The first cancer vaccine, Gardasil, was approved
by the Food and Drug Administration (FDA) in June 2006. Gardasil
is approved to protect girls and women, ages 9 through 26, from
the two types of Human Papillomavirus (HPV) infection that are
responsible for most cervical cancer cases. It has very limited
effectiveness, however, against other types of HPV that cause
approximately 30% of cervical cancers. For that reason, girls
and women who are vaccinated with Gardasil will still need regular
Pap smears to detect cervical cancer in its early stages when
treatment is most effective.
HPV is the name for a group of viruses that cause cervical cancer,
genital warts and several other diseases.
1
There are more than 120 types of HPV, and as many as 40 of them
are spread through sexual contact, affecting the genital areas
of men and women.
2 Although most types
of HPV do not increase the risk of cancer, at least 15 of the
40 types spread by sexual contact have the potential to cause
cancers in male or female genitals, the anus, or the throat area.
3
Two of these-HPV 16 and HPV 18-are responsible for approximately
70% of all cases of cervical cancer. Gardasil offers protection
against infections caused by both of these types. The vaccine
also provides protection against HPV types 6 and 11, which cause
approximately 90% of all cases of genital warts, but do not cause
cancer.
1
HPV is especially dangerous because many of the approximately
6 million people who are infected with genital HPV each year in
the United States have no symptoms and therefore do not even know
that they are infected. The good news is that in 90% of cases,
HPV clears up on its own within 2 years.
4
Although most HPV infections are short-term, women with persistent
infections that last several years are at higher risk for developing
cervical cancer.
4 Not all HPV causes
cancer, but 99% of cervical cancer can be traced to infection
with a strain of HPV.
5 In 2008, approximately
11,000 women in the U.S. were diagnosed with cervical cancer,
and an estimated 3,800 women died from cervical cancer, which
accounts for less than 1% of all cancer deaths in the U.S.
6
Worldwide, however, cervical cancer is the second most common
cancer in women and the third most important cancer in terms of
deaths, killing approximately 300,000 women each year.
7
Public health officials in the U.S. encourage women to have a
Pap smear at least every 3 years beginning at age 21, or when
they become sexually active. Using Pap smears to detect cervical
cancer or precancerous lesions has significantly decreased the
number of deaths from cervical cancer. According to the Centers
for Disease Control and Prevention (CDC), U.S. deaths from cervical
cancer are more likely among women who are uninsured or underinsured.
More than half of all U.S. women diagnosed with cervical cancer
report never having had a Pap smear or not having one in the past
five years.
8
All women still need regular Pap smears, whether or not they are
vaccinated with Gardasil, and whether or not Gardasil remains
effective for a woman's entire life. Approximately 30% of cervical
cancers are not linked to the HPV types 16 and 18 that the vaccine
protects against. It is important to note that cervical cancer
has a long lag time between exposure to HPV and the onset of disease,
so women may incorrectly assume they are no longer at risk because
they are not sexually active or have been in a long-term monogamous
relationship. Unfortunately, those women may still be at risk
because of previous exposure.
While HPV can cause penile cancer in men, and anal cancer in men
and women, these cancers are much rarer than cervical cancer.
About 1,700 men a year in the United States are diagnosed with
penile (800 cases per year) or anal cancer (900 cases per year),
with gay men, bisexual men and men with HIV/AIDS at higher risk.
2,
9, 10
Gardasil: The Only HPV Vaccine Available in the U.S.
Gardasil is administered in three doses over a six-month period.
The vaccine data thus far are short-term, and Gardasil states
very clearly on the home page of its website (
www.Gardasil.com),
although not in its television ads: "The duration of protection
of Gardasil has not been established." Several clinical trials
of varying length have been carried out, but none for 10 years
or longer, and we still cannot be certain whether the immunity
to HPV triggered by Gardasil will last for more than a few years.
Because cancers take so long to develop, we will not know the
true impact of Gardasil on cervical cancer for several decades.
