See also: HPV vaccine

Gardasil (Merck & Co.) is a vaccine against certain types of human papillomavirus (HPV).

Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 currently cause about 70% of cervical cancer cases. Type 16 is also associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.^[1] HPV types 6 and 11 cause about 90% of genital wart cases.

Human papillomavirus (HPV) infection causes nearly all cases of cervical cancer. Cervical cancer is the second leading cause of death from cancer in women world-wide^[2], and the leading cause of cancer-related deaths among women in the majority of developing countries.^[3]

The research that led to the development of the vaccine began in the 1980s by groups at the University of Rochester, Georgetown University, and the US National Cancer Institute. In 1991 investigators at the University of Queensland found a way to form non-infectious virus-like particles (VLP), which could also strongly activate the immune system. However, these VLPs assembled poorly and did not have the same structure as infectious HPV. In 1993, a laboratory at the US National Cancer Institute was able to generate HPV16 VLPs that were morphologically correct. These VLPs were the basis for the HPV16 component of the Gardasil vaccine. The history of the discovery of this vaccine is described by McNeil^[4]. Upon commercialization of the vaccine, controversy involving intellectual property arose between the various groups that played a role in developing the vaccine.

History

Clinical trials

Merck & Co. conducted a Phase III study named FUTURE II. This clinical trial was a randomized double-blind study with one controlled placebo group and one vaccination group. Over 12,000 women aged 16–26 from thirteen countries participated in the study. Each woman was injected with either Gardasil or a placebo on Day 1, Month 2, and Month 6. In total, 6,082 women were given Gardasil and 6,075 received the placebo.^[5] Merck has tested the vaccine in only a few hundred 11- and 12-year-old girls.^[6] On February 27, 2006, the independent Data and Safety Monitoring Board recommended the clinical trials be terminated on ethical grounds, so that young women on placebo could receive Gardasil.^[7]

Indications and prevalence

Main article: HPV vaccine#Prevalence of genital HPV

Gardasil is a prophylactic HPV vaccine, meaning that it is designed to prevent the initial establishment of HPV infections. For maximum efficacy, it is recommended that girls receive the vaccine prior to becoming sexually active. However, women who were already infected with one or more of the four HPV types targeted by the vaccine (6, 11, 16, or 18) were protected from clinical disease caused by the remaining HPV types in the vaccine.

Since Gardasil will not block infection with all of the HPV types that can cause cervical cancer, the vaccine should not be considered a substitute for routine pap smears.

Fewer HPV infections mean fewer complications from the virus and less time and money spent on the detection, work-up, and treatment of cervical cancer and its immediate precursor, cervical dysplasia. It prevents infertility caused by cervical biopsies and reduces the severe respiratory problems of children who are infected by HPV from their mothers. In addition, protection against HPV6 and HPV11 is expected to eliminate 90% of the cases of genital warts. Gardasil also may be useful in preventing anal cancer caused by HPV types 16 and 18.^[8] A 2005 study in San Francisco found that 95 percent of HIV-infected gay men also had anal HPV infection, of which 50 percent had precancerous HPV-caused lesions.^[9]

Administration

Gardasil is given in three injections over six months, the second injection is two months after the first, the third injection is four months after the second shot is administered.

Biotechnology

The HPV major capsid protein, L1, can spontaneously self-assemble into virus-like particles (VLPs) that resemble authentic HPV virions. Gardasil contains recombinant VLPs assembled from the L1 proteins of HPVs 6, 11, 16 and 18. Since VLPs lack the viral DNA, they cannot induce cancer. They do, however, trigger an antibody response that protects vaccine recipients from becoming infected with the HPV types represented in the vaccine.

Safety and efficacy

According to the Food and Drug Administration and Centers for Disease Control, the vaccine has only minor side effects, such as soreness around the injection area. The FDA and CDC consider the vaccine to be safe. It does not contain mercury, thiomersal or live virus or dead virus, only virus-like particles, which cannot reproduce in the human body.^[10] Merck, the manufacturer of Gardasil, will continue to test women who have received the vaccine to determine the vaccine's efficacy over the period of a lifetime.

Fainting is common after injections or vaccinations, especially in adolescents. Patients should remain seated for 15 minutes after they receive the HPV vaccine.^[11]

Efficacy

The National Cancer Institute says, "FDA-approved Gardasil prevented 100 percent of the precancerous cervical cell changes caused by the types of HPV targeted by the vaccine for up to 4 years after vaccination."^[12] The vaccine is believed to be effective for longer, but for how long, and whether a booster shot will be needed is still being studied.

