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Gardasil

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See also: HPV vaccine
Gardasil
Vaccine description
Targethuman papillomavirus (Types 16, 18, 6, and 11)
Vaccine typeProtein subunit
Clinical data
Routes of
administration		injection
ATC code

Gardasil (Merck & Co.), also known as Gardisil or Silgard,[1] is a vaccine against certain types of human papillomavirus (HPV).[2]

Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 that currently cause about 70% of cervical cancer cases,[3][4] and also cause some vulvar, vaginal,[5] penile, and anal[6] warts. HPV types 6 and 11 cause about 90% of genital warts cases.

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.[7]


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 Australian 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.[8] 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.[9] Merck has tested the vaccine in several hundred 11- and 12-year-old girls.[10] 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.[11]

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 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.[5]

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.[12]

HPV infections, including HPV 16, contribute to some head and neck cancer. In principle HPV vaccines may help reduce incidence of such cancers caused by HPV, but this has not been demonstrated.[13]

Use in males

Gardasil is also effective in males, providing protection against genital warts and some potentially precancerous lesions caused by some HPV types.[14] An ongoing study of 4,065 males demonstrated the efficacy of Gardasil in males who did not have HPV infection prior to vaccination.[6] 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.[6]

In December 2008, Merck asked the U.S. Food and Drug Administration (FDA) for permission to market the vaccine in the United States for males between ages 9 to 26,[15] and an FDA advisory committee recommended approval on September 9, 2009.[16] In the UK HPV vaccines are already licensed for males aged 9 to 15 and for females aged 9 to 26.[17]

Gardasil is in particular demand among gay men, who are at significantly increased risk for genital warts and anal cancer caused by HPV.[18]

HPV vaccines may be useful in preventing anal cancer caused by HPV types 16 and 18.[19] 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.[20] Type 16 is also associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.[21]

Ingredients

[22]

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.[7]

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

Main article: HPV Vaccine
File:Gardasil is available-lighter.jpg
"Gardasil is available" poster for a university student health center

According to the US 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. However, 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).[23][24]

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) 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.[23][24]

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).[25]

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."[25] 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 of 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. [26]

Safety

As of February 2009, 40 million doses of Gardasil had been distributed worldwide.[27] According to the Centers for Disease Control, the vaccine was tested in thousands of females (ages 9 to 26).[28] 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.[29]

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.[30] 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.[31] General side effects of the shot may include joint and muscle pain, fatigue, physical weakness and general malaise.[32]

The most recent update on adverse events was published by JAMA and looked at data from the Vaccine Adverse Event Reporting System (VAERS), covering 12,424 reported adverse events after about 23 million doses of vaccine between June 2006 and December 2008.[33] Most adverse effects were minor and not greater than background rates compared with other vaccines, the exception being higher rates for syncope and venous thromboembolic events.[33] Venous thromboembolic events were noted in 56 reports at a rate of 0.2 cases per 100,000 doses distributed and included 19 cases of pulmonary embolism, 4 of which were fatal.[33] Overall, 772 events (6.2% of the total) were described as serious and included 32 deaths (0.1 per 100,000 doses).[33]

Other adverse events include local site reactions ( 7.5 cases per 100,000 doses distributed), headaches (4.1 cases per 100,000 doses distributed), hypersensitivity reactions (3.1 cases per 100,000 doses distributed), and urticaria (hives) (2.6 cases per 100,000 doses distributed).[33]

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.[34] Although more than 20 women who received the Gardasil vaccine have died, officials maintain that there is no evidence that deaths or serious outcomes were connected to the shot.[34] Where information has been available, the cause of death was explained by other factors.[35] Likewise, although a small number of cases of Guillain-Barré Syndrome (GBS) have been reported following vaccination with Gardasil.[36][37], there is no evidence linking GBS to the vaccine.[36]

The FDA and CDC monitor events to see if there are patterns, or more serious events than would be expected from chance alone.[35] The majority (68%) of side effects data were reported by the manufacturer, but in about 90% of the manufacturer reported events, no follow-up information was given that would be useful to investigate the event further.[33] In February 2009, the Health Ministry of Spain suspended use of one batch of Gardasil after health authorities in the Valencia region reported that two girls had become ill after receiving the injection. Merck has stated that there was no evidence Gardasil was responsible for the two illnesses.[27]

The benefit of Gardasil is being debated for populations that are well screened by pap smears; thus in the US the death rate for cervical cancer is low (3/100,000 women) which is similar to the rate of serious side effects events reported for Gardasil (3.4/100,000 doses distributed).[33] Critics suggest that Gardasil should be used primarily in populations at high risk for cervical cancer.[33]

Long-term impact and cost-effectiveness

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.[38] Acting FDA Administrator Dr. Andrew von Eschenbach said the vaccine will have "a dramatic effect" on the health of women around the world.[39] 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.[40]

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).