What we do know is that Gardasil provides short-term protection
against various strains of HPV (those targeted by the vaccine
and one other high risk type) and certain kinds of lesions known
to be precursors of cervical cancer. We know this from clinical
trials in which women ages 16 to 23 were observed for up to 4.5
years after having completed all three doses of the vaccine.
11,12,13,14
We don't yet know what kind of protection Gardasil offers in the
long-term, or whether a booster dose will be needed. According
to the FDA," …actual efficacy data is lacking for recommendation
for a 4th dose."
15 Despite the FDA's
statement, Merck gave all the women in the vaccine group of their
longest study a fourth dose of vaccine at 60 months, and that
booster increased antibodies to HPV back to the levels they were
after initial vaccination.
12 However,
Merck did not study the impact of this booster by comparing new
HPV lesion development in women who had the booster to those who
did not. Moreover, they stopped their study one month after the
booster, making it impossible to determine how long the booster
shot is effective and whether more booster shots will be needed.
12
Merck's decision to provide a booster to all vaccinated women
at 60 months-called a "challenge dose"-is consistent with research
indicating that Gardasil's protection against one of the two cancer-causing
strains of HPV may diminish considerably over time. By administering
the booster, Merck made it impossible to determine what percentage
of women are protected against any of the HPV strains after five
years without a booster. However, even after only three years,
at least one woman in their study developed a grade 1 cervical
lesion caused by HPV 18.
15 It is
clear, therefore, that she was no longer protected by the vaccine.
The questions about whether a booster dose is needed, and when,
and how many more years of protection it would offer are urgent
ones-for vaccinated women who believe themselves protected, and
for state and other health officials who need to budget for the
cost of the vaccine. Gardasil is the most expensive vaccine to
have ever been recommended for school-age children. The vaccine
manufacturer charges $120 for each dose, and the total cost per
patient for the initial 3-shot regimen ranges from $400-$1,000.
The high cost of the vaccine and the unknowns about the cost and
frequency of booster shots raise concerns that uninsured women
and less affluent women will not be able to afford continued vaccine
protection against HPV and cervical cancer as adults, even if
the vaccine is paid for when they are children. An additional
concern is that vaccinated women might misunderstand the amount
of protection from the vaccine and therefore fail to seek regular
Pap screening. Uninsured and low-income women are especially of
concern because they are least likely to get regular Pap smears
and therefore are the most likely to die of cervical cancer.
Ten-year trials are being carried out with young adolescents in
Finland and Sweden, but these will study the impact of the vaccine
on lesions and disease, with less emphasis on monitoring antibody
titers (immunity). Although lesions and disease are the most important
measure of vaccine success, studies that do not also regularly
measure antibodies are unlikely to answer questions about the
need for boosters for at least 10 years, and possibly much longer.
National Recommendations
On June 29, 2006, the CDC's Advisory Committee on Immunization
Practices (ACIP) recommended that Gardasil be given routinely
to all 11-12 year old girls. The recommendation was based on less
than two years of efficacy, safety and immunogenicity data provided
to the FDA from clinical trials with 16-23 year-olds, combined
with safety and immunity studies in 9-15 year old girls.
16
Why was Gardasil recommended for girls 9-15 years old without
efficacy data based on lesions? These younger girls developed
similar antibody titers to the 16-23 year olds, who were protected
from lesions, so the assumption was that the vaccine would be
equally effective. However, rather than recommending the vaccine
for 9 year olds, the ACIP recommended it for 11-12 year olds as
a means of increasing contact with pre-teens, all of whom need
preventive counseling and screening on issues of national concern
such as obesity, depression and the consequences of unprotected
sex. According to the American Academy of Pediatrics, pediatricians
have generally been unsuccessful at persuading parents to bring
in their 11-12 year olds for preventive counseling and screening
for risky health behaviors. It was felt that the HPV vaccine might
be the incentive parents needed to bring in their daughters for
this more inclusive preventive physician visit.
