|Target disease||human papillomavirus|
|ATC code||J07 J07|
|Legal status||℞-only (US)|
The human papillomavirus (HPV) vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers. Two HPV vaccines are currently on the market: Gardasil and Cervarix. Both vaccines protect against two of the HPV types (HPV-16 and HPV-18) that can cause cervical cancer and some other genital cancers; Gardasil also protects against two of the HPV types that cause genital warts. In addition, some commercially available vaccines have been shown to prevent potential precursors to anal, vulvar, vaginal, and penile cancers.
Public health officials in Australia, Canada, Europe, and the United States recommend vaccination of young women against HPV to prevent cervical cancer and genital warts, and to reduce the number of painful and costly treatments for cervical dysplasia, which is caused by HPV. Worldwide, HPV is the most common sexually transmitted infection in adults. For example, more than 80% of American women will have contracted at least one strain of HPV by age fifty.
Although most women infected with genital HPV will not have complications from the virus, worldwide there are an estimated 470,000 new cases of cervical cancer that result in 233,000 deaths per year. About eighty percent of deaths from cervical cancer occur in poor countries. In the United States, most of the approximately 11,000 cervical cancers found annually occur in women who have never had a Pap smear, or not had one in the previous five years. HPV is also the cause of cervical dysplasia (CD). CD is a precursor to cervical cancer, and is painful and costly to treat. It is not known how many women worldwide are diagnosed with cervical dysplasia.
Since the vaccine only covers some high-risk types of HPV, experts still recommend regular Pap smear screening even after vaccination.
Both Gardasil and Cervarix have shown a nearly 100% efficacy in preventing development of cervical cancer for the HPV strains that they are targeted at, that is, types 16, 18, 6, and 11 for Gardasil and types 16 and 18 for Cervarix. This effect has lasted 4 years after vaccination for Gardasil and more than 6 years for Cervarix.
Gardasil is a 3-dose (injection) vaccine. As of 1 September 2009Vaccine Adverse Event Reporting System (VAERS) reports following the vaccination. Ninety-three percent were reports of events considered to be non-serious (e.g., fainting, pain and swelling at the injection site (arm), headache, nausea and fever), and seven percent were considered to be serious (death, permanent disability, life-threatening illness and hospitalization). There is no proven causal link between the vaccine and serious adverse effects; all reports are related by time only. That is, they are only related because the effect happened some time after the vaccination. As of 1 September 2009 , there have been 44 U.S. reports of death among females who have received the vaccine. None of the 27 confirmed deaths of women and girls who had taken the vaccine were linked to the vaccine. Guillain-Barré Syndrome (GBS), a rare disorder that causes muscle weakness, has been reported after vaccination with Gardasil. There is no evidence suggesting that Gardasil causes or raises the risk of GBS. Additionally, there have been rare reports of blood clots forming in the heart, lungs and legs. Most of those who suffered blood clots were already at risk from other factors, such as taking combined oral contraceptive pills.there have been more than 26 million doses distributed in the United States, and there have been 15,037
In work that was initiated in the mid 1980s, the vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute. In 2006, the U.S. Food and Drug Administration (FDA) approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil. According to a Merck press release, in the second quarter of 2007, it had been approved in 80 countries, many under fast-track or expedited review. Early in 2007, GlaxoSmithKline filed for approval in the United States for a similar preventive HPV vaccine, known as Cervarix. In June 2007 this vaccine was licenced in Australia, and it was approved in the European Union in September 2007. Cervarix was approved for use in the U.S. in October 2009.
In addition to preventive vaccines, such as Gardasil and Cervarix, laboratory research and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general these vaccines focus on the main HPV oncogenes, E6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors.
According to the Centers for Disease Control and Prevention, by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. Both men and women can be carriers of HPV. HPV is the most common sexually transmitted infection in the US. A large percentage of the American population is infected with genital HPV because HPV is highly communicable. As a result, American public health experts recommend widespread HPV vaccination.
Only a small percentage of women with HPV develop cervical cancer. However, each year between 250,000 and 1 million American women are diagnosed with cervical dysplasia, which is caused by HPV and is a precursor to cervical cancer. Cervical dysplasia is painful and costly to treat.
About 11,000 American women are diagnosed with cervical cancer every year, and about 4,000 die per year of the disease. Most cancers occur in those who have not had Pap smears within the previous five years.
There are 19 "high-risk" HPV types that can lead to the development of cervical cancer or other genital/anal cancers; some forms of HPV, particularly type 16, have been found to be associated with a form of throat cancer. Studies have found that human papillomavirus (HPV) infection is responsible for virtually all cases of cervical cancer.
