Gardasil

Gardasil is a vaccine against certain types of the human papillomavirus (HPV), manufactured by Merck & Co.. The research that lead to the development of the vaccine began in the 1980's by groups at the University of Rochester, Georgetown University, the University of Queensland, and the US National Cancer Institute. A breakthrough was discovered in 1991 when Ian Fraser and Jian Zhou of the University of Queensland found a way to form non-infectious virus-like particles VLPs, which could also strongly activate the immune system. In 1994, UniQuest, the technology transfer arm of the University of Queensland licensed this technology to Australia's largest biotechnology firm, CSL (who then licensed to Merck & Co.). Upon commercialization of the vaccine, controversy involving intellectual property initiated by GSK arose between the inventors. The history of the discovery of this vaccine is described in the following article. Two vaccines were developed: Gardasil (which the focus of this review) was attributed to the Australian researchers and Cervarix to the US researchers.

Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 cause about 70% of HPV-related 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. HPV types 6 and 11 cause about 90% of genital wart cases. Human papillomavirus (HPV) infection causes virtually all cases of cervical cancer, the 7th most common cause of death from cancer among women worldwide.

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.

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. No evidence proves that condoms do not protect against HPV, but consistent use has been shown to reduce the risk of becoming infected.

All women are encouraged get a yearly pap smear solely to detect cancer cells caused by HPV.

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

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

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)." 

Safety and efficacy of the vaccine
According to the Centers for Disease Control, the vaccine was tested in over 10,000 females (ages 9 to 26). These studies have shown no serious side effects. The most common side effect is soreness at the injection site. 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. 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." 

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 only a few 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.

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

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

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.

Government & public health mandates
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).

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 (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.

Australia
In Australia, the Australian government and the PBS (Pharmaceutical Benefits Scheme) has approved the vaccine for use and in 2007 began a nationwide vaccination program free of charge to schoolgirls in years 10, 11 and 12. These programs are run by local councils with funding and vaccine supplies coming from the government. The subsidisation approval process, however, appears to have been heavily influenced by political interference from politicians of all political parties, and by the Prime Minister who publically advised that it would be approved (before approval). In addition, women between 18 and 26 years of age at the time of the first dose may receive the vaccine for free upon request from their general practitioner. After June 2009, the program will be scaled down to 12–13 year old girls only. Australia also approved Gardasil for boys 9–15 years old, but Australia is not providing government funding for vaccinating boys.

Europe
On March 26, 2007, early approval was granted in both Germany and Italy.

South Korea
On July 27, 2007, South Korean government approved Gardasil for use in girls and women aged 9 to 26 and boys aged 9 to 15. Approval for use in boys was based on safety and immunogenicity, but not efficacy.

Legislation in the United States
Opt-out policies

Almost all pieces of legislation currently pending in the states that would make the vaccine mandatory for school entrance have an "opt-out" policy.

Opposition from health insurance companies

There has been significant opposition from health insurance companies to covering the cost of the vaccine ($360).

Origins

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. On February 22, 2007 a group of Texas families filed a lawsuit to stop the executive order. 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.

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. This has met with wide acceptance, with many young women requesting the vaccine. South Dakota and Washington are considering similar measures.

State-by-State

Other states are also preparing bills to handle issuing the HPV Vaccine:

Source: National Conference of State Legislatures, state legislatures

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 over time is required to answer this question.

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. The American Cancer Society estimated that 9,700 women would develop cervical cancer in the United States 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. 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. There is no scientific evidence to prove this claim. Moreover, HPV is not transmitted solely through sexual contact, but may be transmitted via simple hand to hand contact.

Health freedom organizations and other critics of the political power of pharmaceutical companies have vocally denounced the mandatory vaccination scheme as Merck's way of using forced drugging to pay for Vioxx lawsuits.

Another potential issue is that it is not known whether this vaccine has any long-term adverse side effects. Although it has undergone full FDA trials, some fear that detrimental effects may not appear until years or decades after exposure.

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

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%.

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. 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.

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. One was temporarily paralysed*. Health authorities do not believe that these are directly related to the vaccine.

The following is from the Sunday 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" 

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. 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.

A group called the "National Vaccine Information Center" released an article on Feb 22, 2007, about Gardasil. 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, but is highly critical of most vaccinations, including the influenza, chickenpox, tetanus , and the Measles, Mumps and Rubella (MMR) vaccines. The NVIC article claims "new analysis of the federal Vaccine Adverse Event Reporting System reports of serious health problems following HPV vaccination (Merck's GARDASIL) during the last six months of 2006." However, 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." The FDA does not believe the vaccine causes serious health problems. The NVIC article goes on to say, "event reports to VAERS do[es] not prove causation." At this time, however, the NVIC chooses to draw a causal relationship between Gardasil and what the FDA believes are unrelated illnesses.
 * Anti-vaccination groups

The conservative group Judicial Watch has also interpreted records from VAERS to mean that Gardasil is responsible for 1637 "adverse effects ranging from minor to serious," and three deaths in the United States between July 2006 and May 2007. An FDA spokesperson stated that these deaths are not related to the vaccine, and occurred independently of vaccination.
 * Socially conservative groups

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."