17,
18
The U.S. Department of Health and Human Services accepted the
Committee's recommendation and it is estimated that 85-89% of
children with health insurance are covered for Gardasil and other
routine vaccinations.
19, 20,
21 The CDC Committee has also recommended
that the HPV vaccine be included in the Vaccines for Children
(VFC) Program, the federal program which provides free vaccinations
to children 18 years of age and under who are uninsured, on Medicaid,
protected by the Indian Health Services Act, or underinsured patients
at Federally Qualified Health Centers and Rural Health Clinics.
22
Approximately 41% of all childhood vaccines in the United States
are purchased by and administered through the VFC Program.
23
However, the CDC recommendation does not include a booster shot,
and even if it did, once the girls were older than 18 years, the
VFC Program would not cover the cost of Gardasil or a booster.
The high cost of the vaccine is important to insurance companies
and state health officials. Insurance companies in New Hampshire
opted to contribute a lump sum to state health funds for VFC rather
than reimburse policy-holders for Gardasil and other vaccines
required of 11-18 year olds.
24 Yet
even with monies from private insurance companies, state health
departments will likely not have enough money to purchase 3 doses
of Gardasil for every 9-18 year old in their state who qualifies
under VFC. In 2007, New Hampshire planned to spend $4.9 million-28%
of the state immunization budget-on Gardasil alone.
24
At What Age is Gardasil Most Effective?
The data that Merck presented to the FDA in 2006 indicated that
Gardasil would not be effective against strains of HPV that the
women were currently infected with at the time of vaccination.
This finding has often been misunderstood. For example, the CDC
web site says "Ideally, girls/women should get this vaccine before
their first sexual contact when they could be exposed to HPV.
This is because the vaccine prevents disease in girls/women who
have not previously acquired one or more types of HPV prevented
by the vaccine. It does not work as well for those who were exposed
to the virus before getting the vaccine…The vaccine will not treat
existing infections." This statement fails to clearly distinguish
between active HPV infections (which the vaccine does not cure)
and previous HPV infections (which apparently do not interfere
with the vaccine's effectiveness). This is an important distinction
because the CDC's research shows that approximately 10% of all
children have been exposed to HPV 16, the most cancerous of the
HPV types, in their first decade of life.
25,
26 In addition, the Merck trials showed
that among sexually active 16-23 year old females, 20% had been
exposed to one or more of the four HPV types covered by the vaccine,
but only 15% had a
current infection with one or more of
those four HPV types.
Since HPV exposure can occur even in the first 10 years of life,
there is no age during which Gardasil will always be effective
for everyone. An ideal age to give Gardasil cannot be predicted
by youth or previous sexual exposure. Since HPV can go away by
itself, it is not clear from their statements whether the CDC
believes that women previously exposed to HPV at any time will
benefit less from the vaccine, or only those infected at the time
they are vaccinated.
However, when longer-term data became available in 2008, it became
clear that most teenagers and women who were vaccinated after
being previously exposed to HPV have even more antibodies, and
therefore even better protection, than those who were vaccinated
before they became sexually active.
13
Only the small proportion of girls and women with active HPV 6,
11, 16 or 18 infections at the time of vaccination do not benefit
from Gardasil in the 3-4 years following the vaccination.
Based on the data presented in 2006, Merck concluded that the
vaccine should be prescribed to girls
before they become
sexually active. Since CDC routinely assumes that vaccines provide
life-time protection, vaccinating young girls was also considered
the most cost-effective strategy, costing $43,600 for each healthy
year of life saved.
27 However, given
that Merck administered a fourth dose of vaccine at 60 months,
it appears that Merck believes a booster is necessary, although
the company has not said so in any publicly available written
materials. A cost effectiveness study published in the
New
England Journal of Medicine in 2008 concluded that if the
vaccine provided protection against HPV for only ten years, then
vaccinating preadolescent girls would only provide a "2% marginal
improvement in the reduction in the risk of cervical cancer as
compared with screening alone." Moreover, it would cost $144,100
for each healthy year of life saved, instead of the $43,600 estimated
for a vaccine providing life-long protection.
