Gardasil

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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 cause about 70% of cervical cancer cases. In addition, some types of HPV, particularly type 16, have been found to be 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 in 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, the University of Queensland, 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.

Contents

[edit] 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.

[edit] Prevalence of genital HPV

According to the Centers for Disease Control, by the age of 50 more than 80% of American women will have contracted at least one strain of HPV. HPV is highly communicable. College freshmen women who used condoms consistently had a 37.8% per patient-year incidence of genital HPV, compared to an incidence of 89.3% among those who did not.[5][6][7]

Both men and women can be carriers of HPV.

About 11,000 American women are diagnosed with cervical cancer every year, and about 3,700 die per year of the disease.[8]

[edit] 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)."[9]

[edit] Safety and efficacy of the vaccine

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 rare cases, allergic reactions and swooning has occurred after receiving the injection. Patients should be observed for 15 minutes after they receive the HPV vaccine.[10]

However, an August 27, 2007 report of Association of American Physicians and Surgeons News Release reports additional adverse effects from the HPV vaccine.

As of May 31, 2007, there have been 13 cases of Guillain Barré syndrome (GBS) in association with the HPV vaccine (Gardasil) reported to the Vaccine Adverse Event Reporting System (VAERS).

In another study, "arthritic symptoms" occurred three times as often in subjects who got the vaccine, compared to subjects who only got the control vaccine. An increased risk of juvenile rheumatoid arthritis, "a deforming, devastating, lifelong disease, is being watched for."

And according to Judicial Watch (a public interest group that investigates and prosecutes government corruption), There also have been another 1,824 adverse reactions to the drug, bringing the "known total" of such problems to 3,461. Judicial Watch said it obtained documents from the U.S. Food and Drug Administration under the Freedom of Information Act detailing the new 1,824 cases.

Those cases include as many as eight deaths related to the vaccine, on top of the three deaths reported earlier among 1,637 earlier reports of adverse effects.[11]

The CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use. The vaccine does not contain mercury, thimerosal or live virus.[12]

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."[9]

"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."[13] [14]

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.[14]

[edit] 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.[15] Merck has tested the vaccine in only a few hundred 11- and 12-year-old girls.[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.[17]

[edit] Indications

Gardasil is a prophylactic HPV vaccine, meaning that it is designed to prevent the initial establishment of HPV infections. In worldwide clinical analyses, 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. For maximum efficacy, it is recommended that girls receive the vaccine prior to becoming sexually active. 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. About 11,000 cases of cervical cancer are diagnosed annually in the United States, totalling around 3700 deaths. The lifetime risk of cervical cancer for women in the U.S., estimated by the National Cancer Institute, is 0.73%.[8]

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 inherit HPV from their mothers. In addition, protection against HPV6 and HPV11 also eliminates 90% of the cases of genital warts. Gardasil also may be useful in preventing anal cancer caused by HPV types 16 and 18.[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.[19]

[edit] Administration

Gardasil is given in three injections over six months, namely at enrollment, and two and six months later.

[edit] Government & public health mandates

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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).[20][21]

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.


[edit] United States

The US Food and Drug Administration (FDA) approved Gardasil on June 8, 2006. Gardasil is currently available.[22] The drug is also approved for use in Australia, New Zealand, Canada, Mexico, Croatia, Malaysia, Brazil, Serbia, Israel and countries of the European Union.

On June 29, 2006, a panel of experts, the Advisory Committee on Immunization Practices, gave their approval for the vaccination of Gardasil on children as young as nine years old. The ACIP recommended that Gardasil be placed on the childhood immunization schedule at the eleven to twelve year old visit. They also recommended that the vaccine be included in the federal Vaccines for Children Program, which would provide the vaccines free of charge to children under the age of eighteen who are uninsured.[23]

[edit] Texas

Texas Governor Rick Perry issued an executive order on February 2, 2007 mandating the vaccine be given to all school girls entering sixth grade, beginning September 2008. This ruling would allow parents to opt out of vaccinating their daughters.[24] On February 22, 2007 a group of Texas families filed a lawsuit to stop the executive order.[25] It is to be noted that an executive order is not a law but rather a recommendation. On April 25, 2007, the Texas legislature overruled Governor Perry's order, forbidding mandatory vaccination until at least 2011.[26]

