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ISIS Report 05/01/09
The HPV Vaccine Controversy
uncertainties over efficacy and safety for costly vaccines that only benefit
the drug giants for sure
Prof. Joe Cummins and Dr.
Two years ago
we reported on recombinant vaccines against the human papilloma virus (HPV)
infection and cervical cancer  (Recombinant Cervical Cancer Vaccines, SiS 29).
Clinical trials had been completed on two vaccine formulations, and these
are being commercially released worldwide in government sponsored vaccination
programmes that target women and girls (and even boys) as young as 9 years
of age in a bid to prevent cervical and anogenital cancers . This has
aroused a great deal of controversy, which calls for a fuller discussion.
the US government’s National Cancer Institute , human
papillomaviruses (HPVs) are a group of more than 100 viruses. Certain types
cause warts or papillomas that are benign. The HPVs that cause the common
warts on hands and feet are different from those that cause growth in the
throat or genetial area. Some types are associated with cancer, and are called
“high risk” HPVs.
Of the more than 100 types of HPVs, over 30 can be passed through sexual contact.
Most HPV infections occur without any symptoms and go away without treatment
over the course of a few years. However, HPV infection sometimes persists
for many years, with or without causing detectable cell abnormalities.
Infection with certain “high risk” types of HPV is the major cause of cervical
cancer. Almost all women will have HPV infections at some time in their lives
but very few will develop cervical cancer, as the immune system of most women will
usually suppress or eliminate HPVs. Only HPV infections that persist can lead
to cervical cancer. An estimated 11 000 cases of this kind of cancer is diagnosed
in 2007 in the United States,
with less than
4 000 deaths;
so cervical cancer is not among the major cancers in the US.
Worldwide, cervical cancer strikes nearly half a million women each year,
claiming more than a quarter of a million lives.
High risk” HPV types 16 and 18 are implicated in 70 percent of cervical cancers
and are hence selected for vaccine targets.
The two vaccines are prophylactic,
that is, they prevent cervical cancer but do not cure existing infections. They are based on the L1 virus-like particles
that are required to achieve immunity against HPV. The L1 protein is
capable of self assembling to form empty virus like particles which 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 Gardasil, manufactured
by Merck, and Cervarix, manufactured by GlaxoSmithKline. Both are 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 vaccine contains an aluminum adjuvant. Protection
requires a first inoculation and booster shots at .1 and 6 months after the first. The four L1 proteins are manufactured
using GM baker’s yeast.
against the HPV types 16 and 18, and is a bivalent vaccine containing an aluminum
adjuvant along with a compound called 3-O-deacyclated-4’-monophosphoryl lipid
A. Vaccination is repeated at 1 and 6 months after
the first injection. The vaccine is manufactured using GM baculovirus
produced in cultured insect cells .
HPV prevalence questions
the value and efficacy of the vaccines
A 2007 study
 found that the prevalence of HPV infection among females in the United States was
26.8 percent in a sample of 1 921 individuals between 14 to 59 years: 23.3
percent were among 652 females aged 14 to 19 years, 44.8 percent among 189
women aged 20 to 24 years, 27.4 percent among 174 women aged 25 to 29 years, 27.5 percent
among 328 women aged 30 to 39 years, 25.2 percent among 324 women aged 40
to 49 years, and 19.6 percent among 254 women aged
50 to 59 years. There was a statistically significant trend for increasing
HPV prevalence with each year of age from 14 to 24 followed by a gradual decline
types 6 and 11 (low-risk types) and 16 and 18 (high-risk types), however,
were detected in only 3.4 percent of females: HPV-6 in 1.3 percent,
HPV-11 in 0.1 percent, HPV-16 in 1.5 percent, and HPV-18 in 0.8 percent. Independent
risk factors for HPV detection were age, marital status, and increasing numbers
of lifetime and recent sex partners. The relatively low prevalence of the
vaccine types observed in the study questions the value and effectiveness
of the vaccination programme in the United
In comparison, the HPV prevalence observed in Pap smears of the women in a
rural Nigerian village showed 21.6 percent had HPV, and high risk HPV was present
in 16.6 percent of the women .
answers, more questions”
reports showed a remarkable 100 percent efficacy of the tetravalent vaccine
in women with no previous exposure to the vaccine types of HPVs, reports on
two large, ongoing randomized, placebo-controlled trials give a fuller picture
[7, 8], which elicited an Editorial comment in the New England Journal of
account of the rarity of incident cervical cancer, precancerous cervical lesions
are used as surrogate outcomes for cervical cancer. Adenocarcinoma in the
cervix is a rare lesion widely considered a precursor of cancer. Cervical
neoplasia (abnormal cell growth) is graded from 1 to 3. Grade 1 indicates
active HPV infection and is not considered to be pre-cancerous; current guidelines
discourage treatment of this condition. Grade 2 is treated in most women but
is not an irrefutable cancer surrogate, as up to 40 percent of such lesions
regress spontaneously; current guidelines suggest that some young women with
such lesions do not need treatment. Grade 3 cervical neoplasia has the lowest
likelihood of regression and the strongest potential to become cancerous.