27
Most researchers believe that interventions costing more than
$50,000 per quality-adjusted year of life (QALY) saved are not
cost-effective, while others use a higher ceiling of $100,000.
The discrepancy between Merck's initial claims that the vaccine
was most effective for young girls not yet exposed to HPV, and
new data indicating the vaccine may be
more rather than
less effective for sexually active teenagers and young women has
important policy implications. These data therefore deserve close
scrutiny.
Antibody titers indicate immunity, and for any vaccine these tend
to decrease over time. What is not known is how high titers have
to be in order for a person to be protected from a given disease.
Merck's researchers measured titers to HPV 16 and 18 in girls
9-12 years old 30 months after vaccinating them. For young women
between the ages of 16-26, Merck's researchers measured titers
at 38 to 50 months. Even though the older group's titers were
measured later and would therefore be expected to be lower, the
16-26 year old women who had already been exposed to HPV 16 or
18, and had not had any cervical lesions develop from the infections,
had almost as high or a higher immune response to the vaccine
as the pre-teens.
15
Overall, the latest research suggests that, contrary to what has
been stated by the CDC and Merck, sexually active women--even
those exposed to HPV in the past-will benefit from the vaccine,
because most HPV goes away by itself rather than developing into
cervical cancer.
28 A French researcher
recently presented results of a study on 17,000 women and found
that Gardasil prevented cervical lesions among women with previous
HPV exposure at nearly the same rate as it did among women with
no previous HPV exposure: 40 lesions per 10,000 women as compared
with 30 lesions per 10,000 women.
29
Does the Vaccine Provide More Protection than the Virus?
The purpose of any vaccine is to provide more protection against
the health risks of the virus than would occur naturally if the
person was exposed to the virus. Does Gardasil achieve that goal?
Research data that Merck provided to the FDA suggests that the
vaccine may have limited effectiveness for many girls and women,
because just three years after being vaccinated with Gardasil,
one-third of women had lost all their antibodies to HPV 18 while
the rest had the same level of titers as girls and women exposed
to the virus through sexual contact but never vaccinated.
12
While some viruses such as Hepatitis B do not require that the
vaccine against them stimulate titers higher than natural infection,
there are reasons to doubt that this would be true of HPV. Researchers
are divided on this issue-often based on who is funding their
research. Those who believe that only low amounts of HPV antibodies
are necessary to prevent infection, point to the example of the
Hepatitis B vaccine, which gives direct stimulation to the memory
immune system via the blood stream.

Unlike Hepatitis B, however, HPV is an epithelial infection, which
means it actively avoids the immune system, causing very little
stimulation of the memory response.
__________________________________________________________
i The
direct stimulation to the memory immune system requires low to no detectable
circulating Hepatitis B antibodies for protection, instead relying on
the memory response to make antibodies, which can then neutralize the
Hepatitis B floating in the blood. But HPV is not a blood-borne virus,
and does not stimulate memory responses as quickly as Hepatitis B can.
ii HPV
infections require very high circulating levels of antibodies immediately
available to neutralize the new HPV infection. Natural HPV infection
may stimulate a small memory response to replenish the circulating supply
of antibodies.
All experts agree that natural exposure to HPV can cause and therefore
does not prevent people from possibly developing cervical cancer.
That is the reason why the similarity of titers between vaccinated
women and those naturally exposed to HPV is raising questions
about the long-term efficacy of the vaccine. Those doubts are
exacerbated by Merck's decision to give a booster after five years
to all the vaccinated girls and women in their 5 year study.
Given these concerns, research is needed to determine if a booster
given at a particular time can improve Gardasil's protection.
Otherwise, the only people who will benefit from vaccination may
be the very tiny minority of girls or women whose first exposure
to HPV results in a persistent infection lasting more than two
years that progresses to the precancerous cervical lesions, CIN
2 and CIN 3. And, even in those cases, their lesions would have
been detected by regular Pap screening.
