HPV Vaccines: Who, What, and When?

Available HPV Vaccine Products

Hello, I'm Dr Sandra Fryhofer. Welcome to Medicine Matters. The topic: HPV vaccination, the transition to HPV9, and gender differences in additional cancer protection.

HPV—the human papillomavirus—is linked to cancer, including cervical, vulvar, and vaginal cancer in females; penile cancer in males; and anal and oropharyngeal cancer in both males and in females.

Three HPV vaccines are now available:

HPV2 (Cervarix®), US Food and Drug Administration (FDA)-approved in 2009;
HPV4 (Gardasil®), FDA-approved in 2006; and
HPV9 (Gardasil® 9), FDA approved in December 2014.

What Do They Protect Against?

All three vaccines provide cancer protection against HPV types 16 and 18, the types that cause most (64%) of all HPV cancers. These HPV types are to blame for an estimated 21,300 cases of cancer each year. Types 16 and 18 are linked to 63% of all HPV-related cancers in males. In females, HPV 16 and 18 cause 65% of all HPV-related cancers, as well as 66% of all cervical cancers.^[1] The HPV4 and HPV9 vaccines also protect against types 6 and 11—the types that cause 90% of all anogenital warts.^[1]

The newest HPV vaccine (HPV9) includes additional protection from five cancer-causing HPV strains: 31, 33, 45, 52, and 58. The HPV9 vaccine is more expensive than its HPV4 sibling.

But how much extra cancer protection do patients receive from the additional coverage and cost? Overall, about 10% of HPV-related cancers (about 3400 cancer cases each year) are linked to the five additional strains.

Are gender differences in the additional cancer protection conferred? Most of the added protection from covering the five additional types is for females. For males, HPV9 provides only 4% additional cancer protection. For females, the additional strains cause 14% of HPV cancers overall, including 15% of cervical cancers and 25% of cervical precancers.^[1]

Who, What, and When?

Here is the latest Advisory Committee on Immunization Practices (ACIP) recommendation for HPV vaccination, published in the March 27, 2015, Morbidity and Mortality Weekly Report^[2]:

Three HPV vaccine doses are recommended routinely starting at age 11 or 12 years, but vaccination can begin as early as age 9.
HPV vaccination is recommended through age 26 years for all females and through age 21 years for all males.
Vaccination through age 26 years is also recommended for immunocompromised males, including those with HIV, and for men who have sex with men.
HPV9 is one of three HPV vaccines that can be used for routine vaccination:
- HPV2 is licensed only for females.
- HPV4 and HPV9 are licensed for both males and females.
- Three doses of vaccine are needed. Any of the three vaccines can be used to start, continue, or complete the series for females. Either HPV4 or HPV9 should be used to start, complete, or continue the series in males.

What to Do With Leftover HPV4 Vaccine?

Let's now try to clear up some confusion about HPV9. The package insert says that HPV9 is licensed for females aged 9-26 years and for males aged 9-15 years.^[3]

ACIP reviewed additional data on HPV9 in males aged 16-26 years in making its new HPV9 recommendation. It's fine to use HPV9 in males through age 26 years. The company has submitted these data to the FDA with a request to expand the age indication of HPV9 for males.

The introduction of HPV9 has created some programmatic issues. Many practitioners still have HPV4 vaccine on hand. Merck says it has no plans to exchange remaining HPV4 vaccine for HPV9. It plans to have quadrivalent vaccine available for at least 6 months after FDA approval (when and if that occurs) of the expanded HPV9 age indication of 16-26 years for males.

The incremental cancer protection from HPV9 for males is small. For this reason, one option is to give any remaining HPV4 vaccine to male patients. Although this is not an official ACIP recommendation, it was suggested as a strategy for Vaccines for Children (VFC) awardees at the June 2015 ACIP meeting.

You May Also Be Wondering About...

The ACIP website will soon be posting some official guidance about additional HPV9 vaccine doses and how to complete an HPV vaccination series started with another HPV vaccine. Here are some highlights reviewed at the June ACIP meeting^[4]:

There is no ACIP recommendation for routine additional HPV9 vaccination for anyone who has already completed the bivalent or quadrivalent vaccination series.
Available studies show no serious safety concerns with giving HPV9 to those that have completed a three-dose HPV vaccine series. However, they did have higher rates of injection site swelling and redness.
The guidance also emphasizes gender differences in protection. The benefit of protection against the five additional strains in HPV9 is mostly limited to females, in protecting from cervical cancers and cervical precancers.
The guidance also mentions a study (found in the HPV9 package insert) in which females who had already completed a three-dose HPV4 series were (starting a year later) given three doses of HPV9 vaccine. These patients did make antibodies to the five additional vaccine types, but the titers were lower; they were 25%-63% of the titers found in patients receiving HPV9 without previous HPV vaccination. The clinical significance of these lower antibody titers is not known.

There is a trial under way looking at the effectiveness of two HPV9 doses separated by 6 or 12 months in HPV-vaccine–naive individuals. The results of the study may be available in late 2015.

For Medicine Matters, I'm Dr Sandra Fryhofer.

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