Condoms protect against HPV, but do not completely prevent transmission. 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.
No data is kept by the U.S. government on genital wart incidence rates. It is estimated that in the U.S., at any one time about 1% of adults who have had sex have genital warts. It is estimated that about 20 million people are presently infected with HPV, and there are about six million new cases of HPV every year in the United States.
According to the American National Cancer Institute, "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."
Current preventive vaccines protect against the two HPV types (16 and 18) that cause about 70% of cervical cancers worldwide. Because of the distribution of HPV types associated with cervical cancer, the vaccines are likely to be most effective in Asia, Europe, and North America. Vaccines that protect against more of the types common in cancers would prevent more cancers, and be less subject to regional variation.
Only 41% of women with cervical cancer in the developing world are able to access medical treatment for their illness. Therefore, prevention of HPV by vaccination may be a more effective way of lowering the disease burden in developing countries than cervical screening. However, individuals in many resource-limited nations, Kenya for example, are unable to afford the vaccine.
Gardasil and Cervarix are preventative vaccines and do not treat HPV infection or cervical cancer. They are recommended for women who are 9 to 25 years old who have not been exposed to HPV. However, since it is unlikely that a woman will have already contracted all four viruses, and because HPV is primarily sexually transmitted, the U.S. Centers for Disease Control and Prevention has recommended vaccination for women up to 26 years of age.
When Gardasil was first introduced, it was recommended as a prevention for cervical cancer for women that were 25 years old or younger. New evidence suggests that all Human Papillomavirus (HPV) vaccines are effective in preventing cervical cancer for women up to 45 years of age.
In November 2007, Merck presented new data on Gardasil. In an investigational study, Gardasil reduced incidence of HPV types 6, 11, 16 and 18-related persistent infection and disease in women through age 45. The study evaluated women who had not contracted at least one of the HPV types targeted by the vaccine by the end of the three-dose vaccination series. Merck planned to submit this data before the end of 2007 to the U.S. Food and Drug Administration (FDA), and to seek an indication for Gardasil for women through age 45.
In the Gardasil clinical trials, 1,115 pregnant women received the HPV vaccine. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who received Gardasil and subjects who received placebo. However, the clinical trials had a relatively small sample size. Currently the vaccine is not recommended for pregnant women. The long-term effects of the vaccine on fertility are not known, but no effects are anticipated.
In the UK, HPV vaccines are licensed for boys aged 9–15. On 9 Sep 2009, an advisory panel recommended that the U.S. Food and Drug Administration (FDA) licence Gardasil in the United States for boys and men ages 9–26 for the prevention of genital warts. The vaccine has been FDA approved for use in males age 9 to 26 for prevention of genital warts.
In males, Gardasil may reduce their risk of genital warts and precancerous lesions caused by HPV. This reduction in precancerous lesions might be predicted to reduce the rates of penile and anal cancer in men. 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. From a public health point of view, vaccinating men as well as women decreases the virus pool within the population, but is only cost-effective if the uptake in the female population is extremely low. In the United States, the cost per Quality-adjusted life year is greater than $100,000 for vaccinating the male population, compared to the less than $50,000 for vaccinating the female population. This assumes a 75% vaccination rate.
As with females, the vaccine should be administered before infection with the HPV types covered by the vaccine occurs. Vaccination before adolescence therefore makes it more likely that the recipient has not been exposed to HPV.
The latest generation of preventive HPV vaccines is based on hollow virus-like particles (VLPs) assembled from recombinant HPV coat proteins. The vaccines target the two most common high-risk HPVs, types 16 and 18. Together, these two HPV types currently cause about 70 percent of all cervical cancer. Gardasil also targets HPV types 6 and 11, which together currently cause about 90 percent of all cases of genital warts.
Gardasil and Cervarix are designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine. The vaccines have been shown to offer 100 percent protection against the development of cervical pre-cancers and genital warts caused by the HPV types in the vaccine, with few or no side effects. The protective effects of the vaccine are expected to last a minimum of 4.5 years after the initial vaccination.
While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions (or dysplasias) is believed highly likely to result in the prevention of those cancers.
Although a 2006 study suggests that the vaccines may offer limited protection against a few HPV types that are closely related to HPVs 16 and 18, there are other high-risk HPV types are not affected by the vaccines. Ongoing research is focused on the development of HPV vaccines that will offer protection against a broader range of HPV types. There is also substantial research interest in the development of therapeutic vaccines, which seek to elicit immune responses against established HPV infections and HPV-induced cancers.
