Gardasil (Merck & Co.), also known as Gardisil or Silgard, 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, and also cause some vulvar, vaginal, penile and anal cancers[5]. HPV types 6 and 11 cause about 90% of genital warts cases.
Human papillomavirus (HPV) infections cause nearly all cases of cervical cancer. Cervical cancer is the fifth leading cause of death from cancer in women world-wide[6], and the leading cause of cancer-related deaths among women in the majority of developing countries.
Gardasil is only effective in preventing HPV infections, not in treating those already infected by HPV, and so the vaccine must be given before HPV infection occurs in order to be effective. For this reason it is recommended to administer the vaccine before adolescence and the onset of sexual activity.
Gardasil can also be used to vaccinate males.
History
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. Upon commercialization of the vaccine, controversy involving intellectual property arose between the various groups that played a role in developing the vaccine.
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. Merck has tested the vaccine in several hundred 11- and 12-year-old girls. 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.
Indications and prevalence
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 HPV 6 and HPV 11 is expected to eliminate 90% of the cases of genital warts. Gardasil also protects against vulvar and vaginal cancers caused by HPV types 16 and 18.
Merck is seeking FDA approval to market Gardasil to older women aged 27 to 45. As of early part of 2009, FDA has requested final trial data before it approves the drug for this age group.
Use in males
Gardasil is also effective in males, providing protecton against genital warts and some potentially precancerous lesions caused by some HPV types. An ongoing study of 4,065 males demonstrated the efficacy of Gardasil in males who did not have HPV infection prior to vaccination. The vaccination is expected to protect against penile cancer and anal cancer caused by included HPV types, and research in this area is still underway.
In December 2008, Merck asked the FDA for permission to market the vaccine in the United States for males between ages 9 to 26. In the UK HPV vaccines are already licensed for males aged 9 to 15 and for females aged 9 to 26.
Gardasil is in particular demand among gay men, who are at significantly increased risk for genital warts and anal cancer caused by HPV.
HPV vaccines may be useful in preventing anal cancer caused by HPV types 16 and 18. 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. Type 16 is also associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.
Administration
Gardasil is given in three injections over six months. The second injection is two months after the first, and 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.
Public health advantages
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).
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.
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)."
Efficacy
The National Cancer Institute says, "FDA-approved Gardasil prevented nearly 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." 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.
Safety
According to the Centers for Disease Control, the vaccine was tested in over 11,000 women and girls (ages 9 to 26). The Food and Drug Administration and Centers for Disease Control say that 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. 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 more common among adolescents receiving the Gardasil vaccine than in other kinds of vaccinations. Patients should remain seated for 15 minutes after they receive the HPV vaccine. 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. General side effects of the shot may include joint and muscle pain, fatigue, physical weakness and general malaise.
As of 30 June 2008, out of over 16 million doses of Gardasil distributed in the United States, there have been 9,749 reports to the Vaccine Adverse Event Reporting System (VAERS) following Gardasil vaccination. Gardasil has less than half the average percentage of serious reports. "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."[30] 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, but have nothing to do with the vaccine. 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. Where information was available, the cause of death was explained by other factors. Likewise, although a small number of cases of Guillain-Barré Syndrome (GBS) have been reported following vaccination with Gardasil., there is no evidence linking GBS to the vaccine.
The FDA and CDC monitor events to see if there are patterns, or more serious events than would be expected from chance alone.
Long-term impact
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One unknown property of the vaccines now being researched is the persistence of their protective effects. Since the Gardasil vaccine has been administered for only a few years now, it is unknown whether it will provide life-long immunity to recipients. In coming decades, further study will answer this question.
Whether the effects are temporary or life-long, widespread vaccination could have a substantial public health impact. 270,000 women died of cervical cancer worldwide in 2002. Acting FDA Administrator Dr. Andrew von Eschenbach said the vaccine will have "a dramatic effect" on the health of women around the world.[34] Even in the United States, where screening programs are routine, the National Cancer Institute estimated that 9,700 women would develop cervical cancer in 2006, and 3,700 would die.
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.[36][34][37] 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. 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." The types of HPV the vaccine treats are transmitted by sexual activity.
Both men and women are carriers of HPV. To eradicate these strains, males might eventually need to be vaccinated. Studies are being conducted now to determine the efficacy of vaccinating males with the current vaccine.
Cost effectiveness
Studies using different pharmacoeconomic models predict that vaccinating young women with Gardasil in combination with screening programs may be more cost effective than screening alone. These results have been important in decisions by many countries to start vaccination programs. For example the Canadian government approved $300 million to buy the HPV vaccine in 2008 after deciding from studies that the vaccine would be cost-effective especially by immunizing young women. Marc Steben, an investigator for the vaccine, wrote that the financial burden of HPV related cancers on the Canadian people was already $300 million per year in 2005, so the vaccine could reduce this burden and be cost-effective.
Since penile and anal cancers are much less common than cervical cancer, HPV vaccination of young men is likely to be much less cost-effective than for young women.
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