[edit] Successful implementations

New Hampshire has adopted a voluntary program, in which it supplies the vaccine free of charge to girls between the ages of 11 and 18. Alaska has adopted a similar voluntary program for girls between the ages of 9 and 18. [27] This has met with wide acceptance, with many young women requesting the vaccine. South Dakota and Washington are considering similar measures.[28]

[edit] Long-term impact

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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.[29] Acting FDA Administrator Dr. Andrew von Eschenbach said the vaccine will have "a dramatic effect" on the health of women around the world.[22] The American Cancer Society estimated that 9,700 women would develop cervical cancer in the United States in 2006, and 3,700 would die.[8]

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.[30][22][31] 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.[32][22][33] 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."[34][35] The types of HPV the vaccine treats are transmitted by sexual activity.[34][35]

Both men and women are carriers of HPV. To eradicate these strains, men will eventually need to be vaccinated.[36] Studies are being conducted now to determine the efficacy of vaccinating boys with the current vaccine.[37]

[edit] Criticisms

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[edit] 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.[38][39] 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"[38]

[edit] Canada

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." [40]

[edit] United States

According to the FDA and CDC, the vaccine has only minor side effects, such as soreness around the injection area. The FDA and CDC consider the vaccine to be completely safe. It does not contain mercury, thimerosal or live or dead virus, only virus-like particles, which cannot reproduce in the human body.[41] 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.

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. [42]

Anti-vaccination groups

A group called the "National Vaccine Information Center" (NVIC) released an analysis of Vaccine Adverse Event Reporting System reports for Gardasil immunizations in February 2007.[43] NVIC is a non-governmental, non-profit organization "dedicated to preventing vaccine injuries and deaths through public education." The NVIC does not conduct scientific research, and is highly critical of most vaccinations. Reports from the Vaccine Adverse Event Reporting System database are subject to interpretation as explained at the official website: "When evaluating data from VAERS, it is important to note that for any reported event, no cause and effect relationship has been established... VAERS collects data on any adverse event following vaccination, be it coincidental or truly caused by a vaccine." [34] The NVIC chooses to interpret the information in VAERS to mean that "two thirds of the 385 adverse incidents which the NVIC says are related to Gardasil injections required secondary medical treatment." Most of the events were for fever, nausea, headache or pain. The NVIC article goes on to say, "event reports to VAERS do[es] not prove causation." The FDA does not believe the vaccine causes serious health problems.

Socially conservative groups

In October 2007, the conservative group Judicial Watch reports that the known total numbers of adverse reactions is 3,461 including eleven deaths since FDA approval.[44] Previous to that an FDA spokesperson stated that these deaths are not related to the vaccine, and occurred independently of vaccination.[45]

