(Published January 2009)

HPV Vaccines

Background Information on HPV Vaccines

The quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil^TM), manufactured by Merck, was approved for marketing in the United States by the Food and Drug Administration (FDA) in June of 2006.
In November 2006, the HPV quadrivalent vaccine was included in the Vaccines for Children Program, a federally funded vaccine program that provides vaccines for free to both children and adolescents through their 19th birthday who are uninsured or underinsured.
The Advisory Committee on Immunization Practices (ACIP), an advisory committee of the Centers for Disease Control and Prevention, released recommendations for vaccination using the HPV vaccine in 2007.
GlaxoSmithKline has developed a bivalent vaccine for HPV 16 and 18 (Cervarix^TM), which is currently undergoing FDA review for approval.

Table 5: Comparison of HPV Vaccines^1-5
	Quadrivalent (Gardasil)	Bivalent (Cervarix)
Targeted HPV types	6, 11, 16, 18	16, 18
HPV-related diseases potentially prevented	Cervical cancer and precancer, vulvar and vaginal cancer and precancer, low-grade lesions. External genital warts.	Cervical cancer and precancer, vulvar and vaginal cancer and precancer, low-grade lesions.
Indication	Females ages 9–26 years for prevention of cervical cancer, cervical cancer precursors, vaginal and vulvar cancer precursors, and anogenital warts related to the four HPV types targeted by the vaccine.	Information is not yet available.
Dosing and administration	Intramuscular injection of three separate 0.5-mL doses at 0, 2, and 6 months.	Intramuscular injection of three separate 0.5-mL doses at 0, 1, and 6 months.
Efficacy	Among young women (ages 16–26 years) who previously had not been exposed to any of the four HPV types in the vaccine: 100% efficacy in preventing CIN-2/3 caused by the targeted HPV types (efficacy 30% for CIN-2 and 12% for CIN-3 by ITT analysis) Nearly 100% efficacy in preventing vulvar and vaginal precancers caused by the targeted HPV types (63% by ITT analysis) Nearly 100% efficacy in preventing genital warts caused by the targeted HPV types (73% by ITT analysis)	Among young women (15–25 years of age) who previously had not been exposed to either of the two HPV types in the vaccine: 100% efficacy in preventing CIN-2/3 caused by the targeted HPV types
Local adverse events	Injection site pain, swelling, erythema, pruritus.	Injection site pain, swelling, erythema.
Systemic adverse events	Rate of events similar between placebo and treated groups. Vaccine-related serious adverse events occurred in <0.1% of participants in clinical trials. Postmarketing reports have identified syncope, or fainting, as an adverse event; prescribing information recommends that patients remain seated for 15 minutes after vaccination.	Low rates of events. No subject withdrawals due to serious adverse events.
*ITT = intention-to-treat. ITT analysis includes all subjects who begin treatment, whether or not they complete the study.

Frequently Asked Questions

The answers to these questions are based on information from ACIP and CDC.^2,6

What is the target age for the vaccine? According to ACIP recommendations, the target age is 11 to 12 years old for routine vaccination of females, although the series can be started as young as age 9 years.

What about missed vaccines? If the schedule for the quadrivalent HPV vaccine is interrupted, the vaccine series does not need to be restarted. If the interruption occurs after the first dose, the second dose should be administered as soon as possible, with the second and third doses separated by an interval of at least 12 weeks. If only the third dose is delayed, it should be administered as soon as possible.

Does it make sense for a female older than 12 to be vaccinated? “Catch-up” vaccines can be given to females ages 13 to 26 who were not previously vaccinated or who did not complete the full series. Vaccinating a woman who has already been sexually active also could offer some benefit. Even if she is already sexually active, she may not have been exposed yet to all four of the HPV types against which the vaccine offers protection. Although the vaccine may not provide full protection, it might provide some benefit.

