The FDA reviewed the clinical trial results for safety and efficacy, and approved Gardasil for use against cervical cancer and genital warts in women in 2006, and against anal cancer in anyone aged 9 through 26 in 2010.
Long story: many long-term studies are still going on. For more info, see "A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD" (full text) and "HPV Vaccine Postlicensure Monitoring and Surveillance Activities - CDC" and see my list of completed studies.
See also "Prophylactic HPV Vaccines: Current Knowledge of Impact on Gynecologic Premalignancies" by Diane Harper, which points out
"While Pap testing is effective, there still remain five specific challenges. First, screening must be done repeatedly over most of the woman's lifetime. Second, false negatives can occur; 30% of women developing cervical cancer having had a history of normal cytology screens (Sawaya and Grimes, 1999). Third, abnormal cytology causes much anxiety for many women (Rogstad, 2002). Fourth, for those women whose screening leads to a diagnosis of CIN 2/3, treatment with loop electrosurgical excision procedure (LEEP) can lead to an increased risk in subsequent pregnancies of preterm delivery, low birthweight infants, premature rupture of membranes, and operative delivery at a rate of 70-300% increase (Arbyn et al., 2008). Lastly, there is no lifetime protection from future HPV infections from her natural infection, leaving a woman at a 3-12 fold increased risk of other anogenital cancers about 10 years later (Edgren and Sparen, 2007)."(Note: that paper also contains a much lower estimate of what portion of HPV-caused cancers are noncervical (12% vs. 55%). The difference may be explained in part by our greater knowledge since then of the role of HPV in throat cancer.)
Manufacturers claim 5 years because studies to show it lasts longer aren't finished yet. A trial of 1781 girls and boys ages 9 to 15 given Gardasil or a non-aluminum-containing placebo reported that protection lasted at least five years (full text). The study is continuing, and at 8 years, the vaccine is still working.
A trial of 3000 Nordic women vaccinated with Gardasil is ongoing, and as of year 9, the vaccine is still working.
An earlier study of 290 women vaccinated against HPV16 in 1998-1999 showed that 77%-93% of the women were still protected against HPV16 8.5 years later.
Long story: "CDC HPV Vaccine Information for Young Women" says
Ideally females should get the vaccine before they become sexually active and exposed to HPV. Females who are sexually active may also benefit from vaccination, but they may get less benefit. This is because they may have already been exposed to one or more of the HPV types targeted by the vaccines. However, few sexually active young women are infected with all HPV types prevented by the vaccines, so most young women could still get protection by getting vaccinated.
Long answer: both the US and Australia have done studies to measure what percent of girls and women have HPV before and after the vaccine was introduced.
The United States has recommended vaccinating girls since 2006. A study of the National Health and Nutrition Examination Surveys from 2003 to 2010 said
Results: Among females aged 14-19 years, the vaccine-type HPV prevalence (HPV-6, -11, -16, or -18) decreased from 11.5% (95% confidence interval [CI], 9.2-14.4) in 2003-2006 to 5.1% (95% CI, 3.8-6.6) in 2007-2010, a decline of 56% (95% CI, 38-69). Among other age groups, the prevalence did not differ significantly between the 2 time periods (P> .05). The vaccine effectiveness of at least 1 dose was 82% (95% CI, 53-93).
Conclusions: Within 4 years of vaccine introduction, the vaccine-type HPV prevalence decreased among females aged 14-19 years despite low vaccine uptake. The estimated vaccine effectiveness was high.
Australia has been actively vaccinating girls since 2007. "Fall in Human Papillomavirus Prevalence Following a National Vaccination Program" says
HPV genoprevalence in women aged 18-24 years attending family planning clinics in the prevaccine period (2005-2007) was compared with prevalence among women of the same age group in the postvaccine period (2010-2011). ... The prevalence of vaccine HPV genotypes (6, 11, 16, and 18) was significantly lower in the postvaccine sample than in the prevaccine sample (6.7% vs 28.7%; P < .001), with lower prevalence observed in both vaccinated and unvaccinated women compared with the prevaccine population (5.0% [adjusted odds ratio, 0.11; 95% confidence interval, 0.06-0.21] and 15.8% [adjusted odds ratio, 0.42; 95% confidence interval, 0.19-0.93], respectively).
In Denmark, about 80% of girls born since 1993 have been vaccinated. A study of all girls born in Denmark from 1989 to 1999 found
The relative risk of GWs among girls who had received at least 1 dose of vaccine compared with unvaccinated girls was 0.12, 0.22, 0.25, and 0.62 for those born in 1995-1996, 1993-1994, 1991-1992, and 1989-1990, respectively (P for trend <.0001). No GWs occurred among vaccinated girls in the youngest birth cohort (1997-1999).
Conclusions: The strong, highly significant reduction in the occurrence of GWs among vaccinated girls indicates an early and marked population effect of the national HPV vaccination program and may forecast a similar effect on cervical precancerous lesions.