The US Food and Drug Administration considers grade 2 and 3 cervical lesions
and adenocarcinoma acceptable surrogate outcomes for cervical cancer, while
others consider only grade 3 and adenocarcinoma to be more appropriate surrogates.
trials were called Females United to Unilaterally Reduce Endo/Ectocervical
Disease (Future) I and II. In FUTURE I trial, the rates of grades 1 to 3 cervical
neoplasia or adenocarcinoma per 100 persons were 4.7 and 5.9 in vaccinated
and unvaccinated women respectively. This is a very modest efficacy of 20
percent; moreover, the reduction was largely attributed to the reduction of
grade 1 cervical lesions, and no efficacy was demonstrated by higher grade
disease. Vaccinated women also had lower rates of external anogenital and
vaginal lesions (1.3 vs 2.1).
the larger FUTURE II trial, the rates of grade 2 or 3 cervical neoplasis or
were 1.3 in vaccinated women and 1.5 in unvaccinated women, an efficacy of
17 percent, and only significant for grade 2 neoplasia, not for grade 3 neoplasia
The low efficacy is due to two factors. First, 93 percent of FUTURE II subjects
were nonvirgins. In contrast to the Centers for Disease Control’s guidelines,
the American Cancer Society does not recommend universal vaccination among
women between 18 and 26 years, on ground of probable diminished vaccine efficacy
as the number of lifetime sexual partners increases. Second, at least 15 oncogenic
(cancer associated) HPV types have been identified, so targeting just two
types may be insufficient. FUTURE II trial found that the contribution of
nonvaccine HPV to overall grade 2 or 3 cervical neoplasia or adenocarinoma
was considerable. In contrast to a plateau in the incidence of disease related
to HPV types 16 or 18, among vaccinated women, the overall disease incidence
regardless of HPV type continued to increase over time, raising the possibility
that other oncogenic HPV types have taken over after types 16 and 18 were
eliminated. An interim report submitted to the FDA showed a disproportionate,
though not statistically significant number of cases of grade 2 or 4 cervical
neoplasia related to nonvaccine HIV types among vaccinated women.
Nothing can be inferred from the trials about the potential effect of vaccination
among girls younger than 16, as the trials did not enrol subjects in this
age group. Within these trials, subgroups of subjects with no evidence of
previous exposure to relevant vaccine HPV types were evaluated separately
for vaccine efficacy. In these subgroups, efficacy of nearly 100 percent against
all grades of cervical neoplasia and adenocarcinoma were reported. However,
the overall rates of grade 2 or 3 neoplasia or adenocarinoma regardless of
HPV types were not given. Without these data, the Editorial stated : “it
is difficult to infer both the effectiveness of vaccination and the role of
nonvaccine HPV type in overfal rates of precancerous lesions.”
So, despite the vaccination, the women still need to continue cervical cancer
screening, on account of the risk of exposure to other oncogenic HPV types
and the unknown duration of the anti-HPV immunity. Caution is needed in view
of the unanswered questions, and adverse effects that may emerge, and longer
term studies are called for.
More than a year later, another Editorial in the same Journal repeated these
warnings, as no longer-term results from the studies have been published .
And in the meantime, there has been pressure on policymakers worldwide to
introduce the HPV vaccine in national or statewide vaccination programmes.
“How can policymakers make rational choices about the introduction of medical
interventions that might do good in the future, but for which evidence is
insufficient, especially since we will not know for many years whether the
intervention will work or – in the worst case – do harm?”
events cannot be dismissed
following clinical trial or the vaccination programmes must be reported to
the government. The United States FDA and Center for Disease Control published
compilations of the adverse reports associated with Gardasil . Merck distributed
over 16 million doses of Gardasil up to June 2008, and. 9 749 adverse events
were reported: 94 percent classified as non-serious, and 6 percent serious.
Non-serious events included fainting, pain at the injection site, headache, and nausea. Serious events totalled
589, and included 20 deaths following inoculation but these were explained
away “by factors other than the vaccine” following autopsy. Guillian-Barre
syndrome (an autoimmune disease affecting the nervous system) was observed
in individuals vaccinated but the disease was claimed to have appeared at
the normal frequency for a large population. Blood clots were reported in
some people vaccinated but those individuals were found to be taking oral
contraceptives known to cause blood clotting at low frequency. So according
to the FDA: “Gardasil continues to be safe and effective, and its benefits
continue to outweigh its risks.”