In developed countries, the widespread use of cervical "Pap smear" screening programs has reduced the incidence of invasive cervical cancer by 50% or more. Current preventive vaccines reduce, but do not eliminate the chance of getting cervical cancer. Therefore, experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination.
Commencing in 2007 The Australian federal government began funding a voluntary program to make the Gardasil vaccine available free of charge to women aged 12–26 for a period of two years, with an ongoing vaccination program for 12- and 13-year-olds as part of the pre-existing high school vaccination program.
The Australian government and the PBS (Pharmaceutical Benefits Scheme) have approved the vaccine for use and in 2007 began a nationwide vaccination program free of charge to schoolgirls in years 7 to 12. These programs are run by local councils with funding and vaccine supplies from the government. The subsidization approval process, however, appears to have been heavily influenced by political interference from politicians of all political parties, and by the Prime Minister who publicly 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- and 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.
Canada has approved use of Gardasil. Initiating and funding free vaccination programs has been left to individual Province/Territory Governments. In the provinces of Ontario, Prince Edward Island, Newfoundland and Nova Scotia, free vaccinations to protect women against HPV were slated to begin in September 2007 and will be offered to girls ages 11–14. Similar vaccination programs are being planned in British Columbia and Quebec.
On July 17, 2007, France issued a directive authorizing state-aided voluntary vaccination for girls aged 14–23 years who have not yet become sexually active, or have been sexually active for less than a year. The state refunds 65% of the cost, based on a program of 3 vaccinations at €135 (slightly less than $200) per shot, meaning that the patient covers €141.75 (slightly more than $200).
On February 12, 2007, Greece made HPV vaccination mandatory for girls entering gymnasion (7th grade). All vaccines including hepatitis B are mandatory and are supplied free to everyone in Greece, with parents being allowed to opt out of vaccinating their kids. Cervarix and Gardasil are supplied free to all girls and women between the ages of 12 and 26.
Both Cervarix and Gardasil are approved for use within Kenya by the Pharmacy and Poison's Board. However, at a cost of 20,000 Kenyan shillings, which is more than the average annual income for a family, the director of health promotion in the Ministry of Health, Nicholas Muraguri, states that many Kenyans are unable to afford the vaccine.
In November 2008, Romanian authorities launched a campaign to vaccinate 110,000 girls aged 10 and 11. The Ministry of Health acquired 330,000 vaccine doses for 23 million euros. By an order of the Ministry, the girls' parents must approve or reject the vaccination in writing, and must "fully assume the consequences for their children" if they reject the vaccination.
The publicly-funded New Zealand HPV Immunisation Programme began on 1 September 2008. Gardasil is available free for New Zealand girls and young women born on or after 1 January 1990 through general practices, some family planning clinics and participating schools. HPV immunization is part of the regular immunization schedule for girls in year 8 at school (or age 12 if not delivered through a school-based programme). There is also a catch-up programme for older girls. Girls born in 1990 and 1991 have until 31 December 2011 to start the programme for free. Girls born from 1992 onwards have until their 20th birthday to start the programmme for free. Over 82,000 New Zealand girls and young women have chosen to get the HPV immunisation in the programme's first year.
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.
In the UK the vaccine is licensed for girls aged 9 to 15 and for women aged 16 to 26.
HPV vaccination with Cervarix was introduced into the national immunisation programme in September 2008, for girls aged 12–13 across the UK. A two-year catch up campaign started in Autumn 2009 to vaccinate all girls up to 18 years of age. Catch up vaccination will be offered to:
By the end of the catch up campaign, all girls under 18 will have been offered the HPV vaccine. Women over the age of 18 are not included in the programme as it would not be cost effective in preventing cervical cancer.
It will be many years before the vaccination programme has an effect upon cervical cancer incidence so women are advised to continue accepting their invitations for cervical screening.
As of late 2007, about one quarter of US females age 13–17 years had received at least one of the three HPV shots.