For more data, see HPV and Warts.
A clinical trial designed to help answer this question is scheduled to run through January 2019.
But because cervical cancer progresses in stages, usually starting with an abnormal Pap smear, an early indication of success would be a drop in the rate of abnormal pap smears.
In Victoria, Australia, where 72% of all 15-19 year old women (and 47% of 20-24 year old women) had been vaccinated by 2011, high-grade cervical abnormalities (HSIL) among women under age 20 was found in 7 out of 1000 screened, down 50% by 2011 compared to 2008. And in 20-24 year old women, HSIL was found in 16 out of 1000 screened, down 20% compared to 2008.
A later study that compared the vaccination registry with the cervical cancer screening registry estimated that girls who received all three shots on schedule at the recommended age had about half the risk of a highly abnormal pap smear as unvaccinated girls.
This latter study shows that the observed decrease is specific to vaccinated girls, so it really is due to the vaccine.
One team found that, among HPV-positive women, those with abnormal pap smears and those with persistent HPV infections were less likely to eat papaya or oranges every week than those without.
Another study found that, among HPV positive women, those who cleared their HPV infections were more likely to eat vegetables every day than those who didn't.
Cervarix already provides some cross-protection, so if you're worried about non-vaccine high-risk HPV types, you might consider that instead of Gardasil.
"Introducing HPV vaccine and scaling up screening procedures to prevent deaths from cervical cancer in Japan: a cost-effectiveness analysis" (full text) estimated that vaccination and screening together reduced the lifetime risk of cancer to about half that of screening alone.
"Beyond cervical cancer: burden of other HPV-related cancers among men and women" said
In the United States annually (1998-2003), up to ... 4,753 noncervical cancers among men, and 4,128 noncervical cancers among women are potentially attributable to HPV infection. ... incidence rates for anal, oropharyngeal, and vulvar cancers have increased substantially in recent years.The vaccine has been reported to be effective against early stages of anal and vulvar cancer.
"Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data" says
Cervical screening in women aged 20-24 has little or no impact on rates of invasive cervical cancer up to age 30.Accordingly, the UK does not screen women under 25 for cervical cancer. But a few women under that age do die of cervical cancer, and vaccination can prevent many of those deaths.
Long story: As of September 2011, about 40 million doses of Gardasil had been distributed in the US, and there were 71 reports of death; only 34 of these could be confirmed at all, only 23 of these reports look reputable and have no obvious cause, and there is no discernable pattern in the causes of death.
For more data, see HPV vaccine safety.
Long story: "Postlicensure Vaccine Safety Monitoring, 2006-2013 - United States" said
From June 2006 through March 2013, approximately 56 million doses of HPV4 were distributed in the United States... During June 2006-March 2013, the Vaccine Adverse Event Reporting System (VAERS) received a total of 21,194 adverse event reports occurring in females after receipt of HPV4; 92.1% were classified as nonserious. ... during the last 7 years, reporting patterns have remained consistent with the 2009 published summary of the first 2.5 years of postlicensure reporting to VAERS.i.e. there were 1674 serious reactions reported out of 56 million doses distributed. That's a reporting rate of serious reactions of .0029%, i.e. 3 in 100,000.
The lifetime risk of cervical cancer in the United States is about 1 in 147, or about 680 in 100,000.
So (if one trusts statistics from VAERS, which one should not do), the serious adverse reaction reporting rate from Gardasil is about 230 times lower than the lifetime risk of developing cervical cancer.
Looking at death: the reporting rate for death according to the 2009 summary was about 0.1 per 100,000. The lifetime risk of dying from cervical cancer in the United States is about 1 in 435, or about 230 in 100,000.
Again, the vaccine is safer, by a factor of 2300.
Previous surveys on hypothesized sexual activity changes after human papillomavirus (HPV) vaccination may be subject to self-response biases. To date, no studies measured clinical markers of sexual activity after HPV vaccination. This study evaluated sexual activity-related clinical outcomes after adolescent vaccination. ... Conclusions: HPV vaccination in the recommended ages was not associated with increased sexual activity-related outcome rates.
There are several problems with the paper by Little and Ward.
First: the authors have an axe to grind. They are pro-life activists; Dr. Little serves on the board of advisors of Family Life International, a Catholic group which claimed as in 2007 (and still claims today) that the vaccine promotes promiscuity and VD, which is not supported by the evidence. This should have been disclosed as a conflict of interest in the paper.
Second, the paper claims to have ruled out all causes other than Gardasil for the problem... but they didn't check (as far as I know) for the specific mutations estimated to account for 20%-25% of the risk for premature ovarian failure.
Third, premature ovarian failure happens to about one in ten thousand girls by age 20 regardless of vaccination. One estimate is that 66 unvaccinated sixteen-year-old girls would experience this problem each year in the US, so seeing even fifty of these cases in one year would not neccessarily indicate any risk from Gardasil.