Others disagree. The Washington DC
based group Judicial Watch wants further investigation of the vaccine’s safety
. Because adverse reactions to medication tend to be underreported, the
actual number is likely to be higher. Gardasil was fast-tracked and received
FDA approval before its final safety evaluation trials were complete, and
its final safety evaluation trials won’g be concluded until September 2009.
Despite this, the drug is being aggressively mass-marketed on TV and at the
movies in adverts pitched to young girls, including preteens, and state legislators
were heavily lobbied to make the drug mandatory for school girls ages 11 and
up. Parents are understandably reluctant to give the shots to daughters who
are not yet sexually active, and the long-term impacts of which are entirely
Watch’s own report of adverse events include “vomiting, dizziness, seizuresw,
paralysis and Guillain-Barre Syndrome, swelling at the injection site and
in lymph nodes in the neck and goin, fevers, hives, shortness of breath, nausea
and flu-like symptoms. There were reports of a sudden appearance of blisters
on a 20-year-old’s upper arms and back and anogeniotal warts on a 12-year-old.
A 15-year-old reported blisters in her vaginal area within two days of receiving
the vaccine that spread to her upper body and behind her ears and knees. These
lasted five to seven days, then developed scabs. The Judicial Watch report
recorded only 18 deaths, 11 occurred less than a week after the girl had received
the vaccine, seven in less than two days.
Judicial Watch highlighted 78 cases of groin and genital warts, “which weren’t
supposed to happen considering that Gardasil is a vaccine against the two
strains of HPV that caused 90 percent of such outbreaks.”
Cervarix is dispensed in Britain,
and has been receiving adverse event reports since April 2006. For the most
part, the reports were deemed to be unimportant. Interestingly, 870 women
became pregnant during the clinical trials of Cervarix and the spontaneous
abortion rate was not elevated. Nevertheless, pregnant women are advised not
to take the inoculations. Serious adverse events such as swelling of
the lymph nodes and cardiac disorders were observed at very low frequency,
but were deemed not to have been caused by the inoculation . The adverse
event reports are significant but presumed not as serious as the cancers being
prevented by the inoculation.
Vaccination with the HPV
16/18 L1 vaccine provides no benefit for women with pre-existing infection , and may leave them more susceptible to other
oncogenic HPV types . Pre-screening the potential vaccination candidate
for HPV DNA would be desirable, but is not done.
DNA screening proved superior to Pap tests in identifying infected individuals.
Pap testing was 55 percent effective while the DNA tests were 95 percent
effective in identifying high grade cervical neoplasia (precancerous lesions).
The two tests combined were 100 percent effective in identifying the neoplasia
. The long term effectiveness of the HPV L1
vaccine is uncertain and may require booster shots later in life . Currently,
the cost of the vaccine is an obstacle to global deployment of the HPV L1
vaccine. Gardasil costs US$360 for the required three doses while Cevarix
costs $ 33 5 [16 ].
The production cost of the Gardasil active
ingredient is around $3 million per gram, which seems a bit pricey for yeast
fermentation. Producing edible vaccines in transgenic crop plants is being
posed as a cheaper alternative, but that approach is beset with problems of
contaminating our food crops as well as drinking water and the general environment
HPV in males
is common in males as well as females, indeed males are a major source of
female infections and vice versa. Vaccination young males would not only protect
them against HPV but would also prevent much of the infection of females.
In the United States, the infection
of males with HPV was 31 percent of cancer causing virus infection
at any given time. About 75 percent of infected men were clear of infection
a year after the initial detection of infection . The overall prevalence
of HPV infection in men living in Brazil, Mexico
and the United States was 62.5 percent. HPV prevalence
was higher in Brazil than in the United
States and Mexico . HPV
16 and 18 are implicated in human penile carcinomas. The progression of penile
and cervical cancers follows a similar course . The association of HPV
DNA with several different anogenital cancers other than cervical has been
reported for the vulva, vagina, anus and penis. HPV DNA has also been identified
in head and neck
cancers in the oral cavity, the oropharynx and the larynx in both sexes. In
men, 80-85 percent of anal cancers and close to 50 percent of penile cancers
are associated with HPV16 infection . HPV associated
oral cancers are correlated with oral sex in both males and females. The majority
are associated with HPV 16, and it is suggested that they could be prevented
by vaccination with HPV L1 .
and controversy over safety and efficacy surrounds the two HPV vaccines
currently being marketed and promoted worldwide. They are also more expensive
than they should be.
studies on efficacy and safety are needed before they are widely introduced,
or worse, mandated by government.
Producing oral HPV vaccines using transgenic crop plants released into the
environment too dangerous to be considered because the transgenes from the
modified plants are likely to pollute the food supply. Such inadvertent and
persistent oral vaccination would
likely cause the human s to develop oral tolerance
to HPV allowing the virus to thrive in them.
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