HPV vaccine

For patient information, click here

Overview
Human papillomavirus (HPV) vaccine is a vaccine that targets certain sexually transmitted strains of human papillomavirus associated with the development of cervical cancer and genital warts. Two HPV vaccines are currently on the market: Gardasil and Cervarix.

Background
Of the more than 100 known HPV types, 37 are known to be transmitted through sexual contact. Infection with sexually transmitted HPVs is very common in adult populations worldwide. Although a few HPVs, such as types 6 and 11, can cause genital warts, most genital HPV infections come and go without ever causing any symptoms. However, lingering infections with a subset of about 19 "high-risk" HPV types can lead to the development of cervical cancer or other genital/anal cancers, and some forms of HPV, particularly type 16, have been found to be associated with a form of throat cancer. Only a small percentage of women with HPV go on to develop cervical cancer.

The latest generation of preventive HPV vaccines are 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, it is clear that other high-risk HPV types can circumvent the vaccines, and a 2006 study of HPV infection in female university students found that only 14 of 78 infections with high-risk types of HPV were by types 16 and 18, the remaining 64 infections being with 16 other high-risk types of HPV. 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.

Target populations
Gardasil and Cervarix are preventative (rather than therapeutic) vaccines, recommended for women who are 9 to 25 years old and have not contracted HPV. However, since it is unlikely that a woman will have already contracted all four viruses, and because HPV is primarily sexually transmitted, the US Centers for Disease Control and Prevention has recommended vaccination for women as old as 26.

Although HPV types 6 and 11 do not cause cervical cancer, they can cause genital warts. "Warts cause considerable discomfort and psycho-social trauma, so this makes the vaccine more attractive and also provides a reason other than altruism for men to be immunized," explains John Schiller of the National Cancer Institute. From a public health point of view, vaccinating men as well as women is important because it decreases the vaccine pool within the population. HPV also causes anal and penile cancer. In the UK the drug is licensed for girls and boys aged 9 to 15 and for women aged 16 to 26. Thus, the drug has to be administered to adult men "off license".

Implementation
In developed countries, the widespread use of good-quality cervical "Pap smear" screening programs has reduced the incidence of invasive cervical cancer, by 50% or more. The current generation of preventive vaccines offers protection against the two HPV types (16 & 18) that currently cause about 70% of cervical cancer cases. Therefore, experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination.

Pap smear screening is too expensive for routine use in developing countries and HPV-induced cervical cancer remains the fifth most common cancer in women worldwide. Thus HPV vaccines are most urgently needed in developing countries. With a cost of $360, Gardasil is the most expensive vaccine ever developed. The vaccine will be too expensive for initial use in developing countries unless substantial subsidies are offered. Merck has announced that it intends to support programs to offer Gardasil to disadvantaged women worldwide. The Bill & Melinda Gates Foundation has also expressed interest in helping make preventive HPV vaccines available to women in developing countries. Through the PATH organization, a nonprofit organization whose mission is to improve the health of people worldwide by advancing technologies, the Gates Foundation has donated $27.8 million to implement HPV vaccines. Starting in January 2007, women in India, Peru, Uganda and Vietnam will be receiving the vaccine.

History
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 approved the first preventive HPV vaccine, marketed by Merck & Co. under the tradename Gardasil. According to Merck press release, in the second quarter 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 the European Union, GlaxoSmithKline filed the application for approval in March 2006. In June 2007 this vaccine was licenced in Australia.

Controversy
More than eighteen U.S. states and the District of Columbia are considering making HPV vaccination mandatory for young girls entering middle or high schools. New Hampshire has adopted a voluntary program, in which it supplies the vaccine free of charge on a triage basis. Alaska has adopted a voluntary program for all girls between the ages of 9 and 18.

Texas Governor Rick Perry, without legislative approval, issued an executive order on 2 February,2007 mandating Gardasil be given to all school girls entering sixth grade, beginning September 2008. It being a patent-protected vaccine, Merck is the sole producer of Gardasil. On April 25, 2007, the Texas legislature overruled Governor Perry's order, forbidding mandatory vaccination until at least 2011.

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. Both the Family Research Council and the group Focus on the Family expressed concerns about this.

Many organizations disagree with this assessment. 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."

A group of Canadian public health professionals expressed concern about the vaccine in August, 2007, saying that many questions remain unanswered and a universal vaccination program in Canada "is premature and could have unintended negative consequences."

Some individuals and groups have also raised other similar objections to the HPV vaccine that have been raised to other vaccines (see vaccine controversy).

Dr. Joseph De Soto M.D.,Ph.D.,F.A.I.C of the Uniformed Service University of Health Sciences argues against the mandating of the HPV vaccine based on medical ethics. He states, " Medical Ethics require that patients have autonomy in their medical decisions, with informed consent. They have the right to know what they have , what the prognosis is, what the proposed treatment is, what the alternatives are, and what the possible side effects are prior to any treatment. Indeed, a patient has a right to say no, even if by refusing treatment they may die. I as a medical professional cannot overrule their decision"

Possible adverse reactions after vaccination
As of May 11, 2007, 1,637 adverse reactions to Gardasil vaccination have been reported to the Food and Drug Administration. As of July 31, 2007, the count is up to 3,137. The vast majority are minor, but there have been seven reports of deaths following HPV vaccination. A child, a 12-year-old girl, and a nineteen-year-old woman died of heart problems and/or blood clotting after receiving Gardasil. Other reported adverse events are "neurological symptoms including syncopal episodes and seizures, arthralgia and joint pain, Guillian-Barre Syndrome, and other immunological reactions." Full details are not available and it is not known if these are related to the vaccine. These reports are from the Vaccine Adverse Event Reporting System database: "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."

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.

Therapeutic HPV vaccines
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.