Darren Brown, Indiana University, reported at the 2007 Interscience Conference on Antimicrobial Agents and Chemotherapy that Gardasil had 38% efficacy against 10 other HPV types responsible for >20% of cervical cancer cases. ^[13]

Safety

According to the Centers for Disease Control, the vaccine was tested in over 11,000 females (ages 9 to 26). These studies have shown no serious side effects. The most common side effect is soreness at the injection site. In some cases, fainting has occured. In rare cases, allergic reactions and swooning has occurred after receiving the injection.

The CDC, working with the FDA, monitors the safety of all vaccines in general use. The vaccine does not contain mercury, thimerosal or live virus.^[14]

There have been reports that the shot is more painful than other common vaccines, and the manufacturer Merck partly attributes this to the virus-like particles within the vaccine.^[15] General side effects of the shot may include joint and muscle pain, fatigue, physical weakness and general malaise.^[16]

As of 30 June 2008, out of over 16 million doses^[17] of Gardasil distributed in the United States, and 9,749 Vaccine Adverse Event Reporting System (VAERS) reports of adverse events following Gardasil vaccination.^[18] Of the adverse events, 94% were classified as non-serious events, and 6% as serious events.^[18] Since on average 10 to 15% of VAERS reports for a vaccine are serious events, Gardasil has less than half the average percentage of serious reports.^[18] "It is important to note that a report to VAERS does not mean there is a connection between the vaccine and the event. It means the event took place following vaccination."^[18]

The FDA and CDC said that with millions of vaccinations “by chance alone some serious adverse effects and deaths” will occur in the time period following vaccination.^[19] Although at least 20 women who received the Gardasil vaccine have died, there is no evidence that deaths or serious outcomes were connected to the shot.^[19] Where information was available, the cause of death was explained by other factors.^[17]

Likewise, although a small number of cases of Guillain-Barré Syndrome (GBS) have been reported following vaccination with Gardasil.^[18][20], there is no evidence linking GBS to the vaccine.^[18]

In February 2007, an anti-vaccination group called the "National Vaccine Information Center" (NVIC) called for caution in administering Gardasil in combination with other vaccines, as they said it had not been tested in combination.^[21]

The FDA and CDC monitor events to see if there are patterns, or more serious events than would be expected from chance alone.^[17]

Australia

As of 22 May 2007, 7 Victorian schoolgirls from Sacred Heart Girls' College were briefly hospitalized after receiving an injection of the Gardasil vaccine and were taken to the Monash Medical Centre.^[22][23] One was temporarily paralyzed. Health authorities do not believe that these are directly related to the vaccine.

The following is from the Sydney Morning Herald:

"It is not uncommon for girls of this age group to react to vaccinations in ways that are not necessarily physical in origin."

Professor Frazer said there was no reason to be concerned and it was common for young women to faint after receiving injections.

"It's not what's in the injection, it's the injection process itself and it's entirely avoidable just by having young girls lie down for a minute or two," he said.

"...hospital staff told teachers at the school at the time that the girls' reactions were not related to the vaccination itself"^[22]

Government & public health mandates

Main article: HPV Vaccine

According to the American Centers for Disease Control, getting as many girls vaccinated as early and as quickly as possible will reduce the cases of cervical cancer among middle-aged women in 30 to 40 years and reduce the transmission of this highly communicable disease. Unfortunately, there are hurdles to getting this done. These include the limited understanding by many people that HPV causes cervical cancer, the difficulty of getting pre-teens and teens into the doctor’s office to get a shot, and the high cost of the vaccine ($120/dose, $360 total for the three required doses, plus the cost of doctor visits).^[24][14]

In the United States it is believed that one way to bring down the cost of the vaccine and to educate the public on the benefits of vaccination is to make it mandatory for girls entering school. This approach has been taken with vaccines for mumps, measles, rubella, and hepatitis B (which is also sexually transmitted) so many state legislators have penned bills that do this. Almost all pieces of legislation currently pending in the states that would make the vaccine mandatory for school entrance have an "opt-out" policy.^[24][14]

Long-term impact

It has been suggested that this article or section be merged into HPV vaccine. (Discuss)

One unknown property of the vaccines now being researched is their longevity. Since the studies have been of short duration, it is unknown whether the vaccines will last just a few years or for much longer. Further study is required to answer this question.

