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Vaccines against HPV

Two approved HPV vaccines

In June 2006, the first vaccine against HPV infection was approved and marketed—Merck & Co. Inc.’s Gardasil.® Since that time, Gardasil and the GlaxoSmithKline vaccine, Cervarix,® have been licensed in more than 100 countries worldwide.

Gardasil prevents infection with two of the most common cancer-causing types of HPV, types 16 and 18. Around 70% of cervical cancer cases are associated with these two HPV types. This vaccine also protects against two types of HPV that do not cause cancer—types 6 and 11—but cause about 90% of genital warts. This quadrivalent vaccine is given in a series of three 0.5-mL intramuscular injections over six months, with the second dose given two months after the first and the third about six months after the first.26

Cervarix also protects against infection with HPV types 16 and 18, but does not include protection against any other HPV types. It is also given in a series of three 0.5-mL injections, but the dosing differs slightly from that for Gardasil, with the second dose given one month after the first and the third given six months after the first.27 See Table 1 for further information on the two vaccines.

Table 1 Click for reference list.

Effectiveness and safety of the vaccines

Protection against cervical cancer

Clinical trials of the two HPV vaccines used cervical lesions (cervical intraepithelial dysplasia 2+) as their primary endpoint; that is, they compared the number of cases of precancerous lesions in vaccine and control groups to determine how effective the vaccines were.28,29 They did not wait for cases of cervical cancer to develop because that would have taken several decades and would have been unethical. It is well-known from years of research that cancer is preceded by these precancerous lesions.

Efficacy for preventing precancerous lesions for both vaccines is greater than 92% in women who have not been previously infected.28,29 In all primary analyses for Gardasil and Cervarix, vaccine efficacy was very high; that is, the vaccines are very effective in preventing infection and lesions caused by HPV 16 or 18 if the woman has not been infected previously with those types. These types cause 70% of all cervical cancers.

Duration of effectiveness

Clinical trials show that HPV vaccines are effective for at least five to six years (the duration to date, based on follow-up data from the major trials), but they are likely to be effective for much longer.30,31

Preliminary results from a trial of the HPV 16 component of the quadrivalent vaccine indicate that it is effective for up to 8.5 years.32 During the long-term follow-up, there has been no evidence of decreased efficacy for prevention of infection or lesions. While the two vaccines cannot be compared directly because of differences in the way antibody levels are measured for the clinical trials, they both produce levels between 10 and 80 times that found in natural infections.

Further, a booster shot of the HPV vaccine stimulated a response similar to vaccines that provide long-lasting protection, such as the hepatitis B vaccine.33 These findings suggest that the duration of effectiveness could be long lasting, but definitive data will become available only when clinical trial participants have been followed for a longer time.

Cross-protection against non-vaccine HPV types

Both Gardasil and Cervarix appear to offer some protection against HPV types that are not specifically targeted by the vaccines (types 16 and 18), mainly against type 31, which is related to type 16. Gardasil was 70% effective, and Cervarix 92% effective, against lesions caused by HPV 31 in study participants naïve to that virus. In all women in the clinical trials, including those who had already been exposed to viruses, Gardasil was about 20% effective against all HPV types, while Cervarix was about 30% effective, and statistical analyses showed a lower level of confidence in the results.29,34

Girls meeting with a health care provider in Vietnam

Safety and side effects

The safety of drugs, including vaccines, is assessed in two ways: from data in clinical trials and from reports posted by the public after medicines are approved and in use. Data from randomized clinical trials are highly reliable, since reports of serious adverse events can be investigated and verified and there is a built-in control group for comparison.

Reports from the public after vaccine approval can be made to the Vaccine Adverse Event Reporting System (VAERS) in the United States. These reports provide a signal of possible side effects related to a particular vaccine, which authorities can investigate. A similar system, the Yellow Card Scheme, is used in the United Kingdom (Cervarix is currently the dominant vaccine in the United Kingdom). Both VAERS and Yellow Card reports are available to the public as posted, and without verification. The side effects reported should not be interpreted as confirmed side effects of a vaccine. They are intended to give a signal to investigators that further monitoring may be warranted.

No serious adverse events and no deaths have been verified to have been caused by HPV vaccine in any of the clinical trials, even after more than five years of follow-up.

Some people in low-resource countries have expressed concern that the HPV vaccines are being tested on girls in their communities. In fact, thousands of young women in the United States and Europe, as well as in Asia and Latin America, received vaccine in the clinical trials that led to approval. The vaccines are no longer being tested; they have been approved as safe and effective. As of April 2009, more than 16 million doses of Gardasil had been given in the United States, with a very low rate of adverse events. From September 2008 to September 2009, 1.4 million doses of Cervarix were administered across the United Kingdom, also with a low side effect rate.

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Gardasil

In clinical trial reports for Gardasil,26 the most common side effect was discomfort at the injection site. About 60% of recipients had pain, swelling, itching, bruising, or redness at the injection site; however, about 50% of participants who received the vaccine adjuvant (a mixture of aluminum salts) also had these symptoms, as did about 25% of those receiving a simple salt solution. Other common side effects were headache, fever, nausea, dizziness, vomiting, and fainting. Fainting after any injection is common in adolescents. Other reactions tended to pass within a day or two. Out of the entire study population involved in Gardasil clinical trials at the time of approval (25,274 subjects), only 0.05% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator (but still have not been proven). For all of these events, a similar number of cases were seen in the control groups.

While fainting itself is not usually dangerous, falling may cause serious problems such as head injuries. Because of the reports of fainting, in June 2009, the US Food and Drug Administration required Merck to add a warning to the Gardasil package insert stating that individuals should be watched carefully for 15 minutes after vaccination to avoid potential injury from a fall.

In the VAERS reporting system for tracking Gardasil, the most commonly reported adverse events following HPV immunization have been similar to those found in clinical trials: discomfort at the injection site, fainting, dizziness, nausea, and headache. In regard to serious side effects, these accounted for only 6% of all VAERS reports—and remember, these were not confirmed to be caused by the vaccine. US Centers for Disease Control and Prevention investigators published a review of the data and stated:35
A major limitation of VAERS data is that there is no proven causal association between the vaccine and the adverse event. The only association is in time, meaning that the adverse event occurred sometime after vaccination. Therefore we cannot conclude that the events reported to VAERS were caused by the vaccine.

Cervarix

Side effects for Cervarix are similar to those reported for Gardasil. In clinical trials,27 injection site reactions were the most common side effect. Other frequent effects were headache, nausea, vomiting, and muscle aches. The most common side effects reported in the Yellow Card Scheme have been pain and redness at the injection site, allergic reactions (rash, itching), fainting, dizziness, nausea, headache, and low fever.
Photos: PATH/Amynah Janmohamed (center), PATH/Robin Biellik (right)
Girl getting vaccinated

 

Key resources

Watch videoHPV vaccination video and transcript

Vaccination (RHO Cervical Cancer website)

Global Guidance for Cervical Cancer Prevention and Control (International Federation of Gynecology and Obstetrics, PDF)

World Health Organization position paper on human papillomavirus vaccines (PDF)

Cervarix® vaccine website (GlaxoSmithKline, psc)

Gardasil® vaccine website (Merck & Co. Inc.)

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