Both men and women are carriers of HPV. To eradicate these strains, males might eventually need to be vaccinated.[41] Studies are being conducted to determine the efficacy of vaccinating males with the current vaccine.[42]

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.[43] These results have been important in decisions by many countries to start vaccination programs.[44] 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.[45] 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.[46]

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.[34]

Dr. Diane Harper, one of the lead researchers for Gardasil, has called for more complete warnings for parents and questions its risk-versus-benefit profile because it is not yet know how long the vaccine will be effective once administered.[47] The August 2009 issue of the Journal of the American Medical Association, JAMA, had an article reiterating the safety of Gardasil and another questioning the way it was presented to doctors and parents.

The new vaccine against 4 types of human papillomavirus (HPV), Gardasil, like other immunizations appears to be a cost-effective intervention with the potential to enhance both adolescent health and the quality of their adult lives. However, the messages and the methods by which the vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women's health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers' bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.[48]

In an address at the 4th International Public Conference on Vaccination in October 2009, Dr. Harper stated that Gardasil and Cervarix will do little to reduce cervical cancer rates. She also stated that no efficacy trials for children under 15 have been performed.[49]

Political controversy

The governor of Texas, Rick Perry, issued an executive order mandating vaccination against HPV which was later overturned by the Texas legislature. Through lobbying efforts, Merck has suggested that governments make vaccination with Gardasil mandatory for school attendance, which has upset some conservative groups and libertarian groups.[39][50][51] Groups such as the Moral Majority expressed fears that vaccination with Gardasil might give girls a false sense of security regarding sex and increase their level of promiscuity.[39][51][52]

