Gardasil

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.cite journal | author = Lowy DR, Schiller JT | title = Prophylactic human papillomavirus vaccines. | journal = J. Clin. Invest. | volume = 116 | issue = 5 | pages = 1167–73 | year = 2006 | pmid = 16670757 | doi = 10.1172/JCI28607 | url = http://www.jci.org/articles/view/JCI28607| accessdate = 2007-12-01 ] cite journal| journal = Int J Cancer | date = 2004 Aug 20 | volume = 111 | number = 2 | page = 278-85 | title = Against which human papillomavirus types shall we vaccinate and screen? The international perspective. | author = Muñoz N, Bosch FX, Castellsagué X, Díaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ] Type 16 is also associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.cite journal | last = D'Souza | first = Gypsyamber | last2 = Kreimer | first2 = Aimee R. | last3 = Viscidi | first 3 = Raphael | title = Case – Control Study of Human Papillomavirus and Oropharyngeal Cancer | journal = New England Journal of Medicine | volume = 356 | pages = 1944–1956 | date= May 10, 2007 | year = 2007 | url = http://content.nejm.org/cgi/content/full/356/19/1944 | doi = 10.1056/NEJMoa065497 | pmid = 17494927] 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 [ [http://www.washingtonpost.com/wp-dyn/content/article/2006/05/18/AR2006051800825.html "FDA Panel Endorses Cervical Cancer Vaccine"] By ANDREW BRIDGES Washington Post (A.P.)] , and the leading cause of cancer-related deaths among women in the majority of developing countries. [ [http://www.nccc-online.org/ National Cervical Cancer Coalition] ]

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 [ [http://jncicancerspectrum.oxfordjournals.org/cgi/content/extract/jnci;98/7/433 Who Invented the VLP Cervical Cancer Vaccines?] McNeil, C., "Journal of the National Cancer Institute", 2006, 98(7): 433.] . 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.cite journal |author= |title=Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions |journal=N. Engl. J. Med. |volume=356 |issue=19 |pages=1915–27 |year=2007 |month=May |pmid=17494925 |doi=10.1056/NEJMoa061741 |url=] Merck has tested the vaccine in several hundred 11- and 12-year-old girls. [cite news|url=http://www.vaccinerx.com/news/cervical-cancer/gardasil-efficacy-questioned-by-experts-says-wall-street-journal-20070416-194-26.html|title=Gardasil Efficacy Questioned by Experts says Wall Street Journal|publisher=Vaccine Rx |date=2007-04-16 |accessdate=2007-04-16] 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. [cite news |url=http://www.vaccinerx.com/news/cervical-cancer/gardasil-trials-end-on-tuesday-due-to-success-20070227-93-26.html
title=Gardasil Trials End on Tuesday Due To Success |last=ROBERTS|first=J. |publisher=Vaccine Rx |date=2007-02-27|accessdate=2007-02-27]

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 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. [ [http://www.aidsmap.com/en/news/3429199D-5FE5-4795-B0E6-CD957617C160.asp An HPV vaccine - what it might really mean] , Edwin J. Bernard, AIDSmap, October 24, 2005 (Accessed June 8, 2006) ] 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. [ [http://www.aidsmap.com/en/news/44e54c4a-27d9-45fe-8533-a0e7c70499b8.asp HAART is not reducing risk of anal cancer in gay men] , Edwin J. Bernard, AIDSmap, August 29, 2005 (Accessed June 8, 2006)]

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.

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). [http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm Centers for Disease Control ] [http://www.cdc.gov/std/HPV/STDFact-HPV-vaccine.htm Centers for Disease Control] ]

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. [http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm Centers for Disease Control ]

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)." [http://www.cancer.gov/cancertopics/factsheet/risk/HPV-vaccine Human Papillomavirus (HPV) Vaccines: Q & A - National Cancer Institute] ]

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. [ [http://www.imwr.com/issues/articles/2007-11_24.asp HPV Vaccine Protects Against 10 "Other" Strains,] By John Schieszer, Internal Medicine World Report, November 2007.]

afety

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. [ [http://www.cdc.gov/std/hpv/STDFact-HPV-vaccine.htm#hpvvac1 STD Facts - HPV Vaccine ] ] 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. [ [http://www.gardasil.com/images/grd_yaf_tear_pad.pdf Gardasil Information Sheet] ] 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. [ [http://www.cnn.com/2008/HEALTH/conditions/01/03/painful.shot.ap/index.html Cervical cancer shots gaining reputation as painful] , CNN, January 3, 2008] General side effects of the shot may include joint and muscle pain, fatigue, physical weakness and general malaise. [ [http://www.washingtontimes.com/news/2008/jul/10/merck-fda-expand-gardasil-warnings Merck, FDA expand Gardasil warnings] , Washington Times, July 10, 2008]