At What Age Should Girls be Vaccinated?
Is it a good idea to vaccinate girls as young as 12? Based on
the incorrect information about the ineffectiveness of the vaccine
for sexually active teenagers, several states are considering
laws requiring HPV vaccines for school attendance. In Virginia
and Washington, D.C., for example, all girls entering sixth grade
in the fall of 2009 will be required to be vaccinated against
HPV. While Gardasil may be safe for girls as young as 12, we do
not yet have enough data on how effective it is or how long it
lasts to justify this policy, particularly given the high cost
of the vaccine to working class and middle class parents and to
government health programs for the poor. Gardasil's safety and
antibody response to the vaccine was tested on girls as young
as 9 and 10, but the impact on lesions or disease was not studied
in girls under 16. Given the data indicating a weakening of the
vaccine for HPV 18, a major cause of cervical cancer, a girl vaccinated
with Gardasil at age 12 may have strong protection against cervical
cancer between the ages of 12-15, and then lose much of her immunity
against HPV just as she is likely to become more sexually active
at 15 or 16.
If that is true, scarce public resources could be better spent
to administer the vaccine at age 14, 15, or 16, or to increase
the availability of Pap smears for underinsured or low-income
women.
Another option is to delay making mandatory policy decisions about
the vaccine until Gardasil is compared to the other HPV vaccine,
Cervarix, made by Glaxo Smith Kline. Although Cervarix was approved
in at least 66 countries in Europe and Australia, FDA has required
longer-term studies of Cervarix than they required of Gardasil,
and FDA approval has been delayed while those studies are completed.
Published studies suggest that Cervarix may trigger a greater
immune response than Gardasil, and may provide protections against
both HPV 18 and 16 for at least 6.4 years.
30
Comparisons of the two vaccines would enable policy makers to
make appropriate decisions regarding whether to specifically require
one of the vaccines or give parents a choice. However, neither
parents nor policy makers can make an informed choice until FDA
requires similar long-term research for both products and approves
one or both vaccines on that basis.
As with any sexually transmitted disease, all it takes is exposure
to one infected partner to acquire HPV. However, the chances of
HPV and cervical cancer increase with the number of sexual partners,
and the number of sexual partners of their sexual partners. Research
is now underway to evaluate the effectiveness of Gardasil among
women 27 to 45, and also in boys and men.
Vaccination Effects and Safety
As of August 2008, more than 20 million doses of Gardasil had
been distributed in the U.S. and there were 10,326 reports registered
through the CDC's Vaccine Adverse Event Reporting System (VAERS).
31
Minor side effects, such as pain or tenderness at the injection
site, are quite common. Other reactions, such as headache, fever,
nausea, and dizziness were, at the time of approval, no more likely
after receiving the vaccine than after receiving a placebo.
16
The most common side-effect observed since Gardasil became available
to the public-fainting after receiving the vaccine-is being dealt
with by warning health providers to keep patients under observation
for 15 minutes after giving the shot.
Serious but rare side effects such as Guillain-Barré Syndrome
(GBS), which causes muscle weakness, have been reported, however.
According to the CDC, cases of GBS following administration of
Gardasil do not represent a statistically significant increased
risk, even though 9 of the 13 reported cases of GBS occurred during
a biologically plausible time frame.
32, 33
Therefore, more research is needed to determine if girls or women
vaccinated with Gardasil are at an increased risk for GBS or related
symptoms. Similarly, in Australia, the rate of anaphylaxis shock
after Gardasil injection has been reported as 2.6 per 100,000
doses.
34
Like any public health intervention, a vaccine's risks must be
weighed against its benefits. This is why it is so important to
determine the vaccine's efficacy and how long it lasts. If the
vaccine is offering minimal protection or instilling a false sense
of immunity, almost any risk or adverse reaction becomes unacceptable.