Who should not receive the vaccine? According to ACIP recommendations, the HPV vaccine should not be administered to:

Pregnant women. The quadrivalent vaccine is designated as Pregnancy Category B; its use has not been associated with adverse outcomes of pregnancy or adverse events to the developing fetus. However, because data on vaccination in pregnancy are limited, it is recommended that vaccination be postponed until after delivery. If a woman has started the series and has been found to be pregnant, she should discontinue the series and recommence after delivery.
Individuals with a history of immediate hypersensitivity to any vaccine component or to yeast.

Administration should be delayed in individuals with moderate or severe acute illnesses (although it can be administered to individuals with minor acute illnesses, such as diarrhea or mild upper respiratory infection). The vaccine CAN be administered to immunocompromised individuals; however, efficacy might be less than that in immunocompetent individuals.

How does previous HPV exposure affect the efficacy of the vaccine? The HPV vaccine is a preventive rather than a therapeutic vaccine. The vaccine is effective in preventing HPV-related disease associated with HPV types to which an individual has not yet been exposed. It is not effective in preventing infection with HPV types to which an individual has already been exposed.

Why shouldn’t I test for HPV status before vaccination? Pap testing and screening for HPV DNA are not needed before vaccination. Many women have not been exposed to all four HPV types present in the quadrivalent vaccine, making pretesting an unnecessary and additional burden and expense. Additionally, at this time, FDA-approved type-specific HPV DNA tests are not available.

My patients don’t understand why they need to continue cervical cancer screening after vaccination. What should I tell them? It is important for females who receive the HPV vaccine to continue with regular cervical cancer screening for three reasons:

The vaccine does not protect against all of the HPV types that cause cervical cancer. Rather, the vaccine protects against HPV types that are responsible for 70% of cervical cancers.
An individual may be at risk for HPV-related disease if she was infected with a high-risk type of HPV before vaccination.
An individual who does not complete the vaccine series may not receive the full benefits of the vaccine and thus may be at risk for HPV-related disease.

Do the vaccines provide cross-protection to other HPV types? At this time, there is insufficient evidence to answer this question with certainty.

Does the quadrivalent vaccine provide protection against external genital warts? Yes. In a combined analysis of three clinical trials, the efficacy of the quadrivalent vaccine was 98.9% against external genital warts that were associated with HPV types included in the quadrivalent vaccine.⁴

What about the use of the vaccine in males? Efficacy studies are being conducted in males, but results are not yet available. At this time, in the United States the vaccine is indicated only for use in females. In other parts of the world, the vaccine has been approved for males.

Does the HPV vaccine help treat existing disease? No. Because the HPV vaccine is a preventive rather than a therapeutic vaccine, it is not effective against existing disease, including existing HPV infection, cervical cytological abnormalities, and external genital warts. It is important to note that there is no evidence that the vaccine exacerbates existing disease.

Counseling Points

When counseling a patient about HPV vaccination, make sure she understands these points before she leaves your office or clinic:

The HPV vaccine currently available prevents infection from two of the most common types of HPV that cause 7 of 10 cases of cervical cancer. The HPV vaccine also prevents infection from two of the most common types of HPV which together cause 9 of 10 cases of genital warts. It does not protect against the other, less common, types of HPV.
The vaccine provides the possibility of full protection when given before a person becomes sexually active. For this reason, it is recommended that young girls (as young as age 9) receive the vaccine.
Testing for HPV DNA is not recommended before vaccination.
The HPV vaccine will not treat cervical precancer or cancer that is already present, and it will not treat external genital warts that are already present.
There is no evidence that vaccination will make existing disease worse.
Girls and young women who receive the vaccine will still need cervical cancer screening with the Pap test.

References

Harper DM, Ranco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Marins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367(9518):1247-55.
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007;56(RR-2):1-24.
Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH, et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health. 2007;40:564-71.
Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928-43.
Food and Drug Administration. Information from CDC and FDA on the safety of Gardasil vaccine. Centers for Disease Control and Prevention. HPV and HPV Vaccine: Information for Providers.