270,000 women died of cervical cancer worldwide in 2002.^[25] Acting FDA Administrator Dr. Andrew von Eschenbach said the vaccine will have "a dramatic effect" on the health of women around the world.^[26] The National Cancer Institute estimated that 9,700 women would develop cervical cancer in the United States in 2006, and 3,700 would die.^[27]

Merck and CSL Limited are expected to market Gardasil as a cancer vaccine, rather than an STD vaccine. It remains unclear how widespread the use of the three-shot series will be, in part because of its $360 list price ($120 each for three shots). Merck and CSL have also suggested that governments make vaccination with Gardasil mandatory for school attendance, which has upset some conservative groups and libertarian groups.^[28][26][29] Many such groups also expressed fears that vaccination with Gardasil might give girls a false sense of security regarding sex and increase their level of promiscuity.^[30][26][29] According to the Cleveland Clinic, "Genital HPV is spread through direct skin-to-skin contact with someone who has an HPV infection. Contact includes vaginal, anal, and oral sex. Some types of HPV cause genital warts, which are hard, rough lumps that develop on the skin. Anyone who is sexually active can get HPV and genital warts."^[31][32] The types of HPV the vaccine treats are transmitted by sexual activity.^[31][32]

Both men and women are carriers of HPV. To eradicate these strains, men will eventually need to be vaccinated.^[33] Studies are being conducted now to determine the efficacy of vaccinating boys with the current vaccine.^[34]

Cost effectiveness

A recent opinion article by Abby Lippman PhD, Ryan Melnychuk PhD, Carolyn Shimmin BJ, and Madeline Boscoe RN DU published in the Canadian Medical Association Journal on August 1, 2007 argues that there remain a number of unanswered questions about the HPV vaccine, and that a universal vaccination program in Canada "is premature and could have unintended negative consequences." They also said "we must be certain that spending an estimated $2 billion to vaccinate a population of girls and women in Canada who are already mostly well protected by their own immune systems, safer sex practices and existing screening programs will not perpetuate the existing gaps in care and leave the actual rate of deaths from cervical cancer unchanged." ^[35]

"Misgivings are now common, and include its cost, its marketing as the solution to cancer of the cervix when at best it's expected to prevent about two-thirds of cases, the incorrect and dangerous perception that it might make Pap smears unnecessary, and the difficult question of the best age to give a vaccine whose effect might yet prove to wear off before many recipients even start having sex."^{[36] [37]}

CSL’s director of public affairs, Rachel David, wrote: "I feel Dr Gunn’s comments are inappropriate and inconsistent with the long-standing relationship CSL has with the University of Queensland and given the involvement of the university in the development of Gardasil." A spokesman for UniQuest, the university’s commercial arm, said that the exact value of Gardasil’s returns to the university was confidential but that it amounted to some millions of dollars annually.

On 14 March the university’s secretary and registrar, Douglas Porter, wrote to Dr Gunn, asking him to provide a written apology to CSL stating that the "comments were made by you in your personal capacity and were not endorsed or authorised by the university."^{citation needed} Mr Porter also asked to be sent a copy of Dr Gunn’s letter to CSL.

Academics at the university and elsewhere say that the request is a threat to academic freedom and warn that it raises worrying concerns about universities’ independence and ability to negotiate conflicts of interest.^[37]

Importance of vaccination for public health

The National Cancer Institute writes, "Widespread vaccination has the potential to reduce cervical cancer deaths around the world by as much as two-thirds, if all women were to take the vaccine and if protection turns out to be long-term. In addition, the vaccines can reduce the need for medical care, biopsies, and invasive procedures associated with the follow-up from abnormal Pap tests, thus helping to reduce health care costs and anxieties related to abnormal Pap tests and follow-up procedures (2)."^[12]

References

External links

• Gardasil product website
• Gardasil Product Monograph
• A Cancer Vaccine is Born (press release from University of Rochester)
• AAR.com.au
• Panel Unanimously Recommends Cervical Cancer Vaccine for Girls 11 and Up Gardiner Harris, 30 June 2006, The New York Times
• FDA Product Approval Information - Licensing Action (fda.gov)
• Data on clinical trials (fda.gov)
• Advisory Committee on Immunization Practices Minutes (cdc.gov)
• HPV and You: Girls learn about HPV from the commercials, not the classroom - The Indypendent, Myra Hellerstein and Amanda Thieroff