Other states are also preparing bills to handle issuing the HPV Vaccine.
|State||Proposal||Status||Opt Out Policy|
|Alaska||Voluntary vaccination program||Passed||Not Applicable|
|California||Bill would have required girls entering the sixth grade to be vaccinated.||Withdrawn for further consideration.||Yes|
|Colorado||Bill would require 12-year-old girls to be vaccinated to attend school.||Pending||Yes|
|Connecticut||Bill would require girls receive a first dose of the vaccine before entering the sixth grade. Allows parents to opt their daughters out on medical or religious grounds.||Pending||Yes|
|District of Columbia||Bill would require girls to be vaccinated before they turn 13 to attend school.||Pending||Yes|
|Florida||Bill would have required 11- and 12-year-old girls to be vaccinated to attend school.||Died in committee||Yes|
|Georgia||Bill would require girls entering the sixth grade to be vaccinated unless parents can't afford the vaccine or object to it on medical or religious grounds.||Died in Committee||Yes|
|Illinois||Bill would require girls entering the sixth grade to be vaccinated.||Pending||Yes|
|Kansas||Bill would require girls entering the sixth grade to be vaccinated. Allows parents to opt their daughters out on medical or religious grounds.||Pending||Yes|
|Kentucky||Bill would require girls entering middle school to be vaccinated.||Passed House, to Senate||Yes|
|Maryland||Bill would have required girls entering the sixth grade to be vaccinated.||Withdrawn||Yes|
|Massachusetts||Bill would require girls entering the sixth grade to be vaccinated. Allows parents to opt their daughters out on religious grounds.||Pending||Yes|
|Michigan||Bill would require girls entering the sixth grade to be vaccinated.||Pending.||Yes|
|Missouri||Bill would require girls entering the sixth grade to be vaccinated. Allows parents to opt their daughters out on medical or religious grounds.||Pending||Yes|
|Minnesota||Bill would require 12-year-old girls to be vaccinated to attend school.||Pending||Yes|
|Mississippi||Bill would have required girls entering the sixth grade to be vaccinated.||Died. Sponsor planning to re-introduce it with an opt-out clause.||No|
|Nevada||Bill would require health insurance companies to cover the cost of the vaccine||Passed into law||Not Applicable|
|New Hampshire||Voluntary program provides vaccine free of charge to girls between the ages of eleven and eighteen.||Passed and presently in effect.||Yes|
|New Jersey||Bill would require girls in grades seven through 12 to be vaccinated. Allows parents to opt their daughters out on medical or religious grounds.||Pending||Yes|
|New Mexico||Bill would require nine- to 14-year-old girls to be vaccinated to attend school.||Passed legislature. Vetoed by governor.||Yes|
|Ohio||Bill would require girls entering the sixth grade to be vaccinated.||Pending||Yes|
|Oklahoma||Bill would require girls entering the sixth grade to be vaccinated.||Pending||Yes|
|South Carolina||Bill would require girls entering the seventh grade or 11 years of age to be vaccinated. Allows parents to opt their daughters out on medical or religious grounds.||Pending||Yes|
|Texas||Governor issued executive order requiring that girls entering the sixth grade be vaccinated.||Texas legislature overrode executive order and barred mandatory vaccination until at least 2011.||Yes|
|Vermont||Bill would require girls entering the sixth grade to be vaccinated. Allows parents to opt their daughters out on medical, moral or religious grounds.||Pending||Yes|
|Virginia||Bill requires girls entering the sixth grade to be vaccinated.||Passed the legislature. Goes into effect Oct. 1, 2008; to be implemented in fall of 2009.||Yes|
|West Virginia||Bill would require girls entering the sixth grade to be vaccinated. Allows parents to opt their daughters out on medical grounds.||Died||Yes|
Source: National Conference of State Legislatures, state legislatures
All vaccines recommended by the U.S. government for its citizens are required for green card applicants. Therefore HPV vaccine is required for young women seeking to immigrate to the United States. This requirement has also stirred controversy because of the cost of the vaccine, and because all the other vaccines so required prevent diseases which are spread by respiratory route and considered highly contagious.
Several conservative groups in the U.S. have publicly opposed the concept of making HPV vaccination mandatory for pre-adolescent girls, asserting that making the vaccine mandatory is a violation of parental rights. They also say that it will lead to early sexual activity, giving a sense of immunity to sexually transmitted disease. Both the Family Research Council and the group Focus on the Family support widespread (universal) availability of HPV vaccines but oppose mandatory HPV vaccinations for entry to public school.
Many organizations disagree with the argument that the vaccine increases sexual activity among teens. Dr. Christine Peterson, director of the University of Virginia's Gynecology Clinic, said "The presence of seat belts in cars doesn't cause people to drive less safely. The presence of a vaccine in a person's body doesn't cause them to engage in risk-taking behavior they would not otherwise engage in." 
Dr. Diane Harper, lead researcher for the HPV vaccines, stated that in countries where Pap smear screening is common, it will take vaccination of a large proportion of women in order to further reduce cervical cancer rates. She also stated that no efficacy trials for children under 15 have been performed.