References

  1. ^ "International Approvals: Singulair and Gardasil/Silgard". {{cite web}}: Unknown parameter |accessdatedate= ignored (help)
  2. ^ Reuters
  3. ^ Lowy DR, Schiller JT (2006). "Prophylactic human papillomavirus vaccines". J. Clin. Invest. 116 (5): 1167–73. doi:10.1172/JCI28607. PMID 16670757. Retrieved 2007-12-01.
  4. ^ Muñoz N, Bosch FX, Castellsagué X, Díaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ (2004-08-20). "Against which human papillomavirus types shall we vaccinate and screen? The international perspective". Int J Cancer. 111 (2): 278-85.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b "FDA Approves Expanded Uses for Gardasil to Include Preventing Certain Vulvar and Vaginal Cancers". 2008-09-12. Retrieved 2008-10-12.
  6. ^ a b c Cortez, Michelle Fay and Pettypiece, Shannon. "Merck Cancer Shot Cuts Genital Warts, Lesions in Men". Bloomberg News. (Bloomberg.com) 13 Nov 2008.
  7. ^ a b Prescribing information for Gardasil
  8. ^ Who Invented the VLP Cervical Cancer Vaccines? McNeil, C., Journal of the National Cancer Institute, 2006, 98(7): 433.
  9. ^ "Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions". N. Engl. J. Med. 356 (19): 1915–27. 2007. doi:10.1056/NEJMoa061741. PMID 17494925. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ "Gardasil Efficacy Questioned by Experts says Wall Street Journal". Vaccine Rx. 2007-04-16. Retrieved 2007-04-16.
  11. ^ ROBERTS, J. (2007-02-27). "Gardasil Trials End on Tuesday Due To Success". Vaccine Rx. Retrieved 2007-02-27.
  12. ^ "FDA Wants More Gardasil Data". 2009-01-14. Retrieved 2009-01-15.
  13. ^ Masters, Coco. "Oral Sex Can Add to HPV Cancer Risk". Time Magazine. (Time.com) 11 May 2007.
  14. ^ ""Gardasil, Merck's Cervical Cancer Vaccine, Demonstrated Efficacy in Preventing HPV-Related Disease in Males in Phase III Study: Pivotal Study Evaluating Efficacy of Gardasil in Males in Preventing HPV 6, 11, 16 and 18-Related External Genital Lesions"". Merck Research and Development News. Retrieved 2008-11-15. {{cite web}}: External link in |work= (help)
  15. ^ "Drugmaker Merck seeks Gardasil approval for boys". USA Today. January 6, 2009.
  16. ^ "FDA panel urges HPV vaccine be given to boys". CNN. September 9, 2009.
  17. ^ "Gay men seek 'female cancer' jab". BBC. 2007-02-23.
  18. ^ ""Gay men seeking HPV vaccine"". Cancer Research UK. 23 February 2007. {{cite web}}: External link in |work= (help)
  19. ^ Edwin J. Bernard (October 24, 2005). "An HPV vaccine - what it might really mean". AIDSmap. Retrieved 2006-06-08.
  20. ^ Edwin J. Bernard (August 29, 2005). "HAART is not reducing risk of anal cancer in gay men". AIDSmap. Retrieved 2006-06-08.
  21. ^ D'Souza, Gypsyamber; Kreimer, Aimee R.; Viscidi (May 10, 2007). "Case – Control Study of Human Papillomavirus and Oropharyngeal Cancer". New England Journal of Medicine. 356: 1944–1956. doi:10.1056/NEJMoa065497. PMID 17494927. {{cite journal}}: Cite has empty unknown parameter: |unused_data= (help); Unknown parameter |first 3= ignored (|first3= suggested) (help)
  22. ^ http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_ppi.pdf
  23. ^ a b Lauri Markowitz; et al. (March 12, 2007). "Quadrivalent Human Papillomavirus Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP)". Morbidity and Mortality Weekly Report. Centers for Disease Control. Retrieved 2008-11-18. {{cite journal}}: Explicit use of et al. in: |author= (help)
  24. ^ a b Centers for Disease Control's fact page on HPV vaccine
  25. ^ a b Human Papillomavirus (HPV) Vaccines: Q & A, National Cancer Institute
  26. ^ Schieszer, John. HPV Vaccine Protects Against 10 "Other" Strains, Internal Medicine World Report, November 2007.
  27. ^ a b "Spain halts batch of Merck's Gardasil - Thomson Reuters". Retrieved 2009-02-10.
  28. ^ "HPV Vaccine Information For Young Women". CDC. Retrieved 2009-06-14.
  29. ^ STD Facts - HPV Vaccine
  30. ^ Gardasil Information Sheet
  31. ^ Cervical cancer shots gaining reputation as painful, CNN, January 3, 2008
  32. ^ Merck, FDA expand Gardasil warnings, Washington Times, 10 July 2008.
  33. ^ a b c d e f g h Chustecka Z. "HPV Vaccine:Debate Over Benefits, Marketing, and New Adverse Event Data". Medscape Medical News (August 18, 2009). {{cite web}}: Unknown parameter |access date= ignored (|access-date= suggested) (help)
  34. ^ a b c Rosenthal, Elisabeth (2008-08-19). "Drug Makers' Push Leads to Cancer Vaccines' Fast Rise". The New York Times. Retrieved 2008-08-20.
  35. ^ a b "Information from FDA and CDC on Gardasil and its Safety". July 22, 2008. Retrieved 2008-08-22.
  36. ^ a b "HPV Vaccine - Questions & Answers for the Public". 2008-07-18. Retrieved 2008-08-22.
  37. ^ "Gardasil and GBS" (PDF). Retrieved 2008-08-22.
  38. ^ Cohen J. 2005. "High Hopes and Dilemmas for a Cervical Cancer Vaccine". Science, 308(5722): 618–621.
  39. ^ a b c "FDA approves cervical cancer vaccine", AP, accessed June 8, 2006
  40. ^ National Cancer Institute SEER Fact sheet on cervical cancer. accessed 30 March 2007.
  41. ^ Press release, Science Daily, November 2004.
  42. ^ "Cervical Cancer Vaccine Approved". webmd.com.
  43. ^ Reviewed in Stanley M. Prevention strategies against the human papillomavirus: the effectiveness of vaccination. Gynecol Oncol. 2007 Nov;107(2 Suppl 1):S19-23.
  44. ^ Pallecaros A, Vonau B. "Human papilloma virus vaccine--more than a vaccine." Curr Opin Obstet Gynecol. 2007 Dec;19(6):541-6.
  45. ^ Morris SK, Nguyen CK. "The human papillomavirus vaccine in Canada." Canadian Journal of Public Health. 2008 Mar-Apr;99(2):114-6.
  46. ^ Steben M. "Do you approve of spending $300 million on HPV vaccination?: yes." Canadian Family Physician. 2008 Feb;54(2):174, 176, 178, 180.
  47. ^ http://www.cbsnews.com/stories/2009/08/19/cbsnews_investigates/main5253431.shtml
  48. ^ http://jama.ama-assn.org/cgi/content/abstract/302/7/781
  49. ^ Gardasil Researcher Drops A Bombshell, Susan Brinkmann, the Bulletin, October 25, 2009.
  50. ^ Who's Afraid of Gardasil? (Page 2)
  51. ^ a b "Moral majority take on GSK and Merck over cancer drugs", The Independent. Accessed June 12, 2006.
  52. ^ Barillas, Martin (2006-09-14). "GARDASIL vaccine touted in Michigan". Spero News. Retrieved 2007-01-26.
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