As of 30 June 2008, out of over 16 million dosescite web|url=http://www.cdc.gov/vaccinesafety/vaers/FDA_and_CDC_Statement.htm|title=Information from FDA and CDC on Gardasil and its Safety|date=July 22, 2008|accessdate=2008-08-22] 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.cite web| url=http://www.cdc.gov/vaccines/vpd-vac/hpv/hpv-vacsafe-effic.htm| title=HPV Vaccine - Questions & Answers for the Public|accessdate=2008-08-22 |date=2008-07-18 ] "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." 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.cite news |first=ELISABETH |last=ROSENTHAL|work=The New York Times |date=2008-08-19 |url=http://www.nytimes.com/2008/08/20/health/policy/20vaccine.html?_r=1&hp=&adxnnl=1&oref=slogin&adxnnlx=1219244494-RoSoOUDyGcwdbs6sjLcrEw |title=Drug Makers’ Push Leads to Cancer Vaccines’ Fast Rise| accessdate=2008-08-20] 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.cite web| url=http://www.cdc.gov/vaccines/vpd-vac/hpv/downloads/hpv-gardasil-gbs.pdf |title= Gardasil and GBS|accessdate=2008-08-22|format=PDF] , 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

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. [Cohen J. 2005. High Hopes and Dilemmas for a Cervical Cancer Vaccine. "Science", 308(5722): 618–621.] Acting FDA Administrator Dr. Andrew von Eschenbach said thevaccine will have "a dramatic effect" on the health of women around the world. [http://news.yahoo.com/s/ap/20060608/ap_on_he_me/cervical_cancer_vaccine FDA approves cervical cancer vaccine] , AP, accessed June 8, 2006] The National Cancer Institute estimated that 9,700 women would develop cervical cancer in the United States in 2006, and 3,700 would die.National Cancer Institute SEER [http://seer.cancer.gov/statfacts/html/cervix.html fact sheet on cervical cancer] accessed 30 Mar 2007.]

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. [ [http://www.thenation.com/doc/20070326/houppert/2 Who's Afraid of Gardasil? (Page 2) ] ] [http://news.independent.co.uk/business/news/article755931.ece Moral majority take on GSK and Merck over cancer drugs] , accessed June 12, 2006] 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. [cite news |url=http://www.speroforum.com/site/article.asp?idCategory=33&idsub=128&id=5444&t=GARDASIL+vaccine+touted+in+Michigan |title=GARDASIL vaccine touted in Michigan |last=Barillas |first=Martin |publisher=Spero News |date=2006-09-14 |accessdate=2007-01-26] 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." [http://www.clevelandclinic.org/health/health-info/docs/3800/3808.asp?index=11901] Understanding HPV] Human papillomavirus] The types of HPV the vaccine treats are transmitted by sexual activity.

Both men and women are carriers of HPV. To eradicate these strains, men will eventually need to be vaccinated. [ [http://www.sciencedaily.com/releases/2004/11/041123162300.htm Science Daily] ] Studies are being conducted now to determine the efficacy of vaccinating boys with the current vaccine. [ [http://www.webmd.com/cancer/cervical-cancer/news/20060608/cervical-cancer-vaccine-approved Cervical Cancer Vaccine Approved] ]

Cost effectiveness

A 2007 opinion article in the "Canadian Medical Association Journal" argues that the cost-effectiveness of Gardasil programs cannot be established with existing data. The authors write, "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." [ [http://www.cmaj.ca/cgi/rapidpdf/cmaj.070944v1 Canadian Medical Association Journal August 1, 2007] ]

References

External links

* [http://www.gardasil.com/ Gardasil product website]
* [http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf Gardasil Product Monograph]
* [http://www.rochester.edu/pr/Review/V68N3/feature1.html A Cancer Vaccine is Born] (press release from University of Rochester)
* [http://www.aar.com.au/pubs/bt/21feb06/bio07.htm AAR.com.au]
* [http://www.nytimes.com/2006/06/30/health/30vaccine.html?ex=1309320000&en=73611cb06d9b311d&ei=5090 Panel Unanimously Recommends Cervical Cancer Vaccine for Girls 11 and Up] Gardiner Harris, 30 June 2006, "The New York Times"
* [http://www.fda.gov/cber/products/gardasil.htm FDA Product Approval Information - Licensing Action] (fda.gov)
* [http://www.fda.gov/cber/label/hpvmer013007LB.pdf Data on clinical trials] (fda.gov)
* [http://www.cdc.gov/nip/ACIP/minutes/acip-min-jun06.txt Advisory Committee on Immunization Practices Minutes] (cdc.gov)
* [http://www.indypendent.org/?p=750 HPV and You: Girls learn about HPV from the commercials, not the classroom - The Indypendent, Myra Hellerstein and Amanda Thieroff]