[edit] See also

[edit] References

  1. ^ D'Souza, Gypsyamber (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. 
  2. ^ "FDA Panel Endorses Cervical Cancer Vaccine" By ANDREW BRIDGES Washington Post (A.P.)
  3. ^ National Cervical Cancer Coalition
  4. ^ Who Invented the VLP Cervical Cancer Vaccines? McNeil, C., Journal of the National Cancer Institute, 2006, 98(7): 433.
  5. ^ New England Journal of Medicine. Condom Use and the Risk of HPV Infection. 2006 Sep 28;355(13):1388–1389.
  6. ^ New England Journal of Medicine. Condom use and the risk of genital human papillomavirus infection in young women. 2006 Jun 22;354(25):2645–54
  7. ^ Sexually Transmitted Diseases. Condom use and other factors affecting penile human papillomavirus detection in men attending a sexually transmitted disease clinic. 2004 Oct;31(10):601–7
  8. ^ a b c National Cancer Institute SEER fact sheet on cervical cancer accessed 30 Mar 2007.
  9. ^ a b Human Papillomavirus (HPV) Vaccines: Q & A - National Cancer Institute
  10. ^ Gardasil Information Sheet
  11. ^ 8 more deaths connected to HPV vaccine
  12. ^ STD Facts - HPV Vaccine
  13. ^ Dr Andrew Gunn, senior lecturer in general practice. GPs and their mail. Transcript. [1]
  14. ^ a b Academic freedom is at risk in dispute over Gardasil, lecturers say. Melissa Sweet. British Medical Journal 2008;336:741 (5 April), doi:10.1136/bmj.39535.642025.DB [2]
  15. ^ Merck's Investigational Vaccine GARDASIL Prevented 100 Percent of Cervical Pre-cancers and Non-invasive Cervical Cancers Associated with HPV Types 16 and 18 in New Clinical Study (2005-10-06). Retrieved on 2007-01-26.
  16. ^ "Gardasil Efficacy Questioned by Experts says Wall Street Journal", Vaccine Rx, 2007-04-16. Retrieved on 2007-04-16. 
  17. ^ ROBERTS, J.. "Gardasil Trials End on Tuesday Due To Success", Vaccine Rx, 2007-02-27. Retrieved on 2007-02-27. 
  18. ^ An HPV vaccine - what it might really mean, Edwin J. Bernard, AIDSmap, October 24, 2005 (Accessed June 8, 2006)
  19. ^ HAART is not reducing risk of anal cancer in gay men, Edwin J. Bernard, AIDSmap, August 29, 2005 (Accessed June 8, 2006)
  20. ^ http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm Centers for Disease Control
  21. ^ http://www.cdc.gov/std/HPV/STDFact-HPV-vaccine.htm Centers for Disease Control
  22. ^ a b c d FDA approves cervical cancer vaccine, AP, accessed June 8, 2006
  23. ^ Panel approves Gardasil usage, AP, accessed June 30, 2006
  24. ^ PETERSON, LIZ AUSTIN. "Texas Gov. Orders Anti-Cancer Vaccine", Washington Post, 2007-02-02. Retrieved on 2007-02-02. 
  25. ^ "Cervical Cancer Vaccine Blocked By Texas Families", Vaccine Rx, 2007-02-24. Retrieved on 2007-02-24. 
  26. ^ Blumenthal, Ralph. "Texas Legislators Block Shots for Girls Against Cancer Virus", New York Times, 2007-04-26. Retrieved on 2007-04-26. 
  27. ^ State Government of Alaska
  28. ^ Belluck, Pam. "In New Hampshire, Soft Sell Eases Vaccine Fears", New York Times, 2007-05-12. Retrieved on 2007-05-15. 
  29. ^ Cohen J. 2005. High Hopes and Dilemmas for a Cervical Cancer Vaccine. Science, 308(5722): 618–621.
  30. ^ http://www.thenation.com/doc/20070326/houppert/2
  31. ^ Moral majority take on GSK and Merck over cancer drugs, accessed June 12, 2006
  32. ^ Barillas, Martin. "GARDASIL vaccine touted in Michigan", Spero News, 2006-09-14. Retrieved on 2007-01-26. 
  33. ^ Moral majority take on GSK and Merck over cancer drugs, accessed June 12, 2006
  34. ^ a b [3]Understanding HPV
  35. ^ a b Human papillomavirus
  36. ^ Science Daily
  37. ^ Cervical Cancer Vaccine Approved
  38. ^ a b Schoolgirls ill after cervical cancer jabs - The Sydney Morning Herald
  39. ^ Calm urged on Gardasil - Herald Sun
  40. ^ Canadian Medical Association Journal August 1, 2007
  41. ^ STD Facts - HPV Vaccine
  42. ^ Cervical cancer shots gaining reputation as painful, CNN, January 3, 2008
  43. ^ You must specify title = and url = when using {{cite web}}. (Feb 22, 2007).
  44. ^ Judicial Watch Uncovers New FDA Records Detailing Deaths in 1,824 Adverse Reaction Reports Related to HPV Vaccine
  45. ^ http://www.fda.gov/medwatch/articles/vaers/vaersce.pdf

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