 4 year data for their bivalent vaccine (HPV16 and
18).  Again, protection continued to be excellent.  In these trials, 400-700
women who received the vaccine were analyzed, and a similar number received
the placebo.




3) Are there environmental/toxic-exposure causes for HPV? For cervical

 cancer?



*Comment:* Some (but not all) studies suggest cigarette smoking may be
associated with a higher risk of progression to precancer and cancer.
Erosions in the genital tract may also be associated with viral persistence
and progression.  Immunosuppression (e.g., by HIV infection or with drugs in
renal transplant recipients) is associated with viral persistence and
progression.


4) Can HPV be addressed by other, more natural and less toxic ways,
including removal of any causes due to exposure to pollutants/toxins
and supplementation with L-Lysine?



*Comment:* First, see comments to #3 above.  Second, I am not aware of
relevant clinical trials.  However, a recent publication looked at the
effects of a combination of lysine, proline, ascorbic acid, and green tea
extract on the growth of a couple of cervical cancer cell lines in culture
(Roomi et al, Int J Gynecol Cancer 16:1241-7, 2006).  The clinical relevance
of this study is uncertain.  Third, it is not clear to me that vaccination
is toxic.  From my perspective, the vaccine exposes vaccinees to a higher
dose of the same protein, in essentially the same form, that they are
exposed to during natural infection.  The main difference is that, instead
of being exposed to the protein through the genital tract, the vaccinees are
exposed to the protein through an intramuscular injection, because it is
more effective and socially more acceptable, especially for girls who are
not sexually active.  An adjuvant is used in the vaccine to boost the immune
response to the vaccine.  The adjuvant is needed primarily because it
permits the use of lower levels of the viral protein, and the multivalent
nature of the vaccine (i.e., it contains protein from several different HPV
types) makes it useful to use less protein for each HPV type.







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