The paper by Colafrancesco and Tomljenovic has similar problems; it lists a case of two sisters with premature ovarian failure. When two sisters both come down with a genetically linked disease, it's even more likely that a bad gene is the cause, but that was not mentioned in the paper.
So these case studies don't show that Gardasil is dangerous, they don't show that the four cases were not caused by a genetic problem, and they don't account for the fact that we don't know why the majority of cases of this problem occur with or without Gardasil.
At best, they suggest that a future postlicensure study of the vaccine include premature menopause as a studied endpoint.
( Thanks to Respectful Insolence for posting excerpts of the second paper. )
Long story: Newborn rats injected with the equivalent of the amount of Polysorbate 80 in about 60 doses of Gardasil were found to grow up to be sterile in one experiment in 1993.
Because this was such a high dose, given so early in life when the rats were still developing, it's very hard to say this means Gardasil is risky. Further studies would be needed to establish the level of risk with certainty.
This might need to be rexamined especially if the vaccine is considered for administering to younger children.
Long story: The Phase III trials of Gardasil enrolled thousands of healthy women, checked whether they had HPV at the start, vaccinated them, and then looked at how many of them went on to develop disease. There were two big studies: Study 13, and Study 15. Mostly they analyzed the data from women who didn't have HPV before vaccinating, but they also analyzed the data from women who very definitely had active HPV at the start of the study (about 293 women in Study 13, and 828 women in Study 15).
Because the vaccine works by preventing HPV infection, the expectation was that vaccination wouldn't have any effect on cancer rates.
Here are the results:
|HPV+ Women who developed CIN 2/3 or worse by end of study / total women|
|HPV+ at start of Study 13||31/156||19/137|
|HPV+ at start of Study 15||42/398||48/430|
When they looked closer at the data, they saw that the women who were HPV+ at start of Study 13 weren't randomized very well:
|Study 013 subgroup||Gardasil||Placebo|
|Current smoker at start of study||34.6%||31.4%|
|History of cervicovaginal infection or STD at start of study||35.9%||32.1%|
|Pap test with HSIL at start of study||6.5%||3.7%|
(See Tables 17, 18, and 20, and the conclusion on page 15, of the Phase 3 study summary.)
"The decision (not to recommend the vaccination) does not mean that the vaccine itself is problematic from the viewpoint of safety," said Mariko Momoi, vice president of the International University of Health and Welfare, who headed a ministry task force looking into the matter. "By implementing investigations, we want to offer information that can make the people feel more at ease." ... girls will continue to be able to receive the HPV vaccination for free.The Japanese government web page on the subject has more info. Google Translate does a pretty good job, but not good enough to quote here. I think it says something like this:
"The reason for withholding vaccination encouragementbut I'd appreciate it if someone who reads Japanese could provide a more accurate translation.
A meeting of experts held on June 14 analyzed the medical information that has been collected so far, and concluded the risk is not high enough to stop the routine vaccination.
In that meeting, since not enough is known about side effects such as pain at locations other than the injection site, it was decided to temporarly refrain from agressively promoting cervical cancer vaccination, but to still ensure that those who want the vaccine can get it.
Q. What does "temporarly refrain from agressive promotion of vaccination" mean? Does it mean discontinuing routine vaccination?
A. For Class A diseases, routine vaccination is normally promoted to parents and the public via newspapers, posters, and the Internet.
For some diseases, vaccination is aggressively encouraged, for instance by sending reminders to individual households when it's time for their vaccination.
"Refraining from aggressive vaccination encouragement" means not sending reminders or otherwise promoting the vaccine above and beyond the normal routine vaccine promotion. Nevertheless, the cervical cancer vaccine is still a routine vaccination. For this reason, those who want the vaccine can receive it as a routine vaccination."
"Duration of efficacy is key to the entire question. If duration is at least fifteen years, then vaccinating 11-year-old girls will protect them until they are 26 and will prevent some precancers, but postpone most cancers. If duration of efficacy is less than fifteen years, then no cancers are prevented, only postponed."She then wrote an article laying out her position in detail. (That article was written back when we thought 88% of all HPV-caused cancers were cervical cancer; according to the CDC, the current figure is 45%. Also, that article assumed that HPV vaccination only reduced abnormal pap smears by 10%, but a more current figure is 47.5%.)
More recently, she wrote writing
"US health policy preferences push achieving a high coverage rate of young women instead of relying on possible herd immunity from both sexes of a partially vaccinated population...In other words: she is a cautious advocate for the vaccine, and has never said it should not be used.
A majority of adolescents appear to participate in long chain networks of relationships... Interruption by HPV vaccination may reduce this spanning network into smaller isolated groups, thereby preventing a majority of HPV infections... young men are responsible for infection propagation twice as often as young women. Perhaps... to see a more cost-effective reduction in HPV infections, we should turn our attention to targeting boys before high school entry."
Copyright 2013, Dan Kegel
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